ascorbic-acid and Disease-Models--Animal

Ocoxin Oral Solution (OOS) is a nutritional supplement whose formulation includes several plant extracts and natural products with demonstrated antitumoral properties. This review summarizes the antitumoral action of the different constituents of OOS. The action of this formulation on different preclinical models as well as clinical trials is reviewed, paying special attention to the mechanism of action and quality of life improvement properties of this nutritional supplement. Molecularly, its mode of action includes a double edge role on tumor biology, that involves a slowdown in cell proliferation accompanied by cell death induction. Given the safety and good tolerability of OOS, and its potentiation of the antitumoral effect of other standard of care drugs, OOS may be used in the oncology clinic in combination with conventional therapies.

Topics: Amino Acids; Animals; Antineoplastic Agents; Apoptosis; Ascorbic Acid; Cell Line, Tumor; Cell Proliferation; Cinnamomum zeylanicum; Dietary Supplements; Disease Models, Animal; Drug Evaluation, Preclinical; Folic Acid; Glucosamine; Glycyrrhiza; Humans; Neoplasms; Pantothenic Acid; Plant Extracts; Sucrose; Tea; Vitamin B 12; Vitamin B 6; Zinc Sulfate

Surveys of patients with multiple sclerosis report that most are interested in modifying their diet and using supplements to potentially reduce the severity and symptoms of the disease. This review provides an updated overview of the current state of evidence for the role that vitamins and dietary supplements play in multiple sclerosis and its animal models, with an emphasis on recent studies, and addresses biological plausibility and safety issues.. Several vitamins and dietary supplements have been recently explored both in animal models and by patients with multiple sclerosis. Most human trials have been small or nonblinded, limiting their generalizability. Biotin and vitamin D are currently being tested in large randomized clinical trials. Smaller trials are ongoing or planned for other supplements such as lipoic acid and probiotics. The results of these studies may help guide clinical recommendations.. At the present time, the only vitamin with sufficient evidence to support routine supplementation for patients with multiple sclerosis is vitamin D. Vitamin deficiencies should be avoided. It is important for clinicians to know which supplements their patients are taking and to educate patients on any known efficacy data, along with any potential medication interactions and adverse effects of individual supplements. Given that dietary supplements and vitamins are not subject to the same regulatory oversight as prescription pharmaceuticals in the United States, it is recommended that vitamins and supplements be purchased from reputable manufacturers with the United States Pharmacopeia designation.

Topics: Acetylcarnitine; Animals; Ascorbic Acid; Biotin; Caffeine; Creatine; Curcumin; Dietary Supplements; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Fatty Acids, Unsaturated; Folic Acid; Ginkgo biloba; Humans; Multiple Sclerosis; Niacin; Pantothenic Acid; Plant Preparations; Probiotics; Pyridoxine; Resveratrol; Riboflavin; Tea; Thiamine; Thioctic Acid; Ubiquinone; Vitamin A; Vitamin B 12; Vitamin D; Vitamin E; Vitamins

Vitamin C (Vit C) is considered to be a vital antioxidant molecule in the brain. Intracellular Vit C helps maintain integrity and function of several processes in the central nervous system (CNS), including neuronal maturation and differentiation, myelin formation, synthesis of catecholamine, modulation of neurotransmission and antioxidant protection. The importance of Vit C for CNS function has been proven by the fact that targeted deletion of the sodium-vitamin C co-transporter in mice results in widespread cerebral hemorrhage and death on post-natal day one. Since neurological diseases are characterized by increased free radical generation and the highest concentrations of Vit C in the body are found in the brain and neuroendocrine tissues, it is suggested that Vit C may change the course of neurological diseases and display potential therapeutic roles. The aim of this review is to update the current state of knowledge of the role of vitamin C on neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic sclerosis, as well as psychiatric disorders including depression, anxiety and schizophrenia. The particular attention is attributed to understanding of the mechanisms underlying possible therapeutic properties of ascorbic acid in the presented disorders.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain; Central Nervous System; Disease Models, Animal; Humans; Mental Disorders; Neurodegenerative Diseases; Observational Studies as Topic; Randomized Controlled Trials as Topic

Accumulating evidence in mice models of accelerated senescence indicates a rescuing role of ascorbic acid in premature aging. Supplementation of ascorbic acid appeared to halt cell growth, oxidative stress, telomere attrition, disorganization of chromatin, and excessive secretion of inflammatory factors, and extend lifespan. Interestingly, ascorbic acid (AA) was also found to positively modulate inflamm-aging and immunosenescence, two hallmarks of biological aging. Moreover, ascorbic acid has been shown to epigenetically regulate genome integrity and stability, indicating a key role of targeted nutrition in healthy aging. Growing in vivo evidence supports the role of ascorbic acid in ameliorating factors linked to Alzheimer's disease (AD) pathogenesis, although evidence in humans yielded equivocal results. The neuroprotective role of ascorbic acid not only relies on the general free radical trapping, but also on the suppression of pro-inflammatory genes, mitigating neuroinflammation, on the chelation of iron, copper, and zinc, and on the suppression of amyloid-beta peptide (Aβ) fibrillogenesis. Epidemiological evidence linking diet, one of the most important modifiable lifestyle factors, and risk of Alzheimer's disease is rapidly increasing. Thus, dietary interventions, as a way to epigenetically modulate the human genome, may play a role in the prevention of AD. The present review is aimed at providing an up to date overview of the main biological mechanisms that are associated with ascorbic acid supplementation/bioavailability in the process of aging and Alzheimer's disease. In addition, we will address new fields of research and future directions.

Topics: Aging; Alzheimer Disease; Animals; Ascorbic Acid; Brain; Disease Models, Animal; Epigenomics; Humans; Nutrigenomics; Observational Studies as Topic; Oxidative Stress; Plaque, Amyloid; Randomized Controlled Trials as Topic; Vascular Diseases

Oxidative stress is a common denominator in the pathogenesis of many chronic diseases. Therefore, antioxidants are often used to protect cells and tissues and reverse oxidative damage. It is well known that iron metabolism underlies the dynamic interplay between oxidative stress and antioxidants in many pathophysiological processes. Both iron deficiency and iron overload can affect redox state, and these conditions can be restored to physiological conditions using iron supplementation and iron chelation, respectively. Similarly, the addition of antioxidants to these treatment regimens has been suggested as a viable therapeutic approach for attenuating tissue damage induced by oxidative stress. Notably, many bioactive plant-derived compounds have been shown to regulate both iron metabolism and redox state, possibly through interactive mechanisms. This review summarizes our current understanding of these mechanisms and discusses compelling preclinical evidence that bioactive plant-derived compounds can be both safe and effective for managing both iron deficiency and iron overload conditions.

Topics: Anemia, Iron-Deficiency; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Homeostasis; Humans; Iron; Iron Deficiencies; Iron Overload; Oxidative Stress; Plant Extracts; Polyphenols; Reactive Oxygen Species; Vitamin A

Maternal smoking during pregnancy is the largest preventable cause of abnormal in-utero lung development. Despite well known risks, rates of smoking during pregnancy have only slightly decreased over the last ten years, with rates varying from 5-40% worldwide resulting in tens of millions of fetal exposures. Despite multiple approaches to smoking cessation about 50% of smokers will continue to smoke during pregnancy. Maternal genotype plays an important role in the likelihood of continued smoking during pregnancy and the degree to which maternal smoking will affect the fetus. The primary effects of maternal smoking on offspring lung function and health are decreases in forced expiratory flows, decreased passive respiratory compliance, increased hospitalization for respiratory infections, and an increased prevalence of childhood wheeze and asthma. Nicotine appears to be the responsible component of tobacco smoke that affects lung development, and some of the effects of maternal smoking on lung development can be prevented by supplemental vitamin C. Because nicotine is the key agent for affecting lung development, e-cigarette usage during pregnancy is likely to be as dangerous to fetal lung development as is maternal smoking.

Topics: Animals; Antioxidants; Ascorbic Acid; Asthma; Child; Disease Models, Animal; Epigenesis, Genetic; Female; Humans; Infant, Newborn; Lung; Nicotine; Nicotinic Agonists; Pregnancy; Prenatal Exposure Delayed Effects; Respiratory Tract Diseases; Smoking; Tobacco Smoke Pollution

Polyphenols, found abundantly in plants, display many anticarcinogenic properties including their inhibitory effects on cancer cell proliferation, tumor growth, angiogenesis, metastasis, and inflammation as well as inducing apoptosis. In addition, they can modulate immune system response and protect normal cells against free radicals damage. Most investigations on anticancer mechanisms of polyphenols were conducted with individual compounds. However, several studies, including ours, have indicated that anti-cancer efficacy and scope of action can be further enhanced by combining them synergistically with chemically similar or different compounds. While most studies investigated the anti-cancer effects of combinations of two or three compounds, we used more comprehensive mixtures of specific polyphenols and mixtures of polyphenols with vitamins, amino acids and other micronutrients. The mixture containing quercetin, curcumin, green tea, cruciferex, and resveratrol (PB) demonstrated significant inhibition of the growth of Fanconi anemia head and neck squamous cell carcinoma and dose-dependent inhibition of cell proliferation, matrix metalloproteinase (MMP)-2 and -9 secretion, cell migration and invasion through Matrigel. PB was found effective in inhibition of fibrosarcoma HT-1080 and melanoma A2058 cell proliferation, MMP-2 and -9 expression, invasion through Matrigel and inducing apoptosis, important parameters for cancer prevention. A combination of polyphenols (quercetin and green tea extract) with vitamin C, amino acids and other micronutrients (EPQ) demonstrated significant suppression of ovarian cancer ES-2 xenograft tumor growth and suppression of ovarian tumor growth and lung metastasis from IP injection of ovarian cancer A-2780 cells. The EPQ mixture without quercetin (NM) also has shown potent anticancer activity in vivo and in vitro in a few dozen cancer cell lines by inhibiting tumor growth and metastasis, MMP-2 and -9 secretion, invasion, angiogenesis, and cell growth as well as induction of apoptosis. The presence of vitamin C, amino acids and other micronutrients could enhance inhibitory effect of epigallocatechin gallate (EGCG) on secretion of MMPs. In addition, enrichment of NM with quercetin (EPQ mix) enhanced anticancer activity of NM in vivo. In conclusion, polyphenols, especially in combination with other polyphenols or micronutrients, have been shown to be effective against multiple targets in cancer development and progression, and s

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Biological Availability; Catechin; Cell Line, Tumor; Cell Proliferation; Curcumin; Disease Models, Animal; Humans; Micronutrients; Neoplasms; Plant Extracts; Polyphenols; Quercetin; Resveratrol; Stilbenes; Tea

Lipoic acid (LA) is an antioxidant able to produce its effects in aqueous or lipophilic environments. Lipoate is the conjugate base of lipoic acid, and the most prevalent form of LA under physiological conditions. It presents a highly negative reduction potential, increases the expression of antioxidant enzymes and participates in the recycling of vitamins C and E. Due to these properties, LA is called the "universal antioxidant". LA is also involved with anti-inflammatory action, independently of its antioxidant activity. This review was carried out, aiming to identify, analyze, and rationalize the various clinical, physiopathological and/or physiological situations in which LA, through oral supplementation, was tested on human and animal (rats and mice) models. LA was mainly tested in cardiovascular diseases (CVD), obesity, pain, inflammatory diseases and aging. LA uses in CVD and obesity, in humans, are controversial. On the other hand, beneficial effects on inflammation and pain were observed. LA supplementation in animal models may prolong life, has neuroprotective effects and presents positive effects against cancer. Differences observed in human and animal models can be due, in part, to different treatments (LA combined with other antioxidants, different doses) and to the variety of biomarkers investigated in animal experiments. These results suggest the need for further clinical trials to guide health professionals regarding the safety of prescription of this supplement.

Topics: Aging; Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Clinical Trials as Topic; Disease Models, Animal; Humans; Inflammation; Oxidative Stress; Pain; Reactive Oxygen Species; Thioctic Acid; Vitamin E

Climatic droplet keratopathy (CDK) is an acquired and potentially handicapping cornea degenerative disease that is highly prevalent in certain rural communities around the world. It predominantly affects males over their forties. It has many other names such as Bietti's band-shaped nodular dystrophy, Labrador keratopathy, spheroidal degeneration, chronic actinic keratopathy, oil droplet degeneration, elastoid degeneration and keratinoid corneal degeneration. CDK is characterized by the haziness and opalescence of the cornea's most anterior layers which go through three stages with increasing severity. Globular deposits of different sizes may be histopathologically observed under the corneal epithelium by means of light and electron microscopy. The coalescence and increased volume of these spherules may cause the disruption of Bowman's membrane and the elevation and thinning of the corneal epithelium. The exact aetiology and pathogenesis of CDK are unknown, but they are possibly multifactorial. The only treatment in CDK advanced cases is a corneal transplantation, which in different impoverished regions of the world is not an available option. Many years ago, the clinical and histological aspects of this disease were described in several articles. This review highlights new scientific evidence of the expanding knowledge on CDK's pathogenesis which will open the prospect for new therapeutic interventions.

Topics: Animals; Ascorbic Acid; Cornea; Corneal Dystrophies, Hereditary; Corneal Transplantation; Disease Models, Animal; Humans; Sex Factors

Some studies have considered the association between diet and uterine fibroid risk, but the issue is largely unsettled. To identify potential modifiable risk factors for fibroid development, we have herein systematically reviewed prior publications dealing with this aspect. Comprehensive searches in electronic databases were conducted to collect studies published on association between uterine leiomyomas and both nutrients and food groups. We identified 13 publications deriving from 4 case-control, 3 cross-sectional, and 4 cohort studies. A protective effect has been demonstrated for consumption of fruits and green vegetables in both case-control and cohort studies. Moreover, very recent cross-sectional and case-control studies evaluating serum levels of 25-hydroxyvitamin-D3 tend to indicate that vitamin D insufficiency, which may in part be due to the diet intake, may play an important role in the development of uterine fibroids. No association was found with the intake of fibers, vitamin C and E, phytoestrogens and carotenoids, whereas association was controversial for the consumption of meat, fish, dairy products, and vitamin A. Most data have also been discussed herein in light of the available experimental and animal model results. These findings may be useful in devising nutritional strategies to reduce leiomyoma risk in humans.

Topics: Animals; Ascorbic Acid; Carotenoids; Dairy Products; Diet; Dietary Fats; Dietary Fiber; Disease Models, Animal; Folic Acid; Fruit; Humans; Leiomyoma; Meat; Phytoestrogens; Risk Factors; Seafood; Soy Foods; Vegetables; Vitamin A; Vitamin D; Vitamin E

Iron and ascorbate are vital cellular constituents in mammalian systems. The bulk-requirement for iron is during erythropoiesis leading to the generation of hemoglobin-containing erythrocytes. Additionally; both iron and ascorbate are required as co-factors in numerous metabolic reactions. Iron homeostasis is controlled at the level of uptake; rather than excretion. Accumulating evidence strongly suggests that in addition to the known ability of dietary ascorbate to enhance non-heme iron absorption in the gut; ascorbate regulates iron homeostasis. The involvement of ascorbate in dietary iron absorption extends beyond the direct chemical reduction of non-heme iron by dietary ascorbate. Among other activities; intra-enterocyte ascorbate appears to be involved in the provision of electrons to a family of trans-membrane redox enzymes; namely those of the cytochrome b561 class. These hemoproteins oxidize a pool of ascorbate on one side of the membrane in order to reduce an electron acceptor (e.g., non-heme iron) on the opposite side of the membrane. One member of this family; duodenal cytochrome b (DCYTB); may play an important role in ascorbate-dependent reduction of non-heme iron in the gut prior to uptake by ferrous-iron transporters. This review discusses the emerging relationship between cellular iron homeostasis; the emergent "IRP1-HIF2α axis"; DCYTB and ascorbate in relation to iron metabolism.

Topics: Animals; Ascorbic Acid; Basic Helix-Loop-Helix Transcription Factors; Cytochrome b Group; Cytochromes b; Disease Models, Animal; Duodenum; Erythropoiesis; Humans; Iron Regulatory Protein 1; Iron, Dietary

Vitamin C is an important antioxidant and cofactor that is involved in the regulation of development, function, and maintenance of several cell types in the body. Deficiencies in vitamin C can lead to conditions such as scurvy, which, among other ailments, causes gingivia, bone pain, and impaired wound healing. This review examines the functional importance of vitamin C as it relates to the development and maintenance of bone tissues. Analysis of several epidemiological studies and genetic mouse models regarding the effect of vitamin C shows a positive effect on bone health. Overall, vitamin C exerts a positive effect on trabecular bone formation by influencing expression of bone matrix genes in osteoblasts. Recent studies on the molecular pathway for vitamin C actions that include direct effects of vitamin C on transcriptional regulation of target genes by influencing the activity of transcription factors and by epigenetic modification of key genes involved in skeletal development and maintenance are discussed. With an understanding of mechanisms involved in the uptake and metabolism of vitamin C and knowledge of precise molecular pathways for vitamin C actions in bone cells, it is possible that novel therapeutic strategies can be developed or existing therapies can be modified for the treatment of osteoporotic fractures.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Bone and Bones; Cartilage; Disease Models, Animal; Humans; Models, Biological

This review is focused upon the role of ascorbic acid (AA, vitamin C) in the promotion of healthy brain aging. Particular attention is attributed to the biochemistry and neuronal metabolism interface, transport across tissues, animal models that are useful for this area of research, and the human studies that implicate AA in the continuum between normal cognitive aging and age-related cognitive decline up to Alzheimer's disease. Vascular risk factors and comorbidity relationships with cognitive decline and AA are discussed to facilitate strategies for advancing AA research in the area of brain health and neurodegeneration.

Topics: Aging; Alzheimer Disease; Animals; Ascorbic Acid; Brain; Cognition; Cognition Disorders; Disease Models, Animal; Humans; Observational Studies as Topic; Randomized Controlled Trials as Topic; Risk Factors

The effect of high doses of vitamin C for the treatment of cancer has been controversial. Our previous studies, and studies by others, have reported that vitamin C at concentrations of 0.25-1.0 mM induced a dose- and time-dependent inhibition of proliferation in acute myeloid leukemia (AML) cell lines and in leukemic cells from peripheral blood specimens obtained from patients with AML. Treatment of cells with high doses of vitamin C resulted in an immediate increase in intracellular total glutathione content and glutathione-S transferase activity that was accompanied by the uptake of cysteine. These results suggest a new role for high concentrations of vitamin C in modulation of intracellular sulfur containing compounds, such as glutathione and cysteine. This review, discussing biochemical pharmacologic studies, including pharmacogenomic and pharmacoproteomic studies, presents the different pharmacological effects of vitamin C currently under investigation.

Topics: Animals; Ascorbic Acid; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione; Humans; Neoplasms; Pharmacogenetics; Proteomics

Research progress to understand the role of vitamin C (ascorbic acid) in human health has been slow in coming. This is predominantly the result of several flawed approaches to study design, often lacking a full appreciation of the redox chemistry and biology of ascorbic acid. In this review, we summarize our knowledge surrounding the limitations of common approaches used in vitamin C research. In human cell culture, the primary issues are the high oxygen environment, presence of redox-active transition metal ions in culture media, and the use of immortalized cell lines grown in the absence of supplemental ascorbic acid. Studies in animal models are also limited due to the presence of endogenous ascorbic acid synthesis. Despite the use of genetically altered rodent strains lacking synthesis capacity, there are additional concerns that these models do not adequately recapitulate the effects of vitamin C deprivation and supplementation observed in humans. Lastly, several flaws in study design endemic to randomized controlled trials and other human studies greatly limit their conclusions and impact. There also is anecdotal evidence of positive and negative health effects of vitamin C that are widely accepted but have not been substantiated. Only with careful attention to study design and experimental detail can we further our understanding of the possible roles of vitamin C in promoting human health and preventing or treating disease.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Dietary Supplements; Disease Models, Animal; Humans; Randomized Controlled Trials as Topic

Vitamin C is a pivotal redox modulater in many biological reactions of which several remain poorly understood. Naturally, vitamin C has been the subject of many investigations over the past decades in relation to its possible beneficial effects on cardiovascular disease primarily based on its powerful yet general antioxidant properties. However, growing epidemiological, clinical and experimental evidence now suggests a more specific role of ascorbate in vasomotion and in the prevention of atherosclerosis. For example, in contrast to most other biological antioxidants, administration of vitamin C can apparently induce vasodilation. Millions of people worldwide can be diagnosed with vitamin C deficiency according to accepted definitions. In this perspective, the present review examines the evidence for a specific link between vitamin C deficiency and increased risk of atherosclerosis as well as the possible mechanisms by which vitamin C may exert its protective function.

Topics: Animals; Antioxidants; Ascorbic Acid; Ascorbic Acid Deficiency; Atherosclerosis; Coenzymes; Disease Models, Animal; Dyslipidemias; Endothelium, Vascular; Humans; Lipid Metabolism; Lipids; Nitric Oxide; Nitric Oxide Synthase; Scurvy; Vasodilation

Despite the apparent consensus on the existence of endothelial dysfunction in conduit and resistance arteries of spontaneously hypertensive rats (SHR), a commonly employed experimental model of hypertension, there are a number of reports showing that endothelium-dependent vasodilatory responses are similar, or even increased, in SHR compared with their normotensive counterparts. The present paper aims to discuss the rationale for these apparent discrepancies, including the effect of age, type of artery and methodological aspects. Data from the literature indicate that the age of the animal is a contributing factor and that endothelial dysfunction is likely to be a consequence of hypertension. In addition, the use of antioxidant additives, such as ascorbic acid or ethylene diaminetetraacetic acid, and differences in the level of initial arterial stretch, might also be of importance because they may modify the oxidative status of the artery and the levels of vasoactive factors released by the endothelium.

Topics: Animals; Antioxidants; Ascorbic Acid; Blood Pressure; Disease Models, Animal; Edetic Acid; Endothelium, Vascular; Hypertension; Nitric Oxide; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Species Specificity

Charcot-Marie-Tooth disease (CMT), also called hereditary motor and sensory neuropathy (HMSN), is the most common inherited peripheral neuropathy, comprised by a group of genetically heterogeneous disorders that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, and depressed tendon reflexes. It can be categorized according to its electrophysiological or pathological features, transmission patterns, age of disease onset, and molecular pathology. CMT type 1 (CMT1; MIM 118200) is a group of autosomal dominant-inherited demyelinating neuropathies with a disease onset at or after childhood. Five different subtypes have been identified based on different causative genes. Among them, CMT1A (MIM #118220) is most common and is usually associated with a duplication of a 1.5-Mb region on chromosome 17p11.2, which includes peripheral myelin protein 22 gene (PMP22; MIM *601097). Currently, there is no cure or obviously effective disease-modifying treatment for CMT. Two potential effective therapeutic agents for CMT1A were investigated recently. One is ascorbic acid and another is neurotrophin-3 (NT-3), an important component of the Schwann cell autocrine survival loop. Early diagnosis can facilitate CMT patients to modify their life styles timely for minimizing nerve injury to delay or avoid disability. Molecular diagnosis of CMT can provide the basis for appropriate genetic counseling and further CMT research.

Topics: Animals; Ascorbic Acid; Charcot-Marie-Tooth Disease; Disease Models, Animal; Humans

The generation by genetic engineering of two murine models to investigate atherosclerosis, such as the apoE- and LDLr- deficient mice, is providing an extraordinaire knowledge of the effect of different nutrients on this complex disease. The present revision provides a comprehensive overview of the advances in this field that point to a remarkable complexity. While some controversies over puzzling results could be explained invoking potential nutrient interactions or different food sources of nutrients, it also appears that other factors such as sex, genetic background or immunological status are emerging as generators of differential responses to nutrients during the atherosclerotic process.

Topics: Alcohol Drinking; Allergy and Immunology; Animals; Antioxidants; Apolipoproteins E; Arginine; Arteriosclerosis; Ascorbic Acid; Atherosclerosis; Cell Proliferation; Dietary Fats; Disease Models, Animal; Energy Metabolism; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Genetic Engineering; Genetic Variation; Genomics; Homocysteine; Insulin Resistance; Iron; Magnesium; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Models, Genetic; Phytosterols; Receptors, LDL; Sex Factors; Sodium; Taurine; Vitamin E

The most frequent genetic subtype of Charcot-Marie-Tooth disease is CMT1A, linked to chromosome 17p11.2. In the majority of cases, CMT1A is a gene dosage disease associated with a 1.5 Mb large genomic duplication. Transgenic models with extra copies of the Pmp22 gene have provided formal proof that overexpression of only this candidate gene is sufficent to cause peripheral demyelination, onion bulb formation, secondary axonal loss, and progressive muscle atrophy, the pathological hallmarks of CMT1A. The transgenic CMT rat with about 1.6-fold PMP22 overexpression exhibits clinical abnormalities, such as reduced nerve conduction velocity and lower grip strength that mimick findings in CMT1A patients. Also transgenic mice, carrying yeast artifical chromosomes as Pmp22 transgenes, demonstrate the variability of disease expression as a function of increased gene dosage. Recently, the first rational experimental therapies of CMT1A were tested, using transgenic animal models. In one proof-of-principle study with the CMT rat, a synthetic antagonist of the nuclear progesterone receptor was shown to reduce PMP22 overexpression and to ameliorate the clinical severity. In another study, administration of ascorbic acid, an essential factor of in vitro myelination, prolonged the survival and restored myelination of a dysmyelinated mouse model. Application of gene expression analysis to nerve biopsies that are readily available from such CMT1A animal models might identify additional pharmacological targets.

Topics: Animals; Animals, Genetically Modified; Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Chromosomes, Human, Pair 17; Disease Models, Animal; Gene Dosage; Humans; Myelin Proteins; Neuroprotective Agents; Progesterone

Glucocorticoids (GC) have been widely used as a therapeutic drug for various diseases. However, there are many complications of GC therapy including cataracts. In a series of studies to elucidate the actions of GC using 15-day-old developing chick embryos, we found that GC produced hyperglycemia, hyperlipemia, osteoporosis, and cataractous lenses with a high incidence (>90%) within 48 h. Cataract formation is caused by oxidative stresses, probably derived from GC effects on the main target organ, the liver, and can be prevented by radical scavengers including ascorbic acid, and insulin. Ascorbic acid does not inhibit the inflammatory and immunosuppressive effects of GC. Therefore by analyzing and decreasing risk factors producing side effects, it will be possible to improve GC therapy without the loss of GC activity.

Topics: Animals; Ascorbic Acid; Cataract; Chick Embryo; Disease Models, Animal; Free Radical Scavengers; Glucocorticoids; Glutathione; Insulin; Lipid Peroxides; Liver; Mifepristone; Oxidative Stress; Phosphoprotein Phosphatases; Receptors, Glucocorticoid

It has been hypothesized that decreasing antioxidant (fruit and vegetables), increased n-6 polyunsaturated fatty acid (PUFA; (margarine, vegetable oil), and decreased n-3 PUFA (oily fish) intakes have contributed to the recent increases in asthma and atopic disease. Epidemiologic studies in adults and children have reported beneficial associations between dietary antioxidants and lipids and parameters of asthma and atopic disease. The associations with n-6 and n-3 PUFA appear to be very complex and might differ between asthma and atopic dermatitis. Dietary antioxidants are probably exerting antioxidant and nonantioxidant immunomodulatory effects. Dietary lipids exert numerous complex effects on proinflammatory and immunologic pathways. It has also been suggested that atopic dermatitis is associated with an enzyme defect in lipid metabolism. In spite of this, the results of interventional supplementation studies in established disease have been disappointing, and there is now increasing interest in the possibility that dietary antioxidant and lipid intakes might be important in determining expression of disease during pregnancy and early childhood and that dietary interventions should be targeted at these groups. It also seems likely that there is individual variation in the responses of individuals to lipid, and probably antioxidant, supplementation. Further research to determine whether dietary intervention can reduce the risk of asthma and atopic disease is justified.

Topics: Animals; Antioxidants; Ascorbic Acid; Asthma; Child, Preschool; Clinical Trials as Topic; Diet; Dietary Fats; Dietary Supplements; Disease Models, Animal; Female; Fish Oils; Fruit; Humans; Hypersensitivity, Immediate; Lipid Metabolism; Lipids; Male; Pregnancy; Pregnancy Complications; Risk Factors; Selenium; Vegetables; Vitamin A; Vitamin E

As a non-toxic endogenous antioxidant, the semi-essential amino acid taurine is a potential attenuator of oxidative damage such as that produced by ischaemia-reperfusion injury. Ischaemia-reperfusion injury is a well established if paradoxical phenomenon whereby ischaemic tissue, doomed to necrosis if it is not reperfused, is actually further damaged by oxidative attack when perfusion is restored. This paper is a review of the literature concerning therapeutic strategies in ischaemia-reperfusion injury, including non-pharmacological and pharmacological interventions. There is consistent experimental evidence of an important role of taurine in ischaemia-reperfusion injury, with a clinical role emerging in human trials of taurine administered prior to coronary artery bypass grafting and heart valve surgery.

Topics: Animals; Antioxidants; Ascorbic Acid; Clinical Trials as Topic; Disease Models, Animal; Free Radical Scavengers; Free Radicals; Humans; Ischemic Preconditioning; Lipid Peroxidation; Reperfusion Injury; Taurine; Vitamin E

High-energy impulse noise (BLAST) is a physical event characterized by an abrupt rise in atmospheric pressure above ambient lasting for a very short period, but potentially causing significant material and biological damage. Exposure to high-level BLAST can be destructive and lethal. Low-level BLAST similar to what is encountered repeatedly by military personnel during training and combat from detonation of munitions and firing of large caliber weapons, and during occupational use of explosives and some heavy machinery, can also cause significant injury. Globally, civilians are increasingly exposed to BLAST resulting from terrorist bombings or abandoned unmarked mines following numerous wars and conflicts. We have shown previously in several animal models that exposure to non-lethal BLAST results in pathological changes, mostly to the hollow organs characterized in the lungs, the most sensitive organ, by rupture of alveolar septa, and pulmonary hemorrhage and edema. These events potentially can cause alveolar flooding, respiratory insufficiency and adult respiratory distress syndrome (ARDS), leading to varying degrees of hypoxia, antioxidant depletion and oxidative damage. We have also observed progressive formation of nitric oxide in blood and other tissues. The totality of these observations supports our general hypothesis that exposure to BLAST can lead to antioxidant depletion and oxidative damage. Understanding the mechanism(s) of BLAST-induced oxidative stress may have important implications that include a potential beneficial role for antioxidants as a prophylaxis or as secondary treatment of injury after exposure alongside other protective and therapeutic modalities. In addition, it suggests a role for endogenous nitric oxide in the injury. This report reviews experimental evidence of BLAST-induced antioxidant depletion, and the potential benefit from antioxidant supplementation before exposure.

Topics: Animals; Antioxidants; Ascorbic Acid; Blast Injuries; Disease Models, Animal; Explosions; Glutathione; Humans; Lung; Lung Injury; Oxidative Stress; Vitamin E

Experimental animal studies have unambiguously demonstrated that topical sunscreens can prevent squamous cell carcinoma and photoaging (damage of collagen and elastic fibers of the skin). Although data from clinical studies and surrogate markers also indicate such photoprotective effects in man, there is a lack of controlled, prospective clinical trials to provide definite evidence in man. Because of inadequate data, no definite conclusions can be drawn about the cancer-preventive activity of topical use of sunscreens against basal cell carcinoma and malignant melanoma.

Topics: Administration, Topical; Adult; Animals; Antioxidants; Ascorbic Acid; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Disease Models, Animal; Humans; Melanoma; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Prospective Studies; Randomized Controlled Trials as Topic; Skin Aging; Skin Neoplasms; Sunscreening Agents; Time Factors; Ultraviolet Rays; Vitamin E

FREE RADICALS AND THE THEORY OF AGING: Severe oxidative stress progressively leads to cell dysfunction and ultimately cell death. Oxidative stress is defined as an imbalance between pro-oxidants and/or free radicals on the one hand, and anti-oxidizing systems on the other. The oxygen required for living may indirectly be responsible for negative effects; these deleterious effects are due to the production of free radicals, which are toxic for the cells (superoxide anions, hydroxyl radicals, peroxyl radicals, hydrogen peroxide, hydroperoxides and peroxinitrite anions). Free radical attacks are responsible for cell damage and the targeted cells are represented by the cell membranes, which are particularly rich in unsaturated fatty acids, sensitive to oxidation reactions; DNA is also the target of severe attacks by these reactive oxygen species (ROS).. These are represented by the enzymes and free radical captors. The latter are readily oxidizable composites. The free radical captor or neutralization systems of these ROS use a collection of mechanisms, vitamins (E and C), enzymes [superoxide dismutase (SOD), glutathion peroxidase (GPx) and others], and glutathion reductase (GSH), capable of neutralizing peroxinitrite. The efficacy of this system is dependent on the genome for the enzymatic defence systems, and on nutrition for the vitamins. Some strategies aimed at reducing oxidative stress-related alterations have been performed in animals. However, only a few can be used and are efficient in humans, such as avoidance of unfavourable environmental conditions (radiation, dietary carcinogens, smoking...) and antioxidant dietary supplementation.. Epidemiological data suggest that antioxidants may have a beneficial effect on many age-related diseases: atherosclerosis, cancer, some neurodegenerative and ocular diseases. However, the widespread use of supplements is hampered by several factors: the lack of prospective and controlled studies; insufficient knowledge on the pro-oxidant, oxidant and ant-oxidant properties of the various supplements; growing evidence that free radicals are not only by-products, but also play an important role in cell signal transduction, apoptosis and infection control.. Although current data indicate that antioxidants cannot prolong maximal life span, the beneficial impact of antioxidants on various age-related degenerative diseases may forecast an improvement in life span and enhance quality of life. The current lack of sufficient data does not permit the systematic recommendation of anti-oxidants. Nevertheless, antioxidant-rich diets with fruit and vegetables should be recommended.

Topics: Aging; Alzheimer Disease; Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Carotenoids; Cataract; Chronic Disease; Disease Models, Animal; Evidence-Based Medicine; Free Radicals; Humans; Lutein; Macular Degeneration; Neoplasms; Oxidative Stress; Parkinson Disease; Reactive Oxygen Species; Vitamin E

The premise that oxidative stress, among several other factors, plays an important role in atherogenesis implies that the development and progression of atherosclerosis can be inhibited by antioxidants. In this minireview we discuss several mechanisms by which the antioxidants ascorbate (vitamin C) and alpha-tocopherol (vitamin E) may protect against atherosclerosis. These mechanisms include inhibition of LDL oxidation and inhibition of leukocyte adhesion to the endothelium and vascular endothelial dysfunction. Overall, ascorbate appears to be more effective than alpha-tocopherol in mitigating these pathophysiological processes, most likely as a result of its abilities to effectively scavenge a wide range of reactive oxygen and nitrogen species and to regenerate alpha-tocopherol, and possibly tetrahydrobiopterin, from its radical species. In contrast, alpha-tocopherol can act either as an antioxidant or a pro-oxidant to inhibit or facilitate, respectively, lipid peroxidation in LDL. However, this pro-oxidant activity of alpha-tocopherol is prevented by ascorbate acting as a coantioxidant. Therefore, an optimum vitamin C intake or body status may help protect against atherosclerosis and its clinical sequelae, whereas vitamin E may only be effective in combination with vitamin C.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cell Adhesion; Cells, Cultured; Disease Models, Animal; E-Selectin; Endothelium, Vascular; Enzyme Activation; Humans; Leukocytes; Lipid Peroxidation; Lipoproteins, LDL; Nitric Oxide; Oxidation-Reduction; Protein Kinase C; Reactive Oxygen Species; Vasodilation; Vitamin E

There are at least four mechanisms whereby the nutrient vitamins A, C, D, and E may be related to the processes that impede or give rise to OA. These nutrient vitamins have major roles in modulating oxidative stress, participating in immune responses, and contributing to cell differentiation. There is a substantial need to understand the contribution of these nutrients to OA, because they may provide important insight into ameliorating the initiation and progression of the disease. Simultaneously, greater understanding will add rationality to an area of potential intervention that is often based on anecdote. Investigation will be complex; there is the need to select appropriate systems. Typical animal model systems used in the study of OA are inappropriate because most animals can synthesize ascorbic acid. There is the need to disaggregate, as much as possible, the numerous subsets of OA and the plethora of processes that contribute to that heterogeneity. Certainly, there is the need to recognize the interdependency of the actions of each of these nutrients at the cellular level. Furthermore, humans rarely consume these nutrients as independent products. For example, watermelon is a primary source of both ascorbic acid and beta-carotene. Failure to address these complexities denies the scientist the opportunity to advance our understanding of health and disease processes. More importantly, failure to address these complexities denies the person with OA the opportunity to address his or her own health.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Humans; Osteoarthritis; Vitamin A; Vitamin D; Vitamin E

Topics: Alkaptonuria; Animals; Ascorbic Acid; Disease Models, Animal; History, 19th Century; History, 20th Century; Humans; United Kingdom

In this chapter, we have briefly reviewed the current scientific knowledge of the role of vitamin C in the prevention of atherosclerosis and its associated clinical manifestations. There is good evidence from animal studies that vitamin C can slow the progression of experimental atherosclerosis. Most of these studies, however, were done either in guinea pigs, using ascorbic acid depletion, or in cholesterol-fed rabbits, using ascorbic acid supplementation. Both animal models have limitations, as guinea pigs are not a well-established (nor well-studied) model of atherosclerosis, and rabbits develop atherosclerosis at high serum beta-VLDL cholesterol levels, and in addition can synthesize ascorbic acid. In contrast, humans develop atherosclerosis spontaneously and readily at moderately elevated serum LDL cholesterol levels and have lost the ability to synthesize ascorbic acid. Thus, the animal studies discussed, although quite promising and suggestive of an anti-atherogenic effect of ascorbic acid, need to be expanded to primates before more definitive conclusions can be drawn. Similar to the animal data, the current evidence from epidemiological studies on the role of vitamin C in the prevention of CVD is inconclusive, with some studies showing a very strong correlation between increased vitamin C intake and incidence of CVD events and other studies showing no correlation at all. Studies on CVD risk factors indicate that vitamin C may moderately decrease total serum cholesterol levels, increase HDL levels, and exert a hypotensive effect. These findings are particularly intriguing and should be pursued vigorously in basic research studies to elucidate biological mechanisms. In addition, it appears that large placebo-controlled, double-blind, randomized trials of vitamin C supplementation (without simultaneous supplementation with vitamin E) in populations with a wide range of vitamin C body levels are needed in order to confirm or refute a role for vitamin C in the prevention of CVD. Unfortunately, no such trials are currently being conducted. The possible mechanisms by which ascorbic acid may affect the development of atherosclerosis and the onset of acute coronary events include effects on arterial wall integrity related to biosynthesis of collagen and GAGs, altered cholesterol metabolism mediated by vitamin C-dependent conversion of cholesterol to bile acids, and effects on triglyceride levels via modulation of lipoprotein lipase activity. A particularly

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cardiovascular Diseases; Cholesterol; Diet, Atherogenic; Disease Models, Animal; Epidemiologic Methods; Extracellular Matrix Proteins; Guinea Pigs; Humans; Lipoproteins; Rabbits; Risk Factors

Recent research findings have suggested a role for pharmacologic as well as nutritional antioxidants in the prevention of atherosclerosis. Data from animal studies as well as cell culture experiments have shown that the drug probucol, which has hypocholesterolemic and antioxidant properties, is able to prevent oxidative modification of low density lipoproteins (LDL). Such modification is now believed to play a major part in the initiation and progression of arterial lesions. Nutrients with antioxidant properties such as vitamins C and E, beta-carotene, and mono-unsaturated fatty acids (when they replace polyunsaturated fatty acids) can reduce the susceptibility of LDL to oxidation. Antioxidant therapy, if proven useful, should be considered an adjunct to lipid-lowering therapy in order to have the greatest impact on coronary heart disease.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Carotenoids; Disease Models, Animal; Fatty Acids, Monounsaturated; Humans; Lipoproteins, LDL; Oxidation-Reduction; Rabbits; Vitamin E

The development of buthionine sulfoximine, a selective inhibitor of glutathione biosynthesis, is an important new tool to elucidate the in vivo role of glutathione. Recent investigations have shown that ascorbic acid can serve as an essential antioxidant in the presence of severe glutathione deficiency.

Topics: Animals; Animals, Newborn; Antioxidants; Ascorbic Acid; Buthionine Sulfoximine; Disease Models, Animal; Glutathione; Methionine Sulfoximine; Rats

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Disease Models, Animal; Guinea Pigs; Hypercholesterolemia

Topics: Animals; Ascorbic Acid; Awards and Prizes; beta Carotene; Carotenoids; Disease Models, Animal; Humans; Light; Ophthalmology; Photoreceptor Cells; Retina; Retinal Degeneration; Societies, Medical

Skin carcinogenesis can be operationally and mechanistically divided into at least three stages; tumor initiation, stage I and stage II of promotion. Current information suggests that reactive intermediates of skin tumor initiators are mutagenic and bind convalently to DNA of epidermal stem cells (dark basal keratinocytes) leading to some irreversible alteration in the differentiation capacity of these cells. Inhibitors of skin tumor initiation by polycyclic aromatic hydrocarbons (PAH) decrease the level of the PAH diol-epoxide bound to specific DNA adducts. The tumor promoters have been shown to have many cellular and biochemical effects in the skin. Recent data suggests that free radicals may be important in skin tumor promotion. The first stage of promotion is partially irreversible and can be accomplished by a single treatment of a tumor promoter such as TPA or by non-promoting agents such as 4-0-methyl-TPA, calcium ionophore A23187, and hydrogen peroxide, as well as wounding. These agents increase the number of dark basal keratinocytes, which suggest that these cells are important in the first stage of promotion. Prostaglandin E2 was found to specifically enhance stage I of promotion whereas the protease inhibitor tosyl phenylalanine chloromethylketone (TPCK) specially inhibited stage I of promotion and the TPA-induced dark basal keratinocytes. The second stage of promotion is initially reversible but later becomes irreversible. The weak promoting agent mezerein is an effective stage II promoter. Polyamines and epidermal cell proliferation appear to be important events in stage II of promotion. Putrescine was found to specifically enhance stage II, whereas retinoic acid (RA), diflouromethylornithine (DFMO), and butylated hydroxyanisole (BHA) specially inhibited stage II of promotion and the mezerein-induced polyamine levels. Floucinolone acetonide (FA) was found to inhibit both stages but was more effective in counteracting stage I of promotion. Although, TPA can cause a decrease in the number of glucocorticoid receptors during promotion, FA can effectively prevent this loss. Recent data suggest that skin tumor promotion can be effectively inhibited by a combination of stage I and II inhibitors. Furthermore, skin carcinogenesis can be counteracted by a combination of low and nontoxic doses of BHA, TPCK, DFMO and vitamin E.

Topics: Animals; Ascorbic Acid; Carcinogens; Disease Models, Animal; Humans; Neoplasms; Phorbol Esters; Selenium; Skin Neoplasms; Vitamin E

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Cholelithiasis; Cholesterol; Diet; Disease Models, Animal; Guinea Pigs; Humans; Lipids; Liver; Rats; Triglycerides

Topics: Animals; Ascorbic Acid; Chediak-Higashi Syndrome; Concanavalin A; Cyclic GMP; Disease Models, Animal; Humans; Immunity, Cellular; Leukocytes; Lupus Erythematosus, Systemic; Mice; Mice, Inbred NZB; Prostaglandins

Tyrosinase [EC 1.14.18.1] isolated from mouse melanoma was inactivated during the dopa-tyrosinase reaction. When ascorbate was added to the reaction system, in which dopa-quinone is immediately converted back to dopa by ascorbate thus preventing the formation of melanin, tyrosinase inactivation similarly occurred. If superoxide anions (O2-) or singlet oxygens (1O2), are generated during the reaction they can attack the enzyme protein to be inactivated. Therefore an estimate was made with scavengers for oxygen radicals and with a liquid scintillation counter but neither was detectable. Thus the inactivation involved is not due to reaction products nor oxygen

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Melanins; Melanocytes; Melanoma, Experimental; Mice; Monophenol Monooxygenase; Oxidation-Reduction; Reactive Oxygen Species; Sensitivity and Specificity; Superoxides; Tumor Cells, Cultured

Topics: Acyltransferases; Adult; Animals; Arteries; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Cholesterol; Disease Models, Animal; Evaluation Studies as Topic; Forecasting; Humans; Phosphatidylcholines; Self Medication

Topics: Animal Nutritional Physiological Phenomena; Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Bile Acids and Salts; Carbon Dioxide; Carbon Isotopes; Cholesterol; Chronic Disease; Disease Models, Animal; Feces; Guinea Pigs; Kinetics; Liver; Skin; Spleen

Ascorbate (vitamin C) was an early, unorthodox therapy for cancer, with an outstanding safety profile and anecdotal clinical benefit. Because oral ascorbate was ineffective in two cancer clinical trials, ascorbate was abandoned by conventional oncology but continued to be used in complementary and alternative medicine. Recent studies provide rationale for reexamining ascorbate treatment. Because of marked pharmacokinetic differences, intravenous, but not oral, ascorbate produces millimolar concentrations both in blood and in tissues, killing cancer cells without harming normal tissues. In the interstitial fluid surrounding tumor cells, millimolar concentrations of ascorbate exert local pro-oxidant effects by mediating hydrogen peroxide (H(2)O(2)) formation, which kills cancer cells. We investigated downstream mechanisms of ascorbate-induced cell death. Data show that millimolar ascorbate, acting as a pro-oxidant, induced DNA damage and depleted cellular adenosine triphosphate (ATP), activated the ataxia telangiectasia mutated (ATM)/adenosine monophosphate-activated protein kinase (AMPK) pathway, and resulted in mammalian target of rapamycin (mTOR) inhibition and death in ovarian cancer cells. The combination of parenteral ascorbate with the conventional chemotherapeutic agents carboplatin and paclitaxel synergistically inhibited ovarian cancer in mouse models and reduced chemotherapy-associated toxicity in patients with ovarian cancer. On the basis of its potential benefit and minimal toxicity, examination of intravenous ascorbate in combination with standard chemotherapy is justified in larger clinical trials.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Carboplatin; Cell Death; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Female; Infusions, Parenteral; Mice; Ovarian Neoplasms; Paclitaxel; Xenograft Model Antitumor Assays

No current medications improve neuropathy in subjects with Charcot-Marie-Tooth disease type 1A (CMT1A). Ascorbic acid (AA) treatment improved the neuropathy of a transgenic mouse model of CMT1A and is a potential therapy. A lower dosage (1.5 g/d) did not cause improvement in humans. It is unknown whether a higher dosage would prove more effective.. To determine whether 4-g/d AA improves the neuropathy of subjects with CMT1A.. A futility design to determine whether AA was unable to reduce worsening on the CMT Neuropathy Score (CMTNS) by at least 50% over a 2-year period relative to a natural history control group.. Three referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and University of Rochester).. One hundred seventy-four subjects with CMT1A were assessed for eligibility; 48 did not meet eligibility criteria and 16 declined to participate. The remaining 110 subjects, aged 13 to 70 years, were randomly assigned in a double-masked fashion with 4:1 allocation to oral AA (87 subjects) or matching placebo (23 subjects). Sixty-nine subjects from the treatment group and 16 from the placebo group completed the study. Two subjects from the treatment group and 1 from the placebo group withdrew because of adverse effects.. Oral AA (4 g/d) or matching placebo.. Change from baseline to year 2 in the CMTNS, a validated composite impairment score for CMT.. The mean 2-year change in the CMTNS was -0.21 for the AA group and -0.92 for the placebo group, both better than natural history (+1.33). This was well below 50% reduction of CMTNS worsening from natural history, so futility could not be declared (P > .99).. Both treated patients and those receiving placebo performed better than natural history. It seems unlikely that our results support undertaking a larger trial of 4-g/d AA treatment in subjects with CMT1A.. clinicaltrials.gov Identifier: NCT00484510.

Topics: Adolescent; Adult; Aged; Animals; Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Disease Models, Animal; Disease Progression; Double-Blind Method; Female; Humans; Male; Medical Futility; Mice; Middle Aged; Severity of Illness Index; Time Factors; Young Adult

Elevated plasma homocysteine levels are associated with the risk of atherosclerosis and arterial and venous thrombosis. We have previously demonstrated that rabbits rendered hyperhomocysteinemic by parenteral administration of homocysteine develop a dysfibrinogenemia that is associated with the formation of fibrin clots that are abnormally resistant to fibrinolysis. We suggested that this acquired dysfibrinogenemia contributes to the thrombotic tendency in hyperhomocysteinemia. However, it was possible that the homocysteine-associated dysfibrinogenemia was an artifact of the parenteral administration model. Therefore, the goals of the current study were to develop a diet-induced model of homocysteinemia in rabbits and determine whether a dysfibrinogenemia and evidence of oxidative stress develop in this model as they do when homocysteine is injected. We found that rabbits fed a diet severely deficient in folate and mildly deficient in choline develop mild hyperhomocysteinemia: 14.8+/-4.0 microM in deficient rabbits compared to 9.0+/-1.7 microM in controls. The deficient rabbits also develop evidence of oxidant stress: increased lipid peroxidation in liver, impaired mitochondrial enzyme activities in liver and elevated caspase-3 levels in plasma. Most importantly, the deficient rabbits also develop a dysfibrinogenemia characterized by increased resistance to fibrinolysis. We believe that this dietary model of homocysteinemia is clinically relevant and reproduces many features associated with hyperhomocysteinemia in previous work using in vitro and in vivo models. Our findings suggest that an acquired dysfibrinogenemia could play a role in the increased risk of atherothrombotic disease in mildly hyperhomocysteinemic human subjects.

Topics: Animals; Antioxidants; Ascorbic Acid; Caspase 3; Choline Deficiency; Diet; Disease Models, Animal; Female; Fibrinolysis; Folic Acid Deficiency; Homocysteine; Hyperhomocysteinemia; Mitochondria; Oxidative Stress; Rabbits; Risk Factors; Thrombosis; Vitamin E

There is a growing body of basic science and epidemiologic evidence to support a research thrust to determine whether several natural or synthetic agents, given alone or together, can lower cancer incidence. Candidate agents include analogs of vitamin A and the vitamin A precursor, beta-carotene, vitamins C and E, and the trace metal selenium. Other agents now being studied in the laboratory include phenolic antioxidants, protease inhibitors, prostaglandin synthesis inhibitors, and indoles. Research in chemoprevention involves identifying and characterizing agents with reported activity, efficacy and toxicologic testing to select the most promising agents, and clinical trials to test those with the most potential in humans. Activities are underway in all the above areas, including 24 clinical trials, to evaluate selected compounds in preventing cancer at various cancer sites. Included are studies of individuals at high risk, individuals with precancerous lesions and individuals free of cancer but at risk to second cancers. A number of agents have shown activity in reducing bladder cancer incidence in animal models. The potential applicability of these agents for studies in human cancer risk reduction intervention studies is discussed. Cancer induction is postulated to be a multistage process involving initiation and promotion. Progress in cancer prevention may result from not only reducing exposures to initiators, but also suppressing promotional activity in initiated cells. Newly developed research technologies including cellular, animal, and epidemiologic procedures are being used for identifying, refining, and testing cancer prevention strategies.

Topics: Animals; Ascorbic Acid; beta Carotene; Carotenoids; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation; Epidemiologic Methods; Female; Humans; Male; Mice; Rats; Selenium; United States; Urinary Bladder Neoplasms; Vitamin A; Vitamin E

Tinnitus is a widespread and serious clinical and social problem. Although oxidative injury has been suggested to be one of pathological mechanisms in auditory cortex, whether this mechanism could be applied to inferior colliculus remains unclear. In this study, we used an online electrochemical system (OECS) integrating in vivo microdialysis with selective electrochemical detector to continuously monitor the dynamics of ascorbate efflux, an index of oxidative injury, in inferior colliculus of living rats during sodium salicylate-induced tinnitus. We found that OECS with a carbon nanotubes (CNTs)-modified electrode as the detector selectively responses to ascorbate, which is free from the interference from sodium salicylate and MK-801 that were used to induce tinnitus animal model and investigate the N-methyl-d-aspartate (NMDA) receptor mediated excitotoxicity, respectively. With the OECS, we found that the extracellular ascorbate level in inferior colliculus significantly increases after salicylate administration and such increase was suppressed by immediate injection of NMDA receptor antagonist MK-801. In addition, we found that salicylate administration significantly increases the spontaneous and sound stimuli evoked neural activity in inferior colliculus and that the increases were inhibited by the injection of MK-801. These results suggest that oxidative injury may occur in inferior colliculus following salicylate-induced tinnitus, which is closely relevant to the NMDA-mediated neuronal excitotoxicity. This information is useful for understanding the neurochemical processes in inferior colliculus involved in tinnitus and its related brain diseases.

Topics: Ascorbic Acid; Disease Models, Animal; Dizocilpine Maleate; Electrochemical Techniques; Inferior Colliculi; Oxidative Stress; Salicylates; Sodium Salicylate; Tinnitus

Vitamin C (VC)-based cancer therapy is a promising therapeutic approach for a variety of cancers due to its profound effects on redox reactions and metabolic pathways. However, high administration dosage of VC for necessary therapeutic efficacy for cancers increases the risk of overt side effects and limits its clinical use. Here, we show cutaneous blue light irradiation can specifically upregulate the sodium-dependent vitamin C transporter 2 (SVCT2) of the tumor and increase effectively the VC concentration at the tumor sites by an overall low dosage administration. In the mouse melanoma model, blue light stimulates the SVCT2 expression through the nuclear factor-kappa B (NF-κB) signaling pathway both in vitro and in vivo. The increased cellular VC together with Fe

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Ferroptosis; Melanoma; Mice; Oxidative Stress; Sodium-Coupled Vitamin C Transporters

Gabapentin is a commonly prescribed antiepileptic agent for seizures, which is also used for pain and addiction management. Due to growing evidence of its abuse liability, there has been an incentive to synthesise potentially useful gabapentin derivatives devoid of adverse effects. A gabapentin adduct with a fluoxetine moiety, GBP1F, was assessed for any sedative, cognitive, anxiolytic, or antidepressant-like actions in murine behavioral models.. Selected groups of mice were used for each behavioral paradigm, and the effect of GBP1F (5, 10, and 15 mg/kg) was assessed using spontaneous locomotor activity, the tail suspension test, elevated plus maze test, and the Y maze test models. Immediately following behavioral experiments, postmortem striatal and hippocampal tissues were evaluated for the effect of GBP1F on concentrations of dopamine, DOPAC, HVA, serotonin, 5-HIAA, vitamin C, and noradrenaline using high performance liquid chromatography with electrochemical detection.. GBP1F induced a mild suppression of locomotor activity, ameliorated anxiety and depression-like behavior, did not alter cognitive behavior, and raised serotonin and 5-HIAA concentrations in the hippocampus and striatum. GBP1F also positively enhanced dopamine and vitamin C tissue levels in the striatum. Thus, GBP1F represents a compound with anxiolytic- and antidepressant-like effects though further studies are warranted at the molecular level to focus on the precise mechanism(s) of action.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Ascorbic Acid; Behavior, Animal; Cognition; Depression; Disease Models, Animal; Dopamine; Fluoxetine; Gabapentin; Hydroxyindoleacetic Acid; Mice; Serotonin

Topics: Aging; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Galactose; Gene Expression; Kidney; Levilactobacillus brevis; Liver; Male; Mice; Oxidative Stress; Reactive Oxygen Species; Superoxide Dismutase

Acute myeloid leukemia (AML) patients bearing the ITD mutation in the tyrosine kinase receptor FLT3 (FLT3-ITD) present a poor prognosis and a high risk of relapse. FLT3-ITD is retained in the endoplasmic reticulum (ER) and generates intrinsic proteotoxic stress. We devised a strategy based on proteotoxic stress, generated by the combination of low doses of the differentiating agent retinoic acid (R), the proteasome inhibitor bortezomib (B), and the oxidative stress inducer arsenic trioxide (A).. We treated FLT3-ITD. The combination RBA exerts strong cytotoxic activity on FLT3-ITD. Our findings strengthen our previous work indicating induction of proteotoxic stress as a possible strategy in FLT3-ITD

Topics: Animals; Ascorbic Acid; Cell Death; Cytoprotection; Disease Models, Animal; Humans; Mechanotransduction, Cellular; Mice; Proteotoxic Stress; Tretinoin

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Dysentery, Bacillary; Gastrointestinal Microbiome; Guinea Pigs; Humans; Mammals; Mice; Rabbits; Shigella; Shigella flexneri

Vitamin C deficiency is found in patients with variable kidney diseases. However, the role of vitamin C as an epigenetic regulator in renal homeostasis and pathogenesis remains largely unknown.. Integrated evidence suggested that epigenetic modifications affected the proximal tubule cells and fenestrated endothelial cells, leading to tubule injury and hypoxia through transcriptional regulation. Strikingly, loss of DNA hydroxymethylation and DNA hypermethylation in vitamin C-deficient kidneys preceded the histologic sign of tubule necrosis, indicating the causality of vitamin C-induced epigenetic modification in ATN. Consistently, prophylactic supplementation of an oxidation-resistant vitamin C derivative, ascorbyl phosphate magnesium, promoted DNA demethylation and prevented the progression of cisplatin-induced ATN.. Vitamin C played a critical role in renal homeostasis and pathogenesis in a mouse model, suggesting vitamin supplementation may be an approach to lower the risk of kidney injury.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Disease Models, Animal; Endothelial Cells; Epigenesis, Genetic; Female; Humans; Kidney Tubular Necrosis, Acute; Male; Mice; Necrosis; RNA

Topics: Animals; Ascorbic Acid; Cardiopulmonary Resuscitation; Disease Models, Animal; Heart Arrest; Male; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; Rats, Sprague-Dawley; Syndecan-1

The α thalassemia/mental retardation syndrome X-linked (ATRX) mutation impairs DNA damage repair in glioblastoma (GBM), making these cells more susceptible to treatment, which may contribute to the survival advantage in patients with GBM containing ATRX mutations. To better understand the role of ATRX in GBM, genes correlated with ATRX expression were screened in the Cancer Genome Atlas (702 cases) and Chinese Glioma Genome Atlas (325 cases) databases. Sodium-vitamin C cotransporter 2 (SVCT2) was the most positively correlated gene with ATRX expression. ATRX (about 1.99-fold) and SVCT2 (about 2.25-fold) were upregulated in GBM tissues from 40 patients compared with normal brain tissues from 23 subjects. ShSVCT2 transfection did not alter the in vitro viability of GL261 cells. At the same time, it could inhibit the proliferation of GL261 cells in the orthotopic transplantation model with diminished infiltrating macrophages (CD45

Topics: alpha-Thalassemia; Animals; Ascorbic Acid; Brain Neoplasms; Disease Models, Animal; Glioblastoma; Heterografts; Humans; Macrophages; Mental Retardation, X-Linked; Sodium; Sodium-Coupled Vitamin C Transporters; Symporters; X-linked Nuclear Protein

Atopic dermatitis (AD) is the most common inflammatory skin disease, which is characterized by excessive Th2 immune responses. In AD patients, the expression of the chemokines CCL17 and CCL22 is increased in skin lesions, leading to the infiltration of Th2 cells. In addition, typical pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, have also been shown to be associated with the pathogenesis of AD. Recently, DDH-1, an ascorbic acid derivative, has been synthesized and demonstrated to have a more stabilized structure and better skin penetrability. Furthermore, DDH-1 has been shown to suppress pro-inflammatory cytokine expression in vitro and in vivo. Therefore, using an AD mouse model, we evaluated the effect of DDH-1 to reduce allergic skin inflammation. We found that cutaneous administration of DDH-1 significantly reduced the expression levels of TNF-α, IL-1β and IL-6 in the skin lesions of AD-like mice. Additionally, DDH-1 administration also significantly reduced the expression levels of CCL17 and CCL22, resulting in decreased skin infiltration of Th2 cells. Consequently, DDH-1 reduced ear and epidermal thickness, the serum IgE levels and the number of infiltrating inflammatory cells and mast cells into the AD-like skin lesions. Combination treatment with DDH-1 and corticosteroid more efficiently improved the skin lesions compared with corticosteroid alone. Collectively, our results suggest that DDH-1 has an anti-allergic effect in an AD mouse model by reducing not only the pro-inflammatory cytokine expression but also the Th2-associated chemokine expression. Thus, DDH-1 may be beneficial for AD treatment and prevention as a monotherapy or in combination with corticosteroids.

Topics: Animals; Anti-Allergic Agents; Ascorbic Acid; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Interleukin-6; Mice; Skin; Tumor Necrosis Factor-alpha

In previous studies, the increasing clinical importance of nonalcoholic fatty liver disease (NAFLD) has been recognized. However, the specific therapeutic strategies or drugs have not been discovered. Vitamin C is a water-soluble antioxidant and is a cofactor in many important biosynthesis pathways. Recently, many researchers have reported that the mega-dose vitamin C treatment had positive effects on various diseases. However, the precise relationship between mega-dose vitamin C and NAFLD has not been completely elucidated. This study has been designed to discover the effects of mega-dose vitamin C on the progression of NAFLD. Twelve-week-old wild-type C57BL6 mice were fed chow diets and high-fat and high-fructose diet (fast-food diet) ad libitum for 11 weeks with or without of vitamin C treatment. Vitamin C was administered in the drinking water (1.5 g/L). In this study, 11 weeks of the mega-dose vitamin C treatment significantly suppressed the development of nonalcoholic steatohepatitis (NASH) independently of the catabolic process. Vitamin C supplements in fast-food diet fed mice significantly decreased diet ingestion and increased water intake. Histopathological analysis revealed that the mice fed a fast-food diet with vitamin C water had a mild renal injury suggesting osmotic nephrosis due to fructose-mediated purine derivatives. These data suggest that the mega-dose vitamin C treatment suppresses high-fructose-diet-mediated NAFLD progression by decreasing diet ingestion and increasing water intake.

Topics: Animals; Ascorbic Acid; Diet; Diet, High-Fat; Disease Models, Animal; Fructose; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Vitamins; Water

Postoperative cognitive impairment is more likely to occur in elderly patients and in those with neurodegenerative diseases. The mechanisms underlying this impairment include neuroinflammation and oxidative stress. The increase in reactive oxygen species during oxidative stress causes cellular and molecular injury to neurons, including DNA damage, which aggravate brain dysfunction. Vitamin C has antioxidant effects and improves cognitive function in patients with Alzheimer's disease. However, it is unclear whether it can ameliorate surgery-induced cognitive impairment by inhibiting oxidative stress. In this study, 6-month-old mice overexpressing mutant amyloid precursor protein and presenilin-1 (APP/PS1) were subjected to laparotomy. The open field and fear conditioning tests were used to assess cognitive function. Mice that underwent surgery showed cognitive impairment without changes in spontaneous locomotor activity. Oxidative stress, DNA damage and inflammatory mediators were increased in the hippocampus after surgery. The expression levels of non-homologous end-joining DNA repair-associated proteins, including Ku heterodimer, DNA-dependent protein kinase catalytic subunit, X-ray repair cross complementing 4 (XRCC4) and XRCC4-like factor, were increased after surgery. Vitamin C pretreatment effectively attenuated cognitive dysfunction induced by surgery and reduced oxidative stress and DNA damage. Our findings suggest that DNA damage plays an important role in surgery-induced cognitive dysfunction, and that vitamin C pretreatment may have therapeutic potential as a preventative approach for the cognitive impairment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Ascorbic Acid; Cognitive Dysfunction; Disease Models, Animal; DNA Damage; Mice; Mice, Inbred C57BL; Mice, Transgenic; Presenilin-1

Multiple clinical trials failed to demonstrate the efficacy of hydrocortisone, ascorbic acid, and thiamine (HAT) in sepsis. These trials were dominated by patients with pulmonary sepsis and have not accounted for differences in the inflammatory responses across varying etiologies of injury/illness. Hydrocortisone, ascorbic acid, and thiamine have previously revealed tremendous benefits in animal peritonitis sepsis models (cecal ligation and puncture [CLP]) in contradiction to the various clinical trials. The impact of HAT remains unclear in pulmonary sepsis. Our objective was to investigate the impact of HAT in pneumonia, consistent with the predominate etiology in the discordant clinical trials. We hypothesized that, in a pulmonary sepsis model, HAT would act synergistically to reduce end-organ dysfunction by the altering the inflammatory response, in a unique manner compared with CLP.. Using Pseudomonas aeruginosa pneumonia, a pulmonary sepsis model (pneumonia [PNA]) was compared directly to previously investigated intra-abdominal sepsis models. Machine learning applied to early vital signs stratified animals into those predicted to die (pDie) versus predicted to live (pLive). Animals were then randomized to receive antibiotics and fluids (vehicle [VEH]) vs. HAT). Vitals, cytokines, vitamin C, and markers of liver and kidney function were assessed in the blood, bronchoalveolar lavage, and organ homogenates.. PNA was induced in 119 outbred wild-type Institute of Cancer Research mice (predicted mortality approximately 50%) similar to CLP. In PNA, interleukin 1 receptor antagonist in 72-hour bronchoalveolar lavage was lower with HAT (2.36 ng/mL) compared with VEH (4.88 ng/mL; p = 0.04). The remaining inflammatory cytokines and markers of liver/renal function showed no significant difference with HAT in PNA. PNA vitamin C levels were 0.62 mg/dL (pDie HAT), lower than vitamin C levels after CLP (1.195 mg/dL). Unlike CLP, PNA mice did not develop acute kidney injury (blood urea nitrogen: pDie, 33.5 mg/dL vs. pLive, 27.6 mg/dL; p = 0.17). Furthermore, following PNA, HAT did not significantly reduce microscopic renal oxidative stress (mean gray area: pDie, 16.64 vs. pLive, 6.88; p = 0.93). Unlike CLP where HAT demonstrated a survival benefit, HAT had no impact on survival in PNA.. Hydrocortisone, ascorbic acid, and thiamine therapy has minimal benefits in pneumonia. The inflammatory response induced by pulmonary sepsis is unique compared with the response during intra-abdominal sepsis. Consequently, different etiologies of sepsis respond differently to HAT therapy.

Topics: Animals; Ascorbic Acid; Biomarkers; Cecum; Cytokines; Disease Models, Animal; Hydrocortisone; Ligation; Machine Learning; Mice; Pneumonia; Sepsis; Thiamine

Parkinson's disease (PD) is a neurodegenerative disease characterized by inclusions of aggregated α-synuclein (α-Syn). Oxidative stress plays a critical role in nigrostriatal degeneration and is responsible for α-Syn aggregation in PD. Vitamin C or ascorbic acid acts as an effective antioxidant to prevent free radical damage. However, vitamin C is easily oxidized and often loses its physiological activity, limiting its therapeutic potential. The objective of this study was to evaluate whether NXP031, a new compound we developed consisting of Aptamin C and Vitamin C, is neuroprotective against α-synucleinopathy. To model α-Syn induced PD, we stereotactically injected AAV particles overexpressing human α-Syn into the substantia nigra (SN) of mice. One week after AAV injection, NXP031 was administered via oral gavage every day for eight weeks. We found that oral administration of NXP031 ameliorated motor deficits measured by the rotarod test and prevented the loss of nigral dopaminergic neurons caused by WT-α-Syn overexpression in the SN. Also, NXP031 blocked the propagation of aggregated α-Syn into the hippocampus by alleviating oxidative stress. These results indicate that NXP031 can be a potential therapeutic for PD.

Topics: alpha-Synuclein; Animals; Ascorbic Acid; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Humans; Mice; Neurodegenerative Diseases; Oxidative Stress; Parkinson Disease; Substantia Nigra

The ongoing crisis of antimicrobial resistance demands novel combinations between antimicrobials and nonantimicrobials to manage infections caused by highly resistant pathogens. This study aimed to evaluate the effect of combining sodium ascorbate and/or apo-transferrin with imipenem, forming double and triple combinations, against 20 multiple-carbapenemase-producing Acinetobacter baumannii strains using the checkerboard test, time-kill assay, and disc diffusion test. The results of the checkerboard assay revealed that all double combinations showed indifference, while only triple combination recorded a synergistic effect (fractional inhibitory concentration index [FICI] < 0.8) in 95% the test isolates. Moreover, the MIC of imipenem (MIC

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Ascorbic Acid; Biological Factors; Carbapenems; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Imipenem; Inflammation; Mice; Microbial Sensitivity Tests; Pneumonia; Transferrins

Topics: Animals; Anti-Inflammatory Agents; Ascorbic Acid; COVID-19 Drug Treatment; Dexamethasone; Disease Models, Animal; Drug Combinations; Magnesium Sulfate; Mice; Niacinamide; Pantothenic Acid; Pyridoxine; Riboflavin; Sepsis; Thiamine

Kirsten rat sarcoma (KRAS) protein is an essential contributor to the development of pancreatic ductal adenocarcinoma (PDAC). KRAS G12D and G12V mutant tumours are significant challenges in cancer therapy due to high resistance to the treatment.. To determine how effective is the ATO/D-VC combination in suppression of PDAC the mouse transgenic model. This study investigated the antitumour effect of a novel combination of arsenic trioxide (ATO) and D-ascorbic acid isomer (D-VC). Such a combination can be used to treat KRAS mutant cancer by inducing catastrophic oxidative stress.. In this study, we examined the effectiveness of ATO and D-VC on xenograft models-AK192 cells transplanted into mice. Previously, it has been shown that a high concentration of Vitamin C (VC) selectively can kill the cells expressing KRAS.. The results of this study demonstrated that the combination of VC with a low dose of the oxidizing drug ATO led to the enhancement of the therapeutic effect. These findings suggest that the combined treatment using ATO and D-VC is a promising approach to overcome the limitation of drug selectivity and efficacy.

Topics: Animals; Arsenic Trioxide; Ascorbic Acid; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Disease Models, Animal; Drug Combinations; Humans; Mice; Oxidation-Reduction; Oxidative Stress; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras)

The pumping function of corneal endothelial cells (CECs) plays a pivotal role in the maintenance of corneal water homeostasis. Corneal endothelial dysfunction (CED) leads to corneal edema and opacity, but with the exception of keratoplasty, no optimal therapeutic strategies have been established for CED. In this study, we aimed to investigate the ameliorative effect of ascorbic acid (AA) on CED and the underlying mechanism of action in the corneal endothelium.. Rabbit corneal endothelial damage was induced by anterior chamber injection of benzalkonium chloride (BAK). AA was topically administered to the corneal surface, and the transparency and thickness of the cornea were assessed by external eye photography, slit-lamp photography, and ultrasonic pachymetry. To further analyze the mechanism, rabbit CECs and immortalized human CECs (B4G12 cells) were cultured. A ferric reducing/antioxidant and AA (FRASC) assay was performed to measure the AA concentration. Cell proliferation was evaluated by cell counting and bromodeoxyuridine (BrdU) labeling assays, and protein expression was examined by liquid chromatography-mass spectrometry (LC/MS) and immunoblotting. The involvement of glucose transporter 1 (GLUT1) and phospho-ERK was evaluated via GLUT1-siRNA and phospho-ERK inhibitor (PD98059) treatment.. We observed that topical AA ameliorates BAK-induced rabbit corneal endothelial damage. Furthermore, we demonstrated that AA is transported into B4G12 cells via GLUT1, and afterward, AA increases ERK phosphorylation and promotes cell proliferation. Our findings indicate that CEC proliferation stimulated via the noncanonical AA-GLUT1-ERK axis contributes to AA-enhanced healing of CED.

Topics: Administration, Ophthalmic; Animals; Ascorbic Acid; Benzalkonium Compounds; Cell Line; Cell Proliferation; Corneal Endothelial Cell Loss; Disease Models, Animal; Endothelial Cells; Endothelium, Corneal; Extracellular Signal-Regulated MAP Kinases; Glucose Transporter Type 1; Humans; Phosphorylation; Rabbits; Signal Transduction; Wound Healing

Metabolic disorders often lead to cardiac complications. Metabolic deregulations during diabetic conditions are linked to mitochondrial dysfunctions, which are the key contributing factors in cardiac hypertrophy. However, the underlying mechanisms involved in diabetes-induced cardiac hypertrophy are poorly understood. In the current study, we initially established a diabetic rat model by alloxan-administration, which was validated by peripheral glucose measurement. Diabetic rats displayed myocardial stiffness and fibrosis, changes in heart weight/body weight, heart weight/tibia length ratios, and enhanced size of myocytes, which altogether demonstrated the establishment of diabetic cardiac hypertrophy (DCH). Furthermore, we examined the expression of genes associated with mitochondrial signaling impairment. Our data show that the expression of PGC-1α, cytochrome c, MFN-2, and Drp-1 was deregulated. Mitochondrial-signaling impairment was further validated by redox-system dysregulation, which showed a significant increase in ROS and thiobarbituric acid reactive substances, both in serum and heart tissue, whereas the superoxide dismutase, catalase, and glutathione levels were decreased. Additionally, the expression levels of pro-apoptotic gene PUMA and stress marker GATA-4 genes were elevated, whereas ARC, PPARα, and Bcl-2 expression levels were decreased in the heart tissues of diabetic rats. Importantly, these alloxan-induced impairments were rescued by N-acetyl cysteine, ascorbic acid, and selenium treatment. This was demonstrated by the amelioration of myocardial stiffness, fibrosis, mitochondrial gene expression, lipid profile, restoration of myocyte size, reduced oxidative stress, and the activation of enzymes associated with antioxidant activities. Altogether, these data indicate that the improvement of mitochondrial dysfunction by protective agents such as N-acetyl cysteine, selenium, and ascorbic acid could rescue diabetes-associated cardiac complications, including DCH.

Topics: Acetylcysteine; Animals; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Ascorbic Acid; Biomarkers; Blood Glucose; Body Weight; Calcium; Cardiomegaly; Cardiotonic Agents; Cytochromes c; Diabetic Cardiomyopathies; Disease Models, Animal; Down-Regulation; GATA4 Transcription Factor; Lipid Peroxidation; Lipids; Mitochondria, Heart; Myocardium; Oxidation-Reduction; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR alpha; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger; Selenium

Polycystic ovary syndrome (PCOS) affects up to 10% of women within reproductive ages and has been a cause of infertility and poor quality of life. Alteration in the oxidant-antioxidant profile occurs in PCOS. This study, therefore, investigates the contribution of ascorbic acid (AA) and alpha-tocopherol(ATE) on different PCOS parameters. The mifepristone and letrozole models were used, and young mature female mice were randomly assigned to groups of six per group. On PCOS induction with either mifepristone or letrozole, mice were administered AA and ATE at doses ranging from 10-1000mg/kg to 0.1-1000 mg/kg in the respective models. Vaginal cytology, body weights, and temperature, as well as blood glucose, testosterone, and insulin levels, were measured. Total antioxidant capacity and malondialdehyde levels were analyzed. Determination of gene expression of some reactive oxygen species and histomorphological analysis on the ovaries and uteri were performed. At the end of the experiments, AA and ATE restored reproductive cycling, with AA being more effective. AA and ATE increased fasting blood glucose but had no significant effect on serum insulin levels. AA decreased testosterone levels, but ATE caused slight increases. AA and ATE both increased total antioxidant capacity and decreased malondialdehyde levels. AA and ATE also slightly upregulated the mRNA expressions of catalase, superoxide dismutase, and heme oxygenase 1 mainly. AA and ATE also decreased ovarian weight and mostly resolved cysts in the ovaries and congestion in the uterus. This study has shown that AA and ATE are beneficial in the therapy of PCOS.

Topics: alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; Blood Glucose; Disease Models, Animal; Estrous Cycle; Female; Insulin; Mice; Ovary; Oxidative Stress; Polycystic Ovary Syndrome; Testosterone; Uterus

Accumulating evidence demonstrated that administration of ω-3 polyunsaturated fatty acid (ω-3 PUFA) or ascorbic acid (AA) following cardiac arrest (CA) improves survival. Therefore, we investigate the effects of ω-3 PUFA combined with AA on myocardial function after CA and cardiopulmonary resuscitation (CPR) in a rat model. Thirty male rats were randomized into 5 groups: (1) sham; (2) control; (3) ω-3 PUFA; (4) AA; (5) ω-3 PUFA + AA. Ventricular fibrillation (VF) was induced and untreated for 6 min followed by defibrillation after 8 min of CPR. Infusion of drug or vehicle occurred at the start of CPR. Myocardial function and sublingual microcirculation were measured at baseline and after return of spontaneous circulation (ROSC). Heart tissues and blood were collected 6 h after ROSC. Myocardial function and sublingual microcirculation improvements were seen with ω-3 PUFA or AA compared to control after ROSC (p < 0.05). ω-3 PUFA + AA shows a better myocardial function than ω-3 PUFA or AA (p < 0.05). ω-3 PUFA or AA decreases pro-inflammatory cytokines, cTnI, myocardium malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) modified proteins compared to control (p < 0.05). ω-3 PUFA and AA combined have lower MDA and 4-HNE modified proteins than alone (p < 0.05). ω-3 PUFA or AA treatment reduces the severity of post-resuscitation myocardial dysfunction, improves sublingual microcirculation, decreases lipid peroxidation and systemic inflammation in the early phase of recovery following CA and resuscitation. A combination of ω-3 PUFA and AA treatment confers an additive effect in suppressing lipid peroxidation and improving myocardial function.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Biomarkers; Blood Circulation; Cardiopulmonary Resuscitation; Disease Models, Animal; Fatty Acids, Omega-3; Heart Arrest; Inflammation Mediators; Lipid Peroxidation; Male; Myocardium; Oxidative Stress; Rats, Sprague-Dawley; Recovery of Function; Ventricular Fibrillation

Oxidative stress appears to initiate organ failure in sepsis, justifying treatment with antioxidants such as vitamin C at megadoses. We have therefore investigated the safety and efficacy of megadose sodium ascorbate in sepsis.. Interventional study.. Research Institute.. Adult Merino ewes.. Sheep were instrumented with pulmonary and renal artery flow-probes, and laser-Doppler and oxygen-sensing probes in the kidney. Conscious sheep received an infusion of live Escherichia coli for 31 hours. At 23.5 hours of sepsis, sheep received fluid resuscitation (30 mL/kg, Hartmann solution) and were randomized to IV sodium ascorbate (0.5 g/kg over 0.5 hr + 0.5 g/kg/hr for 6.5 hr; n = 5) or vehicle (n = 5). Norepinephrine was titrated to restore mean arterial pressure to baseline values (~80 mm Hg).. Sepsis-induced fever (41.4 ± 0.2°C; mean ± se), tachycardia (141 ± 2 beats/min), and a marked deterioration in clinical condition in all cases. Mean arterial pressure (86 ± 1 to 67 ± 2 mm Hg), arterial Po2 (102.1 ± 3.3 to 80.5 ± 3.4 mm Hg), and renal medullary tissue Po2 (41 ± 5 to 24 ± 2 mm Hg) decreased, and plasma creatinine doubled (71 ± 2 to 144 ± 15 µmol/L) (all p < 0.01). Direct observation indicated that in all animals, sodium ascorbate dramatically improved the clinical state, from malaise and lethargy to a responsive, alert state within 3 hours. Body temperature (39.3 ± 0.3°C), heart rate (99.7 ± 3 beats/min), and plasma creatinine (32.6 ± 5.8 µmol/L) all decreased. Arterial (96.5 ± 2.5 mm Hg) and renal medullary Po2 (48 ± 5 mm Hg) increased. The norepinephrine dose was decreased, to zero in four of five sheep, whereas mean arterial pressure increased (to 83 ± 2 mm Hg). We confirmed these physiologic findings in a coronavirus disease 2019 patient with shock by compassionate use of 60 g of sodium ascorbate over 7 hours.. IV megadose sodium ascorbate reversed the pathophysiological and behavioral responses to Gram-negative sepsis without adverse side effects. Clinical studies are required to determine if such a dose has similar benefits in septic patients.

Topics: Animals; Antioxidants; Ascorbic Acid; Bacteremia; Disease Models, Animal; Dose-Response Relationship, Drug; Escherichia coli Infections; Sepsis; Sheep

Na+,K+-ATPase is a crucial protein responsible for maintaining the electrochemical gradients across the cell membrane. The Na+,K+-ATPase is comprised of catalytic α, β, and γ subunits. In adult brains, the α3 subunit, encoded by ATP1A3, is predominantly expressed in neurons, whereas the α2 subunit, encoded by ATP1A2, is expressed in glial cells. In foetal brains, the α2 is expressed in neurons as well. Mutations in α subunits cause a variety of neurologic disorders. Notably, the onset of symptoms in ATP1A2- and ATP1A3-related neurologic disorders is usually triggered by physiological or psychological stressors. To gain insight into the distinct roles of the α2 and α3 subunits in the developing foetal brain, whose developmental dysfunction may be a predisposing factor of neurologic disorders, we compared the phenotypes of mouse foetuses with double homozygous knockout of Atp1a2 and Atp1a3 (α2α3-dKO) to those with single knockout. The brain haemorrhage phenotype of α2α3-dKO was similar to that of homozygous knockout of the gene encoding ascorbic acid (ASC or vitamin C) transporter, SVCT2. The α2α3-dKO brain showed significantly decreased level of ASC compared with the wild-type (WT) and single knockout. We found that the ASC content in the basal ganglia and cerebellum was significantly lower in the adult Atp1a3 heterozygous knockout mouse (α3-HT) than in the WT. Interestingly, we observed a significant decrease in the ASC level in the basal ganglia and cerebellum of α3-HT in the peripartum period, during which mice are under physiological stress. These observations indicate that the α2 and α3 subunits independently contribute to the ASC level in the foetal brain and that the α3 subunit contributes to ASC transport in the adult basal ganglia and cerebellum. We propose that decreases in ASC levels may affect neural network development and are linked to the pathophysiology of ATP1A2- and ATP1A3-related neurologic disorders.

Topics: Animals; Ascorbic Acid; Brain; Disease Models, Animal; Mice; Mice, Knockout; Nerve Net; Nervous System Diseases; Phenotype; Sodium-Potassium-Exchanging ATPase; Vitamins

Colistin is a potent antibiotic which is mainly preferred in the treatment of multidrug-resistant (MDR) gram-negative bacilli. However, due to the increased risk of acute kidney injury following its use, the clinical application is limited. This nephrotoxicity is known to be induced by oxidative stress and related inflammation. In this study on rats, potent antioxidants Dexpanthenol (DEX) and Ascorbic acid (Vit C) have been administered in combination with Colistin to find out whether they would weaken Colistin's nephrotoxic effects.. Inflammation biomarkers were studied with enzyme-linked immunosorbent assay (ELISA) kits, and oxidative stress biomarkers were studied with different photometric methods in blood and tissue samples taken after treatment with DEX and Vit C in rats with colistin nephrotoxicity. In addition, inflammation and necrosis in the kidney tissues were examined pathologically.. It has been observed in the serum and tissue samples that DEX and Vit C decrease oxidative stress and inflammation biomarkers, therefore acting as nephroprotective agents.. These compounds have been found to ameliorate the nephrotoxic effects of Colistin, which were demonstrated in the rats treated with Colistin, as well as the combinations.

Topics: Acute Kidney Injury; Animals; Ascorbic Acid; Colistin; Disease Models, Animal; Inflammation; Injections, Intraperitoneal; Male; Neuroprotective Agents; Oxidative Stress; Pantothenic Acid; Rats; Rats, Sprague-Dawley

The process of obtaining ascorbic acid (AA) via intestinal absorption and blood circulation is carrier-mediated utilizing the AA transporters SVCT1 and SVCT2, which are expressed in the intestine and brain (SVCT2 in abundance). AA concentration is decreased in Alzheimer's disease (AD), but information regarding the status of intestinal AA uptake in the AD is still lacking. We aimed here to understand how AA homeostasis is modulated in a transgenic mouse model (5xFAD) of AD. AA levels in serum from 5xFAD mice were markedly lower than controls. Expression of oxidative stress response genes (glutathione peroxidase 1 (GPX1) and superoxide dismutase 1 (SOD1)) were significantly increased in AD mice jejunum, and this increase was mitigated by AA supplementation. Uptake of AA in the jejunum was upregulated. This increased AA transport was caused by a marked increase in SVCT1 and SVCT2 protein, mRNA, and heterogeneous nuclear RNA (hnRNA) expression. A significant increase in the expression of HNF1α and specific protein 1 (Sp1), which drive SLC23A1 and SLC23A2 promoter activity, respectively, was observed. Expression of hSVCT interacting proteins GRHPR and CLSTN3 were also increased. SVCT2 protein and mRNA expression in the hippocampus of 5xFAD mice was not altered. Together, these investigations reveal adaptive up-regulation of intestinal AA uptake in the 5xFAD mouse model.

Topics: Alcohol Oxidoreductases; Alzheimer Disease; Animals; Ascorbic Acid; Biological Transport; Calcium-Binding Proteins; Dietary Supplements; Disease Models, Animal; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Hepatocyte Nuclear Factor 1-alpha; Hippocampus; Homeostasis; Intestinal Absorption; Jejunum; Membrane Proteins; Mice; Mice, Transgenic; Oxidative Stress; RNA, Messenger; Sodium-Coupled Vitamin C Transporters; Superoxide Dismutase-1; Up-Regulation

Apoptosis and antioxidant mechanisms are pathways for the treatment of endometriosis (Endo). Rutin (Rtn) is an antioxidant flavonol that induces apoptosis. This study, for first time, was conducted to evaluate the effects of rutin on Endo through apoptosis and antioxidant mechanisms. The experimental Endo was induced in 24 rats and then the animals were subdivided into Endo-sole, 3000 and 6000 µg/kg rutin (Rtn-3000 and Rtn-6000) and vitamin C groups. After 4 weeks, the expression of Bcl2, Bax, anti Pro Caspase-9, cleaved Caspase-9, pro PARP, pro Cleaved PARP, Pro PARP, pro mTOR and mTOR were assessed by western blotting technique. The protein concentrations of malondialdehyde (MDA), total antioxidant capacity, and super oxide dismutase and gutathione peroxidase were also evaluated. TUNEL staining was also used for the detection of apoptosis. Caspase-9 and concentration of antioxidants were higher in the treated groups compared to Endo-sole group (P < 0.05). The results also showed that rutin decreased the expression of Bcl2 and MDA concentration (P < 0.05). The results for TUNEL staining showed that the animals treated with Rtn-6000 and vitamin C showed higher apoptosis. Rutin induces apoptosis by the expression of Bcl-2, Bax and caspase and also antioxidant activity by increasing antioxidants concentrations.

Topics: Administration, Oral; Animals; Antioxidants; Apoptosis; Ascorbic Acid; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Endometriosis; Female; Humans; Oxidative Stress; Rats; Rutin

Ascorbate (Vitamin C) has been proposed as a promising therapeutic agent against sepsis in clinical trials, but there is little experimental evidence on its anti-septic efficacy. We report that Toll-like receptor 4 (TLR4) activation by LPS stimuli augments ascorbate uptake in murine and human tubular cells through upregulation of two ascorbate transporters SVCT-1 and -2 mediated by Fn14/SCF

Topics: Acute Kidney Injury; Animals; Ascorbic Acid; Cell Line; Disease Models, Animal; Humans; Kidney Tubules; Lipopolysaccharides; Male; Mice; Mitochondria; Mitophagy; Protein Kinases; Sepsis; Signal Transduction; Ubiquitin-Protein Ligases; Vitamins

Chronic fetal hypoxia is one of the most common outcomes in complicated pregnancy in humans. Despite this, its effects on the long-term health of the brain in offspring are largely unknown. Here, we investigated in rats whether hypoxic pregnancy affects brain structure and function in the adult offspring and explored underlying mechanisms with maternal antioxidant intervention. Pregnant rats were randomly chosen for normoxic or hypoxic (13% oxygen) pregnancy with or without maternal supplementation with vitamin C in their drinking water. In one cohort, the placenta and fetal tissues were collected at the end of gestation. In another, dams were allowed to deliver naturally, and offspring were reared under normoxic conditions until 4 months of age (young adult). Between 3.5 and 4 months, the behavior, cognition and brains of the adult offspring were studied. We demonstrated that prenatal hypoxia reduced neuronal number, as well as vascular and synaptic density, in the hippocampus, significantly impairing memory function in the adult offspring. These adverse effects of prenatal hypoxia were independent of the hypoxic pregnancy inducing fetal growth restriction or elevations in maternal or fetal plasma glucocorticoid levels. Maternal vitamin C supplementation during hypoxic pregnancy protected against oxidative stress in the placenta and prevented the adverse effects of prenatal hypoxia on hippocampal atrophy and memory loss in the adult offspring. Therefore, these data provide a link between prenatal hypoxia, placental oxidative stress, and offspring brain health in later life, providing insight into mechanism and identifying a therapeutic strategy.

Topics: Animals; Animals, Newborn; Antioxidants; Ascorbic Acid; Atrophy; Dietary Supplements; Disease Models, Animal; Female; Fetal Growth Retardation; Fetal Hypoxia; Hippocampus; Male; Memory Disorders; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar

The current main treatment for ulcerative colitis (UC) is induction therapy by long-term administration of 5-aminosalicylic acid (5-ASA), but various side effects have been reported. Therefore, a radical cure for UC is desired. A vitamin C (VC) has anti-inflammatory effects. Therefore, this study investigated whether a VC solution enema shortens induction of remission in colitis model rats. Wistar rats (6 wk old/male) were allowed to freely ingest a 1% dextran sulfate sodium (DSS) solution for 10 d and then switched to tap water for normal breeding for 10 d (UC group). At the time of switching to tap water, an enema was performed with a 5-ASA solution (40 mg/kg/d) or VC solution (460 mg/kg/d) for 10 d. The neutrophil number, COX-2, which is an index of inflammation, and type III collagen, which is an early healing marker, were significantly increased in the UC group. However, the VC group showed decreases compared with UC groups. Furthermore, compared with UC and 5-ASA groups, the VC group showed increased expression of type I collagen, which is expressed late in healing, and significant epithelial regeneration was observed in colon tissue. The VC solution enema shortened the induction of remission by directly suppressing inflammation of damaged large intestinal tissues and promoting mucosal healing.

Topics: Animals; Ascorbic Acid; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Enema; Intestinal Mucosa; Male; Rats; Rats, Wistar; Remission Induction; Sulfates

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is exacerbated by social isolation (SI) and protein malnutrition (PM). Antioxidants, physical and mental activities (Ph&M) can maintain cognitive functions and protect against dementia.. To investigate the impact of Epigallocatechin-3-gallate (EGCG), Vitamin E (VE), Vitamin C (VC), and Selenium (Se), in enhancing the potential effect of Ph&M versus SI&PM as risk factors in the progression of AD in rats.. Aluminum chloride (70 mg/kg, I.P for 5 weeks) was used to induce AD in rats that either normally fed or socially isolated and protein malnourished (SI&PM). Simultaneously, rats were weekly exposed to Ph&M either alone or in combination with EGCG (10 mg/kg, I.P), VC (400 mg/kg, P.O), VE (100 mg/kg, P.O), and Se (1 mg/kg, P.O).. The combination protocol of EGCG, VE, VC, and Se together with Ph&M significantly increased brain monoamines, superoxide dismutase (SOD), total antioxidant capacity (TAC) and brain-derived neurotrophic factor (BDNF) in AD, SI&PM and SI&PM/AD groups. Additionally, this regimen significantly mitigated brain acetylcholine esterase (ACHE), β-amyloid (Aβ), Tau protein, β-secretase, malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and Interleukin 1β (IL-1β) as well as DNA fragmentation. These biochemical findings were supported by the histopathological examinations of brain tissue.. The combination protocol of antioxidants with Ph&M activities mitigated SI&PM-induced progressive risk of AD.

Topics: Alzheimer Disease; Animals; Antioxidants; Ascorbic Acid; Catechin; Disease Models, Animal; Disease Progression; Male; Mental Health; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Risk Factors; Selenium; Vitamin E

The dysregulated host response and organ damage following systemic infection that characterizes a septic event predisposes individuals to a chronic immunoparalysis state associated with severe transient lymphopenia and diminished lymphocyte function, thereby reducing long-term patient survival and quality of life. Recently, we observed lasting production of reactive oxygen species (ROS) in mice that survive sepsis. ROS production is a potent mechanism for targeting infection, but excessive ROS production can prove maladaptive by causing organ damage, impairing lymphocyte function, and promoting inflammaging, concepts paralleling sepsis-induced immunoparalysis. Notably, we observed an increased frequency of ROS-producing immature monocytes in septic hosts that was sustained for greater than 100 days postsurgery. Recent clinical trials have explored the use of vitamin C, a potent antioxidant, for treating septic patients. We observed that therapeutic vitamin C administration for sepsis limited ROS production by monocytes and reduced disease severity. Importantly, we also observed increased ROS production by immature monocytes in septic patients both at admission and ∼28 days later, suggesting a durable and conserved feature that may influence the host immune response. Thus, lasting ROS production by immature monocytes is present in septic patients, and early intervention strategies to reduce it may improve host outcomes, potentially reducing sepsis-induced immunoparalysis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Antioxidants; Ascorbic Acid; Case-Control Studies; Disease Models, Animal; Female; Healthy Volunteers; Humans; Leukocytes, Mononuclear; Male; Mice; Middle Aged; Reactive Oxygen Species; Sepsis; Severity of Illness Index; Young Adult

Sepsis survivors present long-term cognitive deficits. The present study was to investigate the effect of early administration of high-dose vitamin C on cognitive function in septic rats and explore its possible cerebral protective mechanism. Rat sepsis models were established by cecal ligation and puncture (CLP). Ten days after surgery, the Morris water maze test was performed to evaluate the behavior and cognitive function. Histopathologic changes in the hippocampus were evaluated by nissl staining. The inflammatory cytokines, activities of antioxidant enzymes (superoxide dismutase or SOD) and oxidative products (malondialdehyde or MDA) in the serum and hippocampus were tested 24 h after surgery. The activity of matrix metalloproteinase-9 (MMP-9) and expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1) in the hippocampus were measured 24 h after surgery. Compared with the sham group in the Morris water maze test, the escape latency of sepsis rats was significantly (P = 0.001) prolonged in the navigation test, whereas the frequency to cross the platform and the time spent in the target quadrant were significantly (P = 0.003) reduced. High-dose vitamin C significantly decreased the escape latency (P = 0.01), but increased the time spent in the target quadrant (P = 0.04) and the frequency to cross the platform (P = 0.19). In the CLP+ saline group, the pyramidal neurons were reduced and distributed sparsely and disorderly, the levels of inflammatory cytokines of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 in the serum and hippocampus were significantly increased (P = 0.000), the blood brain barrier (BBB) permeability in the hippocampus was significantly (P = 0.000) increased, the activities of SOD in the serum and hippocampus were significantly (P = 0.000 and P = 0.03, respectively) diminished while the levels of MDA in the serum and hippocampus were significantly (P = 0.007) increased. High-dose vitamin C mitigated hippocampus histopathologic changes, reduced systemic inflammation and neuroinflammation, attenuated BBB disruption, inhibited oxidative stress in brain tissue, and up-regulated the expression of nuclear and total Nrf2 and HO-1. High-dose vitamin C significantly (P < 0.05) decreased the levels of tumor necrosis factor- (TNF)-α, interleukin-6 (IL-6), MDA in the serum and hippocampus, and the activity of MMP-9 in the hippocampus, but significantly (P < 0.05) increased the levels of SOD, the

Topics: Animals; Ascorbic Acid; Blood-Brain Barrier; Cognitive Dysfunction; Disease Models, Animal; Dose-Response Relationship, Drug; Heme Oxygenase (Decyclizing); Hippocampus; Inflammation; Male; NF-E2-Related Factor 2; Oxidative Stress; Protective Agents; Rats, Sprague-Dawley; Sepsis

Cisplatin (CDDP) is a highly potent anticancer drug that is widely used in the treatment of several cancers. CDDP-induced nephrotoxicity (CIN) is one of the most significant adverse effects, and oxidative stress is thought to be one of the mechanisms underlying CIN. Although there are some studies available on the variability in transporter expression in the kidney after a single CDDP dose, none have reported the change in renal transporter expression after multiple CDDP dose administrations. P-glycoprotein (P-gp), a transporter, is reported to be induced by oxidative stress. Ascorbic acid is a vitamin with antioxidant potential and therefore, may regulate the expression of P-gp transporter and affect CIN. In the present study, our aim was to assess the variability in expression of several renal transporters after multiple CDDP dose administrations and the antioxidant effect of ascorbic acid against transporter expression and CIN. Multiple doses of CDDP affected markers of kidney injury and antioxidants in the kidneys. Also, the expression of P-gp, breast cancer resistance protein, and multidrug resistance-associated protein 4 was upregulated by CDDP. Using a normal kidney cell line, we demonstrated that ascorbic acid attenuated CDDP-induced cytotoxicity due to its high superoxide scavenging ability. CDDP and ascorbic acid were injected into rats once a week for three weeks, and it was observed that co-administration of ascorbic acid attenuated CIN and regulated antioxidant marker. In addition, ascorbic acid reduced P-gp expression, which was upregulated by CDDP. In conclusion, ascorbic acid may attenuate CIN and reverse P-gp-mediated changes in drug pharmacokinetics.

Topics: Animals; Antioxidants; Ascorbic Acid; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Cell Line; Cisplatin; Disease Models, Animal; Drug Evaluation, Preclinical; Epithelial Cells; Humans; Kidney; Male; Multidrug Resistance-Associated Proteins; Rats; Reactive Oxygen Species; Renal Insufficiency; Up-Regulation

Allergy is an excessive immune response to a specific antigen. Type I allergies, such as hay fever and food allergies, have increased significantly in recent years and have become a worldwide problem. We previously reported that an ascorbic acid derivative having palmitoyl and glucosyl groups, 2-

Topics: Animals; Anti-Allergic Agents; Ascorbic Acid; Cell Degranulation; Disease Models, Animal; Hypersensitivity; Mice; Passive Cutaneous Anaphylaxis

An increasing amount of evidence has shown that injection of D-galactose (D-gal) can mimic natural aging that typically is associated with brain injury. Oxidative stress and apoptosis has been shown to play an essential role in aging process. The purpose of this study was to investigate the protective effectsof astilbin (ASB) on D-Gal-induced agingin miceand to further explore the underlying mechanisms. We randomly divided 50 mice into 5 groups.To establish this model of aging, 40micewere intraperitoneally administered D-Gal (500 mg/kg). The mice in the treatmentgroupswere intragastricaly administratedASB at doses of 40 and 80 mg/kg. H&E and TUNEL staining were used to determine the effect of ASB on the number of apoptotic cells in the brain. Furthermore, biochemical indices of serum, oxidative stress factors, and apoptosis factors were determined to clarify the underlying mechanism using reagent test kits and western blotting. The results showed that varying doses of ASB could improve D-Gal-induced histopathological damageand significantly alleviatedthe aging induced by D-Galin mice. ASB remarkably decreased the activities of malondialdehyde (MDA)(p < 0.01)and Acetyl cholinesterase (AChE)(p < 0.05) and markedlyincreased the content of catalase (CAT)(p < 0.01)and superoxide dismutase (SOD)(p < 0.01), respectively. In addition, Western blotting revealed thatASB treatment (40 mg/kg)attenuated the D-gal-induced Bax and Caspase 3 protein expression(p < 0.01) and reversed the increase in Bcl-2protein expressionin brain. Moreover, ASB treatment significantly upregulated the protein expression ofp-PI3K/PI3K and altered the p-Akt/Akt ratio (p < 0.05), while inhibiting the expression of p-m-TOR relative to m-TOR(p < 0.05). Moreover, the expression of P53 tended to decreasein the low ASB treatmentgroup (40 mg/kg), whereas no change was observed in the high ASB treatmentgroup (80 mg/kg). In the intestinal flora, the richness of the normal group and the ASB group was higher than that of the D-Gal group. Heat map analysis also showed that ASB promoted Lactobacillus and other probiotics and also confirmed the advantages of ASB. The observed changes in intestinal flora further verified the efficacy of ASB.

Topics: Acetylcholinesterase; Aging; Animals; Antioxidants; Apoptosis; Ascorbic Acid; Body Weight; Brain; Catalase; Disease Models, Animal; Flavonols; Galactose; Gastrointestinal Microbiome; Male; Malondialdehyde; Mice, Inbred ICR; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Superoxide Dismutase; TOR Serine-Threonine Kinases

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Topics: Animals; Ascorbic Acid; Asthma; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Embryonic Stem Cells; Gene Expression Regulation; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Stem Cell Niche

Oxidative stress is associated with neuronal damage in many brain regions including the hippocampus; an area in the brain responsible of memory processing. Oxidative stress is also linked with many psychiatric conditions including post-traumatic stress disorder (PTSD). PTSD is triggered by traumatic experience and many PTSD patients show signs of memory impairment. Vitamin C is a water-soluble vitamin with antioxidant properties. Herein, we hypothesized that memory impairment observed during PTSD could be a result of oxidative stress in hippocampal tissues and that prophylactic vitamin C administration may reduce oxidative stress in the hippocampus and prevent memory impairment. The above hypothesis was tested in a rat model where PTSD-like behavior was induced through single prolonged stress (SPS). Short and long-term memory was tested using a radial arm water maze (RAWM). We found that SPS induced a significant increase in the oxidized glutathione levels of the hippocampus. This reduction was accompanied with a significant decrease in glutathione peroxidase and catalase enzyme activity, and a significant increase in lipid peroxidation. Intriguingly, vitamin C administration successfully attenuated memory impairment and all of the changes observed in oxidative stress markers. Our findings demonstrate that vitamin C could prevent oxidative stress and memory impairment induced by SPS model of PTSD-like behavior in rat.

Topics: Animals; Antioxidants; Ascorbic Acid; Behavior, Animal; Disease Models, Animal; Hippocampus; Male; Maze Learning; Memory Disorders; Memory, Long-Term; Memory, Short-Term; Oxidative Stress; Rats; Rats, Wistar; Stress Disorders, Post-Traumatic; Stress, Psychological

Major efforts are underway to identify agents that can potentiate effects of immune checkpoint inhibition. Here, we show that ascorbic acid (AA) treatment caused genomewide demethylation and enhanced expression of endogenous retroviral elements in lymphoma cells. AA also increased 5-hydroxymethylcytosine (5hmC) levels of CD8+ T cells and enhanced their cytotoxic activity in a lymphoma coculture system. High-dose AA treatment synergized with anti-PD1 therapy in a syngeneic lymphoma mouse model, resulting in marked inhibition of tumor growth compared with either agent alone. Analysis of the intratumoral epigenome revealed increased 5hmC with AA treatment, consistent with in vitro findings. Analysis of the tumor immune microenvironment revealed that AA strikingly increased intratumoral infiltration of CD8+ T cells and macrophages, suggesting enhanced tumor immune recognition. The combination treatment markedly enhanced intratumoral infiltration of macrophages and CD8+ T lymphocytes, granzyme B production by cytotoxic cells (cytotoxic T cells and natural killer cells), and interleukin 12 production by antigen-presenting cells compared with single-agent anti-PD1. These data indicate that AA potentiates anti-PD1 checkpoint inhibition through synergistic mechanisms. The study provides compelling rationale for testing combinations of high-dose AA and anti-PD1 agents in patients with aggressive B cell lymphoma as well as in preclinical models of other malignancies.

Topics: 5-Methylcytosine; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Ascorbic Acid; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Survival; Combined Modality Therapy; Disease Models, Animal; Drug Synergism; Female; Granzymes; Immunotherapy; Lymphoma; Mice; Mice, Inbred BALB C; Programmed Cell Death 1 Receptor; Tumor Microenvironment

Topics: Allografts; Animals; Antineoplastic Agents; Ascorbic Acid; Cell Survival; Disease Models, Animal; Doxorubicin; Drug Carriers; Drug Liberation; Female; Fibroblasts; Humans; Hydrogen-Ion Concentration; MCF-7 Cells; Methacrylates; Mice; Mice, Inbred BALB C; Micelles; Neoplasms; Phosphorylcholine; Polymers; Surface Properties; Tumor Burden

Autophagy, a conserved cellular degradation and recycling process, can be enhanced by nutrient depletion, oxidative stress or other harmful conditions to maintain cell survival. 6-Hydroxydopamine/ascorbic acid (6-OHDA/AA) is commonly used to induce experimental Parkinson's disease (PD) lesions by causing oxidative damage to dopaminergic neurons. Activation of autophagy has been observed in the 6-OHDA-induced PD models. However, the mechanism and exact role of autophagy activation in 6-OHDA PD model remain inconclusive. In this study, we report that autophagy was triggered via mucolipin 1/calcium/calcineurin/TFEB (transcription factor EB) pathway upon oxidative stress induced by 6-OHDA/AA. Interestingly, overexpression of TFEB alleviated 6-OHDA/AA toxicity. Moreover, autophagy enhancers, Torin1 (an mTOR-dependent TFEB/autophagy enhancer) and curcumin analog C1 (a TFEB-dependent and mTOR-independent autophagy enhancer), significantly rescued 6-OHDA/AA-induced cell death in SH-SY5Y cells, iPSC-derived DA neurons and mice nigral DA neurons. The behavioral abnormality of 6-OHDA/AA-treated mice can also be rescued by Torin 1 or C1 administration. The protective effects of Torin 1 and C1 can be blocked by autophagy inhibitors like chloroquine (CQ) or by knocking down autophagy-related genes TFEB and ATG5. Taken together, this study supports that TFEB-mediated autophagy is a survival mechanism during oxidative stress and pharmacological enhancement of this process is a neuroprotective strategy against oxidative stress-associated PD lesions.

Topics: Animals; Antiparkinson Agents; Ascorbic Acid; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Behavior, Animal; Brain; Cell Line, Tumor; Curcumin; Disease Models, Animal; Dopaminergic Neurons; Female; Humans; Mice, Inbred C57BL; Mitophagy; Naphthyridines; Oxidative Stress; Oxidopamine; Parkinsonian Disorders; Signal Transduction; TOR Serine-Threonine Kinases

Pheochromocytomas and paragangliomas (PCPG) are usually benign neuroendocrine tumors. However, PCPGs with mutations in the succinate dehydrogenase B subunit (. We studied the genetic alterations of cluster I PCPGs compared with cluster II PCPGs, which usually present as benign tumors. By targeting the signature molecular pathway, we investigated the therapeutic effect of ascorbic acid on PCPGs using. By investigating PCPG cells with low SDHB levels, we show that pseudohypoxia resulted in elevated expression of iron transport proteins, including transferrin (TF), transferrin receptor 2 (TFR2), and the divalent metal transporter 1 (. The data here demonstrate that targeting redox homeostasis as a cancer vulnerability with pharmacologic ascorbic acid is a promising therapeutic strategy for

Topics: Animals; Antioxidants; Apoptosis; Ascorbic Acid; Cell Line, Tumor; Disease Models, Animal; DNA Damage; Drug Screening Assays, Antitumor; Female; Gene Knockdown Techniques; Humans; Iron; Mice; Mutation; Oxidative Stress; Paraganglioma; Pheochromocytoma; Reactive Oxygen Species; Succinate Dehydrogenase

Topics: Alveolar Bone Loss; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Male; Periodontitis; Rats; Rats, Sprague-Dawley; Vitamins

Vitamin C (ascorbate, ASC) is a critical antioxidant in the body with specific roles in the brain. Despite a recent interest in vitamin C therapies for critical care medicine, little is known about vitamin C regulation during acute inflammation and critical illnesses such as sepsis. Using a cecal slurry (CS) model of sepsis in mice, we determined ASC and inflammatory changes in the brain following the initial treatment. ASC levels in the brain were acutely decreased by approximately 10% at 4 and 24 h post CS treatment. Changes were accompanied by a robust increase in liver ASC levels of up to 50%, indicating upregulation of synthesis beginning at 4 h and persisting up to 7 days post CS treatment. Several key cytokines interleukin 6 (IL-6), interleukin 1β (IL-1β), tumor necrosis factor alpha (TNFα), and chemokine (C-X-C motif) ligand 1 (CXCL1, KC/Gro) were also significantly elevated in the cortex at 4 h post CS treatment, although these levels returned to normal by 48 h. These data strongly suggest that ASC reserves are directly challenged throughout illness and recovery from sepsis. Given the timescale of this response, decreases in cortical ASC are likely driven by hyper-acute neuroinflammatory processes. However, future studies are required to confirm this relationship and to investigate how this deficiency may subsequently impact neuroinflammation.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain; Cytokines; Disease Models, Animal; Inflammation; Mice; Mice, Inbred C57BL; Organ Specificity; Sepsis

Arterial tortuosity syndrome (ATS) is a recessively inherited connective tissue disorder, mainly characterized by tortuosity and aneurysm formation of the major arteries. ATS is caused by loss-of-function mutations in SLC2A10, encoding the facilitative glucose transporter GLUT10. Former studies implicated GLUT10 in the transport of dehydroascorbic acid, the oxidized form of ascorbic acid (AA). Mouse models carrying homozygous Slc2a10 missense mutations did not recapitulate the human phenotype. Since mice, in contrast to humans, are able to intracellularly synthesize AA, we generated a novel ATS mouse model, deficient for Slc2a10 as well as Gulo, which encodes for L-gulonolactone oxidase, an enzyme catalyzing the final step in AA biosynthesis in mouse. Gulo;Slc2a10 double knock-out mice showed mild phenotypic anomalies, which were absent in single knock-out controls. While Gulo;Slc2a10 double knock-out mice did not fully phenocopy human ATS, histological and immunocytochemical analysis revealed compromised extracellular matrix formation. Transforming growth factor beta signaling remained unaltered, while mitochondrial function was compromised in smooth muscle cells derived from Gulo;Slc2a10 double knock-out mice. Altogether, our data add evidence that ATS is an ascorbate compartmentalization disorder, but additional factors underlying the observed phenotype in humans remain to be determined.

Topics: Animals; Arteries; Ascorbic Acid; Ascorbic Acid Deficiency; Disease Models, Animal; Glucose Transport Proteins, Facilitative; Homozygote; Humans; Joint Instability; L-Gulonolactone Oxidase; Mice; Mice, Knockout; Mitochondria; Respiration; Signal Transduction; Skin Diseases, Genetic; Vascular Malformations

Retinal pigment epithelial (RPE) cell replacement therapy has provided promising outcomes in the treatment of retinal degenerative diseases (RDDs), but the resulting limited visual improvement has raised questions about graft survival and differentiation. Through combined treatment with vitamin C and valproic acid (together, VV), we activated human fetal RPE (fRPE) cells to become highly proliferative fetal RPE stem-like cells (fRPESCs). In this study, we report that SOX2 (SRY-box 2) activation contributed to mesenchymal-epithelial transition and elevated the retinal progenitor and mesenchymal stromal markers expressions of fRPESCs. These fRPESCs could differentiate into RPE cells, rod photoreceptors, and mesenchymal lineage progenies under defined conditions. Finally, fRPESCs were transplanted into the subretinal space of an RDD mouse model, and a photoreceptor rescue benefit was demonstrated. The RPE and rod photoreceptor differentiation of transplanted fRPESCs may account for the neural retinal recovery. This study establishes fRPESCs as a highly proliferative, multi-lineage differentiation potential (including RPE, rod photoreceptor, and mesenchymal lineage differentiation), mesenchymal-to-epithelial-transitioned retinal stem-like cell source for cell-based therapy of RDDs.

Topics: Animals; Ascorbic Acid; Biomarkers; Cell Differentiation; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Epithelial-Mesenchymal Transition; Fetal Stem Cells; Gene Expression Regulation; Humans; Mice; Retinal Degeneration; Retinal Pigment Epithelium; SOXB1 Transcription Factors; Treatment Outcome; Up-Regulation; Valproic Acid

The development of type 2 diabetes mellitus (T2DM) depends on interactions between genetic and environmental factors, and a better understanding of gene-diet interactions in T2DM will be useful for disease prediction and prevention. Ascorbic acid has been proposed to reduce the risk of T2DM. However, the links between ascorbic acid and metabolic consequences are not fully understood. Here, we report that glucose transporter 10 (GLUT10) maintains intracellular levels of ascorbic acid to promote adipogenesis, white adipose tissue (WAT) development and protect mice from high-fat diet (HFD)-induced metabolic dysregulation. We found genetic polymorphisms in SLC2A10 locus are suggestively associated with a T2DM intermediate phenotype in non-diabetic Han Taiwanese. Additionally, mice carrying an orthologous human Glut10G128E variant (Glut10G128E mice) with compromised GLUT10 function have reduced adipogenesis, reduced WAT development and increased susceptibility to HFD-induced metabolic dysregulation. We further demonstrate that GLUT10 is highly expressed in preadipocytes, where it regulates intracellular ascorbic acid levels and adipogenesis. In this context, GLUT10 increases ascorbic acid-dependent DNA demethylation and the expression of key adipogenic genes, Cebpa and Pparg. Together, our data show GLUT10 regulates adipogenesis via ascorbic acid-dependent DNA demethylation to benefit proper WAT development and protect mice against HFD-induced metabolic dysregulation. Our findings suggest that SLC2A10 may be an important HFD-associated susceptibility locus for T2DM.

Topics: 3T3-L1 Cells; Adipogenesis; Adipose Tissue, White; Adult; Aged; Animals; Ascorbic Acid; CCAAT-Enhancer-Binding Proteins; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; DNA Methylation; Female; Gene Expression Regulation; Glucose Transport Proteins, Facilitative; Glycated Hemoglobin; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Mutation; PPAR gamma

Oxidative stress plays an essential role in the vascular tone in hypertension; however, the mechanisms remain unclear.. This study aimed to determine the antioxidant effect of tempol and vitamin C (Vit-C) on the basal tone and vascular remodeling of the aorta in nitric oxide (NO) deficiency-induced hypertensive rats.. Male Sprague-Dawley rats were induced to hypertension by Nω-nitro-L-arginine methyl ester (L-NAME). Animals were randomized as follows: vehicle (Control: CR), CR-tempol, CR-Vit-C, L-NAME, L-NAME-tempol, and L-NAME-Vit-C. After 6 weeks of treatment, the basal aortic tone was evaluated by sodium nitroprusside (SNP) and calcium-free medium. Endothelial function, NO, reduced-to-oxidized glutathione (GSH/GSSG) ratio, resting membrane potential (mP), and vascular remodeling were also measured.. L-NAME rats showed an increased basal tone that was blunted by both SNP (-547 ± 69; n = 7 vs. CR: -7.5 ± 6.7 mg; n = 7; p < 0.001) and calcium-free medium. Tempol or Vit-C did not reverse hypertension, and the high basal tone was decreased only with tempol. In L-NAME rats, only tempol partially improved endothelial function, GSH-to-GSSG ratio, mP values, and vascular remodeling.. Tempol decreased calcium-dependent basal aortic tone and improved vascular homeostasis in L-NAME rats. Vit-C did not lead to a similar effect, suggesting that alterations in the superoxide dismutase pathway may play a role in the basal aortic tone.

Topics: Animals; Antioxidants; Aorta, Thoracic; Ascorbic Acid; Cyclic N-Oxides; Dietary Supplements; Disease Models, Animal; Glutathione; Hypertension; Male; Membrane Potentials; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxidation-Reduction; Oxidative Stress; Rats, Sprague-Dawley; Spin Labels; Vascular Remodeling; Vasoconstriction

Type 2 diabetes is clinically associated with progressive necroinflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Advanced glycation end-products (AGEs) accumulate during prolonged hyperglycemia, but the mechanistic pathways that lead to accelerated liver fibrosis have not been well defined. In this study, we show that the AGEs clearance receptor AGER1 was downregulated in patients with NASH and diabetes and in our NASH models, whereas the proinflammatory receptor RAGE was induced. These findings were associated with necroinflammatory, fibrogenic, and pro-oxidant activity via the NADPH oxidase 4. Inhibition of AGEs or RAGE deletion in hepatocytes in vivo reversed these effects. We demonstrate that dysregulation of NRF2 by neddylation of cullin 3 was linked to AGER1 downregulation and that induction of NRF2 using an adeno-associated virus-mediated approach in hepatocytes in vivo reversed AGER1 downregulation, lowered the level of AGEs, and improved proinflammatory and fibrogenic responses in mice on a high AGEs diet. In patients with NASH and diabetes or insulin resistance, low AGER1 levels were associated with hepatocyte ballooning degeneration and ductular reaction. Collectively, prolonged exposure to AGEs in the liver promotes an AGER1/RAGE imbalance and consequent redox, inflammatory, and fibrogenic activity in NASH.

Topics: Animals; Ascorbic Acid; Cholecalciferol; Dehydroepiandrosterone; Diabetes Mellitus, Type 2; Disease Models, Animal; Down-Regulation; Hepatocytes; Liver Cirrhosis; Mice; Mice, Knockout; NF-E2-Related Factor 2; Nicotinic Acids; Non-alcoholic Fatty Liver Disease; Plant Extracts; Receptor for Advanced Glycation End Products

Oxidative stress and the production of intracellular reactive oxygen species (ROS) have been implicated in the pathogenesis of sepsis. In excess, oxidative stress is not deemed an unbalanced biochemical reaction in the critically ill rats, but it is a key pathological factor in driving systemic inflammatory response that can result in multiple organ failure in sepsis. Thus, we aimed to explore whether antioxidant nutrients could reduce or delay the oxidative stress condition of sepsis rats, and then play a prospective role in the oxidative stress condition of critical disease. In this investigation, the ability of exogenous and endogenous antioxidant nutrients (ascorbate, taurine and glutathione) to prevent sepsis-induced changes in liver injury was examined using a rat model of sepsis induced by cecal ligation and puncture (CLP), and the underlying mechanisms were also investigated. The effects of three antioxidants on sepsis were assessed based on biochemical assays in combination with an NMR-based metabolomics approach and correlation network analysis. Our results suggested that ascorbate, taurine and glutathione had broadly similar protective effects on reducing oxidative stress. Compared with CLP rats, antioxidant-treated rats exhibited alleviated (P<.05) organ dysfunction and improved liver pathology. Moreover, taurine showed a better efficacy compared with ascorbate and glutathione, evidenced by significantly reversed metabolomics profiles toward normal state. Under conditions of sepsis, antioxidants suppressed inflammatory responses by restraining key signaling pathways, including the redox-sensitive transcription factor pathways of NF-κB and MAPK. Collectively, our findings suggested that antioxidant nutrients exerted beneficial effects on septic rats via protecting mitochondrial.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Glutathione; Liver Diseases; Magnetic Resonance Spectroscopy; Male; Metabolome; Metabolomics; Nutrients; Oxidative Stress; Rats; Sepsis; Taurine

This study aimed to investigate the role of endothelin-1 (ET-1), originally known as the potent vasoconstrictor, and its receptors in chondrocyte senescence and osteoarthritis (OA) development.. Temporal changes of ET-1 and its receptors with OA development were characterized in a posttraumatic OA (PTOA) mouse model at time zero, 1-month and 4-month after surgical induction via destabilization of medial meniscus (DMM). A transgenic ET-1 overexpression (TET-1) mouse model was deployed to assess the impact of upregulated ET-1 on chondrocyte senescence and cartilage degradation. Effects of endothelin receptor blockade on chondrocyte senescence and OA development were further examined both in vitro and in vivo.. Local expression of ET-1 in subchondral bone and synovium upregulated after DMM with an increase of plasma ET-1 level from 3.18 ± 0.21 pg/ml at time zero to 6.47 ± 0.34 pg/ml at 4-month post-surgery. Meanwhile, endothelin type B receptor (ET. ET-1 could induce chondrocytes senescence and cartilage damages via ET

Topics: Animals; Antioxidants; Ascorbic Acid; Cartilage, Articular; Cellular Senescence; Chondrocytes; Cyclin-Dependent Kinase Inhibitor p16; Disease Models, Animal; Endothelin-1; Mice, Transgenic; Osteoarthritis; Receptors, Endothelin; Up-Regulation

Epidemiological studies support the association between inadequate vitamin C (Vc) intake and non-alcoholic fatty liver disease (NAFLD). However, the intervention dose of Vc, and the prophylactic and therapeutic effects on NAFLD are unclear. This study aimed to investigate the prophylactic and therapeutic effects of low (LVc), medium (MVc) and high (HVc) doses of Vc on NAFLD. C57BL/6 mice were randomly assigned to prophylactic groups (mice received a high-fat diet (HFD) concomitant with different doses of Vc) and therapeutic groups (HFD-induced NAFLD mice treated with different doses of Vc). Results showed that prophylactic LVc and MVc administration reduced the risk of NAFLD development in HFD-fed mice, as evidenced by significantly lowered body weight, perirenal adipose tissue mass, and steatosis, whereas prophylactic HVc administration did not prevent HFD-induced NAFLD development. Furthermore, therapeutic MVc administration significantly ameliorated HFD-induced increase in body weight, perirenal adipose tissue mass and steatosis, whereas therapeutic LVc and HVc administration did not ameliorate NAFLD symptoms. In fact, therapeutic HVc administration significantly increased body weight, perirenal adipose tissue mass, and lobular inflammation. Moreover, prophylactic LVc administration was more effective than therapeutic LVc administration as evidenced by significantly lower body weight, perirenal adipose tissue mass, steatosis, ballooned hepatocytes, and lobular inflammation in prophylactic LVc administration. The same trends were observed between prophylactic HVc administration and therapeutic HVc administration. In addition, all Vc-administered mice exhibited low blood glucose, triglycerides and homeostasis model assessment of insulin resistance values and high adiponectin levels compared to HFD-fed mice. Our study suggested that MVc was beneficial for HFD-induced NAFLD prophylaxis and therapy. LVc prevented HFD-induced NAFLD development, while HVc for NAFLD management was risky. This study offers valuable insight into the effect of various Vc doses on NAFLD management.

Topics: Adiponectin; Animals; Antioxidants; Ascorbic Acid; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Inflammation; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Triglycerides; Weight Gain

Although antibiotic-induced hepatotoxicity is recoverable with mild impairment, and some cases were reported to cause morbidity. However, an adjuvant is essential in reducing such incidences.. The aim of this study is to evaluate the protective effect of ascorbic acid on antibiotic induced liver toxicity using liver slices.. Fresh liver slices were incubated with different concentrations of sulfamethoxazole tetracycline and clavulanic acid along with ascorbic acid (200μg/ml) for 2 hours. The liver homogenate was assessed for markers like ALT, AST, MDA and CAT levels. Cytotoxicity assessment was performed using MTT assay.. Incubating liver slices with all three antibiotics shows elevated levels of aminotransferases, MDA and CAT enzyme when compared to the control groups which indicates the level of hepatotoxicity. In the presence of ascorbic acid, the elevated levels of TBARS, ALT and AST were significantly reduced which showcases the protective effect of ascorbic acid. The percentage survival of cell was also shown to have improved while accessed using cell viability assay.. Obtained data suggests that consuming vitamin C or vitamin C containing food like citrus fruits or green leafy vegetables equivalent to 3g/day during antibiotic treatment, perhaps put down the risk of liver toxicity to a greater extent.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Ascorbic Acid; Cell Survival; Chemical and Drug Induced Liver Injury; Chickens; Clavulanic Acid; Disease Models, Animal; Drug Evaluation, Preclinical; Hepatocytes; Humans; Lipid Peroxidation; Liver; Mice; Oxidative Stress; Primary Cell Culture; Sulfamethoxazole; Tetracycline

Inflammation is our body's normal defense mechanism, but in some cases, it may be responsible for causing different kinds of disorders. Several antiinflammatory drugs are present for the treatment of these disorders; however, the conventional anti-inflammatory drugs cause side effects when used in the long term and therefore, it is better to use them in a low dose for a shorter duration of time. This study was designed to find out whether there is an augmentation of the therapeutic effectiveness of the antiinflammatory drugs like diclofenac sodium (NSAID), prednisolone (steroid) and atorvastatin (statin) when used in combination with ascorbic acid (antioxidant).. Wistar Rats (n=144) were selected and divided into 24 groups of 6 rats in each. Carrageenan and formalin were used to induce local inflammation and neuropsychiatric effects, respectively. The inhibitions of such responses were measured after administering a drug alone and in combination with ascorbic acid.. In case of carrageenan mediated inflammation, the combination of 5 mg/kg diclofenac and 200 mg/kg ascorbic acid gave the highest inhibition of 74.19% compared to other groups of drugs. The combination of 5 mg/kg diclofenac and 200 mg/kg ascorbic acid gave 97.25% inhibition for formalin-mediated inflammation group. In both cases, combination therapy showed statistically significant anti-inflammatory activities compared to monotherapy (p values <0.05).. All the data clearly indicate new combinations of drug therapy comprising diclofenac sodium, prednisolone, atorvastatin with ascorbic acid, which may be more effective against both local edema and the neuropsychiatric effect caused due to inflammation.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Atorvastatin; Diclofenac; Disease Models, Animal; Drug Combinations; Drug Dosage Calculations; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Prednisolone; Rats; Treatment Outcome

A small clinical trial showed HAT therapy improved survival but no studies have been reported in animal models to examine potential mechanisms.. Sepsis was induced in female mice using the cecal ligation and puncture (CLP) model. Physiologic parameters including heart rate (HR), pulse distension (PD), and respiratory rate (RR) were measured noninvasively at baseline, 6 and 24 h post CLP. These measurements stratified mice into predicted to live (Live-P) or die (Die-P). Mice were randomized to receive HAT therapy or vehicle. Oxidative stress was measured in peritoneal exudative cells 24 h after CLP.. HR, PD, and RR all declined within the first 6 h of sepsis and were significantly lower in the Die-P mice compared with Live-P. HR 6 h post-CLP best predicted mortality and continued to decline between 6 and 24 h post CLP. Oxidative stress in peritoneal cells harvested 24 h post CLP (determined by 8 isoprostaglandin F2α and protein carbonyl derivatives) was significantly higher in the Die-P mice. HAT therapy was initiated 7 h post-CLP after mortality prediction and stratification. HAT significantly reduced oxidative stress in the Die-P mice without altering these parameters in the Live-P mice. HAT treatment prevented the decline in HR, again only in the Die-P mice. Mice treated with HAT therapy had significantly better survival.. Physiologic parameters accurately predicted mortality. Die-P mice had significant oxidative stress compared with Live-P. HAT therapy significantly decreased oxidative stress, increased HR, and improved survival in the Die-P mice. These data suggest that HAT exerts a beneficial effect through reducing oxidative stress and improving cardiovascular function.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Blood Pressure; Disease Models, Animal; Female; Heart Rate; Hydrocortisone; Mice; Mice, Inbred ICR; Oxidative Stress; Sepsis; Thiamine; Vitamin B Complex

Tendon rupture is a very frequent accident involving average people and high-performance athletes. Clinical studies describe tendon recovery as a painful and slow process involving different biochemical and histological events. Ascorbic acid (AA) is a potent antioxidant as well as an important cofactor for collagen synthesis. In the current study, we evaluated if local treatment with AA is able to promote tendon repair in tenotomized rats. Animals were submitted to Achilles tendon rupture followed by surgical suture. Control and AA groups received in loco injection of saline solution (0.9% NaCl) and 30 mM AA, respectively. Histological and functional recovery of Achilles tendon tissue was evaluated at 7, 14, and 21 days post-surgery. Hematoxylin/eosin staining and collagen fluorescence analysis showed intense disarrangement of tendon tissue in the saline group. Tenotomized animals also showed hypercellularity in tendon tissue compared with non-tenotomized animals. The Achilles functional index (AFI) showed a significant decrease of tendon functionality in tenotomized animals at 7, 14, and 21 days post-surgery. AA accelerated tissue organization and the recovery of function of the Achilles tendons. The beneficial effect of AA treatment was also observed in the organization of the collagen network. Data presented in the current work showed that in loco treatment with AA accelerated the recovery of injured Achilles tendon post-surgery.

Topics: Achilles Tendon; Animals; Ascorbic Acid; Collagen; Disease Models, Animal; Male; Rats; Rats, Wistar; Recovery of Function; Tendon Injuries; Tenotomy; Wound Healing

In this study, the effects of 2-

Topics: Animals; Ascorbic Acid; Bacteria; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Fruit; Gastrointestinal Microbiome; Humans; Lycium; Male; Mice; Mice, Inbred C57BL; Plant Extracts

In this study, we investigated the ability of a single coadministration of subeffective doses of ascorbic acid and ketamine to reverse the depressive-like behavior induced by chronic unpredictable stress (CUS) in mice. Moreover, we examined the effect of combined administration of ascorbic acid and ketamine on hippocampal phosphorylation of p70S6K and immunocontents of GLUA1 and PSD-95 in mice submitted to the CUS procedure. CUS procedure was applied for 21 days. Animals received a single coadministration of subeffective doses of ascorbic acid (0.1 mg/kg) and ketamine (0.1 mg/kg) and were subjected to behavioral evaluation 24 h after the treatments. Immediately after the behavioral observations the hippocampi were dissected for Western blotting analyses. Our results revealed that a single administration of subeffective doses of ascorbic acid and ketamine completely reversed the depressive-like behavior induced by CUS, however, this effect was not accompanied by changes in the phosphorylation of p70S6K and immunocontent of GLUA1 or PSD95 in the hippocampus. These findings point to a synergistic antidepressant-like effect of ascorbic acid and ketamine, paving the way for additional studies on the combined use of these compounds for the management of major depressive disorder (MDD).

Topics: Animals; Antidepressive Agents; Ascorbic Acid; Behavior, Animal; Depression; Depressive Disorder, Major; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Hindlimb Suspension; Hippocampus; Ketamine; Locomotion; Mice; Stress, Psychological; Treatment Outcome

Lead (Pb) is a toxic heavy metal pollutant with adverse effects on the liver and other body organs. Curcumin (CUR) is the principal curcuminoid of turmeric and possesses strong antioxidant and anti-inflammatory activities. This study explored the protective effect of CUR on Pb hepatotoxicity with an emphasis on oxidative stress, inflammation and Akt/GSK-3β signaling. Rats received lead acetate and CUR and/or ascorbic acid (AA) for seven days and samples were collected for analyses. Pb(II) induced liver injury manifested by elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), as well as histopathological alterations, including massive hepatocyte degeneration and increased collagen deposition. Lipid peroxidation, nitric oxide, TNF-α and DNA fragmentation were increased, whereas antioxidant defenses were diminished in the liver of Pb(II)-intoxicated rats. Pb(II) increased hepatic NF-κB and JNK phosphorylation and caspase-3 cleavage, whereas Akt and GSK-3β phosphorylation was decreased. CUR and/or AA ameliorated liver function, prevented tissue injury, and suppressed oxidative stress, DNA damage, NF-κB, JNK and caspase-3. In addition, CUR and/or AA activated Akt and inhibited GSK-3β in Pb(II)-induced rats. In conclusion, CUR prevents Pb(II) hepatotoxicity via attenuation of oxidative injury and inflammation, activation of Akt and inhibition of GSK-3β. However, further studies scrutinizing the exact role of Akt/GSK-3β signaling are recommended.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Ascorbic Acid; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Curcumin; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Glycogen Synthase Kinase 3 beta; L-Lactate Dehydrogenase; Male; Organometallic Compounds; Oxidative Stress; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Signal Transduction

Adoptive transfer of induced regulatory T cells (iTregs) can ameliorate graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). CD4+ iTregs can effectively prevent GVHD but impair the graft-versus-leukemia (GVL) effect, whereas CD8+ iTregs preserve the GVL effect but have limited efficacy in GVHD control because of their instability under inflammatory conditions. Thus, we aimed to stabilize CD8+ iTregs via treatment with vitamin C (Vit C) to improve their efficacy in controlling GVHD. We found that addition of Vit C significantly improved the stability of forkhead box P3 (Foxp3) expression in CD8+ iTregs. Moreover, Vit C-treated CD8+ iTregs exhibited high efficacy in attenuating acute and chronic GVHD. The mechanistic study revealed that addition of Vit C to CD8+ iTreg culture markedly increased DNA demethylation in the conserved noncoding sequence 2 region and, hence, maintained higher Foxp3 expression levels compared with untreated controls. In acute GVHD, Vit C-treated CD8+ iTregs were able to inhibit pathogenic T-cell expansion and differentiation while reducing thymus damage and B-cell activation in cGVHD. Importantly, in contrast to CD4+ iTregs, Vit C-treated CD8+ iTregs retained the ability to control tumor relapse. These results provide a strong rationale to use Vit C in the clinic to stabilize CD8+ iTregs for the control of GVHD and preservation of GVL after allo-HCT.

Topics: Adoptive Transfer; Animals; Ascorbic Acid; Biomarkers; CD8-Positive T-Lymphocytes; Disease Models, Animal; DNA Methylation; Forkhead Transcription Factors; Graft vs Host Disease; Heterografts; Interferon-gamma; Leukemia; Lymphocyte Activation; Mice; Mice, Knockout; Recurrence; T-Lymphocytes, Regulatory

Boldine is a natural antioxidant that exhibits some important pharmacological properties, which is due to its free radical scavenging effects. And at the same time, reactive oxygen species (ROS) has an important role in pathogenesis of seizure; hence, reducing it via antioxidants like boldine seems to be effective in treating seizure. This study was designed to investigate whether acute treatment with boldine could alter seizures induced by pentylenetetrazole or electroshock in mice. We also evaluated to see if boldine's antioxidant properties play a role in its anti-convulsant activity. Boldine acute administration increased time latencies to the onset of myoclonic jerks and clonic seizures induced by intraperitoneal pentylenetetrazole model. Moreover, boldine increased seizure threshold induced by intravenous infusion of pentylenetetrazole. Additionally, acute doses of boldine reduced the duration of tonic hind-limb extension in the electroshock-induced seizure model. Non-effective dose of vitamin C (as an antioxidant agent) and boldine had anti-convulsant effect in intraperitoneal pentylenetetrazole, intravenous pentylenetetrazole and electroshock models. Boldine administration increased glutathione and superoxide dismutase levels in mice whole brain. The result showed boldine anti-seizure properties, which might be due to its antioxidant activity.

Topics: Animals; Anticonvulsants; Antioxidants; Aporphines; Ascorbic Acid; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Male; Mice; Pentylenetetrazole; Seizures; Superoxide Dismutase

Ascorbate is a low-cost compound with a known bactericidal-synergy to antibitics. However, the synergy depends on concentrations and organisms. Thus, the synergy test by time-kill assay might be appropriate for the screening of the synergy.. We aimed to test the adjuvant property of ascorbate with ceftriaxone, a frequently prescribed β-lactam antibiotic.. Ascorbate was tested with several bacteria from the American Type Culture Collection (ATCC) including Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii and Escherichia coli for i) bactericidal property of ascorbate, alone or with ceftriaxone-combination, by time-kill assay, ii) an influence on the killing-activity of bone -marrow-derived macrophage and iii) the attenuation of myositis mouse model.. The bactericidal synergy (determined with time-kill assay at 24 h) against S. aureus, but not other selected bacteria, was demonstrated in ascorbate (10 and 40 mM) plus ceftriaxone at the minimal inhibitory concentration (1x MIC). Ascorbate alone, without antibiotic, enhanced macrophage killing-activity and directly eliminated bacteria at the concentration 10-40mM and 250mM, respectively (both properties presented against S. aureus and P. aeruginosa, but not other bacteria). Ascorbate with ceftriaxone also reduced bacterial burdens in muscle and serum cytokines of S. aureus -myositis mouse model. Moreover, the synergy against the clinical isolated methicillin resistant S. aureus (MRSA) by time-kill assay and myositis model also presented.. Ascorbate-ceftriaxone synergy against S. aureus was demonstrated by time-kill assay and myositis model. Time-kill assy might be valuable as a screening test to select the patients that potentially benefit from ascorbate- ceftriaxone adjuvant therapy.

Topics: Animals; Anti-Bacterial Agents; Ascorbic Acid; Bacteria; Ceftriaxone; Cytotoxicity, Immunologic; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Macrophages; Male; Mice; Phagocytosis; Staphylococcal Infections; Staphylococcus aureus

Osteoarthritis (OA) is one of the most common degenerative diseases especially in the knee joint. The definitive method for the treatment of this disease is not known. In recent years, use of platelet-derived products has been considered as a new therapeutic approach because of its low cost, easy to use, and minimum side effects. Serum rich of growth factors (SRGF) is one of the biological compounds used to healing and regeneration. Its effects may improve in combination with antioxidants such as vitamin C. This vitamin increases the synthesis of proteoglycans by chondrocytes. The present study investigated effect of xenogenous SRGF in combination with vitamin C on the monosodium iodoacetate-induction osteoarthritis in rats.. Animals were randomly categorized into three groups including OA, SRGF, and vitamin C+SRGF. Treatments were performed with 3 time intra-articular injection in weekly intervals. Knee samples were taken after two weeks of the last treatment for histopathologic investigations.. In the OA group, surface fibrillation and irregularity, multiple clefts, loss of chondrocytes, proteoglycan depletion with Toluidine blue staining were detected. In the treated group with SRGF/vitamin C, the severity of degenerative lesions was decreased. Chondrocytes had proliferated and matrix proteoglycan increased in compared to the SRGF and OA groups. Also, osteoarthritis stage was markedly reduced in this group rather than two other groups.. The results of this study show the synergic effect of vitamin C and growth factors on accelerating articular repair.

Topics: Animals; Ascorbic Acid; Cartilage, Articular; Chondrocytes; Disease Models, Animal; Injections, Intra-Articular; Intercellular Signaling Peptides and Proteins; Iodoacetic Acid; Knee Joint; Male; Osteoarthritis; Proteoglycans; Random Allocation; Rats; Rats, Wistar

Pharmacologic ascorbate (P-AscH

Topics: Animals; Ascorbic Acid; Cell Line, Tumor; Disease Models, Animal; Drug Synergism; Electron Spin Resonance Spectroscopy; Humans; Metalloporphyrins; Oxidation-Reduction; Pancreatic Neoplasms; Radiation-Sensitizing Agents

Streptococcus gordonii is commonly found in the periapical endodontic lesions of patients with apical periodontitis, a condition characterized by inflammation and periapical bone loss. Since bone metabolism is controlled by osteoclastic bone resorption and osteoblastic bone formation, we investigated the effects of S. gordonii on the differentiation and function of osteoclasts and osteoblasts. For the determination of bone resorption activity in vivo, collagen sheets soaked with heat-killed S. gordonii were implanted on mouse calvaria, and the calvarial bones were scanned by micro-computed tomography. Mouse bone marrow-derived macrophages (BMMs) were stimulated with M-CSF and RANKL for 2 days and then differentiated into osteoclasts in the presence or absence of heat-killed S. gordonii. Tartrate-resistant acid phosphatase staining was performed to determine osteoclast differentiation. Primary osteoblast precursors were differentiated into osteoblasts with ascorbic acid and β-glycerophosphate in the presence or absence of heat-killed S. gordonii. Alkaline phosphatase staining and alizarin red S staining were conducted to determine osteoblast differentiation. Western blotting was performed to examine the expression of transcription factors including c-Fos, NFATc1, and Runx2. Heat-killed S. gordonii induced bone destruction in a mouse calvarial implantation model. The differentiation of RANKL-primed BMMs into osteoclasts was enhanced in the presence of heat-killed S. gordonii. Heat-killed S. gordonii increased the expression of c-Fos and NFATc1, which are essential transcription factors for osteoclast differentiation. On the other hand, heat-killed S. gordonii inhibited osteoblast differentiation and reduced the expression of Runx2, an essential transcription factor for osteoblast differentiation. S. gordonii exerts bone resorptive activity by increasing osteoclast differentiation and reducing osteoblast differentiation, which may be involved in periapical bone resorption.

Topics: Alkaline Phosphatase; Animals; Ascorbic Acid; Bone Resorption; Cell Differentiation; Core Binding Factor Alpha 1 Subunit; Cytokines; Disease Models, Animal; Glycerophosphates; Macrophage Colony-Stimulating Factor; Macrophages; Male; Mice; Mice, Inbred C57BL; NFATC Transcription Factors; Osteoblasts; Osteoclasts; Osteogenesis; Periapical Periodontitis; Proto-Oncogene Proteins c-fos; RANK Ligand; Streptococcus gordonii; Transcription Factors; Up-Regulation; X-Ray Microtomography

Exposure to toxic elements is greatly unavoidable in our daily activities due to several routes of coming in contact with these elements. Thus lead (Pb), is one of the major causes of health hazard in human. In this study, evaluation of Zingiber officinale as mitigating measure against Pb induced biochemical and cytogenic toxicity in albino rats was investigated. Experimental rats were grouped into five with five animals per group, group I serves as control and groups 2-5 were induced intraperitoneal with lead acetate dissolved in distilled water at 3 mg/kg body weight whereas group 3-5 were orally administered with 200 mg/kg vitamin C, 200 mg/kg, and 100 mg/kg of Z. officinale, respectively for 7 d. The obtained results show that aspartate aminotransferase (AST), alkaline phosphatase (ALP), lipid peroxidation, urea, creatinine, bilirubin, and gamma-glutamyl transferase (GGT) were significantly increased (p < 0.05) and catalase (CAT) were reduced progressively in Pb alone induced rats. Hematological parameters showed a progressive reduction (p < 0.05) in lead acetate alone rats. There were significant changes in micronuclei (MN), chromosomal aberrations (CA) frequency, and oxidative damages in the bone marrow cells from lead acetate alone induced rats, although, mitotic index scores in these cells were reduced gradually (p < 0.05). The altered parameters were significantly reversed toward the levels observed in normal control rats administered with vitamin C and aqueous extract of Z. officinale. Hence, these results suggest that Z. officinale roots might contain therapeutic potential that can ameliorate the hazard effect of lead acetate poison.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Lead Poisoning; Lipid Metabolism; Male; Micronuclei, Chromosome-Defective; Organometallic Compounds; Plant Extracts; Rats, Wistar; Zingiber officinale

Menopause is associated with increased oxidative stress and memory impairment. Based on the antioxidant property of ascorbic acid (AA), It's effect on cognitive function, the serum level of the brain-derived neurotrophic factor (BDNF) and the activity of antioxidant enzymes within the brain in ovariectomized (OVX) mice was investigated.. AA (100, 300 and 500 mg/kg), was orally administrated per day in OVX mice for 30 days. Tactile learning and working memory were evaluated by the novel object recognition task and T-maze continuous alternation task, respectively. The levels of serum BDNF were measured and animals' brains were analyzed for the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity.. AA prevented from the deleterious effects of ovariectomy on learning memory (300 and 500 mg/kg) and working memory (100 and 500 mg/kg). The serum BDNF level was also increased in OVX animals treated with AA (100 and 500 mg/kg). Furthermore, AA (500 mg/kg) increased the SOD and GPx activity in the brain of OVX animals.. Collectively, the results of the present study suggest that AA might be an appropriate choice in loss or reduction of estradiol for the amelioration of cognitive impairment.

Topics: Animals; Antioxidants; Ascorbic Acid; Behavior, Animal; Brain; Brain-Derived Neurotrophic Factor; Cognition; Cognition Disorders; Disease Models, Animal; Female; Glutathione Peroxidase; Maze Learning; Memory, Short-Term; Menopause; Mice; Ovariectomy; Oxidative Stress; Recognition, Psychology; Superoxide Dismutase

L-ascorbate (L-ASC) is a widely-known dietary nutrient which holds promising potential in cancer therapy when given parenterally at high doses. The anticancer effects of L-ASC involve its autoxidation and generation of H

Topics: Animals; Ascorbic Acid; B-Lymphocytes; Cell Line; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; Humans; Hydrogen Peroxide; Iron; Leukemia, B-Cell; Lymphoma, B-Cell; Mice; Thioredoxins; Xenograft Model Antitumor Assays

The present study was designed to investigate the effect of ascorbic acid (AA) treatment on the anxiety related behavioral and neurochemical alterations. AA (50, 100 and 200 mg/kg, i.p.) was administered to the mice and anxiety related behavior and levels of glutamate and nitrite in the brain of mice were determined. The results obtained revealed that the administration of AA (100 mg/kg, i.p.) significantly reduced the anxiety related behavior and the levels of nitrite in the brain of mice. Nitrergic interactions were further determined by the pretreatment of mice with nitric oxide (NO) modulator and AA treatment followed by behavioral and neurochemical measurements. The results obtained suggested that NO inhibition potentiated the anxiolytic like activity of AA in mice. It was also observed that the glutamate and nitrite level in the brain of mice were significantly reduced by the NO inhibitor pretreatment. Thus, the present study demonstrated the possible nitrergic pathways modulation in the anxiolytic like activity of AA in mice.

Topics: Affect; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Ascorbic Acid; Behavior, Animal; Brain; Disease Models, Animal; Glutamic Acid; Male; Maze Learning; Mice; Motor Activity; Nitrates; Nitrergic Neurons; Nitric Oxide; Signal Transduction

Tinnitus may cause anxiety, depression, insomnia, which impair the quality of life of millions worldwide. However, the mechanism of tinnitus remains to be understood, it has been previously hypothesized that the activation of N-methyl-D-aspartate (NMDA) receptor is involved in the tinnitus processes and blockade of the NMDA receptor is regarded as a therapeutic strategy for tinnitus treatment even if the rescue treatment is still proved invalid in some cases. To demonstrate the therapeutic effect of the NMDA receptor blocker on tinnitus, we examined here the spontaneous firing rate (SFR) and the neurochemical dynamics in the auditory cortex (AC) of rats after sodium salicylate (SS) injection, which is a widely used model for tinnitus research. We also recorded their responses to MK-801 treatment. Electrophysiological studies showed that MK-801 significantly suppresses SFR in AC of rats with SS-induced tinnitus. In addition, by using a technique that combining in vivo microdialysis with an online electrochemical system (OECS) and a high-performance liquid chromatography (HPLC), we found that the levels of both glutamate and ascorbate in AC dramatically increased after SS injection and that MK-801 administration attenuated those response. Further studies found that MK-801 given at a time point of 30 min pre- or post-injection of SS were more effective than that given at a time point of 60 min post-SS injection, indicating that the time point of MK-801 intervention has a critical impact on the therapeutic effect. These findings suggest that MK-801 plays a neuroprotective role against hyperactivity during tinnitus induced by SS and that the therapeutic effect depends on the time point of MK-801 intervention, which would advance the studies on understanding of the therapeutic potential of NMDA receptor antagonist in tinnitus therapy.

Topics: Animals; Ascorbic Acid; Auditory Cortex; Disease Models, Animal; Dizocilpine Maleate; Drug Administration Schedule; Evoked Potentials, Auditory; Glutamic Acid; Humans; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Sodium Salicylate; Tinnitus

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Ascorbic Acid; Brain; Catechin; Disease Models, Animal; Drug Carriers; Drug Liberation; Endothelial Cells; Male; Mice, Inbred C57BL; Mice, Transgenic; Nanoparticles; Polyethylene Glycols; Polylactic Acid-Polyglycolic Acid Copolymer; Rats

As a promising therapeutic treatment, ischemic postconditioning has recently received considerable attention. Although the neuroprotection effect of postconditioning has been observed, a reliable approach that can evaluate the neuroprotective efficiency of postconditioning treatment during the acute period after ischemia remains to be developed. This study investigates the dynamics of cortex ascorbic acid during the acute period of cerebral ischemia before and after ischemic postconditioning with an online electrochemical system (OECS). The cerebral ischemia/reperfusion injury and the neuronal functional outcome are evaluated with triphenyltetrazolium chloride staining, immunohistochemistry, and electrophysiological recording techniques. Electrochemical recording results show that cortex ascorbic acid sharply increases 10 min after middle cerebral artery occlusion and then reaches a plateau. After direct reperfusion following ischemia (i.e., without ischemic postconditioning), the cortex ascorbic acid further increases and then starts to decrease slowly at a time point of about 40 min after reperfusion. In striking contrast, the cortex ascorbic acid drops and recovers to its basal level after ischemic postconditioning followed by reperfusion. With the recovery of cortex ascorbic acid, ischemic postconditioning concomitantly promotes the recovery of neural function and reduces the oxidative damage. These results demonstrate that our OECS for monitoring cortex ascorbic acid can be used as a platform for evaluating the neuroprotective efficiency of ischemic postconditioning in the acute phase of cerebral ischemia, which is of great importance for screening proper postconditioning parameters for preventing ischemic damages.

Topics: Acute Disease; Animals; Ascorbic Acid; Brain Ischemia; Cerebral Cortex; Disease Models, Animal; Electrophysiological Phenomena; Infarction, Middle Cerebral Artery; Ischemic Postconditioning; Male; Monitoring, Physiologic; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Stroke

Bromodomain and extra-terminal inhibitors (BETi) have shown efficacy for the treatment of aggressive triple negative breast cancer (TNBC). However, BETi are plagued by a narrow therapeutic window as manifested by severe toxicities at effective doses. Therefore, it is a limitation to their clinical implementation in patient care.. The impact of vitamin C on the efficacy of small compounds including BETi was assessed by high-throughput screening. Co-treatment of TNBC by BETi especially JQ1 and vitamin C was evaluated in vitro and in vivo.. High-throughput screening revealed that vitamin C improves the efficacy of a number of structurally-unrelated BETi including JQ1, I-BET762, I-BET151, and CPI-203 in treating TNBC cells. The synergy between BETi and vitamin C is due to suppressed histone acetylation (H3ac and H4ac), which is in turn caused by upregulated histone deacetylase 1 (HDAC1) expression upon vitamin C addition. Treatment with JQ1 at lower doses together with vitamin C induces apoptosis and inhibits the clonogenic ability of cultured TNBC cells. Oral vitamin C supplementation renders a sub-therapeutic dose of JQ1 able to inhibit human TNBC xenograft growth and metastasis in mice.. Vitamin C expands the therapeutic window of BETi by sensitizing TNBC to BETi. Using vitamin C as a co-treatment, lower doses of BETi could be used to achieve an increased therapeutic index in patients, which will translate to a reduced side effect profile. FUND: University of Miami Sylvester Comprehensive Cancer Center, Bankhead Coley Cancer Research program (7BC10), Flight Attendant Medical Research Institute, and NIH R21CA191668 (to GW) and 1R56AG061911 (to CW and CHV).

Topics: Acetylation; Animals; Antineoplastic Agents; Apoptosis; Ascorbic Acid; Azepines; Cell Line, Tumor; Dietary Supplements; Disease Models, Animal; Drug Synergism; Female; Gene Expression Profiling; Gene Silencing; Histone Deacetylase 1; Humans; Mice; Proteins; Triazoles; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Epidemiological studies have demonstrated that vitamin C decreases the risk of stroke, which has generally been ascribed to its function as antioxidant and free radical scavenger. However, whether there is a defined molecular target for vitamin C on stroke is unknown. Utilizing middle cerebral artery occlusion (MCAO) in rats as a model for ischemic stroke, we demonstrated that long-term, low-dose administration of vitamin C prior to MCAO could exert significant neuroprotective effect on the brain damage. The long-term, low-dose vitamin C pretreated rats had decreased brain infarct size and decreased neurological deficit score compared with the vehicle or single high dose pretreated MCAO rats. Furthermore, electrophysiological experiments using patch clamp technique showed that vitamin C increased the whole-cell current of the large-conductance Ca

Topics: Animals; Ascorbic Acid; Brain Infarction; CHO Cells; Cricetulus; Disease Models, Animal; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Male; Rats; Rats, Sprague-Dawley; Stroke

Multiple pathogeneses are involved in Alzheimer's disease (AD), such as amyloid-β accumulation, neuroinflammation, and oxidative stress. The pathological impact of chronic cerebral hypoperfusion on Alzheimer's disease is still poorly understood.. APP23 mice were implanted to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive chronic cerebral hypoperfusion (CCH). The effects of the administration of Twendee X (TwX) were evaluated by behavioral analysis, immunohistochemical analysis, and immunofluorescent histochemistry.. In the present study, chronic cerebral hypoperfusion, which is commonly found in aged Alzheimer's disease, significantly exacerbated motor dysfunction of APP23 mice from 5 months and cognitive deficit from 8 months of age, as well as neuronal loss, extracellular amyloid-β plaque and intracellular oligomer formations, and amyloid angiopathy at 12 months. Severe upregulations of oxidative markers and inflammatory markers were found in the cerebral cortex, hippocampus, and thalamus at 12 months. Twendee X treatment (20 mg/kg/d, from 4.5 to 12 months) substantially rescued the cognitive deficit and reduced the above amyloid-β pathology and neuronal loss, alleviated neuroinflammation and oxidative stress.. The present findings suggested a potential therapeutic benefit of Twendee X for Alzheimer's disease with chronic cerebral hypoperfusion.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Behavior, Animal; Brain; Cerebrovascular Circulation; Cerebrovascular Disorders; Chronic Disease; Cognition; Cystine; Dietary Supplements; Disease Models, Animal; Female; Glutamine; Inflammation Mediators; Male; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Mutation; Neuroprotective Agents; Oxidative Stress; Plaque, Amyloid

This study focused on potential of vitamin C loaded human serum albumin (HSA) nanoparticles for treatment of wound. Nanocarrier were prepared and assessed for their effect on growth of 3T3 fibroblast cells, cell migration, wound healing rate and expression of miR-155, TGF-β1 and SMAD 1,2 genes. Wound healing assay was done and wounds were treated with vitamin C loaded HSA nanoparticles. Nanoparticles were prepared with size and zeta potential of 180±6 and -29 mV, respectively. Vitamin C loaded HSA nanoparticles showed controlled release of vitamin C into the buffer solution. Also, yield and encapsulation efficacy of loaded nanoparticles were obtained as 70.6 and 52.1 %, respectively. MTT results showed that the growth of 3T3 fibroblast cells was promoted in culture medium with 20 µg/ml of vitamin C loaded HSA nanoparticles. Cell migration assay indicated the positive effect of loaded nanoparticles on wound healing. The in-vivo results showed that the rate of wound healing was increased after treatment with 20 µg/ml of vitamin C loaded HSA nanoparticles. The wounds were healed faster when treated with vitamin C loaded HSA nanoparticles in comparison with control group. The expression of miR-155 was downregulated after treatment. Furthermore, expression of TGF-β1 and SMAD 1,2 were increased while the wounds were treated with these nanoparticles. In conclusion, these results showed for the first time that wounds were healed after treatment with albumin nanocarrier loaded with vitamin C. This nanocarrier changed expression of miR-155 and TGF-β1 towards faster healing of wounds.

Topics: Animals; Ascorbic Acid; Cell Movement; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Down-Regulation; Fibroblasts; Humans; Mice; Mice, Inbred Strains; MicroRNAs; Nanoparticles; Random Allocation; Reference Values; Serum Albumin, Human; Skin; Wound Healing; Wounds and Injuries

Topics: Acetaminophen; Animals; Ascorbic Acid; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Male; Oxidative Stress; Protective Factors; Rats; Rats, Sprague-Dawley; Silymarin; Thioctic Acid

Vitamin C is a natural nutrient with antioxidant properties and is used as a health supplement. In this study, we examined the effects of intraperitoneal administration of high-dose vitamin C (4 g/kg) on dextran sodium sulfate (DSS)-induced ulcerative colitis. We prepared a mouse ulcerative colitis model by administering DSS for 7 d along with high-dose vitamin C each day during DSS treatment. Ulcerative colitis induced by DSS was ameliorated by high-dose vitamin C administration. Blood levels of interleukin-6, tumor necrosis factor-α, hydrogen peroxide (H

Topics: Animals; Antioxidants; Ascorbic Acid; Colitis, Ulcerative; Collagen Type I; Collagen Type II; Colon; Dextran Sulfate; Disease Models, Animal; Fibroblasts; Hydrogen Peroxide; Interleukin-6; Male; Mice, Hairless; Tumor Necrosis Factor-alpha; Vitamins

The sequence of events in hepatic encephalopathy (HE) remains unclear. Using the advantages of in vivo 1H-MRS (9.4T) we aimed to analyse the time-course of disease in an established model of type C HE by analysing the longitudinal changes in a large number of brain metabolites together with biochemical, histological and behavioural assessment. We hypothesized that neurometabolic changes are detectable very early, and that these early changes will offer insight into the primary events underpinning HE.. Wistar rats underwent bile-duct ligation (BDL) and were studied before BDL and at post-operative weeks 2, 4, 6 and 8 (n = 26). In vivo short echo-time. Plasma ammonium increased early after BDL and remained high during the study. Brain glutamine increased (+47%) as early as 2-4 weeks post-BDL while creatine (-8%) and ascorbate (-12%) decreased. Brain glutamine and ascorbate correlated closely with rising plasma ammonium, while brain creatine correlated with brain glutamine. The increases in brain glutamine and plasma ammonium were correlated, while plasma ammonium correlated negatively with distance moved. Changes in astrocyte morphology were observed at 4 weeks. These early changes were further accentuated at 6-8 weeks post-BDL, concurrently with the known decreases in brain organic osmolytes.. Using a multimodal, in vivo and longitudinal approach we have shown that neurometabolic changes are already noticeable 2 weeks after BDL. These early changes are suggestive of osmotic/oxidative stress and are likely the premise of some later changes. Early decreases in cerebral creatine and ascorbate are novel findings offering new avenues to explore neuroprotective strategies for HE treatment.. The sequence of events in chronic hepatic encephalopathy (HE) remains unclear, therefore using the advantages of in vivo proton magnetic resonance spectroscopy at 9.4T we aimed to test the hypothesis that neurometabolic changes are detectable very early in an established model of type C HE, offering insight into the primary events underpinning HE, before advanced liver disease confounds the findings. These early, previously unreported neurometabolic changes occurred as early as 2 to 4 weeks after bile-duct ligation, namely an increase in plasma ammonium and brain glutamine, a decrease in brain creatine and ascorbate together with behavioural and astrocyte morphology changes, and continued to progress throughout the 8-week course of the disease.

Topics: Ammonium Compounds; Animals; Ascorbic Acid; Astrocytes; Chronic Disease; Creatine; Disease Models, Animal; Glutamine; Hepatic Encephalopathy; Hippocampus; Male; Oxidative Stress; Proton Magnetic Resonance Spectroscopy; Rats; Rats, Wistar

Fluid resuscitation plays a prominent role in stabilizing trauma patients with hemorrhagic shock yet there remains uncertainty with regard to optimal administration time, volume, and fluid composition (e.g., whole blood, component, colloids) leading to complications such as trauma-induced coagulopathies (TIC), acidosis, and poor oxygen transport. Synthetic fluids in combination with antioxidants (e.g., vitamin C) may resolve some of these problems.. We applied quantitative mass spectrometry-based proteomics [liquid chromatography-mass spectrometry (LC-MS/MS)] to map the effects of fluid resuscitation and intravenous vitamin C (VitC) in a pig model of polytrauma (hemorrhagic shock, tissue injury, liver reperfusion, hypothermia, and comminuted bone fracture). The goal was to determine the effects of VitC on plasma protein expression, with respect to changes associated with coagulation and trauma-induced coagulopathy (TIC).. Longitudinal blood samples were drawn from nine male Sinclair pigs at baseline, 2 h post trauma, and 0.25, 2, and 4 h post fluid resuscitation with 500 mL hydroxyethyl starch. Pigs were treated intravenously (N = 3/treatment group) with saline, 50 mg VitC/kg (Lo-VitC), or 200 mg VitC/kg (Hi-VitC) during fluid resuscitation.. A total of 436 plasma proteins were quantified of which 136 changed following trauma and resuscitation; 34 were associated with coagulation, complement cascade, and glycolysis. Unexpectedly, Lo-VitC and Hi-VitC treatments stabilized ADAMTS13 levels by ~4-fold (P = .056) relative to saline and enhanced ADAMTS13/von Willebrand factor (VWF) cleavage efficiency based on LC-MS/MS evidence for the semitryptic VWF cleavage product (VWF. This study provides the first comprehensive map of trauma-induced changes to the plasma proteome, especially with respect to proteins driving the development of TIC.

Topics: Administration, Intravenous; Animals; Antioxidants; Ascorbic Acid; Biomarkers; Blood Coagulation; Blood Proteins; Chromatography, Liquid; Disease Models, Animal; Fluid Therapy; Male; Multiple Trauma; Proteomics; Resuscitation; Shock, Hemorrhagic; Sus scrofa; Tandem Mass Spectrometry; Time Factors

The aim of this work was evaluate the antioxidant effect of ascorbyl laurate (ASC12) based nanostructures applied topically to the cornea of ocular normotensive and hypertensive rabbits. The ASC12 was chosen for its capacity to form liquid lyotropic crystal and keeps its free radical trapping power.. The hypertension model was performed in six rabbits and was obtained by the application of intracameral injections of alpha-chymotrypsin in the right eye. A single 50 ml dose of ascorbyl laurate coagel 2% w/v (COA-ASC12) was applied topically to the cornea of six normotensive and six hypertensive rabbits. The aqueous humor samples were obtained before and after instillation of COA-ASC12 at different times (2 h and 4 h). Antioxidant capacity was determined via the reduction reaction with iron and tripyridyltriazine (FRAP) and the total proteins were measured using the Bradford reagent.. The kinetic antioxidant capacity in the aqueous humor of normotensive and hypertensive rabbits showed a maxim increment at 4 h instillation. Also, the antioxidant capacity in the aqueous humor of hypertensive rabbits was ten times lower than in normotensive rabbits.. This type of nanostructures has the potential to significantly improve the topical formulation for the prophylaxis and treatment of several eye diseases.

Topics: Administration, Ophthalmic; Animals; Antioxidants; Aqueous Humor; Ascorbic Acid; Disease Models, Animal; Gels; Intraocular Pressure; Nanostructures; Ocular Hypertension; Rabbits

The pathological impact of chronic cerebral hypoperfusion (CCH) on Alzheimer's disease (AD) is still poorly understood. In the present study, we investigated the role of CCH on an AD mouse model in phosphorylated tau and α-synuclein pathology, neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of a new antioxidant Twendee X (TwX).. APP23 mice were implanted to bilateral common carotid arteries stenosis with ameroid constrictors to gradually decrease the cerebral blood flow. The effects of the administration of TwX were evaluated by immunohistochemical analysis and Immunofluorescent histochemistry.. Our findings indicate that administration of a new antioxidative mixture TwX substantially reduced the above neuropathologic abnormalities, suggesting a potential therapeutic benefit of TwX for AD with CCH.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Antioxidants; Ascorbic Acid; Brain; Cerebrovascular Disorders; Cystine; Dietary Supplements; Disease Models, Animal; Female; Genetic Predisposition to Disease; Glutamine; Male; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neurovascular Coupling; Phenotype; Phosphorylation; tau Proteins

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple factors associated with its pathogenesis. Our strategy against AD involves design of multi-targeted 2-substituted-4,5-diphenyl-1H-imidazole analogues which can interact and inhibit AChE, thereby, increasing the synaptic availability of ACh, inhibit BuChE, relieve induced oxidative stress and confer a neuroprotective role. Molecular docking was employed to study interactions within the AChE active site. In silico ADME study was performed to estimate pharmacokinetic parameters. Based on computational studies, some analogues were synthesized and subjected to pharmacological evaluation involving antioxidant activity, toxicity and memory model studies in animals followed by detailed mechanistic in vitro cholinesterase inhibition study. Amongst the series, analogue 13 and 20 are the most promising multi-targeted candidates which can potentially increase memory, decrease free radical levels and protect neurons against cognitive deficit.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Electrophorus; Female; Horses; Imidazoles; Male; Maze Learning; Memory Disorders; Mice; Molecular Structure; Neuroprotective Agents; Structure-Activity Relationship

Boldine is an aporphine alkaloid which is best known for its antioxidant, anti-inflammatory and cytoprotective characteristics. It seems that all these activities are related to boldine ability to scavenge reactive free radicals. As indicated by several pieces of evidence, free radicals generation are involved in initiation and propagation of epilepsy.. In this study, we investigated the sub-chronic effects of boldine on intraperitoneal and intravenous pentylenetetrazole (PTZ) models and electroshock-induced seizure in mice. Mice in treatment groups received different doses of boldine (once in a day for 8 days, ip.) and control group received solvent. We also evaluated the role of antioxidant activity of boldine as a part of its anti-seizure activity.. The results demonstrated that sub-chronic administration of boldine increased time latencies to the onset of myoclonic and clonic seizure induced by intraperitoneal PTZ model and increased clonic seizure threshold in intravenous PTZ model. It also decreased tonic hind limb extension duration in the electroshock-induced seizure model. Co-administration of boldine with a non-effective dose of vitamin C induced the anticonvulsant activity of vitamin C. Superoxide dismutase (SOD) activity in the brain tissue of animals was increased following sub-chronic administration of boldine which all indicated antioxidant activity of boldine may be a part of its anticonvulsant activity.. The anticonvulsant effects of boldine in three different animal models of epilepsy have been indicated. We have also shown that the antioxidant role of boldine might be a part of its anticonvulsant effect.

Topics: Animals; Anticonvulsants; Antioxidants; Aporphines; Ascorbic Acid; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Male; Mice; Pentylenetetrazole; Seizures; Superoxide Dismutase; Time Factors

The treatment of drug-susceptible tuberculosis (TB) is long and cumbersome. Mismanagement of TB treatment can lead to the emergence of drug resistance in patients, so shortening the treatment duration could significantly improve TB chemotherapy and prevent the development of drug resistance. We previously discovered that high concentrations of vitamin C sterilize cultures of drug-susceptible and drug-resistant

Topics: Animals; Antitubercular Agents; Ascorbic Acid; Disease Models, Animal; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Female; Humans; Injections, Intraperitoneal; Isoniazid; Lung; Mice; Mice, Inbred CBA; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Oligodendrocyte-formed myelin sheaths play important roles in the neuronal functions in the central nervous system. In demyelinating diseases, such as Multiple Sclerosis, the myelin sheaths are damaged and the remyelinating process is somehow hindered. Restoration of the myelin sheaths requires the differentiation of the oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs). To discover small molecule compounds that might promote the OPC to OL differentiation, a high-throughput screening system is established and L-ascorbyl-2-phosphate (As-2P), a stable form of Vitamin C (Vc), is found to greatly enhance the OPC to OL differentiation. As-2P promotes gradual expression of OL lineage markers, including O4, CNPase and MBP, in a dose- and time-dependent manner. It also facilitates the formation of myelin sheaths in OPC-neuron co-culture. As-2P also promotes the repair of the myelin sheaths in vivo and provides significant therapeutic effect in a cuprizone-mediated demyelination animal model. Interestingly, As-2P's function in promoting OPC differentiation is not related to its antioxidant activity. And an intracellular rather than an extracellular mechanism might be involved. Considering the safe use of Vc as a dietary supplement for many years, it might also be used as an alternative medicine for CNS demyelinating diseases.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain; Cell Differentiation; Coculture Techniques; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Ganglia, Spinal; Mice; Mice, Inbred C57BL; Neurons; Neuroprotective Agents; Oligodendroglia; Remyelination; Time Factors

The purpose of this study was to establish a 2-stage model of urinary bladder carcinogenesis in male Sprague-Dawley rats to identify tumor promoters. In phase 1 of the study, rats ( n = 170) were administered 100 mg/kg of the tumor initiator, N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), twice weekly by oral gavage (po) for a period of 6 weeks. Phase 2 consisted of dividing rats into 4 groups ( n = 40 per group) and administering one of the following for 26 weeks to identify putative tumor promoters: (1) vehicle po, (2) 25 mg/kg/day rosiglitazone po, (3) 5% dietary sodium l-ascorbate, and (4) 3% dietary uracil. Rats were necropsied after 7.5 months, and urinary bladders were evaluated by histopathology. BBN/vehicle treatments induced the development of urothelial hyperplasia (83%) and papillomas (15%) but no transitional cell carcinomas (TCCs). Rosiglitazone increased the incidence and severity of papillomas (93%) and resulted in TCC in 10% of treated rats. Uracil was the most effective tumor promoter in our study and increased the incidence of papillomas (90%) and TCC (74%). Sodium ascorbate decreased the incidence of urothelial hyperplasia (63%) and did not increase the incidence of urothelial papillomas or TCC. These data confirm the capacity of our 2-stage model to identify urinary bladder tumor promoters.

Topics: Animals; Ascorbic Acid; Carcinogens; Carcinoma, Transitional Cell; Disease Models, Animal; Male; Rats; Rats, Sprague-Dawley; Rosiglitazone; Uracil; Urinary Bladder; Urinary Bladder Neoplasms

Some studies have demonstrated that ascorbic acid, similarly to ketamine, exhibits antidepressant-like effects mediated, at least in part, by modulation of the glutamatergic system. Despite the involvement of glutamatergic system in the pathophysiology of anxiety disorders, the ability of ascorbic acid and ketamine to elicit anxiolytic effects in animal models remains to be established. Therefore, this study investigated the effects of a single administration of ascorbic acid, ketamine or diazepam (positive control) in different animal models of anxiety. Mice were treated with ascorbic acid (1, 3 and 10 mg∕kg, p.o.), ketamine (1 and 10 mg∕kg, i.p.) or diazepam (2 mg∕kg, p.o) and their behavioral responses were assessed in the elevated plus maze, open field test (OFT), ligh∕dark preference test and marble burying test. Ascorbic acid increased total time spent in the open arms of elevated plus maze, increased total time in the center of the OFT, decreased rearing responses, increased the latency to grooming, decreased the rostral grooming, but did not affect body grooming. Furthermore, ascorbic acid increased the latency time and total time in light area in the ligh∕dark preference test, but did not affect the performance of mice in the marble burying test. Ketamine demonstrated an anxiolytic-like effect in elevated plus maze, OFT, and ligh∕dark preference test. Diazepam exhibited an anxiolytic-like effect in all the behavioral tests. Altogether, the results indicate the potential anxiolytic effect of ascorbic acid and ketamine, providing a possible new avenue for the management of anxiety-related disorders.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Ascorbic Acid; Behavior, Animal; Diazepam; Disease Models, Animal; Female; Ketamine; Mice

Vitamin E (vit. E) and vitamin C (vit. C) are antioxidants that inhibit nociception. The effect of these vitamins on oxidative-stress markers in the spinal cord of rats with chronic constriction injury (CCI) of the sciatic nerve is unknown. This study investigated the effect of intraperitoneal administration of vit. E (15 mg·kg-1·day-1) and vit. C (30 mg·kg-1·day-1), given alone or in combination, on spinal cord oxidative-stress markers in CCI rats. Adult male Wistar rats weighing 200-250 g were divided equally into the following groups: Naive (rats did not undergo surgical manipulation); Sham (rats in which all surgical procedures involved in CCI were used except the ligature), and CCI (rats in which four ligatures were tied loosely around the right common sciatic nerve), which received injections of vitamins or vehicle (saline containing 1% Tween 80) for 3 or 10 days (n=6/each group). The vitamins prevented the reduction in total thiol content and the increase in superoxide-anion generation that were found in vehicle-treated CCI rats. While nitric-oxide metabolites increased in vehicle-treated CCI rats 3 days after surgery, these metabolites did not show significant changes in vitamin-treated CCI rats. In all rats, total antioxidant capacity and hydrogen-peroxide levels did not change significantly. Lipid hydroperoxides increased 25% only in vehicle-treated CCI rats. These changes may contribute to vit. C- and vit. E-induced antinociception, because scavenging reactive oxygen species seems to help normalize the spinal cord oxidative status altered by pain.

Topics: alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; Biomarkers; Disease Models, Animal; Male; Oxidative Stress; Pain Measurement; Pain Threshold; Rats; Rats, Wistar; Sciatic Neuropathy; Spinal Cord

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Many factors have been shown to contribute to its pathogenesis including genetic and environmental factors. Ubiquitin C-terminal hydrolase L1 (UCHL1) is also known to be involved in the pathogenesis of PD. We herein modeled the study of UCHL1 in Drosophila melanogaster and investigated its functions in PD. The specific knockdown of the Drosophila ortholog of UCHL1 (dUCH) in dopaminergic neurons (DA neurons) led to the underdevelopment and/or degeneration of these neurons, specifically in DL1 DA neuron cluster in the larval brain lobe and PPM2, PPM3, PPL2ab, and VUM DA neuron clusters in the adult brain. These defects were followed by a shortage of dopamine in the brain, which subsequently resulted in locomotor dysfunction. The degeneration of DA neurons in dUCH knockdown adult brain, which occurred progressively and severely during the course of aging, mimics the epidemiology of PD. DA neuron and locomotor defects were rescued when dUCH knockdown flies were treated with vitamin C, a well-known antioxidant. These results suggest that dUCH knockdown fly is a promising model for studying the pathogenesis and epidemiology of PD as well as the screening of potential antioxidants for PD therapeutics.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Drosophila melanogaster; Drosophila Proteins; Gene Knockdown Techniques; Humans; Male; Oxidative Stress; Parkinson Disease; Ubiquitin Thiolesterase

Coagulopathy and inflammation induced by hemorrhagic shock and traumatic injury are associated with increased mortality and morbidity. Vitamin C (VitC) is an antioxidant with potential protective effects on the proinflammatory and procoagulant pathways. We hypothesized that high-dose VitC administered as a supplement to fluid resuscitation would attenuate inflammation, coagulation dysfunction, and end-organ tissue damage in a swine model of multiple injuries and hemorrhage.. Male Sinclair swine (n = 24; mean body weight, 27 kg) were anesthetized, intubated, mechanically ventilated, and instrumented for physiologic monitoring. Following stabilization, swine were subjected to shock/traumatic injury (hypothermia, liver ischemia and reperfusion, comminuted femur fracture, hemorrhagic hypotension), resuscitated with 500 mL of hydroxyethyl starch, and randomized to receive either intravenous normal saline (NS), low-dose VitC (50 mg/kg; LO), or high-dose VitC (200 mg/kg; HI). Hemodynamics, blood chemistry, hematology, and coagulation function (ROTEM) were monitored to 4 hours postresuscitation. Histological and molecular analyses were obtained for liver, kidney, and lung.. Compared with VitC animals, NS swine showed significant histological end-organ damage, elevated acute lung injury scores, and increased mRNA expression of tissue proinflammatory mediators (IL-1β, IL-8, TNFα), plasminogen activation inhibitor-1 and tissue factor. There were no statistically significant differences between treatment groups on mean arterial pressure or univariate measures of coagulation function; however, NS showed impaired multivariate clotting function at 4 hours.. Although correction of coagulation dysfunction was modest, intravenous high-dose VitC may mitigate the proinflammatory/procoagulant response that contributes to multiple organ failure following acute severe multiple injuries.. Prospective randomized controlled blinded trial study, Preclinical (animal-based).

Topics: Animals; Anti-Inflammatory Agents; Anticoagulants; Ascorbic Acid; Blood Coagulation Disorders; Disease Models, Animal; Inflammation; Male; Multiple Trauma; Random Allocation; Resuscitation; Shock, Hemorrhagic; Swine

Zearalenone (ZEN), one of the more virulent mycotoxins occurred in various cereals and feed during recent decades and made serious health hazards to plants, animals and humans. Vitamin C (Vc) has been shown to be an effective antidote to zearalenone. In this paper, the effects of diets containing zearalenone on the growth performance, genital organ and immunoglobulin of weaning piglets and the toxicity alleviation of vitamin C were studied. Piglets were weaned at 21 days of age and 32 healthy female hybrid weaning piglets (Duroc × Landrace × Large white) with a mean weight of 12.27 ± 0.30 kg were randomly selected. The thirty-two female weaning piglets were divided into four treatment groups according to body weight: control; basal diet + vitamin C (150 mg/kg); basal diet + 1.0 mg/kg ZEN; basal diet + 1 mg/kg ZEN+vitamin C (150 mg/kg). There were eight replicates in each group. The test period was twenty-eight days. The results demonstrated that dietary zearalenone could significantly increase the length, width and area of vulva (P < 0.05), the genital organ coefficient (P < 0.05), the level of IgA, IgG and IgM (P < 0.05), the level of BUN, CRE, AST and TBIL (P < 0.05), and significantly decrease the level of E2, PROG, LH and FSH (P < 0.05). However, the addition of 150 mg/kg vitamin C to dietary zearalenone prevented deformities in the vulva, decrease in immune response capacity, changes in serum biochemical indicators and disorders in hormones level of the piglets that received the diet containing only zearalenone. In conclusion, feeding ZEN of 1.0 mg/kg can result in a deleterious effect on piglets, which was totally or partly ameliorated by dietary supplementation of vitamin C at concentrations about 150 mg/kg diet. This study systematically investigated the inhibition mechanism of vitamin C on ZEN-induced reproductive toxicity, immunotoxicity and hematological toxicity of piglets, and which provided new ideas for reducing the harm of mycotoxins to the animals through means of nutrition regulation.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Ascorbic Acid; Aspartate Aminotransferases; Biomarkers; Cholesterol; Creatinine; Disease Models, Animal; Estradiol; Female; Follicle Stimulating Hormone; Immunoglobulins; Kidney; Luteinizing Hormone; Progesterone; Reproduction; Serum Albumin; Swine; Triglycerides; Weaning; Zearalenone

Trypanosoma cruzi infection stimulates inflammatory mediators which cause oxidative stress, and the use of antioxidants can minimize the sequelae of Chagas disease. In order to evaluate the efficacy of vitamin C in minimizing oxidative damage in Chagas disease, we orally administered ascorbic acid to Swiss mice infected with 5.0 × 10

Topics: Acute Disease; Animals; Antioxidants; Ascorbic Acid; Bilirubin; Chagas Disease; Chronic Disease; Disease Models, Animal; Inflammation; Iron; Male; Mice; Nitric Oxide; Oxidative Stress; Parasitemia; Peroxynitrous Acid; Trypanosoma cruzi

This study sought to determine the effects of oral vitamin C (VitC) and mesenchymal stem cells (MSCs) on wound healing in diabetic nude mice.. Bilateral, full-skin thickness wounds were created as an in vivo wound model in BALB/C diabetic nude mice. The mice were separated into five groups: control (CON); diabetes mellitus (DM, from a streptozotocin injection); DM treated with MSCs (DM+MSCs); DM treated with VitC (DM+VitC), and DM treated with MSCs and VitC (DM+MSCs+VitC). After wounding, daily oral-feeding of high dose VitC (1.5g/l) was administered, and a single dose of MSCs (1x10. At day seven, the lowest rate of wound healing, in terms of percentage of wound closure, appeared in the DM group, as compared with the CON and all other treatment groups (mean percentage of wound closure and standard deviation), CON=75.94±7.09%; DM=55.65±9.59%; DM+MSCs=78.57±6.46%; DM+VitC=77.52±3.31%; and DM+MSCs+VitC=84.61±2.87%, p≤0.05. At day 14 post-wounding, the combination of oral high dose VitC and MSCs accelerated wound healing (91.44±3.19%, p≤0.05). In addition, the highest capillary density in DM+MSCs+VitC was obtained at 14 days post-wounding (29.49±7.30%, p≤0.05).. The findings of this study highlight the possibility of using oral high dose VitC in adjunct to MSCs to increase angiogenesis and accelerate diabetic wound healing in an animal model. This novel therapeutic approach should be studied further to test if it could be a useful adjunct of existing therapies to prevent infection and amputation in patients with diabetes.

Topics: Animals; Ascorbic Acid; Diabetes Mellitus, Experimental; Disease Models, Animal; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Wound Healing; Wounds and Injuries

Infection-induced endometritis is associated with infertility. The outcome with oral antibiotics remains poor. This study therefore investigates the role of ascorbic acid in resolving endometritis.. Animals with established oestrus cycles were inoculated with Escherichia coli. Two days post-inoculation, the animals were administered ascorbic acid (10, 100 and 1000 mg/kg) and amoxicillin (500 mg/kg) for 5 days. Other groups included water only and E. coli inoculated with no treatment. Body temperatures, weights and vaginal cytology were examined. On the sixth day, after anaesthesia, blood samples were obtained for haematological analysis. Uterine organs were weighed, ex-vivo functionality analysed and histopathological analysis performed.. Ascorbic acid (AA) (100 and 1000 mg/kg) regularized the cycle of the endometritic animals comparable to amoxicillin. AA (1000 mg/kg) and amoxicillin, significantly decreased (P < .05) the endometritis-induced increase in uterine weights, restored the endometrial architecture and significantly (P < .05) normalized uterine contractions to control values. Improved haematological profiles were additionally observed on treatment with ascorbic acid (100 and 1000 mg/kg).. AA compared favourably with amoxicillin in endometritis management, suggesting that AA can be used in the management of infection-induced endometritis, normal cycling and normal uterine function.

Topics: Amoxicillin; Animals; Anti-Bacterial Agents; Ascorbic Acid; Disease Models, Animal; Endometritis; Endometrium; Escherichia coli; Escherichia coli Infections; Female; Hematologic Tests; Humans; Mice; Mice, Inbred Strains; Uterus

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Fenitrothion; Lipid Peroxidation; Liver; Male; Oxidative Stress; Rats, Wistar; Sodium Selenite

The current study highlighted several changes in measures of oxidative stress and antioxidant status that take place in the mouse brain over the course of 24 h post-mortem. Ascorbic acid (vitamin C) and glutathione both decreased significantly in cortex in as little as 2 h and malondialdehyde levels increased. Further change from baseline was observed up to 24 h, including carbonyl and sulfhydryl formation. The greatest changes were observed in brains that began with low ascorbic acid levels (gulo

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Animals; Antioxidants; Ascorbic Acid; Autopsy; Biomarkers; Brain; Case-Control Studies; Disease Models, Animal; Female; Glutathione; Humans; L-Gulonolactone Oxidase; Male; Malondialdehyde; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Oxidative Stress; Postmortem Changes; Protein Carbonylation; Sulfhydryl Compounds; Time Factors

Drugs currently used for the treatment of Chagas' disease, nifurtimox and benznidazole, have a limited effectiveness and toxic side effects. With the aim of finding new therapeutic approaches, in vitro and in vivo anti-Trypanosoma cruzi activity of vitamin C alone and combined with benznidazole were investigated.. The trypanocidal activity on epimastigote and trypomastigote forms was evaluated by counting parasites in a Neubauer chamber after treatment with the compounds. For the amastigote stage, transgenic parasites expressing β-galactosidase were used and quantified by measuring the β-galactosidase activity. The cytotoxicity of compounds was tested on Vero cells. The redox state of the parasite was evaluated by determining the reduced thiol levels (spectrophotometric assay) and the intracellular oxidative state (by flow cytometry). The in vivo trypanocidal activity was evaluated on a murine model of Chagas' disease. The trypanocidal activity of vitamin C and benznidazole was similar for the three parasite forms. When combining both drugs, vitamin C did not induce any change in the antiparasitic activity of benznidazole on trypomastigotes; however, on mammal cells, vitamin C diminished the cytotoxicity degree of benznidazole. Two mechanisms of action may be postulated for vitamin C: a lethal pro-oxidant effect on the parasite when used alone, and an antioxidant effect, when combined with benznidazole. A similar behavior was observed on infected mice; i.e., parasite counts in infected mice treated with vitamin C were lower than that of the control group. Animals treated with benznidazole presented lower parasitemia levels, as compared with those treated with vitamin C alone. Again, vitamin C did not cause any effect on the antiparasitic profile of benznidazole. Even though a combined treatment was employed, the antioxidant effect of vitamin C on the host was evidenced; a 100% survival was observed and the weight loss occurring during the acute phase of the infection was reduced.. Based on these results, the combination of vitamin C with benznidazole could be considered as an alternative treatment for Chagas' disease. These preliminary results encourage further research to improve the treatment of Chagas' disease.

Topics: Animals; Ascorbic Acid; Body Weight; Chagas Disease; Chlorocebus aethiops; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Female; Mice, Inbred C3H; Nitroimidazoles; Parasite Load; Parasitemia; Survival Analysis; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi; Vero Cells

Identification of renin-angiotensin system in the interplay of hypertension and neurodegeneration has paved the way for the repurposing of antihypertensive drugs against Parkinsonism. Losartan carboxylic acid (LCA), the potent AT1 blocker metabolite of losartan, suffers from poor bioavailability and brain access. Since ascorbate transporters have earlier shown enough flexibility as carriers, we have conjugated losartan carboxylic acid to ascorbic acid with the aim of achieving higher oral/brain availability. Ester of LCA and ascorbic acid (FED) was developed keeping in view the substrate specificity of ascorbate transporters. Oral/brain bioavailability was assessed using in vivo pharmacokinetic model. Effect on central nervous system (CNS) and protection against Parkinsonism was evaluated using in vivo models. FED enhanced bioavailability of LCA. The higher brain availability of LCA enabled CNS protection as evident from the increase in locomotor activity, improved motor coordination, and protection against drug-induced catatonia. In conclusion, FED offers an approach to repurpose LCA against Parkinsonism. This can encourage further investigation to simultaneously address hypertension and neurodegeneration.

Topics: Administration, Oral; Angiotensin II Type 1 Receptor Blockers; Animals; Ascorbic Acid; Behavior, Animal; Biological Availability; Brain; Disease Models, Animal; Drug Evaluation, Preclinical; Haloperidol; Humans; Losartan; Male; Parkinsonian Disorders; Rats; Rats, Wistar; Renin-Angiotensin System

We investigated the role of oxidative stress and the inflammasome in trauma-induced axon degeneration and vision loss using a mouse model. The left eyes of male mice were exposed to over-pressure air waves. Wild-type C57Bl/6 mice were fed normal, high-vitamin-E (VitE), ketogenic or ketogenic-control diets. Mice lacking the ability to produce vitamin C (VitC) were maintained on a low-VitC diet. Visual evoked potentials (VEPs) and retinal superoxide levels were measured in vivo. Tissue was collected for biochemical and histological analysis. Injury increased retinal superoxide, decreased SOD2, and increased cleaved caspase-1, IL-1α, IL-1β, and IL-18 levels. Low-VitC exacerbated the changes and the high-VitE diet mitigated them, suggesting that oxidative stress led to the increase in IL-1α and activation of the inflammasome. The injury caused loss of nearly 50% of optic nerve axons at 2 weeks and astrocyte hypertrophy in mice on normal diet, both of which were prevented by the high-VitE diet. The VEP amplitude was decreased after injury in both control-diet and low-VitC mice, but not in the high-VitE-diet mice. The ketogenic diet also prevented the increase in superoxide levels and IL-1α, but had no effect on IL-1β. Despite this, the ketogenic diet preserved optic nerve axons, prevented astrocyte hypertrophy, and preserved the VEP amplitude. These data suggest that oxidative stress induces priming and activation of the inflammasome pathway after neurotrauma of the visual system. Further, blocking the activation of the inflammasome pathway may be an effective post-injury intervention.

Topics: Animals; Antioxidants; Ascorbic Acid; Axons; Diet, Ketogenic; Disease Models, Animal; Evoked Potentials, Visual; Inflammasomes; Inflammation; Interleukin-1alpha; Interleukin-1beta; Male; Mice; Mice, Inbred C57BL; Optic Nerve Injuries; Oxidative Stress; Reactive Oxygen Species; Retina; Superoxides; Vitamin E

Neuroinflammation is believed to be one of the primary causes of cognitive impairment. Previous studies showed that the antioxidant vitamin C (Vit C) performs many beneficial functions such as immunostimulant and anti-inflammatory actions, but its role in inflammatory cognitive impairment is unclear. In the current study, we investigated the effect and possible mechanism of action of Vit C in lipopolysaccharide (LPS)-induced cognitive impairment. Intracerebroventricular LPS-induced memory impairment was used as the model for neuroinflammatory cognitive dysfunction. Vit C was administered by intracerebroventricular microinjection 30 min prior to LPS exposure. It was found that Vit C significantly protected animals from LPS-induced memory impairment as evidenced by improved performance in the Morris water maze and novel object recognition tests without changes in spontaneous locomotor activity. Vit C pretreatment inhibited the activation of microglia and the production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Furthermore, Vit C pretreatment markedly decreased the malondialdehyde (MDA) level, increased superoxide dismutase (SOD) activity, and modulated the Bax/Bcl-2 ratio and p-p38 MAPK activation in the hippocampus of LPS-treated mice. Together, these results suggest that vitamin C pretreatment could protect mice from LPS-induced cognitive impairment, possibly through the modulation of oxidative stress and inflammatory responses.

Topics: Animals; Anti-Inflammatory Agents; Ascorbic Acid; Cognitive Dysfunction; Cytokines; Disease Models, Animal; Humans; Lipopolysaccharides; Male; Malondialdehyde; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Neurogenic Inflammation; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Signal Transduction

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Female; Glaucoma; Humans; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors; Rats; Recombinant Proteins; rho-Associated Kinases; Structure-Activity Relationship

Contrast induced nephropathy (CIN) is the commonest cause of iatrogenic renal injury and its incidence has increased with the advent of complex endovascular procedures. Evidence suggests that ascorbic acid (AA) has a nephroprotective effect in percutaneous coronary interventions when contrast media are used. A variety of biomarkers (NGAL, NGAL:creatinine, mononuclear cell infiltration, apoptosis and RBP-4) in both the urine and kidney were assayed using a mouse model of CIN in order to determine whether AA can reduce the incidence and/or severity of renal injury.. Twenty-four BALB/c mice were divided into 4 groups. Three groups were exposed to high doses of contrast media (omnipaque) in a well-established model of CIN, and then treated with low or high dose AA or placebo (saline). CIN severity was determined by measurement of urinary neutrophil gelatinase-associated lipocalin (NGAL):creatinine at specific time intervals. Histological analysis was performed to determine the level of mononuclear inflammatory infiltration as well as immunohistochemistry to determine apoptosis in the glomeruli by staining for activated caspase-3 and DNA nicking (TUNEL assays). Reverse transcriptase PCR (rtPCR) of mRNA transcripts prepared from mRNA extracted from mouse kidneys was also performed for both lipocalin-2 (Lcn2) encoding NGAL and retinol binding protein-6 (RBP4) genes. NGAL protein expression was also confirmed by ELISA analysis of kidney lysates.. Urinary NGAL:creatinine ratio was significantly lower at 48 h with a 44% and 62% (204.3μg/mmol versus 533.6μg/mmol, p = 0.049) reduction in the low and high dose AA groups, respectively. The reduced urinary NGAL:creatinine ratio remained low throughout the time period assessed (up to 96 h) in the high dose AA group. In support of the urinary analysis ELISA analysis of NGAL in kidney lysates also showed a 57% reduction (12,576 ng/ml versus 29,393 ng/ml) reduction in the low dose AA group. Immunohistochemistry for apoptosis demonstrated decreased TUNEL and caspase-3 expression in both low and high dose AA groups.. Ascorbic acid reduced the frequency and severity of renal injury in this murine model of CIN. Further work is required to establish whether AA can reduce the incidence of CIN in humans undergoing endovascular procedures.

Topics: Acute Kidney Injury; Animals; Antioxidants; Apoptosis; Ascorbic Acid; Caspase 3; Contrast Media; Creatinine; Disease Models, Animal; Endovascular Procedures; Immunohistochemistry; In Situ Nick-End Labeling; Iohexol; Kidney; Lipocalin-2; Mice; Mice, Inbred BALB C; Retinol-Binding Proteins, Plasma

A number of neurological disorders such as epidural hematoma can cause compression of cerebral cortex. We here tested the hypothesis that sustained compression of primary somatosensory cortex may affect stellate neurons and thalamocortical afferent (TCA) fibers. A rat model with barrel cortex subjected to bead epidural compression was used. Golgi-Cox staining analyses showed the shrinkage of dendritic arbors and the stripping of dendritic spines of stellate neurons for at least 3 months post-lesion. Anterograde tracing analyses exhibited a progressive decline of TCA fiber density in barrel field for 6 months post-lesion. Due to the abrupt decrease of TCA fiber density at 3 days after compression, we further used electron microscopy to investigate the ultrastructure of TCA fibers at this time. Some TCA fiber terminal profiles with dissolved or darkened mitochondria and fewer synaptic vesicles were distorted and broken. Furthermore, the disruption of mitochondria and myelin sheath was observed in some myelinated TCA fibers. In addition, expressions of oxidative markers 3-nitrotyrosine and 4-hydroxynonenal were elevated in barrel field post-lesion. Treatment of antioxidant ascorbic acid or apocynin was able to reverse the increase of oxidative stress and the decline of TCA fiber density, rather than the shrinkage of dendrites and the stripping of dendritic spines of stellate neurons post-lesion. Together, these results indicate that sustained epidural compression of primary somatosensory cortex affects the TCA fibers and the dendrites of stellate neurons for a prolonged period. In addition, oxidative stress is responsible for the reduction of TCA fiber density in barrels rather than the shrinkage of dendrites and the stripping of dendritic spines of stellate neurons.

Topics: Acetophenones; Afferent Pathways; Aldehydes; Animals; Antioxidants; Ascorbic Acid; Biotin; Brain Injuries; Dendrites; Dextrans; Disease Models, Animal; Electron Transport Complex IV; Epidural Space; Functional Laterality; Male; Neurons; Oxidative Stress; Rats; Somatosensory Cortex; Thalamus; Time Factors; Tyrosine

Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) can simultaneously measure hundreds of biomolecules directly from tissue. Using different sample preparation strategies, proteins and metabolites have been profiled to study the molecular changes in a 3×Tg mouse model of Alzheimer's disease. In comparison with wild-type (WT) control mice MALDI-MSI revealed Alzheimer's disease-specific protein profiles, highlighting dramatic reductions of a protein with m/z 7560, which was assigned to neurogranin and validated by immunohistochemistry. The analysis also revealed substantial metabolite changes, especially in metabolites related to the purine metabolic pathway, with a shift towards an increase in hypoxanthine/xanthine/uric acid in the 3×Tg AD mice accompanied by a decrease in AMP and adenine. Interestingly these changes were also associated with a decrease in ascorbic acid, consistent with oxidative stress. Furthermore, the metabolite N-arachidonyl taurine was increased in the diseased mouse brain sections, being highly abundant in the hippocampus. Overall, we describe an interesting shift towards pro-inflammatory molecules (uric acid) in the purinergic pathway associated with a decrease in anti-oxidant level (ascorbic acid). Together, these observations fit well with the increased oxidative stress and neuroinflammation commonly observed in AD. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Ascorbic Acid; Disease Models, Animal; Hippocampus; Male; Mice; Mice, Knockout; Mice, Transgenic; Neurogranin; Oxidative Stress; Purines; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Uric Acid

This study was to determine the impact of maternal exposure to di-n-butyl phthalate (DBP) on renal development and fibrosis in adult offspring. Pregnant rats received DBP at a dose of 850 mg/kg BW/day by oral perfusion during gestational days 14-18. In DBP exposed newborn offspring, gross observation and histopathological examination revealed the dysplasia of kidney. The expression of genes related to renal development was also changed. In DBP exposed adult offspring, histopathological examination and Masson's trichrome staining revealed the pathological changes of renal fibrosis. Furthermore, higher expression levels of transforming growth factor- β (TGF-β) and alpha-smooth muscle actin (α-SMA) were also detected. In vitro studies reveal that DBP promoted the activation of NRK49F cells and G2/M arrest in NRK52E cells at a sublethal dose. The effect of DBP on these cell lines was linked to the generation of oxidative stress. In addition, DBP induced oxidative stress in both renal fibroblasts and tubular epithelial cells, whereas vitamin C ameliorated the changes caused by DBP. In conclusion, our results showed that prenatal exposure to DBP may generate oxidative stress in both renal fibroblasts and tubular epithelial cells, leading to kidney dysplasia and renal fibrosis.

Topics: Animals; Apoptosis; Ascorbic Acid; Cell Proliferation; Dibutyl Phthalate; Disease Models, Animal; Endocrine Disruptors; Female; Fibrosis; G2 Phase Cell Cycle Checkpoints; Kidney Diseases; Maternal Exposure; Oxidative Stress; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Transforming Growth Factor beta

Nonalcoholic fatty liver disease (NAFLD) has become highly prevalent, now considered the most common liver disease in the western world. Approximately one-third of patients with NASH develop non-alchoholic steatohepatitis (NASH), histologically defined by lobular and portal inflammation, and accompanied by marked oxidative stress. Patients with NASH are at increased risk for cirrhosis and hepatocellular carcinoma, and diagnosis currently requires invasive biopsy. In animal models of NASH, particularly the methionine-choline deficient (MCD) model, profound changes are seen in redox enzymes and key intracellular antioxidants. To study antioxidant status in NASH non-invasively, we applied the redox probe hyperpolarized [1-

Topics: Animals; Ascorbic Acid; Carbon-13 Magnetic Resonance Spectroscopy; Choline Deficiency; Dehydroascorbic Acid; Diet; Disease Models, Animal; Lipid Metabolism; Liver; Magnetic Resonance Imaging; Male; Methionine; Mice; Non-alcoholic Fatty Liver Disease; Oxidative Stress

Three-dimensional cultured clumps of a mesenchymal stem cell (MSC)/extracellular matrix (ECM) complex (C-MSC) consists of cells and self-produced ECM. C-MSC can regulate the cellular function in vitro and induce successful bone regeneration using ECM as a cell scaffold. Potentiating the immunomodulatory capacity of C-MSCs, which can ameliorate the allo-specific immune response, may be helpful in developing beneficial "off-the-shelf" cell therapy for tissue regeneration. It is well reported that interferon (IFN)-γ stimulates the immunosuppressive properties of MSC via upregulation of the immunomodulatory enzyme IDO. Therefore, the aim of this study was to investigate the effect of IFN-γ on the immunomodulatory capacity of C-MSC in vitro and to test the bone regenerative activity of C-MSC or IFN-γ-pretreated C-MSC (C-MSCγ) xenografts in a mice calvarial defect model.. IFN-γ stimulated IDO expression in C-MSC. C-MSCγ, but not C-MSC, attenuated CD3/CD28-induced T cell proliferation and its suppressive effect was reversed by an IDO inhibitor. C-MSCγ showed upregulation of HLA-DR expression, but its co-stimulatory molecule, CD86, was not detected. Xenotransplantation of C-MSCγ into immunocompetent mice calvarial defect induced bone regeneration, whereas C-MSC xenograft failed and induced T cell infiltration in the grafted area. On the other hand, both C-MSC and C-MSCγ xenotransplantation into immunodeficient mice caused bone regeneration.. Xenotransplantation of C-MSCγ, which exerts immunomodulatory properties via the upregulation of IDO activity in vitro, may attenuate xenoreactive host immune response, and thereby induce bone regeneration in mice. Accordingly, C-MSCγ may constitute a promising novel allograft cell therapy for bone regeneration.

Topics: Animals; Ascorbic Acid; Bone Marrow Cells; Bone Regeneration; Cell Proliferation; Cells, Cultured; Disease Models, Animal; HLA-DR Antigens; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Interferon-gamma; Leukocytes, Mononuclear; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Skull; T-Lymphocytes; Transplantation, Heterologous

Senescence marker protein-30 (SMP30) decreases androgen-independently with aging and is a lactone-hydrolyzing enzyme gluconolactonase (GNL) that is involved in vitamin C biosynthesis. In the present study, bone properties of SMP30/GNL knockout (KO) mice with deficiency in vitamin C synthesis were investigated to reveal the effects of SMP30/GNL and exogenous vitamin C supplementation on bone formation. Mineral content (BMC) and mineral density (BMD) of the mandible and femur of SMP30/GNL KO and wild-type mice at 2 and 3 months of age with or without vitamin C supplementation were measured by dual-energy X-ray absorptiometry. Body and bone weight of both age groups decreased and became significantly lower than those of wild-type mice. The bones of SMP30/GNL KO mice were rough and porous, with BMC and BMD significantly below wild-type. Oral supplementation with vitamin C eliminated differences in body weight, bone weight, BMC, and BMD between SMP30/GNL KO and wild-type mice at each age. These results indicate that bone degeneration in SMP30/GNL KO mice was caused by lack of vitamin C, and that this mouse strain is an appropriate model for bone metabolism in humans, which have no ability to synthesize vitamin C.

Topics: Absorptiometry, Photon; Aging; Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Body Weight; Bone Density; Bone Diseases, Metabolic; Calcium-Binding Proteins; Carboxylic Ester Hydrolases; Dietary Supplements; Disease Models, Animal; Female; Femur; Intracellular Signaling Peptides and Proteins; Male; Mandible; Mice, Inbred C57BL; Mice, Knockout; Osteoporosis

Peripheral nerve myelination involves rapid production of tightly bound lipid layers requiring cholesterol biosynthesis and myelin protein expression, but also a collagen-containing extracellular matrix providing mechanical stability. In previous studies, we showed a function of ascorbic acid in peripheral nerve myelination and extracellular matrix formation in adult mice. Here, we sought the mechanism of action of ascorbic acid in peripheral nerve myelination using different paradigms of myelination in vivo and in vitro. We found impaired myelination and reduced collagen expression in Sodium-dependent Vitamin C Transporter 2 heterozygous mice (SVCT2

Topics: Animals; Ascorbic Acid; Cells, Cultured; Collagen; Demethylation; Disease Models, Animal; Female; Gait Disorders, Neurologic; Ganglia, Spinal; Male; Mice; Mice, Transgenic; Peripheral Nerve Injuries; Peripheral Nerves; Remyelination; RNA, Messenger; Rotarod Performance Test; Sensory Receptor Cells; Sodium-Coupled Vitamin C Transporters; Time Factors

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the brain and formation of α-synuclein-containing intracellular inclusions. Excess intraneuronal iron in the SNpc increases reactive oxygen species (ROS), which identifies removing iron as a possible therapeutic strategy. Desferrioxamine B (DFOB, 1) is an iron chelator produced by bacteria. Its high Fe(iii) affinity, water solubility and low chronic toxicity is useful in removing iron accumulated in plasma from patients with transfusion-dependent blood disorders. Here, lipophilic analogues of DFOB with increased potential to cross the blood-brain barrier (BBB) have been prepared by conjugating ancillary compounds onto the amine terminus. The ancillary compounds included the antioxidants rac-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (rac-trolox, rac-TLX (a truncated vitamin E variant)), R-TLX, S-TLX, methylated derivatives of 3-(6-hydroxy-2-methylchroman-2-yl)propionic acid (α-CEHC, γ-CEHC, δ-CEHC), or 4-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)benzoic acid (carboxylic acid derivative of edaravone, EDA). Compounds 2-8 could have dual function in attenuating ROS by chelating Fe(iii) and via the antioxidant ancillary group. A conjugate between DFOB and an ancillary unit without antioxidant properties (3,5-dimethyladamantane-1-carboxylic acid (AdA

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antioxidants; Ascorbic Acid; Benzothiazoles; Blood Proteins; Deferoxamine; Disease Models, Animal; Iron; Iron Chelating Agents; Mice; Nerve Degeneration; Neurons; Parkinson Disease; Sulfonic Acids

The Duchenne Muscular Dystrophy (DMD) is a genetic disorder characterized by the absence of dystrophin protein, causing severe myopathy from increases of oxidative stress. Injuries of intestinal muscle can compromise the myenteric plexus. This study aimed to evaluate the disorders occurred in the muscular layer and in the acetylcholinesterase myenteric neurons (ACHE-r) of ileum of mdx mice, and the effects of supplementation with ascorbic acid (AA) in both components. 30 male mice C57BL/10, and 30 male mice C57BL/10Mdx were separated according to the age and treatment (n=10/group): 30-days-old control group (C30); 30-days-old dystrophic group (D30); 60-days-old control group (C60); 60-days-old dystrophic group (D60); 60-days-old control group supplemented with AA (CS60); and 60-days-old dystrophic group supplemented with AA (DS60). The animals were euthanized and the ileum was collected and processed. Semi-serial sections were stained by Masson's trichrome, and acetylcholinesterase histochemical technique in whole-mounts preparations to identify the myenteric neurons. The muscular layer thickness and the area of smooth muscle of ileum were lower in dystrophic groups, especially in D30 group. The DS60 group showed the muscular layer thickness similar to C60. The density of ACHE-r neurons of myenteric plexus of ileum was lower in D30 animals; however, it was similar in animals of 60-days-old without treatment (C60 and D60) and, higher in DS60. The cell body profile area of ACHE-r neurons was similar in C30-D30 and C60-D60; however, it was higher in DS60. DMD caused damage to the ileum's musculature and myenteric plexus, and the AA prevented the ACHE-r neuronal loss.

Topics: Acetylcholinesterase; Animals; Antioxidants; Ascorbic Acid; Cell Count; Cell Nucleus; Cell Size; Cytoplasm; Disease Models, Animal; Ileum; Male; Mice, Inbred C57BL; Mice, Inbred mdx; Muscle, Smooth; Muscular Dystrophy, Duchenne; Myenteric Plexus; Neurons; Organ Size

The Pinus densiflora leaf has been traditionally used to treat mental health disorders as a traditional Chinese medicine. Here we examined the ethnopharmacological relevance of pine needle on memory impairment caused by stress.. To elucidate the possible modulatory actions of 30% ethanolic pine needle extract (PNE) on stress-induced hippocampal excitotoxicity, we adopted an acute restraint stress mouse model.. Mice were orally administered with PNE (25, 50, or 100mg/kg) or ascorbic acid (100mg/kg) for 9 days, and were then subjected to restraint stress (6h/day) for 3 days (from experimental day 7-9). To evaluate spatial cognitive and memory function, the Morris water maze was performed during experimental days 5-9.. Restraint stress induced the memory impairment (the prolonged escape latency and cumulative path-length, and reduced time spent in the target quadrant), and these effects were significantly prevented by PNE treatment. The levels of corticosterone and its receptor in the sera/hippocampus were increased by restraint stress, which was normalized by PNE treatment. Restraint stress elicited the hippocampal excitotoxicity, the inflammatory response and oxidative injury as demonstrated by the increased glutamate levels, altered levels of tumor necrosis factor (TNF)-α and imbalanced oxidant-antioxidant balance biomarkers. Two immunohistochemistry activities against glial fibrillary acidic protein (GFAP)-positive astrocytes and neuronal nuclei (NeuN)-positive neurons supported the finding of excitotoxicity especially in the cornu ammonis (CA)3 region of the hippocampus. Those alterations were notably attenuated by administration of PNE.. The above findings showed that PNE has pharmacological properties that modulate the hippocampal excitotoxicity-derived memory impairment under severe stress conditions.

Topics: Administration, Oral; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Hippocampus; Male; Maze Learning; Memory; Memory Disorders; Mice; Mice, Inbred C57BL; Oxidants; Pinus; Plant Extracts; Stress, Psychological

The incidence of accidental and intentional acid skin burns is rising. Current treatment strategies are mostly inadequate, leaving victims disfigured and without treatment options. Here, we have shown that transplantation of adipose-derived stem cells (ASCs) accelerates the process of acid burn wound-healing. Pre-conditioning of ASCs using ascorbic acid (AA) or hypoxic conditions provided additional benefit. While the wounds were ultimately healed in all mice, histological analysis revealed that, in non-transplanted animals, the number of hair follicles was reduced. Bioluminescent imaging (BLI) of transplanted ASCs revealed a gradual loss of transplanted cells, with a similar rate of cell death for each treatment group. The signal of fluorinated cells detected by a clinically applicable

Topics: Acids; Adipocytes; Animals; Ascorbic Acid; Burns, Chemical; Cell Hypoxia; Cell Survival; Cells, Cultured; Disease Models, Animal; Fluorine-19 Magnetic Resonance Imaging; Humans; Luminescent Measurements; Male; Mice; Multimodal Imaging; Skin Diseases; Stem Cell Transplantation; Treatment Outcome; Wound Healing

Diabetes mellitus and depression are the common comorbid disorders affecting humans worldwide. There is an unmet need to develop therapeutic strategies to treat both diabetes mellitus and comorbid depression. The present study evaluated the effectiveness of metformin and ascorbic acid against type 2 diabetes mellitus and comorbid depression in rats. Four groups of diabetic rats were orally administered with vehicle (1mL/kg), metformin (25mg/kg), ascorbic acid (25mg/kg), or combination of metformin (25mg/kg) and ascorbic acid (25mg/kg) for 11 consecutive days. Diabetes was induced by single-dose administration of streptozotocin (65mg/kg, i.p.) with nicotinamide (120mg/kg, i.p.). Comorbid depression was induced by five inescapable foot-shocks (2mA, 2ms duration) at 10s intervals on days 1, 5, 7, and 10. One group of healthy rats received only vehicles to serve as nondiabetic control group. On day 11, animals were sacrificed, and blood and brain samples were collected from each rat following forced swim test. Plasma glucose, insulin, and corticosterone levels were estimated in plasma. The levels of monoamines, proinflammatory cytokines, and oxidative stress were measured in prefrontal cortex. The combination therapy significantly reduced immobility period, glucose, and corticosterone levels relative to diabetes with comorbid depression group. Furthermore, the combination therapy increased the levels of insulin and monoamines, and caused a significant reductions in oxidative stress and proinflammatory cytokines. In conclusion, the present study revealed that metformin and ascorbic acid combination therapy could be a potential strategy to treat type 2 diabetes mellitus and comorbid depression.

Topics: Animals; Ascorbic Acid; Biogenic Monoamines; Blood Glucose; Comorbidity; Corticosterone; Cytokines; Depression; Depressive Disorder; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Therapy, Combination; Insulin; Male; Metformin; Oxidative Stress; Rats; Rats, Inbred Strains

Cultured neural stem/precursor cells (NSCs) are regarded as a potential systematic cell source to treat Parkinson's disease (PD). However, the therapeutic potential of these cultured NSCs is lost during culturing. Here, we show that treatment of vitamin C (VC) enhances generation of authentic midbrain-type dopamine (mDA) neurons with improved survival and functions from ventral midbrain (VM)-derived NSCs. VC acted by upregulating a series of mDA neuron-specific developmental and phenotype genes via removal of DNA methylation and repressive histone code (H3K9m3, H3K27m3) at associated gene promoter regions. Notably, the epigenetic changes induced by transient VC treatment were sustained long after VC withdrawal. Accordingly, transplantation of VC-treated NSCs resulted in improved behavioral restoration, along with enriched DA neuron engraftment, which faithfully expressed midbrain-specific markers in PD model rats. These results indicate that VC treatment to donor NSCs could be a simple, efficient, and safe therapeutic strategy for PD in the future.

Topics: Animals; Ascorbic Acid; Behavior, Animal; Biomarkers; Cell Differentiation; Cell Proliferation; Cell- and Tissue-Based Therapy; Cells, Cultured; Disease Models, Animal; Dopaminergic Neurons; Epigenesis, Genetic; Female; Gene Expression Regulation; Mesencephalon; Neural Stem Cells; Neurogenesis; Parkinson Disease; Phenotype; Presynaptic Terminals; Promoter Regions, Genetic; Rats; Stem Cell Transplantation

Antigen-specific regulatory T cells (Tregs) possess the potential to reduce excess immune responses in autoimmune diseases, allergy, rejection after organ transplantation and graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. Although in vitro-expanded antigen-specific induced Tregs (iTregs) have been considered to be a promising therapeutic agent against such excessive immune reactions, the instability of iTregs after transfer is a fundamental problem in their clinical application. In this study, we searched for the optimal way to generate stable iTregs for the prevention of the murine GVHD model, in which conventional iTregs are reported to be inefficient. Allo-antigen-specific iTregs were generated by co-culturing naive T cells with allogenic dendritic cells in the presence of TGF-β and retinoic acid. By examining various agents and genes, we found that vitamin C stabilized Foxp3 expression most effectively in adoptively transferred iTregs under a GVHD environment. Vitamin C treatment caused active DNA demethylation specifically on the conserved non-coding sequence 2 (CNS2) enhancer of the Foxp3 gene locus in allo-antigen-specific iTregs and reduced iTreg conversion into pathogenic exFoxp3 cells. Vitamin C-treated iTregs suppressed GVHD symptoms more efficiently than untreated iTregs. Vitamin C also facilitated induction of a FOXP3high iTreg population from human naive T cells, which was very stable even in the presence of IL-6 in vitro. The treatment of vitamin C for iTreg promises innovative clinical application for adoptive Treg immunotherapy.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Graft vs Host Disease; Humans; Immunotherapy, Adoptive; Isoantigens; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; T-Lymphocytes, Regulatory; Tretinoin

Chronic lymphocytic thyroiditis (CLT) is a common autoimmune disorder. The possible pathogenic role and mechanism of dibutyl phthalate (DBP) in CLT is still controversial. Experiments were conducted after 35-days of oral exposure to the three concentrations of DBP or saline, and three immunizations with thyroglobulin (TG). Healthy female Wistar rats were randomly divided into ten exposure groups (n = 8 each): (A) saline control, (B) 0.5 mg/kg/d DBP, (C) 5 mg/kg/d DBP, (D) 50 mg/kg/d DBP, (E) TG-immunized group, (F) TG- combined with 0.5 mg/kg/d DBP, (G) TG- combined with 5 mg/kg/d DBP, (H) TG- combined with 50 mg/kg/d DBP, (I) TG- combined with 50 mg/kg/d DBP plus 100 mg/kg/d vitamin C; (J) 100 mg/kg/d vitamin C. We showed that oral exposure DBP can aggravate CLT in rats. This deterioration was concomitant with increased thyroid auto antibodies, Th1/Th2 imbalance and Th17 immune response, activated pro-inflammatory and apoptosis pathways, and increased thyroid dysfunction in rats. Our results also suggested that DBP could promote oxidative damage. The study also found that vitamin C reduced the levels of oxidative stress and alleviated CLT. In short, the study showed that DBP exacerbated CLT through oxidative stress.

Topics: Administration, Oral; Animals; Antioxidants; Apoptosis; Ascorbic Acid; Autoantibodies; Dibutyl Phthalate; Disease Models, Animal; Disease Progression; Environmental Pollutants; Female; Hashimoto Disease; Oxidative Stress; Rats; Rats, Wistar; Thyroglobulin

Intrauterine adhesion (IUA) is a common uterine cavity disease which can be caused by mechanical damage that may eventually lead to infertility and pregnancy abnormalities. Since the effect of therapeutic drugs appears disappointing, cell therapy has emerged as an alternative choice for endometrium regeneration. The aim of this study is to investigate whether the combination of hydrogel Pluronic F-127 (PF-127), Vitamin C (Vc), and a bone marrow stromal cell (BMSC) mixture could be a feasible strategy to improve the endometrial regeneration in a mechanical damage model of IUA in rats.. Firstly, PF-127 cytotoxicity and the effect of Vc was tested in vitro using the Annexin V/propidium iodide (PI) apoptosis test, cell count kit (CCK) growth test, and enzyme-linked immunosorbent assay (ELISA). For the establishment of the rat IUA model, a 2-mm transverse incision in the uterus was prepared at the upper end, and 1.5- to 2.0-cm endometrial damage was scraped. Rats were randomly assigned to five groups to investigate the combined strategy on IUA uterine regeneration: a sham group, an IUA control group, an IUA BMSC encapsulated in PF-127 plus Vc group, an IUA BMSC plus Vc group, and an IUA PF-127 plus Vc group. A cell mixture was injected into the uterine horn while making the IUA model. Eight weeks after cell transplantation, the rats were sacrificed and the uterine was dissected for analysis. Endometrial thickness, gland number, fibrosis area, and the expression of marker proteins for endometrial membrane were examined by hematoxylin and eosin staining, Masson's staining, and immunohistochemistry.. Vc promoted the survival and health of PF-127-encapsulated BMSCs in vitro. When this combination was transplanted in vivo, the endometrium showed better restoration as the endometrium membrane became thicker and had more glands and less fibrosis areas. The expression of cytokeratin, von Willebrand Factor (vWF), was also restored. The proinflammatory cytokine interleukin-1β (IL-1β) was significantly lower compared with the control group.. Vc alleviates the cytotoxic effect of PF-127 and promotes cell survival and growth in rat BMSC encapsulation. Thus, a cell therapy strategy containing biomaterial scaffold, BMSCs and the modulatory factor Vc promotes the restoration of damaged IUA endometrium.

Topics: Animals; Ascorbic Acid; Biomarkers; Cells, Immobilized; Disease Models, Animal; Endometrium; Female; Gene Expression; Humans; Hydrogels; Interleukin-1beta; Keratins; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Poloxamer; Pregnancy; Rats; Rats, Sprague-Dawley; Regeneration; Tissue Adhesions; von Willebrand Factor

To evaluate the preventive effect of ascorbic acid on sevoflurane-induced acute renal failure in an experimental rat model.. Twenty-four adult male Wistar rats were randomly distributed into three groups. Subjects were allocated into 3 groups: Group I received sevoflurane only, whereas Groups II and III had moderate (150 mg/kg) and high (300 mg/kg) doses of AA in addition to sevoflurane, respectively. Rhabdomyolysis and myohemoglobinuric ARF was formed by intramuscular administration of glycerol on the upper hind limb on the 15th minute of inhalation anesthesia. Biochemical parameters consisted of serum levels of blood urea nitrogen, creatinine, neutrophil gelatinase-associated lipocalin (NGAL), total antioxidant capacity (TAC), and protein carbonyl content. Histopathological variables were tubular necrosis, fibrin, and cast formation.. NGAL levels were significantly lower in Group III than Group II and Group I. On the other hand, TAC, PCO, urea and creatinine levels were notably higher in Group I compared with Groups II and III. There was a significant difference between 3 groups on frequencies of acute tubular necrosis (p=0.003), fibrin (p<0.001) and cast (p<0.001). Acute tubular necrosis and fibrin formation were more prominent in Group I. Casts were more common in Groups II and III.. The ascorbic acid serve as a prophylactic agent against renal damage in patients receiving sevoflurane anesthesia and higher doses were associated with more apparent protective effects.

Topics: Acute Kidney Injury; Anesthesia, General; Anesthetics, Inhalation; Animals; Ascorbic Acid; Biomarkers; Disease Models, Animal; Male; Methyl Ethers; Random Allocation; Rats; Rats, Wistar; Sevoflurane; Vitamins

Long-term d-galactose injection induces accelerated aging in experimental rodent models. The aim of this study was to determine the effects of dietary fructo-oligosaccharide (FO) on the brain β-amyloid (Aβ), amyloid-associated enzymes, cognitive function, and plasma antioxidant levels in d-galactose-treated Balb/c mice.. The subcutaneous (s.c.) injection and the dietary treatment were conducted simultaneously for 49 days. Mice (12 weeks of age) were divided into five groups (n = 14/group): control (s.c. saline, control diet) serving as a young control, DG (s.c. 1.2 g d-galactose/kg body weight, control diet), DG + LFO (2.5% w/w FO, low-dose FO diet), DG + HFO (5% w/w FO, high-dose FO diet), and DG + E (α-tocopherol 0.2% w/w, vitamin E diet) as an antioxidant reference group. Another group of older mice (64 weeks of age) without any injection served as a natural aging (NA) group.. The DG and NA groups had greater Aβ levels in the cortex, hippocampus, and the whole brain. High-dose FO, similar to α-tocopherol, attenuated the d-galactose-induced Aβ density in the cortex and hippocampus. In addition, FO attenuated the d-galactose-induced protein expression of Aβ and beta-site amyloid precursor cleaving enzyme of the whole brain in a dose-response manner. Either dose of FO supplementation, similar to α-tocopherol, attenuated the d-galactose-induced cognitive dysfunction. In addition, FO improved the plasma ascorbic acid level in a dose-response manner.. Dietary FO (2.5-5% w/w diet) could attenuate the development of Alzheimer's disease, which was likely to be associated with its systematic antioxidant effects.

Topics: alpha-Tocopherol; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Antioxidants; Ascorbic Acid; Brain; Cognition; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Galactose; Male; Mice; Mice, Inbred BALB C; Oligosaccharides

The neuroprotective effects of both garlic and ascorbic acid (AA) have been documented. In this study the effects of garlic and ascorbic acid on memory deficits and brain tissue oxidative damages induced by lead exposure was investigated.. The juvenile rats were divided and treated: (1) Control, (2) Lead (lead acetate in drinking water, 8 weeks), (3) Lead - Ascorbic Acid (Lead-AA), (4)  Lead - Garlic (100 mg/kg, daily, gavage) (Lead-Gar).. In Morris water maze (MWM), the escape latency and traveled path in the Lead group were significantly higher while, the time spent in the target quadrant (Q1) was lower than Control. Both Lead-Gar and Lead-AA groups spent more times in Q1than to lead group. There were no significant differences in swimming speed between the groups. In passive avoidance (PA) test, the time latency for entering the dark compartment by Lead group was lower than Control. Treatment of the animals by AA and garlic significantly increased the time latency. In Lead group, the total thiol concentration in brain tissues was significantly lower while, MDA was higher than Control. Treatment by both garlic and AA increased total thiol concentrations and decreased MDA. Both garlic and AA decreased the lead content of brain tissues.. It is suggested that treatment with garlic attenuates the learning and memory impairments due to lead exposure during juvenile rat growth which is comparable to AA. The possible mechanism may be due to its protective effects against brain tissues oxidative damage as well the lowering effects of brain lead content.

Topics: Age Factors; Animals; Antioxidants; Ascorbic Acid; Behavior, Animal; Brain; Disease Models, Animal; Escape Reaction; Garlic; Lead Poisoning, Nervous System, Childhood; Male; Malondialdehyde; Maze Learning; Memory; Memory Disorders; Neuroprotective Agents; Nootropic Agents; Organometallic Compounds; Oxidative Stress; Phytotherapy; Plant Extracts; Plant Roots; Plants, Medicinal; Rats, Wistar; Reaction Time; Sulfhydryl Compounds; Time Factors

The AKR1A1 protein is a member of the aldo-keto reductase superfamily that is responsible for the conversion of D-glucuronate to L-gulonate in the ascorbic acid (vitamin C) synthesis pathway. In a pCAG-eGFP transgenic mouse line that was produced by pronuclear microinjection, the integration of the transgene resulted in a 30-kb genomic DNA deletion, including the Akr1A1 gene, and thus caused the knockout (KO) of the Akr1A1 gene and targeting of the eGFP gene. The Akr1A1 KO mice (Akr1A1eGFP/eGFP) exhibited insufficient serum ascorbic acid levels, abnormal bone development and osteoporosis. Using micro-CT analysis, the results showed that the microarchitecture of the 12-week-old Akr1A1eGFP/eGFP mouse femur was shorter in length and exhibited less cortical bone thickness, enlargement of the bone marrow cavity and a complete loss of the trabecular bone in the distal femur. The femoral head and neck of the proximal femur also showed a severe loss of bone mass. Based on the decreased levels of serum osteocalcin and osteoblast activity in the Akr1A1eGFP/eGFP mice, the osteoporosis might be caused by impaired bone formation. In addition, administration of ascorbic acid to the Akr1A1eGFP/eGFP mice significantly prevented the condition of osteoporotic femurs and increased bone formation. Therefore, through ascorbic acid administration, the Akr1A1 KO mice exhibited controllable osteoporosis and may serve as a novel model for osteoporotic research.

Topics: Aldehyde Reductase; Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Disease Models, Animal; Female; Femur; Gene Knockout Techniques; Genetic Predisposition to Disease; Mice, Knockout; Osteoblasts; Osteocalcin; Osteogenesis; Osteoporosis; Phenotype; Time Factors; X-Ray Microtomography

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic relapsing disorders of the intestines. They cause severe problems, such as abdominal cramping, bloody diarrhea, and weight loss, in affected individuals. Unfortunately, there is no cure yet, and treatments only aim to alleviate symptoms. Current treatments include anti-inflammatory and immunosuppressive drugs that may cause severe side effects. This warrants the search for alternative treatment options, such as nutritional supplements, that do not cause side effects. Before their application in clinical studies, such compounds must be rigorously tested for effectiveness and security in animal models. A reliable experimental model is the dextran sulfate sodium (DSS) colitis model in mice, which reproduces many of the clinical signs of ulcerative colitis in humans. We recently applied this model to test the beneficial effects of a nutritional supplement containing vitamins C and E, L-arginine, and ω3-polyunsaturated fatty acids (PUFA). We analyzed various disease parameters and found that this supplement was able to ameliorate edema formation, tissue damage, leukocyte infiltration, oxidative stress, and the production of pro-inflammatory cytokines, leading to an overall improvement in the disease activity index. In this article, we explain in detail the correct application of nutritional supplements using the DSS colitis model in C57Bl/6 mice, as well as how disease parameters such as histology, oxidative stress, and inflammation are assessed. Analyzing the beneficial effects of different diet supplements may then eventually open new avenues for the development of alternative treatment strategies that alleviate IBD symptoms and/or that prolong the phases of remission without causing severe side effects.

Topics: Animals; Arginine; Ascorbic Acid; Colitis; Cytokines; Dextran Sulfate; Dietary Supplements; Disease Models, Animal; Fatty Acids, Omega-3; Intestines; Leukocytes; Mice; Mice, Inbred C57BL; Oxidative Stress; Reactive Oxygen Species; Tight Junctions

We aimed to evaluate the protective effects of Yuk-Mi-Jihwang-Tang (YJT) against acute restraint stress-induced brain oxidative damage. A water extract of YJT was prepared and subjected to high performance liquid chromatography - diode array detector-mass spectrometry (HPLC-DAD-MS). Thirty-six heads of C57BL/6J male mice (7 weeks) were divided into six groups (n = 6/group). The mice were orally administrated YJT (0, 50, 100, or 200 mg/kg) or vitamin C (100 mg/kg) for 5 consecutive days before 6 h of acute restraint stress. In the brain tissue, lipidperoxidation, antioxidant components, and pro-inflammatory cytokines were measured, and the serum corticosterone level was determined. Acute restraint stress-induced notably increased lipid peroxidation in brain tissues, and pretreatment with YJT showed a significant decreased the lipid peroxidation levels (p< 0.05). The levels of antioxidant components including total glutathione contents, activities of SOD and catalase were remarkably depleted by acute restraint stress, whereas these alterations were significantly restored by treatment with YJT (p< 0.05 or p< 0.01). The restraint stress markedly increased pro-inflammatory cytokines, such as TNF-α and IL-6 in the gene expression and protein levels (p< 0.05 or p< 0.01). Pretreatment with YJT significantly attenuated serum corticosterone (200 mg/kg, p < 0.05). YJT drastically attenuated the levels of 4- HNE, HO-1, Nox 2 and iNOSwhich were elevated during acute restraint stress, whereas the Nrf2 level was increased in brain tissue protein levels. Our data suggest that YJT protects the brain tissue against oxidative damage and regulates stress hormones.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Brain; Brain Diseases; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Enzymes; Gene Expression Regulation, Enzymologic; Hydrocortisone; Immobilization; Inflammation Mediators; Lipid Peroxidation; Male; Mice, Inbred C57BL; Nerve Degeneration; Neuroprotective Agents; Oxidative Stress; Stress, Psychological

Ascorbic acid (AA) levels are closely correlated with physiological and pathological events in brain diseases, but the mechanism remains unclear, mainly due to the difficulty of accurately analyzing AA levels in live brain. In this study, by engineering tunable defects and oxygen-containing species in carbon nanotubes, a novel aligned carbon nanotube fiber was developed as an accurate microsensor for the ratiometric detection of AA levels in live rat brains with Alzheimer's disease (AD). AA oxidation is greatly facilitated on the fiber surface at a low potential, leading to high sensitivity as well as high selectivity against potential sources of interference in the brain. Additionally, an unexpected, separate peak from the fiber surface remains constant as the AA concentration increases, enabling real-time and ratiometric detection with high accuracy. The results demonstrated that the AA levels were estimated to be 259 ± 6 μM in cortex, 264 ± 20 μM in striatum, and 261 ± 21 μM in hippocampus, respectively, in normal condition. However, the overall AA level was decreased to 210 ± 30 μM in cortex, 182 ± 5 μM in striatum, and 136 ± 20 μM in hippocampus in the rat brain model of AD. To the best of our knowledge, this work is the first to accurately detect AA concentrations in the brains of live animal model of AD.

Topics: Alzheimer Disease; Animals; Ascorbic Acid; Biosensing Techniques; Brain; Cerebral Cortex; Corpus Striatum; Disease Models, Animal; Electrochemical Techniques; Hippocampus; Male; Microelectrodes; Nanofibers; Nanotubes, Carbon; Oxidation-Reduction; Oxygen; Rats, Wistar; Reproducibility of Results

Metastasis-associated protein 1 (MTA1) is involved in tumor growth and metastasis of cancers. Being a component of nucleosome remodeling and histone deacetylase complex, the protein is also associated with DNA damage response pathway. Since the protein is involved in cancer pathology, we first investigated the effects of bleomycin, etoposide, and cisplatin (BEP) on MTA1 signaling in the testis. Second, since the antioxidants (AOs) have protective effects, we further investigated whether or not an AO cocktail modulates the effects of the drugs. Adult male Sprague Dawley rats (N = 4) were treated either with saline, or AO (α-tocopherol, l-ascorbic acid, zinc, and selenium), or therapeutic dose levels of etoposide (15 mg/kg) and cisplatin (3 mg/kg) from day 1-4 of the week and B (1.5 mg/kg) on the second day of the week, or BEP + AO. The real-time polymerase chain reaction showed that MTA1 and MTA1s (short form) gene expression was downregulated in AO (100% and 100%), BEP (86% and 71%), and BEP + AO (97% and 93%) groups. Western blotting and immunohistochemistry results showed that unnormalized MTA1 protein expression was upregulated in AO (38%) and BEP + AO (34%) groups; however, the MTA1/β-actin ratio was upregulated in all treated groups (21, 19, and 15%, respectively). In conclusion, the results indicate that both BEP and AO suppress MTA1 and MTA1s transcription, which may render the germ cells to be more prone to apoptosis. However, upregulation of MTA1 protein expression may be related to induced DNA damage. Modulation of MTA1 signaling is a novel mechanism of action of BEP and AO, which may be useful in developing newer anticancer drugs.

Topics: Actins; alpha-Tocopherol; Animals; Antineoplastic Agents; Antioxidants; Apoptosis; Ascorbic Acid; Bleomycin; Cisplatin; Disease Models, Animal; DNA Damage; Dose-Response Relationship, Drug; Etoposide; Histone Deacetylases; Male; Proteins; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Selenium; Signal Transduction; Testicular Neoplasms; Testis; Up-Regulation

Parquetina nigrescens is a medicinal herb with recognized antioxidant properties and potential to alleviate conditions associated with oxidative stress, including gastric ulcers. We investigated the protective potential of methanol extract of Parquetina nigrescens (MEPN) against ischemia-reperfusion injury in the intestine of rats. Thirty (30) male Wistar albino rats were randomly assigned into five groups with Group I made up of control rats and Group II consisting of rats experimentally subjected to ischemia and reperfusion (IR) by clamping of the superior mesenteric artery (SMA) for 30 minutes and 45 minutes, respectively. Groups III and IV rats also had IR, but were initially pre-treated with MEPN at 500 mg/kg and 1000 mg/kg respectively, for seven days. Rats in Group V were also pre-treated with Vitamin C, for seven days, before induction of IR. The results showed marked reduction in intestinal epithelial lesions in groups treated with MEPN, compared to the IR group which had severe villi erosion, inflammatory cell infiltration and hemorrhages. There were significant increases in Malondialdehyde (MDA) and significant reductions in reduced glutathione (GSH) and Glutathione S-transferase (GST) activity with IR injury, while pre-treatment with either MEPN or Vitamin C prevented these effects. Increases in Glutathione peroxidase (GPX), Catalase (CAT) and Superoxide dismutase (SOD) with IR provided evidence for adaptive responses to oxidative injury during IR and preservation of enzyme activity by MEPN and Vitamin C. Taken together, Parquetina nigrescens provided considerable alleviation of intestinal injury produced by IR, at values much as effective as that offered by Vitamin C.

Topics: Animals; Antioxidants; Ascorbic Acid; Catalase; Cryptolepis; Disease Models, Animal; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Intestinal Diseases; Male; Malondialdehyde; Methanol; Oxidative Stress; Plant Extracts; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Superoxide Dismutase

Treatment of tendon-derived stem cells (TDSCs) with connective tissue growth factor (CTGF) and ascorbic acid promoted their tenogenic differentiation. We investigated the effects of TDSCs pre-treated with CTGF and ascorbic acid on tendon repair in a patellar tendon window injury rat model.. Green fluorescent protein-TDSCs (GFP-TDSCs) were pre-treated with or without CTGF and ascorbic acid for 2 weeks before transplantation. The patellar tendons of rats were injured and divided into three groups: fibrin glue-only group (control group), untreated and treated TDSC group. The rats were followed up until week 16.. The treated TDSCs accelerated and enhanced the quality of tendon repair compared with untreated TDSCs up to week 8, which was better than that in the controls up to week 16 as shown by histology, ultrasound imaging and biomechanical test. The fibrils in the treated TDSC group showed better alignment and larger size compared with those in the control group at week 8 (P = 0.004). There was lower risk of ectopic mineralization after transplantation of treated or untreated TDSCs (all P ≤ 0.050). The transplanted cells proliferated and could be detected in the window wound up to weeks 2 to 4 and week 8 for the untreated and treated TDSC groups, respectively.. The transplantation of TDSCs promoted tendon repair up to week 16, with CTGF and ascorbic acid pre-treatment showing the best results up to week 8. Pre-treatment of TDSCs with CTGF and ascorbic acid may be used to further enhance the rate and quality of tendon repair after injury.

Topics: Animals; Ascorbic Acid; Biomechanical Phenomena; Calcification, Physiologic; Cell Differentiation; Connective Tissue Growth Factor; Disease Models, Animal; Fibrillar Collagens; Fibrin Tissue Adhesive; Green Fluorescent Proteins; Immunohistochemistry; Male; Patellar Ligament; Proliferating Cell Nuclear Antigen; Rats, Sprague-Dawley; Stem Cell Transplantation; Stem Cells; Tendon Injuries; Tendons; Tomography, X-Ray Computed; Ultrasonography; Wound Healing

There is a functional relationship between the heparan sulfate proteoglycan glypican-1 and the amyloid precursor protein (APP) of Alzheimer disease. In wild-type mouse embryonic fibroblasts, expression and processing of the APP is required for endosome-to-nucleus translocation of anhydromannose-containing heparan sulfate released from S-nitrosylated glypican-1 by ascorbate-induced, nitrosothiol-catalyzed deaminative cleavage. In fibroblasts from the transgenic Alzheimer mouse Tg2576, there is increased processing of the APP to amyloid-β peptides. Simultaneously, there is spontaneous formation of anhydromannose-containing heparan sulfate by an unknown mechanism. We have explored the effect of hypoxia on anhydromannose-containing heparan sulfate formation in wild-type and Tg2576 fibroblasts by deconvolution immunofluorescence microscopy and flow cytometry using an anhydromannose-specific monoclonal antibody and by (35)SO4-labeling experiments. Hypoxia prevented ascorbate-induced heparan sulfate release in wild-type fibroblasts, but induced an increased formation of anhydromannose-positive and (35)S-labeled heparan sulfate in Tg2576 fibroblasts. This appeared to be independent of glypican-1 S-nitrosylation as demonstrated by using a monoclonal antibody specific for S-nitrosylated glypican-1. In hypoxic wild-type fibroblasts, addition of nitrite to the medium restored anhydromannose-containing heparan sulfate formation. The increased release of anhydromannose-containing heparan sulfate in hypoxic Tg2576 fibroblasts did not require addition of nitrite. However, it was suppressed by inhibition of the nitrite reductase activity of xanthine oxidoreductase/aldehyde oxidase or by inhibition of p38 mitogen-activated protein kinase or by chelation of iron. We propose that normoxic Tg2576 fibroblasts maintain a high level of anhydromannose-containing heparan sulfate production by a stress-activated generation of nitric oxide from endogenous nitrite. This activation is enhanced by hypoxia.

Topics: Alzheimer Disease; Animals; Antibodies, Monoclonal; Ascorbic Acid; Cell Hypoxia; Deferoxamine; Disease Models, Animal; Enzyme Inhibitors; Fibroblasts; Glypicans; Heparitin Sulfate; Humans; Iron Chelating Agents; Mannose; Mice; Mice, Transgenic; Microscopy, Fluorescence; Nitric Oxide; Nitrite Reductases; Nitrites; Oxidation-Reduction; Oxygen; p38 Mitogen-Activated Protein Kinases; Primary Cell Culture

Ethanol induces oxidative stress and its exposure during early developmental age causes neuronal cell death which leads to several neurological disorders. We previously reported that vitamin C can protect against ethanol-induced apoptotic cell death in the developing rat brain. Here, we extended our study to understand the therapeutic efficacy of vitamin C against ethanol-induced oxidative stress, neuroinflammation mediated neurodegeneration in postnatal day 7 (PND7) rat. A single episode of ethanol (5g/kg) subcutaneous administration to postnatal day 7 rat significantly induced the production of reactive oxygen species (ROS), and activated both microglia and astrocytes followed by the induction of different apoptotic markers. On the other hand, due to its free radical scavenging properties, vitamin C treatment significantly reduced the production of reactive oxygen species, suppressed both activated microglia and astrocytes and reversed other changes including elevated level of Bax/Bcl-2 ratio, cytochrome c and different caspases such as caspase-9 and caspase-3 induced by ethanol in developing rat brain. Moreover, vitamin C treatment also reduced ethanol-induced activation of Poly [ADP-Ribose] Polymerase 1(PARP-1) and neurodegeneration as evident from Flouro-Jade-B and Nissl stainined neuronal cell death in PND7 rat brain. These findings suggest that vitamin C mitigated ethanol-induced oxidative stress, neuroinflammation and apoptotic neuronal loss and may be beneficial against ethanol damaging effects in brain development.

Topics: Animals; Animals, Newborn; Apoptosis; Ascorbic Acid; bcl-2-Associated X Protein; Brain; Caspase 3; CREB-Binding Protein; Disease Models, Animal; Encephalitis; Ethanol; Fluoresceins; Glial Fibrillary Acidic Protein; Neurodegenerative Diseases; Neuroprotective Agents; Poly (ADP-Ribose) Polymerase-1; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

lntravitreal injection of substances dissolved in a vehicle solution is a common tool used to assess retinal function. We examined the effect of injection procedures (three groups) and vehicle solutions (four groups) on the development of form deprivation myopia (FDM) in juvenile tree shrews, mammals closely related to primates, starting at 24 days of visual experience (about 45 days of age). In seven groups (n = 7 per group), the myopia produced by monocular form deprivation (FD) was measured daily for 12 days during an 11-day treatment period. The FD eye was randomly selected; the contralateral eye served as an untreated control. The refractive state of both eyes was measured daily, starting just before FD began (day 1); axial component dimensions were measured on day 1 and after eleven days of treatment (day 12). Procedure groups: the myopia (treated eye - control eye refraction) in the FD group was the reference. The sham group only underwent brief daily anesthesia and opening of the conjunctiva to expose the sclera. The puncture group, in addition, had a pipette inserted daily into the vitreous. In four vehicle groups, 5 μL of vehicle was injected daily. The NaCl group received 0.85% NaCl. In the NaCl + ascorbic acid group, 1 mg/mL of ascorbic acid was added. The water group received sterile water. The water + ascorbic acid group received water with ascorbic acid (1 mg/mL). We found that the procedures associated with intravitreal injections (anesthesia, opening of the conjunctiva, and puncture of the sclera) did not significantly affect the development of FDM. However, injecting 5 μL of any of the four vehicle solutions slowed the development of FDM. NaCl had a small effect; myopia development in the last 6 days (-0.15 ± 0.08 D/day) was significantly less than in the FD group (-0.55 ± 0.06 D/day). NaCl + Ascorbic acid further slowed the development of FDM on several treatment days. H2O (-0.09 ± 0.05 D/day) and H2O + ascorbic acid (-0.08 ± 0.05 D/day) both almost completely blocked myopia development. The treated eye vitreous chamber elongation, compared with the control eye, in all groups was consistent with the amount of myopia. When FD continued (days 12-16) without injections in the water and water + ascorbic acid groups, the rate of myopia development quickly increased. Thus, it appears the vehicles affected retinal signaling rather than causing damage. The effect of water and water + ascorbic acid may be due to reduced osmolality or ionic conce

Topics: Animals; Antioxidants; Ascorbic Acid; Axial Length, Eye; Disease Models, Animal; Intravitreal Injections; Myopia; Ophthalmic Solutions; Pharmaceutical Vehicles; Refraction, Ocular; Sensory Deprivation; Sodium Chloride; Tupaiidae

Antioxidants have been tested to treat neuropathic pain, and α-Tocopherol (vitamin E--vit. E) and ascorbic acid (vitamin C--vit. C) are potent antioxidants. We assessed the effect of intraperitoneal administration of vit. C (30 mg/kg/day) and vit. E (15 mg/kg/day), given alone or in combination, on the mechanical and thermal thresholds and the sciatic functional index (SFI) in rats with chronic constriction injury (CCI) of the sciatic nerve. We also determined the lipid hydroperoxides and total antioxidant capacity (TAC) in the injured sciatic nerve. Further, we assessed the effects of oral administration of vit. C+vit. E (vit. C+E) and of a combination of vit. C+E and gabapentin (100mg/kg/day, i.p.) on the mechanical and thermal thresholds of CCI rats. The vitamins, whether administered orally or i.p., attenuated the reductions in the mechanical and thermal thresholds induced by CCI. The antinociceptive effect was greater with a combination of vit. C+E than with each vitamin given alone. The SFI was also improved in vitamin-treated CCI rats. Co-administration of vit. C+E and gabapentin induced a greater antinociceptive effect than gabapentin alone. No significant change occurred in TAC and lipid hydroperoxide levels, but TAC increased (45%) while lipid hydroperoxides decreased (38%) in the sciatic nerve from vit. C+E-treated CCI rats. Thus, treatment with a combination of vit. C+E was more effective to treat CCI-induced neuropathic pain than vitamins alone, and the antinociceptive effect was greater with co-administration of vit. C+E and gabapentin than with gabapentin alone.

Topics: Alanine Transaminase; Analgesics; Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; Aspartate Aminotransferases; Constriction; Disease Models, Animal; gamma-Glutamyltransferase; Hyperalgesia; Locomotion; Male; Nociception; Pain Measurement; Pain Threshold; Physical Stimulation; Rats; Rats, Wistar; Sciatica; Time Factors; Vitamin E

Chemoprevention is considered as one of the most promising and realistic approaches in the prevention of lung cancer. Chrysin, a naturally occurring dietary flavone widely found in Passiflora family of plants and honey, has been studied extensively for its chemopreventive properties. The objective of present study is to divulge the chemopreventive role of chrysin against benzo(a)pyrene [B(a)P] induced lung carcinogenesis in Swiss albino mice.. B(a)P was administered orally (50mg/kg body weight) twice a week for four weeks to induce lung cancer in mice. The body weight, lung weight, tumor incidence, lipid peroxidation, carcinoembryonic antigen, enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase) and non-enzymatic antioxidants (reduced glutathione, vitamin E and vitamin C) were estimated. Further, histopathological analysis of lung tissue and western blotting analysis of PCNA, COX-2 and NF-κB were also carried out.. Administration of B(a)P resulted in increased lipid peroxides and carcinoembryonic antigen with concomitant decrease in the levels of both enzymatic antioxidants and non-enzymatic antioxidants. Chrysin treatment (250mg/kg body weight) significantly attenuated all these changes thereby showing potent anti lung cancer effect. Further, the anticancer effect of chrysin was confirmed by histopathology of lungs, and immunoblotting analysis of PCNA, COX-2 and NF-κB, where chrysin supplementation downregulated the expression of these proteins and maintained cellular homeostasis.. Overall, these findings confirm the chemopreventive potential of chrysin against B(a)P induced lung cancer in Swiss albino mice.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; Benzo(a)pyrene; Carcinogenesis; Catalase; Chemoprevention; Diet; Disease Models, Animal; Flavones; Flavonoids; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Lipid Peroxidation; Lung; Lung Neoplasms; Male; Mice; NF-kappa B; Superoxide Dismutase; Vitamin E

Garlic capsule (GAR) and/or selenium- vitamin A, C, E (S-VACE) might be useful in the treatment of lung diseases. The present study evaluated the toxicity of lisinopril (LIS) in the lungs of male rats and the reversal effect of GAR and/or selenium-vitamins A, C, and E (S-VACE).. Group I served as the control, whereas animals in groups II, III, IV, and V received 28 mg of LIS/kg body weight by gavage. Group III was co-treated with GAR at a therapeutic dosage of 250 mg/kg body weight per day. Group IV was co-treated with S-VACE at dosage of 500 mg/kg body weight per day. Lastly, group V was co-treated with GAR and S-VACE at dosages of 250 and 500 mg/kg body weight per day, respectively. The experiment lasted for 8 days (sub-acute exposure).. Administration of therapeutic dose of LIS to male rats depleted enzymatic antioxidants (superoxide dismutase and catalase) and cellular adenosine triphosphate content with concomitant increase in lipid peroxidation. Histopathology examination showed damage to the epithelial cells of the airways. These effects were prevented by both single and combination treatment of GAR and S-VACE in male rats with LIS-induced lung toxicity.. We therefore concluded that the combination of GAR and S-VACE can be a novel therapy for the management of lung diseases in humans.

Topics: Adenosine Triphosphate; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Garlic; Lipid Peroxidation; Lisinopril; Lung Diseases; Male; Rats; Rats, Wistar; Respiratory Mucosa; Selenium; Vitamin A; Vitamin E; Vitamins

Endometriosis is a chronic inflammatory disease pathologically defined as the presence of endometrial-like tissue outside the uterine cavity. It is one of the most important diseases affecting women of reproductive age. The process of endometriotic implant growth is mediated by many complex interactions of immunologic, hormonal, genetic, and environmental mediators. Vitamin C (ascorbic acid), besides playing a role in preventing invasion and metastasis, is an antioxidant having anti-inflammatory and -angiogenic effects. In this study, we aimed to investigate the effect of vitamin C on the prevention and regression of endometriotic implants in a rat model of endometriosis.. This was a prospective, comparative, experimental animal study. After endometriotic implants were induced simultaneously, rats were divided into three groups. Group A was given 500 mg/kg of intravenous vitamin C every 2 days, starting immediately after implantation (n = 11). All rats had a second operation 21 days after the initial one and had the lesion volumes measured. Group B was given 500 mg/kg of intravenous vitamin C every 2 days, starting 21 days after this operation (n = 11). All rats were sacrificed 21 days after the third operation. Implant volume, weight measurements, and histopathological evaluation of the lesions were carried out. Group A received vitamin C throughout the study, while Group C (n = 11) was not given any medication. The findings in the three groups were compared.. At the second laparotomy after the induction, Group A had the smallest implant volume with a statistically significant difference compared to Group B (p = 0.012). The end-of-study volumes of endometriotic implants of group B were significantly smaller than the first volumes (p < 0.05).. Intravenous vitamin C treatment might have a suppressive effect on the prevention of endometriotic implant induction and regression of endometriotic implant volumes.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Endometriosis; Female; Prospective Studies; Rats; Rats, Wistar

Werner syndrome (WS) is a premature aging disorder that mainly affects tissues derived from mesoderm. We have recently developed a novel human WS model using WRN-deficient human mesenchymal stem cells (MSCs). This model recapitulates many phenotypic features of WS. Based on a screen of a number of chemicals, here we found that Vitamin C exerts most efficient rescue for many features in premature aging as shown in WRN-deficient MSCs, including cell growth arrest, increased reactive oxygen species levels, telomere attrition, excessive secretion of inflammatory factors, as well as disorganization of nuclear lamina and heterochromatin. Moreover, Vitamin C restores in vivo viability of MSCs in a mouse model. RNA sequencing analysis indicates that Vitamin C alters the expression of a series of genes involved in chromatin condensation, cell cycle regulation, DNA replication, and DNA damage repair pathways in WRN-deficient MSCs. Our results identify Vitamin C as a rejuvenating factor for WS MSCs, which holds the potential of being applied as a novel type of treatment of WS.

Topics: Animals; Ascorbic Acid; Cell Cycle Checkpoints; Cell Line; Cellular Senescence; Disease Models, Animal; DNA Damage; DNA Repair; DNA Replication; Heterochromatin; Humans; Mesenchymal Stem Cells; Mice; Nuclear Lamina; Reactive Oxygen Species; Telomere Homeostasis; Werner Syndrome

Recent evidences suggest that cerebral ischemia-reperfusion insult plays significant role in pathogenic diseases like Alzheimer's disease (AD) and other neurodegenerative diseases. Toxic reactive oxygen species (ROS) generated by induced oxidative stress in the episodes of cerebral ischemia-reperfusion (CIR) plays major role in neurodegeneration. As the prime source of ROS generation, neuronal mitochondria, the cellular energy metabolic centre experience severe damage because of CIR-induced oxidative stress. The process of mitochondrial dysfunction is accelerated by CIR that may pave the pathway for neurodegeneration in AD among aged individuals. Prevention of CIR injury may be a shunt in order to minimize the risk of dementia of Alzheimer's type in aged individuals. The use of chemical antioxidants in CIR is not suitable as the blood- brain barrier (BBB) doesn't allow the entry of molecules from blood circulation into the brain. Thus L-ascorbic acid loaded polylactide nanocapsules were prepared and fed orally to assess the role of nanocapsulated ascorbic acid (NAA) against CIR induced oxidative injury in mitochondrial region of rat brains. Mitochondrial injury was assessed by the extent of lipid peroxidation and in situ antioxidant enzyme status. The levels of cytochrome c (cyt c), cyclooxygenase- 2 (COX-2) and iNOS were determined. Results showed that in comparison to free ascorbic acid (AA), NAA exerted better protection to the brain mitochondria by preventing oxidative damage in ROS mediated CIR injury.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain; Brain Ischemia; Catalase; Disease Models, Animal; Female; Glutathione Peroxidase; Glutathione Reductase; Lipid Peroxidation; Mitochondria; Nanocapsules; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Superoxide Dismutase

It has been suggested that dysregulation of γ-aminobutyric acid (GABA)-mediated neurotransmission is involved in the etiology of major depressive disorder and in the action of the fast-acting antidepressant ketamine. Considering that recent evidence has suggested that ascorbic acid may exert an antidepressant-like effect through mechanisms similar to ketamine, this study evaluated the involvement of GABAA and GABAB receptors in the antidepressant-like effect of ascorbic acid, comparing the results with those obtained with ketamine.. To investigate the involvement of GABAA in the antidepressant-like effect of ascorbic acid and ketamine in the tail suspension test (TST), mice were treated with a sub-effective dose of ascorbic acid (0.1mg/kg, po), ketamine (0.1mg/kg, ip) or vehicle and 30minutes later, a sub-effective dose of muscimol (0.1mg/kg, ip, GABAA receptor agonist) or vehicle was administered. In another set of experiments, mice were treated with ascorbic acid (1mg/kg, po, active dose in the TST) or vehicle and 30minutes later, baclofen (1mg/kg, ip, GABAB receptor agonist) was administered. A similar experimental protocol was performed with ketamine (1mg/kg, ip).. The administration of muscimol combined with ascorbic acid or ketamine produced a synergistic antidepressant-like effect in the TST. Moreover, the antidepressant-like effects of ascorbic acid and ketamine were abolished by baclofen. There was no alteration in spontaneous locomotion in any experimental group.. Results indicate that the anti-immobility effect of ascorbic acid and ketamine in TST may involve an activation of GABAA receptors and a possible inhibition of GABAB receptors.

Topics: Animals; Antidepressive Agents; Ascorbic Acid; Depression; Depressive Disorder, Major; Disease Models, Animal; Female; gamma-Aminobutyric Acid; Hindlimb Suspension; Ketamine; Mice; Motor Activity; Receptors, GABA-A; Synaptic Transmission

Sulfonamide hypersensitivity has a high incidence in HIV infection and correlates with low CD4+ counts, but the mechanisms are not understood. The aims of this study were to determine whether trimethoprim/sulfamethoxazole (TMP/SMX) led to SMX adduct formation, immunogenicity, or signs of drug hypersensitivity in SIV-infected rhesus macaques, and whether differences in antioxidants, pro-inflammatory mediators, or SMX disposition were predictive of drug immunogenicity.. Four of 9 of SIV-positive (44%), and 3 of 7 SIV negative (43%) macaques had drug-responsive T cells or antibodies to SMX. Two macaques developed facial or truncal rash; these animals had the highest levels of lymph node drug adducts. Antioxidants, pro-inflammatory mediators, and SMX metabolites were not predictive of drug immunogenicity; however, the Mamu DRB1*0401/0406/0411 genotype was significantly over-represented in immune responders.. Unlike other animal models, macaques develop an immune response, and possible rash, in response to therapeutic dosages of TMP/SMX. Studying more animals with CD4+ counts <200cells/μl, along with moderately restricted ascorbate intake to match deficiencies seen in humans, may better model the risk of SMX hypersensitivity in HIV-infection. In addition, the role of Mamu-DRB1 genotype in modeling drug hypersensitivity in retroviral infection deserves further study.

Topics: Animals; Anti-Infective Agents; Antioxidants; Ascorbic Acid; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cytochrome-B(5) Reductase; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Hypersensitivity; Female; Glutathione; HIV Infections; Interferon-gamma; Lipopolysaccharides; Lymph Nodes; Macaca mulatta; Male; Trimethoprim, Sulfamethoxazole Drug Combination

Antioxidants are potential therapeutic agents for reducing stress-induced organ damage. We investigated the effects of ascorbic acid and β-carotene on oxidative stress-induced cerebral, cerebellar, cardiac and hepatic damage using microscopy and biochemistry. Male Wistar albino rats were divided into five groups: untreated control, stressed, stressed + saline, stressed + ascorbic acid and stressed + β-carotene. The rats in the stressed groups were subjected to starvation, immobilization and cold. The histopathological damage scores for the stressed and stressed + saline groups were higher than those of the control group for all organs examined. The histopathological damage scores and mean tissue malondialdehyde levels for the groups treated with antioxidants were lower than those for the stressed and stressed + saline groups. Mean tissue superoxide dismutase activities for groups that received antioxidants were higher than those for the stressed + saline group for most organs evaluated. Ascorbic acid and β-carotene can reduce stress-induced organ damage by both inhibiting lipid oxidation and supporting the cellular antioxidant defense system.

Topics: Animals; Antioxidants; Ascorbic Acid; beta Carotene; Disease Models, Animal; Lipid Peroxidation; Male; Oxidation-Reduction; Oxidative Stress; Rats, Wistar

The aim of this study was to evaluate the probable protective effect of vitamin C and vitamin E on diclofenac-induced acute nephrotoxicity using biochemical, molecular and histopathological examination in rats following administration of diclofenac sodium (50mg/kg, I.M).. Ninety male Wister rats were allotted in six equal groups. Rats in the 1st group (control group) were injected with physiological saline, while rats in the 2nd group (C-group) were given vitamin C (100mg/kg orally via stomach tube) for 5 successive days. The 3rd group (E-group) was given vitamin E (250mg/kg orally in diet) for 5 successive days. Rats in the 4th group (D-group) were injected by diclofenac sodium (50mg/kg, I.M) for 5 successive days. The 5th group (DvC-group) was given diclofenac sodium (50mg/kg, I.M) and vitamin C (100mg/kg orally via stomach tube) for 5 successive days. Rats in the 6th group (DvE-group) were given diclofenac sodium (50mg/kg, I.M) and vitamin E (250mg/kg orally in diet) for 5 successive days. Blood samples were collected two days post treatment (1st week of experiment), 2nd and 4th week of the experiment for assessment of urea, creatinine, malondialdehyde, nitric oxide and superoxide dismutase activities. At the end of 4th week, rats were sacrificed and kidneys were excised for biochemical analyses, histopathological evaluation and determination of kidney interleukin-1β, interleukin-18, demsin and nepherin expressions in by reverse transcriptase-polymerase chain reaction (RT-PCR).. The results showed that, diclofenac induced severe kidney damage as indicated by histopathological changes and increased serum oxidative stress parameters. Behavioral changes were monitored; a significant increase in uremia in intoxicated animals was also noted indicating that diclofenac sodium provoked kidney damage in rats. Application of vitamin C (DvC-group) and vitamin E (DvE-group) were found to improve the abovementioned abnormalities.. The present data suggest that, vitamin C and vitamin E might play an important role in reducing oxidative stress and kidney damage induced by diclofenac sodium.

Topics: Acute Kidney Injury; Animals; Antioxidants; Ascorbic Acid; Biomarkers; Cytoprotection; Diclofenac; Disease Models, Animal; Kidney; Male; Oxidative Stress; Rats, Wistar; Uremia; Vitamin E

The mechanism underlying the vascular dysfunction induced by ethanol is not totally understood. Identification of biochemical/molecular mechanisms that could explain such effects is warranted.. To investigate whether acute ethanol intake activates the vascular RhoA/Rho kinase pathway in resistance arteries and the role of NAD(P)H oxidase-derived reactive oxygen species (ROS) on such response. We also evaluated the requirement of p47phox translocation for ethanol-induced NAD(P)H oxidase activation.. Male Wistar rats were orally treated with ethanol (1g/kg, p.o. gavage) or water (control). Some rats were treated with vitamin C (250 mg/kg, p.o. gavage, 5 days) before administration of water or ethanol. The mesenteric arterial bed (MAB) was collected 30 min after ethanol administration.. Vitamin C prevented ethanol-induced increase in superoxide anion (O2-) generation and lipoperoxidation in the MAB. Catalase and superoxide dismutase activities and the reduced glutathione, nitrate and hydrogen peroxide (H2O2) levels were not affected by ethanol. Vitamin C and 4-methylpyrazole prevented the increase on O2- generation induced by ethanol in cultured MAB vascular smooth muscle cells. Ethanol had no effect on phosphorylation levels of protein kinase B (Akt) and eNOS (Ser1177 or Thr495 residues) or MAB vascular reactivity. Vitamin C prevented ethanol-induced increase in the membrane: cytosol fraction ratio of p47phox and RhoA expression in the rat MAB.. Acute ethanol intake induces activation of the RhoA/Rho kinase pathway by a mechanism that involves ROS generation. In resistance arteries, ethanol activates NAD(P)H oxidase by inducing p47phox translocation by a redox-sensitive mechanism.. O mecanismo da disfunção vascular induzido pelo consumo de etanol não é totalmente compreendido. Justifica-se, assim a identificação de mecanismos bioquímicos e moleculares que poderiam explicar tais efeitos.. Investigar se a ingestão aguda de etanol ativa a via vascular RhoA/Rho quinase em artérias de resistência e o papel das espécies reativas de oxigênio (ERO) derivadas da NAD(P)H oxidase nessa resposta. Nós também avaliamos se ocorreu translocação da p47phox e ativação da NAD(P)H oxidase após o consumo agudo de etanol.. Ratos Wistar machos foram tratados com etanol via oral (1g/kg, p.o. gavagem) ou água (controle). Alguns ratos foram tratados com vitamina C (250 mg/kg, p.o. gavagem, 5 dias) antes de água ou etanol. O leito arterial mesentérico (LAM) foi coleado 30 min após a administração de etanol.. A vitamina C preveniu o aumento da geração de ânion superóxido (O2 -) e lipoperoxidação no LAM induzidos pelo etanol. A atividade da catalase (CAT), da superóxido dismutase (SOD) e os níveis de glutationa reduzida(GSH), nitrato e peróxido de hidrogênio (H2O2) não foram afetados após a ingestão aguda de etanol. A vitamina C e o 4-metilpirazol preveniram o aumento na geração de O2 - induzido pelo etanol em cultura de células do músculo liso vascular (CMLV). O etanol não afetou a fosforilação da proteína quinase B (Akt) e nem da óxido nítrico sintase endotelial (eNOS) (nos resíduos de Ser1177 ou Thr495) ou a reatividade vascular do LAM. A vitamina C preveniu o aumento da razão membrana:citosol da p47phox e a expressão da RhoA no LAM de rato induzido pelo etanol.. A ingestão aguda de etanol induz a ativação da via RhoA/Rho quinase por um mecanismo que envolve a geração de ERO. Nas artérias de resistência, o etanol ativa NAD(P)H oxidase induzindo a translocação da p47phox por um mecanismo redox-sensível.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Enzyme Activation; Ethanol; Male; NADPH Oxidases; Oxidative Stress; Protein Transport; Rats; Rats, Wistar; rhoA GTP-Binding Protein

In this paper, the design, synthesis and biological evaluation of a set of quinazoline-2,4,6-triamine derivatives (1-9) as trypanocidal, antileishmanial and antiplasmodial agents are explained. The compounds were rationalized basing on docking studies of the dihydrofolate reductase (DHFR from Trypanosoma cruzi, Leishmania major and Plasmodium vivax) and pteridin reductase (PTR from T. cruzi and L. major) structures. All compounds were in vitro screened against both bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and promatigotes of Leishmania mexicana (MHOM/BZ/61/M379 strain), and also for cytotoxicity using Vero cell line. Against T. cruzi, three compounds (5, 6 and 8) were the most effective showing a better activity profile than nifurtimox and benznidazole (reference drugs). Against L. mexicana, four compounds (5, 6, 8, and 9) exhibited the highest activity, even than glucantime (reference drug). In the cytotoxicity assay, protozoa were more susceptible than Vero cells. In vivo Plasmodium berghei assay (ANKA strain), the compounds 1, 5, 6 and 8 showed a more comparable activity than chloroquine and pyrimethamine (reference drugs) when they were administrated by the oral route. The antiprotozoal activity of these substances, endowed with redox properties, represented a good starting point for a medicinal chemistry program aiming for chemotherapy of Chagas' disease, leishmaniosis and malaria.

Topics: Administration, Oral; Animals; Antimalarials; Antiprotozoal Agents; Chlorocebus aethiops; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Female; Leishmania major; Malaria; Mice; Mice, Inbred Strains; Models, Molecular; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium vivax; Quinazolines; Structure-Activity Relationship; Trypanosoma cruzi; Vero Cells

Reactive oxygen species have been implicated in several diseases, particularly in ischemia-reperfusion injury. Quercetin 3-O-methyl ether has been reported to show potent antioxidant and neuroprotective activity against neuronal damage induced by reactive oxygen species. Several aminoethyl-substituted derivatives of quercetin 3-O-methyl ether have been synthesized to increase water solubility while retaining antioxidant and neuroprotective activity. Among such derivatives, compound 3a shows potent and well-balanced antioxidant activity in three types of cell-free assay systems and has in vivo neuroprotective effects on transient focal ischemic injury induced by the occlusion of the middle cerebral artery in rats.

Topics: Animals; Antioxidants; Brain; Disease Models, Animal; Infarction, Middle Cerebral Artery; Lipid Peroxidation; Male; Neuroprotective Agents; Quercetin; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Structure-Activity Relationship

In neurosurgery practice glucocorticoids are commonly used. Steroids may have central nervous system side effects affecting whole body, including steroid-induced mental agitation and psychosis. In experimental and clinical studies conducted by using dexamethasone (DEX), it has been reported that DEX adversely affects learning and memory skills. Unfortunately, there are yet no clinically accepted clinical approaches to prevent DEX-induced cognitive dysfunction. In this experimental study it was aimed to investigate the effect of chronic DEX administration on learning-memory and locomotor behaviors in adult male Sprague Dawley rats. In addition, it was also aimed to explore the potential favorable contribution of melatonin (MEL) and vitamin C (Vit C) having antioxidant and neuroprotective properties to the effects of DEX on learning-memory and locomotor behaviors. For this purpose, rats were injected 10mg/kg DEX intraperitoneally, both alone and in combination with MEL (40 mg/kg) and Vit C (100mg/kg), for 9 days, and the animals were tested using the radial arm maze and open field apparatus. The test results revealed that DEX caused a significant decrease in spatial memory and locomotor activities and MEL and Vit C failed to reverse losses in these activities. Furthermore, DEX led to a gradual weight loss that reached 30% of the initial weight at 9th day of the injection. DEX administration causes a generalized loss of behavioral activity of rats. Experimental studies devised to investigate effects of DEX should take into account this DEX-induced generalized behavioral loss when assessing the effects of DEX on learning and memory skills. This article is part of a Special Issue entitled SI: Brain and Memory.

Topics: Adrenocortical Hyperfunction; Animals; Antioxidants; Ascorbic Acid; Cholinergic Antagonists; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Glucocorticoids; Male; Maze Learning; Melatonin; Memory Disorders; Motor Activity; Rats; Rats, Sprague-Dawley; Scopolamine; Statistics, Nonparametric; Time Factors

Cigarette smoke (CS) is the strongest risk factor for emphysema. However, the mechanism of the disease is not clear. One reason is that each puff of CS is a complex mixture of approximately 4,000 chemicals, and it is yet to be known which of these chemical(s) are directly involved in the pathogenesis of lung injury in emphysema. The purpose of this study was to demonstrate that p-benzoquinone (p-BQ) produced in the lungs of CS-exposed guinea pigs is a causative factor for destruction of alveolar cells resulting in emphysema that is prevented by vitamin C. Vitamin C-restricted guinea pigs were subjected to whole-body CS exposure from five Kentucky research cigarettes (3R4F) per day or intramuscular injection of p-BQ in amounts approximately produced in the lung from CS exposure with and without oral supplementation of vitamin C. Progressive exposure of CS or p-BQ treatment caused progressive accumulation of p-BQ in the lung that was accompanied by destruction of alveolar cells and emphysema. The pathogenesis involved was arylation, oxidative stress, inflammation, and apoptosis. Vitamin C (30 mg/kg body weight/d), a potential antagonist of p-BQ, prevented accumulation of p-BQ in the lung and the pathogenesis of emphysema. Our study provides the first proof that inactivation of p-BQ, a causative factor of emphysema in CS-exposed lung, could constitute a novel and effective approach in the prevention of emphysema. We consider that a moderately high dose of vitamin C may be a simple preventive therapy for emphysema in chronic smokers.

Topics: Animals; Apoptosis; Ascorbic Acid; Benzoquinones; Disease Models, Animal; Guinea Pigs; Inflammation; Oxidative Stress; Pulmonary Alveoli; Pulmonary Emphysema; Smoke; Smoking

Hypoxia-inducible factor-1 (HIF-1) governs cellular adaption to the hypoxic microenvironment and is associated with a proliferative, metastatic, and treatment-resistant tumor phenotype. HIF-1 levels and transcriptional activity are regulated by proline and asparagine hydroxylases, which require ascorbate as cofactor. Ascorbate supplementation reduced HIF-1 activation in vitro, but only limited data are available in relevant animal models. There is no information of the effect of physiological levels of ascorbate on HIF activity and tumor growth, which was measured in this study. C57BL/6 Gulo(-/-) mice (a model of the human ascorbate dependency condition) were supplemented with 3300 mg/L, 330 mg/L, or 33 mg/L of ascorbate in their drinking water before and during subcutaneous tumor growth of B16-F10 melanoma or Lewis lung carcinoma (LL/2). Ascorbate levels in tumors increased significantly with elevated ascorbate intake and restoration of wild-type ascorbate levels led to a reduction in growth of B16-F10 (log phase P < 0.001) and LL/2 tumors (lag growth P < 0.001, log phase P < 0.05). Levels of HIF-1α protein in tumors decreased as dietary ascorbate supplementation increased for both tumor models (P < 0.001). Similarly, tumor ascorbate was inversely correlated with levels of the HIF-1 target proteins CA-IX, GLUT-1, and VEGF in both B16-F10 and LL/2 tumors (P < 0.05). The extent of necrosis was similar between ascorbate groups but varied between models (30% for B16-F10 and 21% for LL/2), indicating that ascorbate did not affect tumor hypoxia. Our data support the hypothesis that restoration of optimal intracellular ascorbate levels reduces tumor growth via moderation of HIF-1 pathway activity.

Topics: Animals; Ascorbic Acid; Carcinoma, Lewis Lung; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Glucose Transporter Type 1; Hypoxia-Inducible Factor 1, alpha Subunit; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Transgenic; Signal Transduction; Vitamins

Spinal cord injury [SCI] leads to complex cellular and molecular interactions which affects various organ systems. The present study focused on determining the protection offered by Vitamin C against spinal injury-induced kidney damage in wistar rats. The experimental protocol was performed with three groups; Sham, SCI and Vitamin C [20 mg/kg/bw] followed by SCI. The kidney tissue was investigated for oxidative stress parameters [reactive oxygen species, protein carbonyl, sulphydryl content, thiobarbituric acid reactive species [TBARS], and myeloperoxidase activity] and antioxidant status [glutathione, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase activity]. Further, inflammation studies were performed by analyzing expression of NF-κB, cycloxygenase-2, iNOS through western blot analysis and inflammatory cytokines by TNF-α and IL-1β levels. The present study shows clear evidence that Vitamin C treatment abrogated spinal injury-induced oxidative stress and inflammatory responses and enhanced the antioxidant status. Thus, the protection offered by Vitamin C against spinal cord injury-induced kidney damage is attributed to its anti-oxidant and anti-inflammatory effects.

Topics: Animals; Antioxidants; Ascorbic Acid; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Down-Regulation; Glutathione; Laminectomy; Male; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Protein Carbonylation; Rats; Rats, Wistar; Reactive Oxygen Species; Retinal Diseases; Spinal Cord Injuries

The essential use of riboflavin is the prevention of migraine headaches, although its effect on migraines is considered to be associated with the increased mitochondrial energy metabolism. Oxidative stress is also important in migraine pathophysiology. Vitamin E is a strong antioxidant in nature and its analgesic effect is not completely clear in migraines. The current study aimed to investigate the effects of glyceryl trinitrate (GTN)-sourced exogen nitric oxide (NO), in particular, and also riboflavin and/or vitamin E on involved in the headache model induced via GTN-sourced exogen NO on oxidative stress, total brain calcium levels, and microsomal membrane Ca(2+)-ATPase levels. GTN infusion is a reliable method to provoke migraine-like headaches in experimental animals and humans. GTN resulted in a significant increase in brain cortex and microsomal lipid peroxidation levels although brain calcium, vitamin A, vitamin C, and vitamin E, and brain microsomal-reduced glutathione (GSH), glutathione peroxidase (GSH-Px), and plasma-membrane Ca(2+)-ATPase values decreased through GTN. The lipid peroxidation, GSH, vitamin A, β-carotene, vitamin C, and vitamin E, and calcium concentrations, GSH-Px, and the Ca(2+)-ATPase activities were increased both by riboflavin and vitamin E treatments. Brain calcium and vitamin A concentrations increased through riboflavin only. In conclusion, riboflavin and vitamin E had a protective effect on the GTN-induced brain injury by inhibiting free radical production, regulation of calcium-dependent processes, and supporting the antioxidant redox system. However, the effects of vitamin E on the values seem more important than in riboflavin.

Topics: Animals; Antioxidants; Ascorbic Acid; beta Carotene; Brain; Calcium; Calcium-Transporting ATPases; Disease Models, Animal; Enzyme Activation; Female; Glutathione; Glutathione Peroxidase; Headache; Lipid Peroxidation; Microsomes; Nitroglycerin; Oxidative Stress; Rats; Riboflavin; Vitamin A; Vitamin E

Recently, we reported that preferential maternal-fetal vitamin C (vitC) transport across the placenta is likely to be impaired by prolonged maternal vitC deficiency. Maintenance of a basal maternal vitC supply at the expense of the fetus may impair fetal development; however, the knowledge of vitC's impact on intrauterine development is sparse. The aim of this study was to explore the effect of maternal vitC status on fetal and placental development in guinea pigs.. Twenty pregnant Dunkin Hartley guinea pigs were randomized into four groups to receive diets either sufficient (918 mg/kg CTRL) or deficient (100 mg/kg DEF) in vitC. Cesarean sections at gestational day (GD) 45 or 56 allowed for fetal and placental measurements.. At GD45, body, brain and placental weights were significantly reduced in DEF pups compared with CTRL (p < 0.05, p < 0.001 and p < 0.05, respectively). DEF plasma vitC levels were ~6% of those of CTRL (p < 0.0001), and the fetal/maternal plasma vitC ratio was significantly reduced at GD56 in the DEF animals compared with controls (p = 0.035). Placental vitC levels were reduced in DEF animals (p < 0.0001) and the ascorbate oxidation ratio and glutathione elevated compared with controls (p < 0.0001).. Although no clinical differences between CTRL and DEF pups were observed at GD56, the present data suggest that vitC plays a role in early fetal development. Although no clinical differences between CTRL and DEF pups were observed at GD56, the present data suggest that vitC plays a role in early fetal development. Low maternal vitC intake during pregnancy may compromise maternal weight gain, placental function and intrauterine development.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Diet; Disease Models, Animal; Euthanasia; Female; Fetal Development; Fetal Growth Retardation; Fetus; Guinea Pigs; Linear Models; Maternal Nutritional Physiological Phenomena; Maternal-Fetal Exchange; Placenta; Pregnancy; Sodium-Coupled Vitamin C Transporters

The intracerebral antioxidant ability of mature rats after neonatal hypoxic-ischemic (HI) brain injury was estimated using the microdialysis-electron spin resonance method.. Seven-day-old Wistar rats were subjected to a modified Levine's procedure for producing HI brain injury. After HI insult, pups were returned and reared with their dams. Seven weeks after HI insult, their intracerebral antioxidant abilities were measured using the microdialysis-electron spin resonance method after the intraperitoneal injection of 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl. Ascorbic acid, L-cysteine, and glutathione (GSH) were also determined. The rats without HI insult were used as a control.. The decay rate of 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl in the non-ligated side of the cerebral hemisphere of the HI group was significantly larger than that of the control group. The amounts of ascorbic acid in the perfusate from the non-ligated side of the HI group were about four times larger than those of the control group. The amounts of L-cysteine and GSH of the HI group were about 10 times larger than those of the control group.. The antioxidant ability in the non-ligated sides of the cerebral hemispheres of the mature rats 7 weeks after neonatal HI insult was higher than that of the control group. Higher amounts of ascorbic acid and GSH supported the higher antioxidant ability. The increase of the intracerebral antioxidant ability of the non-ligated side indicates the compensation of motor function for the lost side. The present results should offer important insights into the prognosis for hypoxic-ischemic encephalopathy.

Topics: Animals; Antioxidants; Ascorbic Acid; Birth Injuries; Cerebral Cortex; Cyclic N-Oxides; Cysteine; Disease Models, Animal; Disease Progression; Electron Spin Resonance Spectroscopy; Glutathione; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Microdialysis; Neurons; Oxidative Stress; Pyrrolidines; Rats, Wistar; Spin Labels

Seizures are a known co-occurring symptom of Alzheimer's disease, and they can accelerate cognitive and neuropathological dysfunction. Sub-optimal vitamin C (ascorbic acid) deficiency, that is low levels that do not lead the sufferer to present with clinical signs of scurvy (e.g. lethargy, hemorrhage, hyperkeratosis), are easily obtainable with insufficient dietary intake, and may contribute to the oxidative stress environment of both Alzheimer's disease and epilepsy. The purpose of this study was to test whether mice that have diminished brain ascorbic acid in addition to carrying human Alzheimer's disease mutations in the amyloid precursor protein (APP) and presenilin 1 (PSEN1) genes, had altered electrical activity in the brain (electroencephalography; EEG), and were more susceptible to pharmacologically induced seizures. Brain ascorbic acid was decreased in APP/PSEN1 mice by crossing them with sodium vitamin C transporter 2 (SVCT2) heterozygous knockout mice. These mice have an approximately 30% decrease in brain ascorbic acid due to lower levels of SVCT2 that supplies the brain with ASC. SVCT2+/-APP/PSEN1 mice had decreased ascorbic acid and increased oxidative stress in brain, increased mortality, faster seizure onset latency following treatment with kainic acid (10 mg/kg i.p.), and more ictal events following pentylenetetrazol (50 mg/kg i.p.) treatment. Furthermore, we report the entirely novel phenomenon that ascorbic acid deficiency alone increased the severity of kainic acid- and pentylenetetrazol-induced seizures. These data suggest that avoiding ascorbic acid deficiency may be particularly important in populations at increased risk for epilepsy and seizures, such as Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Brain; Disease Models, Animal; Electrodes, Implanted; Electroencephalography; Female; Humans; Kainic Acid; Male; Malondialdehyde; Mice, Knockout; Mice, Transgenic; Oxidative Stress; Pentylenetetrazole; Presenilin-1; Seizures; Sodium-Coupled Vitamin C Transporters

The GluN2B subunit of NMDA receptors (NMDARs) is an attractive drug target for therapeutic intervention in Parkinson's disease (PD). We have used whole-cell patch clamp recordings in brain slices to examine the contribution of GluN2B and GluN2D to functional NMDARs in the striatum of the unilateral 6-hydroxydopamine-lesioned mouse model of PD. We found that current/voltage relationships of NMDAR-mediated excitatory post synaptic currents were altered in a population of medium spiny projection neurons (MSNs) in the dopamine-depleted striatum. Using antagonists for GluN2B- and GluN2D-containing NMDARs, we found that GluN2B contributes to functional NMDARs in MSNs in the intact striatum and in the striatum of control mice. The function of GluN2B-containing NMDARs is however reduced in MSNs from the dopamine-depleted striatum. GluN2D is absent in MSNs from intact striatum and from control mice, but the contribution of this subunit to functional NMDARs is increased in the dopamine-depleted striatum. These changes in the subunit composition of NMDARs are associated with a decreased protein level of GluN2B and an increased level of GluN2D in the dopamine-depleted striatum. In cholinergic interneurons from the intact striatum and control mice, both GluN2B and GluN2D contribute to functional NMDARs. The functions of GluN2D, and to some extent GluN2B, are reduced in the dopamine-depleted striatum. Our findings demonstrate a cell-type specific reorganization of GluN2B and GluN2D in a mouse model of PD and suggest GluN2D as a potential target for the management of the disease.

Topics: Adrenergic Agents; Animals; Antioxidants; Ascorbic Acid; Brain Injuries; Corpus Striatum; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Excitatory Amino Acid Agents; Excitatory Postsynaptic Potentials; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Neurons; Oxidopamine; Patch-Clamp Techniques; Receptors, N-Methyl-D-Aspartate; Tyrosine 3-Monooxygenase

Subclinical vitamin C deficiency is widespread in many populations, but its role in both Alzheimer's disease and normal aging is understudied. In the present study, we decreased brain vitamin C in the APPSWE/PSEN1deltaE9 mouse model of Alzheimer's disease by crossing APP/PSEN1(+) bigenic mice with SVCT2(+/-) heterozygous knockout mice, which have lower numbers of the sodium-dependent vitamin C transporter required for neuronal vitamin C transport. SVCT2(+/-) mice performed less well on the rotarod task at both 5 and 12 months of age compared to littermates. SVCT2(+/-) and APP/PSEN1(+) mice and the combination genotype SVCT2(+/-)APP/PSEN1(+) were also impaired on multiple tests of cognitive ability (olfactory memory task, Y-maze alternation, conditioned fear, Morris water maze). In younger mice, both low vitamin C (SVCT2(+/-)) and APP/PSEN1 mutations increased brain cortex oxidative stress (malondialdehyde, protein carbonyls, F2-isoprostanes) and decreased total glutathione compared to wild-type controls. SVCT2(+/-) mice also had increased amounts of both soluble and insoluble Aβ1-42 and a higher Aβ1-42/1-40 ratio. By 14 months of age, oxidative stress levels were similar among groups, but there were more amyloid-β plaque deposits in both hippocampus and cortex of SVCT2(+/-)APP/PSEN1(+) mice compared to APP/PSEN1(+) mice with normal brain vitamin C. These data suggest that even moderate intracellular vitamin C deficiency plays an important role in accelerating amyloid pathogenesis, particularly during early stages of disease development, and that these effects are likely modulated by oxidative stress pathways.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anxiety; Ascorbic Acid; Ascorbic Acid Deficiency; Brain; Cognition Disorders; Disease Models, Animal; Female; Learning; Male; Memory; Mice, Transgenic; Motor Activity; Oxidative Stress; Peptide Fragments; Presenilin-1; Sodium-Coupled Vitamin C Transporters

Deltamethrin (DLM) is a synthetic class II pyrethroid acaricide and insecticide widely used for veterinary and agricultural purposes. However, its animal and human exposure leads to nephrotoxicity. Our experimental objective was to evaluate protective effects of ceftriaxone and/or ascorbic acid against DLM-induced renal injury in male Wistar albino rats. DLM-treated animals revealed significant alterations in serum biochemical parameters related to renal injury; urea, uric acid and creatinine. There was a significant increase in renal lipid peroxidation and a significant inhibition in antioxidant biomarkers. Moreover, DLM significantly reduced serum acetylcholinesterase (AChE) activity. In addition, It induced serum and kidney tumor necrosis factor-α (TNF-α). Both ceftriaxone and ascorbic acid protect against DLM-induced biochemical alterations in serum and renal tissue when used alone or in combination along with DLM-intoxication. Furthermore, both ceftriaxone and ascorbic acid produced synergetic nephroprotective and antioxidant effects. Therefore, it could be concluded that ceftriaxone and/or ascorbic acid administration able to minimize the toxic effects of DLM through their free radical-scavenging and potent antioxidant activity.

Topics: Acetylcholinesterase; Animals; Antioxidants; Ascorbic Acid; Ceftriaxone; Creatinine; Disease Models, Animal; Insecticides; Kidney Diseases; Lipid Peroxidation; Male; Nitriles; Oxidative Stress; Protective Agents; Pyrethrins; Rats; Rats, Wistar; Treatment Outcome; Tumor Necrosis Factor-alpha; Uric Acid

Chronic ethanol exposure is known to cause neuronal damage in both humans and experimental animal models. Ethanol treatment induces neurotoxicity via the generation of reactive oxygen species (ROS), while anthocyanins (extracted from black soybean) and ascorbic acid (vitamin C) are free radical scavengers that can be used as neuroprotective agents against ROS. In this study the underlying neuroprotective potential of black soybean anthocyanins and vitamin C was determined. For this purpose, adult rats were exposed to 10% (v/v) ethanol for 8 weeks, followed by co-treatment with anthocyanins (24 mg/kg) and vitamin C (100 mg/kg) during the last 4 weeks. Our results showed that ethanol administration increased the expression of γ -aminobutyric acid B1 receptor (GABAB1R) and induced neuronal apoptosis via alterations to the Bax/Bcl-2 ratio, release of cytochrome C and activation of caspase-3 and caspase-9. Anthocyanins alone and supplementation with vitamin C showed an additive effect in reversing the trend of apoptotic signals induced by ethanol in the cortex and hippocampus. Consequently, anthocyanins also decreased the expression of poly (ADP ribose) polymerase-1 induced by ethanol and prevented DNA damage. Furthermore, anthocyanins and vitamin C reversed the ethanol-induced expression of GABAB1R and its downstream signaling molecule phospho-cAMP response element binding protein. Moreover, histopathology and immunohistochemistry results showed that anthocyanins and vitamin C significantly reduced ethanol-induced neuronal cell death. Our study revealed a neuroprotective role of anthocyanins and vitamin C via modulation of GABAB1R expression in the adult brain. Hence, we suggest that anthocyanins or co-treatment with anthocyanins and vitamin C may be a new and potentially effective neuroprotective agent for alcohol abuse.

Topics: Animals; Anthocyanins; Antioxidants; Ascorbic Acid; Brain; Caspase 3; Central Nervous System Depressants; CREB-Binding Protein; Disease Models, Animal; Drug Therapy, Combination; Ethanol; Male; Neurodegenerative Diseases; Rats; Rats, Sprague-Dawley; Receptors, GABA-B; Signal Transduction

Dysfunctional inflammation following traumatic hemorrhage can lead to multiple-organ failure and death. In our polytrauma swine model, lyophilized plasma (LP) reconstituted with sterile water and ascorbic acid suppressed systemic inflammation and attenuated DNA damage. However, it remains unknown whether the inflammatory response is affected by the type of fluid used to reconstitute LP. We hypothesized that common resuscitation fluids such as normal saline (LP-NS), lactated Ringer's solution (LP-LR), Hextend (LP-HX), or sterile water (LP-SW) would yield similar inflammation profiles and DNA damage following LP reconstitution and transfusion.. This was a randomized, prospective, blinded animal study. LP was reconstituted to 50% of original volume with NS, LR, HX, or SW buffered with 15-mM ascorbic acid. Forty swine were subjected to a validated model of polytrauma, hemorrhagic shock, and Grade V liver injury and resuscitated with LP. Serum interleukin 6 (IL-6), IL-10, plasma C-reactive protein, and 8-hydroxy-2-deoxyguanosine concentrations were assessed for systemic inflammation and DNA damage at baseline, 2 hours, and 4 hours following liver injury. Lung inflammation was evaluated by Real Time Polymerize Chain Reaction (RT-PCR).. Reconstituted LP pH was similar between groups before resuscitation. IL-6 and IL-10 increased at 2 hours and 4 hours compared with baseline in all groups (p < 0.017). DNA damage increased at 2 hours and 4 hours compared with baseline and from 2 hours to 4 hours in the LP-NS, LP-LR, and LP-SW groups (all p < 0.017). Animals resuscitated with LP-HX not only demonstrated increased DNA damage at 4 hours versus baseline but also had the lowest C-reactive protein level at 2 hours and 4-hours (p < 0.017). Overall, differences between groups were similar for DNA damage and lung inflammation.. Reconstitution fluid type does not affect inflammatory cytokine profiles or DNA damage following LP transfusion in this swine polytrauma model. Based on universal availability, these data suggest that sterile water is the most logical choice for LP reconstitution in humans.. Prognostic, level II.

Topics: Animals; Antioxidants; Ascorbic Acid; C-Reactive Protein; Disease Models, Animal; DNA Damage; Female; Femoral Fractures; Fluid Therapy; Freeze Drying; Hemorrhage; Hydrogen-Ion Concentration; Inflammation; Liver; Lung; Oxidative Stress; Plasma; Prospective Studies; Random Allocation; Real-Time Polymerase Chain Reaction; Swine; Water

We investigated the effects of ascorbic acid on depressive-like behavior induced by tumor necrosis factor (TNF-α) in mice. Additionally, we examined the effects of combined administration of ascorbic acid and antidepressants, MK-801 and 7-nitroindazole in mice exposed or not to TNF-α and the capacity of TNF-α and ascorbic acid to modulate hippocampal and cerebrocortical phosphorylation of extracellular signal-regulated kinase (ERK), p38(MAPK) and c-Jun N-terminal kinase (JNK). In control animals, ascorbic acid reduced the immobility time in the tail suspension test (TST). Unilateral intracerebroventricular administration of TNF-α produced a depressive-like behavior in the TST, and the treatment with ascorbic acid prevented this effect. Sub-effective dose of ascorbic acid combined with sub-effective doses of fluoxetine, imipramine, bupropion, MK-801 or 7-nitroindazole produced a synergistic antidepressant-like effect in mice exposed or not to TNF-α. No treatment caused significant alterations in the locomotor activity of mice. Administration of TNF-α increased the phosphorylation of p38(MAPK) in hippocampus and cerebral cortex, and the treatment with ascorbic acid prevented this effect. Ascorbic acid increased phosphorylation of ERK1 in the hippocampus of saline- and TNF-α-treated animals, however it did not produce alterations in the cerebral cortex. No effects on phosphorylation of ERK2 or JNK were found. The observed effect of ascorbic acid seems to be associated, at least partially, with a reduced p38(MAPK) phosphorylation, activation of the monoaminergic systems as well as inhibition of N-methyl-D-aspartate (NMDA) receptors and nitric oxide (NO) synthesis.

Topics: Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Exploratory Behavior; Female; Mice; Mitogen-Activated Protein Kinase 14; Phenotype; Signal Transduction; Tumor Necrosis Factor-alpha

Delayed treatment of stroke with recombinant tissue plasminogen activator (r-tPA) induces overexpression of matrix metalloproteinase 9 (MMP-9) which leads to breakdown of the blood-brain barrier (BBB) and causes more injuries to the brain parenchyma. In this study, the effect of ascorbic acid (AA), an antioxidant agent, on the delayed administration of r-tPA in a rat model of permanent middle cerebral artery occlusion (MCAO) was investigated. Forty male rats were randomly divided into four groups: untreated control rats (ischaemic animals), AA-treated (500 mg/kg; 5 hr after stroke) rats, r-tPA-treated (5 hr after stroke 1 mg/kg) rats and rats treated with the combination of AA and r-tPA. Middle cerebral artery occlusion was induced by occluding the right middle cerebral artery (MCA). Infarct size, BBB, brain oedema and the levels of MMP-9 were measured at the end of study. Neurological deficits were evaluated at 24 and 48 hr after stroke. Compared to the control or r-tPA-treated animals, AA alone (p < 0.001) or in combination with r-tPA (p < 0.05) significantly decreased infarct volume. Ascorbic acid alone or r-tPA + AA significantly reduced BBB permeability (p < 0.05), levels of MMP-9 (p < 0.05 versus control; p < 0.01 versus r-tPA) and brain oedema (p < 0.001) when compared to either the control or the r-tPA-treated animals. Latency to the removal of sticky labels from the forepaw was also significantly decreased after the administration of AA + r-tPA (p < 0.05) at 24 or 48 hr after stroke. Based on our data, acute treatment with AA may be considered as a useful candidate to reduce the side effects of delayed application of r-tPA in stroke therapy.

Topics: Animals; Antioxidants; Ascorbic Acid; Behavior, Animal; Blood-Brain Barrier; Brain; Brain Edema; Capillary Permeability; Disease Models, Animal; Drug Administration Schedule; Fibrinolytic Agents; Infarction, Middle Cerebral Artery; Male; Matrix Metalloproteinase 9; Motor Activity; Rats; Recombinant Proteins; Thrombolytic Therapy; Time Factors; Time-to-Treatment; Tissue Plasminogen Activator

This study investigated whether exercise or antioxidant supplementation with vitamin C and E during exercise affects bone structure and markers of bone metabolism in obese rat. Sprague-Dawley rats, 6-week old, were fed a normal-fat diet (NF, 10 % kcal as fat) and a high-fat diet (HF, 45 % with extra fat from lard) ad libitum for 14 weeks. Then, rats on the high-fat diet were assigned randomly to three treatment groups for additional 12 weeks with forced exercise: HF; HF + exercise (HF + Ex); and HF with vitamin C (0.5 g ascorbate/kg diet) and vitamin E (0.4 g α-tocopherol acetate/kg diet) supplementation + exercise (HF + Ex + VCE). At the end of the study, body weight and fat (%) were similar among NF, HF + Ex, and HF + Ex + VCE, whereas HF had greater body weight and fat (%) than other groups. Compared to NF, HF had elevated serum leptin, tartrate-resistant acid phosphatase (TRAP), and IGF-1; increased trabecular separation and structural model index; and lowered bone mineral density, trabecular connectivity density, and trabecular number in distal femur, while HF + Ex and HF + Ex + VCE had elevated serum TRAP and decreased bone volume/total volume and trabecular number of distal femurs. Compared to HF, HF + Ex and HF + Ex + VCE had decreased serum TRAP and osteocalcin and improved bone structural properties of the distal femur. These findings suggest that exercise, while decreasing body fat, does not fully protect against the negative skeletal effects of existing obesity induced by a high-fat diet. Furthermore, vitamin C and E supplementation has no additional benefits on bone structural properties during exercise.

Topics: Adiposity; Animals; Antioxidants; Ascorbic Acid; Bone and Bones; Bone Density; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Obesity; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Vitamin A; X-Ray Microtomography

Several data suggest that excitotoxicity due to excessive glutamatergic neurotransmission may be an important factor in the mechanisms of motor neuron (MN) death occurring in amyotrophic lateral sclerosis (ALS). We have previously shown that the overactivation of the Ca(2+)-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) glutamate receptor type, through the continuous infusion of AMPA in the lumbar spinal cord of adult rats during several days, results in progressive rear limb paralysis and bilateral MN degeneration. Because it has been shown that energy failure and oxidative stress are involved in MN degeneration, in both ALS and experimental models of spinal MN degeneration, including excitotoxicity, in this work we tested the protective effect of the energy substrates pyruvate and β-hydroxybutyrate (βHB) and the antioxidants glutathione ethyl ester (GEE) and ascorbate in this chronic AMPA-induced neurodegeneration.. AMPA infusion induced remarkable progressive motor deficits, assessed by two motor tasks, that by day seven reach bilateral rear limb paralysis. These effects correlate with the death of >80% of lumbar spinal MNs in the infused and the neighbor spinal cord segments, as well as with notable astrogliosis in the ventral horns, detected by glial fibrillary acidic protein immunohistochemistry. Co-infusion with pyruvate or βHB notably prevented the motor deficits and paralysis, decreased MN loss to <25% and completely prevented the induction of astrogliosis. In contrast, the antioxidants tested were ineffective regarding all parameters analyzed.. Chronic progressive excitotoxicity due to AMPA receptors overactivation results in MN death and astrogliosis, with consequent motor deficits and paralysis. Because of the notable protection against these effects exerted by pyruvate and βHB, which are well established mitochondrial energy substrates, we conclude that deficits in mitochondrial energy metabolism are an important factor in the mechanisms of this slowly developed excitotoxic MN death, while the lack of protective effect of the antioxidants indicates that oxidative stress seems to be less significant factor. Because excitotoxicity may be involved in MN degeneration in ALS, these findings suggest possible preventive or therapeutic strategies for the disease.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Antioxidants; Ascorbic Acid; Cell Death; Disease Models, Animal; Extremities; Gliosis; Glutathione; Hydroxybutyrates; Male; Mitochondria; Motor Activity; Motor Neurons; Nerve Degeneration; Neuroprotection; Oxidative Stress; Paralysis; Pyruvic Acid; Rats; Rats, Wistar; Receptors, AMPA; Spinal Cord; Treatment Outcome

The developing brain of a neonate is particularly susceptible to damage by vitamin C deficiency because of its rapid growth and immature antioxidant system. Cognitive impairment and sensory motor deficits are found in the adult brain upon vitamin C deficiency. Therefore, the aim of this study was to clarify the role of vitamin C in its own right and its related mechanisms in Gulo(-/-) mice incapable of synthesizing vitamin C.. When vitamin C supplementation was ceased for 2 weeks until delivery, stillbirths and a significant reduction in neonatal mice were observed and the growth of neonates was remarkably decreased. In addition, intraparenchymal hemorrhages were found in most of the brains, especially in the stillborn neonates. In addition, the levels of malondialdehyde (MDA) and 8-isoprostanes were increased and structural abnormalities were found in the cortex, hippocampus, and cerebellum. Especially, vitamin C deficiency caused the failure of or a delay in the formation of cerebellar fissures accompanied by abnormal foliation and altered Purkinje cell alignment. In the developed adult brains from vitamin C-deficient Gulo(-/-) mice, the levels of glutathione, MDA, nitrate, IL-6, TNF-α, and Bax were increased and the expression of the GABRA6 and calbindin-28k was decreased. Due to atrophy of the granule and Purkinje cells, the motor behavior of vitamin C-deficient Gulo(-/-) mice declined.. Vitamin C deficiency during gestation induces intraparenchymal hemorrhages and severe defects in the development of the cerebellum. In fully developed brains, it induces the functional impairment by altering the cellular composition in the cerebellum.

Topics: Animals; Animals, Newborn; Ascorbic Acid; Ascorbic Acid Deficiency; Brain; Brain-Derived Neurotrophic Factor; Cerebellum; Disease Models, Animal; Interleukin-6; Intracranial Hemorrhages; L-Gulonolactone Oxidase; Mice; Mice, Knockout; Motor Activity; Neurodevelopmental Disorders; Oxidative Stress; Stillbirth; Tumor Necrosis Factor-alpha

Amphotericin B (Ampho B) isa fungicidal drug that causes cell wall injury. Pharmacological ascorbate induces the extracellular prooxidants, which might enter the Ampho B-induced cell wall porosity and act synergistically.W e tested low-dose Ampho B with a short course of pharmacological ascorbate using a mouse model of sepsis preconditioned with an injection of Candida albicans 6 h prior to cecal ligation and puncture (CLP). In this model, candidemia reappeared as early as 6 h after CLP with a predictably high mortality rate. This characteristic mimics sepsis in the phase of immunosuppression inpatients. Using the model, at 12- and 18-h post-CLP, we administered isotonic (pH neutralized) pharmacological ascorbate intravenously with low-dose Ampho B or sodium deoxycholate, vehicle-controlled, administered IP. The survival rate of low-dose Ampho B plus ascorbate was 53%, compared with < 11% for low-dose Ampho B or high-dose Ampho B alone. In addition, a beneficial effect was demonstrated in terms of kidney damage,liver injury, spleen histopathology, and serum markers at 24 h after CLP. Kidney injury was less severe in low-dose Ampho B plus ascorbate combination therapy due to less severe sepsis. Moreover, ascorbate enhanced the effectiveness of phagocytosis against C. albicans in human phagocytic cells. Taken together, the data indicate that the new mouse model simulates sepsis-induced immunosuppression and that the combination of pharmacological ascorbate with an antifungal drug is a potentially effective treatment that may reduce nephrotoxicity, and perhaps also increase fungicidal activity in patients with systemic candidiasis caused by Candida albicans.

Topics: Amphotericin B; Animals; Ascorbic Acid; Candidemia; Disease Models, Animal; Drug Combinations; Kidney; Liver; Male; Mice, Inbred BALB C; Sepsis; Spleen

Visceral leishmaniasis caused by Leishmania donovani is the most severe systemic form of the disease. There are still no vaccines available for humans and there are limitations associated with the current therapeutic regimens for leishmaniasis. Recently, we reported functional importance of Arabino-1, 4-lactone oxidase (ALO) enzyme from L. donovani involved in ascorbate biosynthesis pathway. In this study, we have shown that ΔALO parasites do not affect the ability of null mutants to invade visceral organs but severely impair parasite persistence beyond 16 week in BALB/c mice and hence are safe as an immunogen. Both short term (5 week) and long term (20 week) immunization with ΔALO parasites conferred sustained protection against virulent challenge in BALB/c mice, activated splenocytes and resulted in induction of pro-inflammatory cytokine response. Protection in immunized mice after challenge correlated with the stimulation of IFN-γ producing CD4(+) and CD8(+) T cells. Antigen-mediated cell immunity correlated with robust nitrite and superoxide generation, macrophage-derived oxidants critical in controlling Leishmania infection. Our data shows that live attenuated ΔALO parasites are safe, induce protective immunity and can provide sustained protection against Leishmania donovani. We further conclude that the parasites attenuated in their anti-oxidative defence mechanism can be exploited as vaccine candidates.

Topics: Animals; Antibodies, Protozoan; Antigens, Protozoan; Ascorbic Acid; Cytokines; Disease Models, Animal; Female; Immunization; Immunoglobulin G; Leishmania donovani; Leishmaniasis Vaccines; Leishmaniasis, Visceral; Mice; Mutation; Nitric Oxide; Parasite Load; Reactive Oxygen Species; T-Lymphocyte Subsets

The attendant side effects associated with some synthetic drugs used in the management of diseases have led to the search for safer alternative therapies that are relatively cheaper with minimal side effects.. The methanol extract of Calliandra portoricensis root bark (CPRB) was orally administered at the doses of 5, 10, 20, and 25 mg/kg body weight for 14 consecutive days of 5 rats in each group. The control rats were given distilled water.. The 95% methanol extract of CPRB significantly (p<0.05) scavenged NO• and OH• radicals compared to vitamin C. The level of lipid peroxidative products (malondialdehyde, MDA) was significantly (p<0.05) attenuated in a dose-dependent manner. Antioxidant enzymes including superoxide dismutase and catalase were significantly (p<0.05) exercabated in both liver and kidney in a dose-dependent manner. Furthermore, serum AST, alanine aminotransaminase and γ-glutamyltransferase (GGT) activity depicted non-significant (p>0.05) increase in the treated animals. The histological examination showed mild vacuolar, portal congestion and cell infiltration by mononuclear of the hepatic tissues.. The study then concluded that a therapeutic dose of the methanol extract of CPRB triggered the antioxidant defence systems in male rats. It is, therefore, recommended that the doses should be carefully and clinically chosen because higher doses may cause some health risks.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Fabaceae; Free Radical Scavengers; Hydroxides; Inhibitory Concentration 50; Kidney; Lipid Peroxidation; Liver; Male; Malondialdehyde; Nitric Oxide; Plant Extracts; Plant Roots; Rats; Rats, Wistar

Venezuelan equine encephalitis (VEE) virus causes an acute central nervous system infection in human and animals. Melatonin (MLT), minocycline (MIN) and ascorbic acid (AA) have been shown to have antiviral activities in experimental infections; however, the mechanisms involved are poorly studied. Therefore, the aim of this study was to determine the effects of those compounds on the viral titers, NO production and lipid peroxidation in the brain of mice and neuroblastoma cultures infected by VEE virus. Infected mouse (10 LD50) were treated with MLT (500 μg/kg bw), MIN (50mg/kg bw) or AA (50mg/kg bw). Infected neuroblastoma cultures (MOI: 1); MLT: 0.5, 1, 5mM, MIN: 0.1, 0.2, 2 μM or AA: 25, 50, 75 μM. Brains were obtained at days 1, 3 and 5. In addition, survival rate of infected treated mice was also analyzed. Viral replication was determined by the plaque formation technique. NO and lipid peroxidation were measured by Griess׳ reaction and thiobarbituric acid assay respectively. Increased viral replication, NO production and lipid peroxidation were observed in both, infected brain and neuroblastoma cell cultures compared with uninfected controls. Those effects were diminished by the studied treatments. In addition, increased survival rate (50%) in treated infected animals compared with untreated infected mice (0%) was found. MLT, MIN and AA have an antiviral effect involving their anti-oxidant properties, and suggesting a potential use of these compounds for human VEE virus infection.

Topics: Animals; Antiviral Agents; Ascorbic Acid; Brain; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis Virus, Venezuelan Equine; Encephalomyelitis, Venezuelan Equine; Lipid Peroxidation; Male; Melatonin; Mice; Minocycline; Neuroblastoma; Neuroprotective Agents; Nitric Oxide; Oxidative Stress; Survival Rate; Treatment Outcome; Viral Load

In the present study, tympanic membranes (TM) harvested from myringotomized rats were analyzed histopathologically to compare the systemic and local effects of ascorbic acid on the development of myringosclerosis.. Forty male Wistar-Albino rats weighing between 350-400 g were included in this study. Under otomicroscopic examination, a standard 2-mm myringotomy incision was made on the posteroinferior quadrant of the TM of both ears. Rats were randomized into five groups as control, topical ascorbic acid 50 mg/kg, systemic ascorbic acid 50, 100, and 200 mg/kg groups, each group containing eight rats. On the 15th day of the study, the rats were decapitated, and bullas of the rats were extracted. Sections were stained with hematoxylin-eosin and examined through light microscopy. Inflammation, distribution width of plaques, edema, and neovascularization were observed on the lamina propria. Thickness of the TM was evaluated under the microscope and scored semiquantitatively.. When intergroup comparisons of parameters related to total TM thickness were performed, differences between the control group and topical AA (ascorbic acid) or systemic treatment groups were found to be statistically significant (p<0.005). A statistically significant difference was detected among control, topical and systemic 200 mg/kg ascorbic acid groups for the edematous lamina propria (p=0.003 and p<0.05, respectively).. For the total TM thickness, systemic and topical ascorbic acid use was effective when compared with the control group. It has been concluded that systemic use of higher doses of (200 mg/kg) ascorbic acid is beneficial in the resolution of the edematous lamina propria.

Topics: Administration, Topical; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Male; Myringosclerosis; Rats; Rats, Wistar; Tympanic Membrane; Tympanic Membrane Perforation; Wounds and Injuries

The benefits of regular exercise on brain health are undeniable. Long-term exercise increases the production of reactive oxygen species in brain. Therefore, athletes often consume antioxidant supplements to remedy exercise-related damage and fatigue during exercise. The aim of this study is to evaluate the role of ascorbic acid in the effects of different intensities of swimming exercise on the brain susceptibility to experimental epilepsy in rats. Ascorbic acid was administered intraperitoneally (ip) during three different swimming exercise programme for 90 days (15 min, 30 min, 90 min/day). The anticonvulsant activity regarding the frequency of epileptiform activity appeared in the 80 min after 500 units intracortical penicillin injection in 30 min and 90 min/day exercise groups. The administration of ascorbic acid (100 mg/kg, ip) did not alter the anticonvulsant properties seen in the in short-duration (15 min/day) swimming exercise group. The amplitude of epileptiform activity also became significant in the 110 and 120 min after penicillin injection in the moderate (30 min/day) and long duration (60 min/day) groups, respectively. The results of the present study provide electrophysiologic evidence that long-term administration of ascorbic acid causes anticonvulsant activities in the moderate and long-duration swimming exercise. Antioxidant supplementation such as ascorbic acid might be suggested for moderate and long-duration swimming exercise in epilepsy.

Topics: Animals; Anticonvulsants; Ascorbic Acid; Brain; Disease Models, Animal; Electroencephalography; Epilepsy; Exercise Therapy; Male; Physical Conditioning, Animal; Rats, Wistar; Swimming; Time Factors

Our previous studies demonstrated that the combination of treatment with ascorbic acid (AsA) and X‑ray irradiation results in increased apoptosis in HL60 cells. The present study was performed to investigate the effects of the combined use of AsA and X‑ray irradiation on epithelial cancer and sarcoma cells, and its potential use in future clinical treatment. X‑ray irradiation combined with AsA treatment resulted in increased suppression of cell growth of HT1080, SAS and A549 cells in vitro compared with X‑ray irradiation alone. The combined treatment also suppressed tumor growth in implanted HT‑1080 cells in vivo. Using annexin V/propidium iodide staining and the detection of activated caspase 3, it was found that X‑ray irradiation increased the apoptotic rate of HT1080 cells and resulted in G2/M arrest. However, apoptosis in the HT1080 cells treated with 5 mM AsA remained unchanged, and no changes were observed in the G2/M fraction. By contrast, AsA treatment caused increased suppression of proliferation compared with X‑ray irradiation. These results suggested that 5 mM AsA slowed the cell cycle and reduced tumor growth. Therefore, X‑ray irradiation combined with AsA treatment may be effective against epithelial cancer and sarcoma cells.

Topics: Animals; Apoptosis; Ascorbic Acid; Caspase 3; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Humans; Mice; X-Rays; Xenograft Model Antitumor Assays

This study investigated the ability of hesperetin, a natural flavonoid, to prevent selenite-induced cataracts in a rat model.. Animals were divided into four treatment groups: G1 (control group), G2 (hesperetin-treated group), G3 (selenite-induced cataract group), and G4 (hesperetin-treated selenite cataract group). Animals in the G1 and G3 groups were injected with vehicle alone, while those in the G2 and G4 groups received a subcutaneous injection of hesperetin (0.4 μg/g bodyweight on days 0, 1, and 2, corresponding to P13, P14, and P15). Sodium selenite (20 μmol/g bodyweight given 4 h after the hesperetin injection on day 0) was administered to rats in the G3 and G4 groups to induce cataract formation. Lenses were observed with slit-lamp microscopy, and filensin degradation and the decreased glutathione (GSH) and ascorbic acid levels in the lens were measured on day 6.. Lenses in the G3 group showed mature central opacity, while some lenses in the G4 group lacked central opacity and had lower-grade cataracts. All lenses in the G1 and G2 groups were transparent. Expression of the 94 kDa and 50 kDa forms of filensin was significantly decreased in the lenses in the G3 group compared with those in the G1 and G2 groups. Interestingly, these forms of filensin rescued the rat lenses in the G4 group. In the G3 group lenses, the GSH and ascorbic acid levels were lower than in the control group but were normalized in the G4 group lenses.. The results suggest that hesperetin can prevent selenite-induced cataract formation.

Topics: Animals; Antioxidants; Ascorbic Acid; Cataract; Disease Models, Animal; Eye Proteins; Female; Free Radical Scavengers; Glutathione; Hesperidin; Intermediate Filament Proteins; Lens, Crystalline; Oxidative Stress; Proteolysis; Rats; Rats, Sprague-Dawley; Sodium Selenite

In our previous studies, veratric acid (VA) shows beneficial effect on hypertension and its associated dyslipidaemia. In continuation, this study was designed to investigate the effect of VA, one of the major benzoic acid derivatives from vegetables and fruits, on cardiovascular remodelling in hypertensive rats, primarily assessed by functional studies using Langendorff isolated heart system and organ bath system. Hypertension was induced in male albino Wistar rats by oral administration of N ω -nitro-l-arginine methyl ester hydrochloride (l-NAME) (40 mg/kg body weight (b.w.)) in drinking water for 4 weeks. VA was orally administered at a dose of 40 mg/kg b.w. l-NAME-treated rats showed impaired cardiac ventricular and vascular function, evaluated by Langendorff isolated heart system and organ bath studies, respectively; a significant increase in the lipid peroxidation products such as thiobarbituric acid-reactive substances and lipid hydroperoxides in aorta; and a significant decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase and levels of GSH, vitamin C and vitamin E in aorta. Fibrotic remodelling of the aorta and heart were assessed by Masson's Trichrome staining and Van Gieson's staining, respectively. In addition, l-NAME rats showed increased heart fibronectin expression assessed by immunohistochemical analysis. VA supplementation throughout the experimental period significantly normalised cardiovascular function, oxidative stress, antioxidant status and fibrotic remodelling of tissues. These results of the present study conclude that VA acts as a protective agent against hypertension-associated cardiovascular remodelling.

Topics: Administration, Oral; Animals; Antioxidants; Aorta; Ascorbic Acid; Cardiovascular Diseases; Cardiovascular System; Catalase; Disease Models, Animal; Dose-Response Relationship, Drug; Fruit; Glutathione; Glutathione Peroxidase; Hypertension; Lipid Peroxidation; Lipid Peroxides; Male; NG-Nitroarginine Methyl Ester; Oxidative Stress; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Vanillic Acid; Vascular Remodeling; Vegetables; Vitamin E

Failure in energy metabolism and oxidative damage are associated with Huntington's disease (HD). Ascorbic acid released during synaptic activity inhibits use of neuronal glucose, favouring lactate uptake to sustain brain activity. Here, we observe a decreased expression of GLUT3 in STHdhQ111 cells (HD cells) and R6/2 mice (HD mice). Localisation of GLUT3 is decreased at the plasma membrane in HD cells affecting the modulation of glucose uptake by ascorbic acid. An ascorbic acid analogue without antioxidant activity is able to inhibit glucose uptake in HD cells. The impaired modulation of glucose uptake by ascorbic acid is directly related to ROS levels indicating that oxidative stress sequesters the ability of ascorbic acid to modulate glucose utilisation. Therefore, in HD, a decrease in GLUT3 localisation at the plasma membrane would contribute to an altered neuronal glucose uptake during resting periods while redox imbalance should contribute to metabolic failure during synaptic activity.

Topics: Animals; Antioxidants; Ascorbic Acid; Blotting, Western; Cell Membrane; Cells, Cultured; Disease Models, Animal; Energy Metabolism; Female; Fluorescent Antibody Technique; Glucose; Glucose Transporter Type 3; Huntington Disease; Male; Mice; Neurons; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

A complex of lincomycin was synthesized with technetium-99m. The synthesis was carried out by using SnCl2.2H2O as reducing agent and ascorbic acid as stabilizer. The effect of various parameters such as amount of ligand/reducing agent, pH value and reaction time on radio labeling process was studied. The characterization of the (99m)Tc-Lincomycin was performed by HPLC and electrophoresis Biodistribution studies were carried out by analyzing the model of bacterial infectious rats (Sprague-Dawley). The uptake of infectious lesions at different time interval was also studied by using scintigraphic technique. The complex showed effective target to non-target ratio for various inflammatory or infectious lesions. The (99m)Tc-Lincomycin effective binding to living bacteria and could be used successfully as an infection imaging agent.

Topics: Animals; Anti-Bacterial Agents; Ascorbic Acid; Chromatography, High Pressure Liquid; Disease Models, Animal; Excipients; Lincomycin; Male; Oxidation-Reduction; Rabbits; Radioisotopes; Radionuclide Imaging; Radiopharmaceuticals; Rats, Sprague-Dawley; Reducing Agents; Staphylococcal Infections; Staphylococcus aureus; Technetium; Tin Compounds; Tissue Distribution

Vitamin C has efficient antioxidant properties and is involved in important physiological processes such as collagen synthesis. As such, vitamin C deficiency leads to serious complications, including vascular diseases. The aim of this study was to investigate the effects of vitamin C treatment on collar-induced intimal thickening. Rabbits were fed a normocholesterolemic diet and a non-occlusive silicon collar was placed around the left carotid artery for 3, 7, and 14 days. The rabbits were treated with or without vitamin C (150 mg/kg/day). Collar-induced intimal thickening became apparent at day 7. The effect of the collar on intimal thickening was more prominent at day 14. Vitamin C treatment significantly inhibited collar-induced intimal thickening at day 14. The placement of the collar around the carotid artery decreased maximum contractile responses against contractile agents (KCl, phenylephrine, 5-hydroxytryptamine). The effect of the collar on contractile responses was enhanced as days elapsed. Decreased contractile responses of collared carotid arteries normalized at day 14 in the vitamin C treatment group. Vitamin C treatment also restored sensitivity to phenylephrine. The collar also significantly decreased acetylcholine-induced relaxations at day 3 and day 7. Acetylcholine-induced relaxations normalized in collared-arteries in the placebo group at day 14. Vitamin C treatment significantly increased acetylcholine-induced relaxations of both normal and collared carotid arteries at day 14. MMP-9 expression increased in collared arteries at day 3 and day 7 but did not change at day 14. MMP-2 expression increased in collared arteries at day 14. However, vitamin C treatment reduced collar-stimulated expression of MMP-2 at day 14. These findings indicate that vitamin C may have potentially beneficial effects on the early stages of atherosclerosis. Furthermore these results, for the first time, may indicate that vitamin C can also normalize decreased contractile response through perivascular collar placement.

Topics: Animals; Antioxidants; Ascorbic Acid; Carotid Arteries; Carotid Artery Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neointima; Plaque, Atherosclerotic; Rabbits; Time Factors; Vascular Remodeling; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

In our overall goal to develop multifunctional dopamine D2/D3 agonist drugs for the treatment of Parkinson's disease (PD), we previously synthesized potent D3 preferring agonist D-264 (1a), which exhibited neuroprotective properties in two animal models of PD. To enhance the in vivo efficacy of 1a, a structure-activity relationship study was carried out. Competitive binding and [(35)S]GTPγS functional assays identified compound (-)-9b as one of the lead molecules with preferential D3 agonist activity (EC50(GTPγS); D3 = 0.10 nM; D2/D3 (EC50): 159). Compounds (-)-9b and (-)-8b exhibited high in vivo activity in two PD animal models, reserpinized and 6-hydroxydopamine (OHDA)-induced unilateral lesioned rats. On the other hand, 1a failed to show any in vivo activity in these models unless the compound was dissolved in 5-10% beta-hydroxy propyl cyclodextrin solution. Lead compounds exhibited appreciable radical scavenging activity. In vitro experiments with dopaminergic MN9D cells indicated neuroprotection by both 1a and (-)-9b from toxicity of MPP+.

Topics: Animals; Benzothiazoles; Biphenyl Compounds; Cell Line; Disease Models, Animal; Mice; Neuroprotective Agents; Parkinson Disease; Piperazines; Rats; Structure-Activity Relationship; Thiazoles

CV247 (CV), an aqueous mixture of copper (Cu) and manganese (Mn) gluconates, vitamin C and sodium salicylate increased the antitumour effects of cisplatin (CDPP; cis-diamminedichloroplatinum) in vitro. We hypothesized that the antioxidant and cyclooxygenase-2 (COX-2; prostaglandin-endoperoxide synthase 2) inhibitory components of CV can protect the kidneys from CDPP nephrotoxicity in rats. CDPP (6.5 mg/kg, intraperitoneally) slightly elevated serum creatinine (Crea) and blood urea nitrogen (BUN) 12 days after treatment. Kidney histology demonstrated extensive tubular epithelial damage and COX-2 immunoreactivity increased 14 days after treatment. A large amount of platinum (Pt) accumulated in the kidney of CDPP-treated rats. Furthermore, CDPP decreased renal iron (Fe), molybdenum (Mo), zinc (Zn), Cu and Mn concentrations and increased plasma Fe and Cu concentrations. CDPP elevated plasma free radical concentration. Treatment with CV alone for 14 days (twice 3 ml/kg/day orally) did not influence these parameters. Chronic CV administration after CDPP reduced renal histological damage and slightly decreased COX-2 immunoreactivity, while failed to prevent the increase in Crea and BUN levels. Blood free radical concentration was reduced, that is, CV improved redox homeostasis. CV restored plasma Fe and renal Fe, Mo and Zn, while decreased Pt and elevated Cu and Mn concentrations in the kidney. Besides the known synergistic antitumour effects with CDPP, CV partially protected the kidneys from CDPP nephrotoxicity probably through its antioxidant effect.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Blood Urea Nitrogen; Cisplatin; Creatinine; Cyclooxygenase 2; Cytoprotection; Disease Models, Animal; Gluconates; Kidney; Kidney Diseases; Male; Metals; Oxidation-Reduction; Oxidative Stress; Rats, Wistar; Reactive Oxygen Species; Sodium Salicylate; Time Factors

Owing to its ability to inactivate harmful radicals, vitamin C plays a key role in antioxidant defense. The bioavailability of this vitamin depends upon the nutritional intake and its uptake by cells, mainly through the sodium-dependent transporters SVCT1/Svct1 and SVCT2/Svct2 (human/rat). Here, we investigated the effect of liver metabolic/oxidative stress on the expression of these transporters in extrahepatic tissues.. In Zucker rats, used here as a model of liver steatosis, Svct1-2 mRNA levels were similar in obese and lean animals, except for lung tissue, where Svct2 was up-regulated. Diabetes mellitus, developed by streptozotocin administration, was accompanied by a down-regulation of Svct1 in liver and kidney, together with a down-regulation of Svct2 in kidney and brain. Complete obstructive cholestasis due to bile duct ligation for 1 week induced a significant down-regulation of both Svct1 and Svct2 in ileum, whereas Svct2 was up-regulated in liver, and no significant changes in the expression of either transporter were found in kidney, brain or lung. In rat hepatoma Can-10 cells, bile acids, but not the FXR agonist GW4064, induced an up-regulation of Svct1 and Svct2. In human hepatoma Alexander cells transfected with FXR/RXRα/OATP1B1, neither GW4064 nor unconjugated or glycine-/taurine-conjugated major bile acids were able to up-regulate either SVCT1 or SVCT2.. Pathological circumstances characterized by the presence of metabolic/oxidative stress in the liver induce different responses in the expression of ascorbic acid transporters in intrahepatic and extrahepatic tissues, which may affect the overall bioavailability and cellular uptake of this vitamin.

Topics: Animals; Ascorbic Acid; Bile Acids and Salts; Biological Availability; Carcinoma, Hepatocellular; Cell Line, Tumor; Cholestasis; Diabetes Mellitus, Experimental; Disease Models, Animal; Fatty Liver; Gene Expression; Humans; Kidney; Liver; Liver Neoplasms; Male; Obesity; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Zucker; RNA, Messenger; Sodium-Coupled Vitamin C Transporters; Stress, Physiological

Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis characterized by diminished cholesterol and increased 7-dehydrocholesterol (7-DHC) levels. 7-Dehydrocholesterol is highly reactive, giving rise to biologically active oxysterols.. 7-DHC-derived oxysterols were measured in fibroblasts from SLOS patients and an in vivo SLOS rodent model using high-performance liquid chromatography tandem mass spectrometry. Expression of lipid biosynthesis genes was ascertained by quantitative polymerase chain reaction and Western blot. The effects of an antioxidant mixture of vitamin A, coenzyme Q10, vitamin C, and vitamin E were evaluated for their potential to reduce formation of 7-DHC oxysterols in fibroblast from SLOS patients. Finally, the effect of maternal feeding of vitamin E enriched diet was ascertained in the brain and liver of newborn SLOS mice.. In cultured human SLOS fibroblasts, the antioxidant mixture led to decreased levels of the 7-DHC-derived oxysterol, 3β,5α-dihydroxycholest-7-en-6-one. Furthermore, gene expression changes in SLOS human fibroblasts were normalized with antioxidant treatment. The active ingredient appeared to be vitamin E, as even at low concentrations, it significantly decreased 3β,5α-dihydroxycholest-7-en-6-one levels. In addition, analyzing a mouse SLOS model revealed that feeding a vitamin E enriched diet to pregnant female mice led to a decrease in oxysterol formation in brain and liver tissues of the newborn Dhcr7-knockout pups.. Considering the adverse effects of 7-DHC-derived oxysterols in neuronal and glial cultures and the positive effects of antioxidants in patient cell cultures and the transgenic mouse model, we believe that preventing formation of 7-DHC oxysterols is critical for countering the detrimental effects of DHCR7 mutations.

Topics: alpha-Tocopherol; Animals; Animals, Newborn; Antioxidants; Ascorbic Acid; Brain; Cell Line, Transformed; Disease Models, Animal; Female; Fibroblasts; Gene Expression Regulation; Humans; Liver; Male; Mice; Mice, Transgenic; Oxidoreductases Acting on CH-CH Group Donors; Smith-Lemli-Opitz Syndrome; Ubiquinone

Abdominal aortic aneurysms (AAAs) are associated with oxidative stress and inflammatory response. We investigated the hypothesis that the known antioxidant ascorbic acid, which can also promote elastin and collagen production by smooth muscle cells, would prevent AAA formation in a rat model.. An intraluminal elastase and extraluminal calcium chloride-induced rat AAA model was used, and the animals were divided into three groups: control (group C, n = 18), the aorta wrapped with a saline-impregnated gelatin hydrogel sheet (group G, n = 18), and the aorta wrapped with a gelatin hydrogel sheet incorporating ascorbic acid (group A, n = 18). Wrapping of the sheet was completed at the end of treatment for AAA creation. The aortic dilatation ratio was measured, and aortic tissues were further examined for oxidative stress and oxidative DNA damage using biochemical and histologic techniques.. Aortic dilatation at both 4 and 8 weeks was inhibited in group A (dilatation ratio [%] at 4 weeks: 186.2 ± 21.8 in group C, 152.3 ± 10.2 in group G, 126.8 ± 11.6 in group A; P < .0001; dilatation ratio [%] at 8 weeks: 219.3 ± 37.5 in group C, 194.0 ± 11.6 in group G, 145.7 ± 8.3 in group A; P = .0002). Elastin and collagen content were significantly preserved in group A (elastin, P = .0015; collagen, P < .0001). The messenger RNA expressions of matrix metalloproteinase (MMP)-9, monocyte chemotactic protein-1, interleukin-1β, and tissue necrosis factor-α (P = .0024, P < .0001, P < .0001, and P < .0001, respectively) were downregulated in group A (P = .0024), whereas tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 were both upregulated in group A (TIMP-1, P = .0014; TIMP-2, P < .0001). Gelatin zymography showed activities of pro-MMP-2, MMP-2, and MMP-9 were significantly suppressed in group C (P < .0001 for each). Reactive oxygen species expression and 8-hydroxydeoxyguanosine and cluster of differentiation 68 staining were significantly suppressed in group A (reactive oxygen species expression, P < .0001; 8-hydroxydeoxyguanosine-positive cells, P < .0001; cluster of differentiation 68 positive cells, P < .0001).. Controlled release of ascorbic acid using gelatin hydrogel sheet-attenuated AAA formation through antioxidant and anti-inflammatory effect, regulation of MMP-2, TIMP-1, and TIMP-2, and preserving elastin and collagen in this animal model.

Topics: Animals; Antioxidants; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Ascorbic Acid; Calcium Chloride; Chemistry, Pharmaceutical; Chemokine CCL2; Collagen; Delayed-Action Preparations; Dilatation, Pathologic; Disease Models, Animal; DNA Damage; Drug Carriers; Elastin; Gelatin; Gene Expression Regulation; Hydrogels; Inflammation Mediators; Interleukin-1beta; Male; Matrix Metalloproteinase 9; Oxidative Stress; Pancreatic Elastase; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tumor Necrosis Factor-alpha

Vitamin C (VC) is a potent antioxidant and is essential for collagen synthesis. We investigated whether VC treatment prevents and cures smoke-induced emphysema in senescence marker protein-30 knockout (SMP30-KO) mice, which cannot synthesize VC. Two smoke-exposure experiments using SMP30-KO mice were conducted. In the first one (a preventive study), 4-month-old mice received minimal VC (0.0375 g/l) [VC(L)] or physiologically sufficient VC (1.5 g/l) [VC(S)] and exposed to cigarette smoke or smoke-free air for 2 months. Pulmonary evaluations followed when the mice were 6 months of age. The second study began after the establishment of smoke-induced emphysema (a treatment study). These mice no longer underwent smoke exposure but received VC(S) or VC(L) treatment for 2 months. Morphometric analysis was performed, and measurements of oxidative stress, collagen synthesis, and vascular endothelial growth factor in the lungs were evaluated. Chronic smoke exposure caused emphysema (29.6% increases of mean linear intercepts [MLI] and 106.5% increases of destructive index compared with the air-only group) in 6-month-old SMP30-KO mice, and this emphysema closely resembled human chronic obstructive pulmonary disease. Smoke-induced emphysema persisted in the VC(L) group after smoking cessation, whereas VC treatment provided pulmonary restoration (18.5% decrease of MLI and 41.3% decrease of destructive index compared with VC(L) group). VC treatment diminished oxidative stress, increased collagen synthesis, and improved vascular endothelial growth factor levels in the lungs. Our results suggest that VC not only prevents smoke-induced emphysema in SMP30-KO mice but also restores emphysematous lungs. Therefore, VC may provide a new therapeutic strategy for treating chronic obstructive pulmonary disease in humans.

Topics: Animals; Ascorbic Acid; Calcium-Binding Proteins; Disease Models, Animal; Intracellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Nicotiana; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Smoke

Ardisia elliptica Thunb Lam. (Myrsinaceae) is widely used traditionally in the treatment of diarrhea related health disorders in Bangladesh.. The crude ethanol extract of Ardisia elliptica fruits (EFA) was evaluated for its antioxidant and antidiarrhoeal activities.. DPPH radical scavenging, nitric oxide scavenging, reducing power and Fe(++) ion chelating ability were used for determining antioxidant activities and animal models were used for antidiarrheal activities such as the castor oil and magnesium sulfate-induced diarrhea, enteropooling induced by the administration of castor oil and magnesium sulfate at the doses of 250 and 500 mg/kg.. The extract possessed a significant DPPH free radical scavenging activity with an IC50 value of 30.75 μg/ml compared to ascorbic acid (IC50: 7.89 μg/ml). The IC50 values of the extract and ascorbic acid were 51.72 and 38.68 μg/ml, respectively, in nitric oxide scavenging assay. The IC50 value of the extract for Fe(++) ion chelating ability (41.30 μg/ml) was also found to be significant compared to the IC50 value of EDTA (22.57 μg/ml). The EFA also showed a significant protection (p < 0.001) against experimentally induced diarrhea by castor oil and magnesium sulfate as evidenced by a decrease in the number of defecation with respect to control. The diarrhea induced by castor oil and magnesium sulfate enteropooling was prevented by all the tested doses.. Therefore, the obtained results confirm the antioxidant and antidiarrheal activity of EFA and thus support the traditional uses of this plant as a modality for antioxidant and antidiarrheal activity.

Topics: Animals; Antidiarrheals; Antioxidants; Ardisia; Ascorbic Acid; Bangladesh; Diarrhea; Disease Models, Animal; Ethanol; Female; Free Radical Scavengers; Fruit; Inhibitory Concentration 50; Male; Medicine, Traditional; Mice; Plant Extracts; Rats; Rats, Wistar

Senescence marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice are incapable of synthesizing L-ascorbic acid (AA) in vivo. As AA is known to be a water-soluble anti-oxidant, we assessed protein oxidation levels in livers from SMP30/GNL KO mice maintained in an AA-insufficient condition.. Livers were collected from male SMP30/GNL KO mice at the ages of 3, 6 and 12 months, and wild-type (WT) mice at the ages of 3, 6, 12 and 24 months. To assess protein oxidation, we measured the content of protein carbonyl, which is a major protein oxidation marker. AA levels were measured by 2,4-dinitrophenylhydrazine method using high-performance liquid chromatography.. Livers of SMP30/GNL KO mice had just ∼5% as much AA as those of WT mice from 3 to 12 months-of-age. Protein carbonyl levels in livers from SMP30/GNL KO mice were a significant 1.8- to 2.3-fold higher than those from age-atched WT mice. To establish that the AA-insufficiency caused this difference, we added AA to some drinking water, and examined the effect on AA and protein carbonyl levels in livers from SMP30/GNL KO and WT mice. Livers from SMP30/GNL KO mice given extra AA had a significantly higher content than those from their deprived counterparts. Furthermore, protein carbonyl levels in livers from AA-supplemented SMP30/GNL KO mice were significantly lower than those from the SMP30/GNL KO mice without AA supplementation. However, added AA did not affect the protein carbonyl levels in WT mice.. These results strongly suggest that AA plays an important role in preventing protein oxidation in vivo, thus enhancing overall health.

Topics: Aging; Animals; Antioxidants; Ascorbic Acid; Calcium-Binding Proteins; Carboxylic Ester Hydrolases; Chromatography, High Pressure Liquid; Disease Models, Animal; Intracellular Signaling Peptides and Proteins; Lipid Metabolism; Liver; Male; Mice; Mice, Knockout; Oxidation-Reduction; Protein Carbonylation; Scurvy

The present study investigated the involvement of the PI3K, GSK-3β, heme oxygenase-1 (HO-1) and mTOR in the antidepressant-like effect of ascorbic acid in the tail suspension test (TST). Male Swiss mice were pretreated with ascorbic acid (1 mg/kg, p.o.) or vehicle and 45 min after, LY294002 (10 μg/site, i.c.v., reversible PI3K inhibitor), rapamycin (0.2 nmol/site, i.c.v., selective mTOR inhibitor), zinc protoporphyrin (ZnPP - 10 ng/site, i.c.v., HO-1 inhibitor) or vehicle was administered. We also investigated the synergistic effect of ascorbic acid (0.1 mg/kg, p.o., sub-effective dose in the TST) with lithium chloride (10 mg/kg, p.o., non-selective GSK-3β inhibitor), AR-A014418 (0.01 μg/site, i.c.v., selective GSK-3β inhibitor) or cobalt protoporphyrin (CoPP - 0.01 μg/site, i.c.v., HO-1 inducer) in the TST. The antidepressant-like effect of ascorbic acid (1 mg/kg, p.o.) was prevented by the treatment of mice with LY294002, rapamycin or ZnPP. In addition, sub-effective doses of lithium chloride, AR-A014418 or CoPP, combined with a sub-effective dose of ascorbic acid produced a synergistic antidepressant-like effect. We also demonstrated that 1 h after its administration, ascorbic acid increased the phosphorylation of p70S6K and the immunocontent of PSD-95 in the hippocampus of mice. These results indicate that the antidepressant-like effect of ascorbic acid in the TST might be dependent on the activation of PI3K and mTOR, inhibition of GSK-3β as well as induction of HO-1, reinforcing the notion that these are important targets for antidepressant activity and contributing to better elucidate the mechanisms underlying the antidepressant-like effect of ascorbic acid.

Topics: Animals; Antidepressive Agents; Ascorbic Acid; Depression; Disease Models, Animal; Disks Large Homolog 4 Protein; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Exploratory Behavior; Gene Expression Regulation; Guanylate Kinases; Hindlimb Suspension; Hippocampus; Immobility Response, Tonic; Male; Membrane Proteins; Mice; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Ascorbic acid (AA) is an established antioxidant and has been used for treatment of various disorders. Recent reports suggest that administration of AA increases the level of steroids such as progesterone in the body. The present study investigated the protective role of progesterone against ischemia-reperfusion-induced acute kidney injury (AKI) and possible involvement of progesterone receptors in AA-mediated renoprotection in rats.. The male rats were subjected to bilateral renal ischemia for 40 min followed by reperfusion for 24 h to induce AKI. The rats were treated with progesterone (5 and 10 mg/kg, intraperitoneally) and AA (500 mg/kg, intraperitoneally for 1, 2, and 5 d) before AKI. In separate groups, mifepristone, the progesterone receptor antagonist was administered to rats before progesterone (10 mg/kg) and AA treatment (5 d). Various parameters including creatinine clearance, serum urea, uric acid, potassium level, fractional excretion of sodium, lactate dehydrogenase, and microproteinuria were used to assess kidney injury. Moreover, renal tissues were subjected to quantification of oxidative stress and evaluation of histopathologic changes.. The exogenous administration of progesterone afforded protection against AKI in a dose-dependent manner that was abolished by mifepristone. The administration of AA for 1, 2, and 5 d induced significant increase in serum progesterone levels and afforded protection against AKI. The antioxidant and renoprotective effect of AA was abolished by prior treatment with mifepristone.. It is concluded that exogenous administration of progesterone exerts significant antioxidant and renoprotective effect. Moreover, the progesterone receptors find their explicit involvement in AA-mediated renoprotection against ischemia-reperfusion-induced AKI in rats.

Topics: Acute Kidney Injury; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Iron; Male; Oxidative Stress; Potassium; Progesterone; Rats; Receptors, Progesterone; Reperfusion Injury; Urea; Uric Acid

Experimental, controlled, animal study.. To assess the effects of vitamins C and E (VCE) treatment on oxidative stress and programmed cell deaths after rat spinal cord injury (SCI), as well as functional recovery.. Taiwan.. Fifty-four Sprague-Dawley rats were used for the experimental procedure. In the sham group, laminectomy at T10 was performed, followed by impactor contusion of the spinal cord. In the control group, only a laminectomy was performed without contusion. Oxidative stress status was assessed by measuring the spinal cord tissue content of superoxide dismutase (SOD) and gluthatione peroxidase (GSH-Px) activities. We also evaluated the effects of combined VCE treatment using western blot to analyze expression of cleaved caspase-3 and microtubule-associated protein light chain 3 (LC3), and the Basso, Beattie and Bresnahan (BBB) scale to evaluate functional outcomes.. Combined treatment of VCE significantly counteracted the effects of spinal cord contusion on oxidative stress represented by activities of SOD and GSH-Px (P<0.05). The VCE treatment also significantly enhanced LC3-II expression and decreased cleaved caspase-3 compared with the sham (P<0.05). Furthermore, BBB scores significantly improved in the VCE-treated group compared with the sham group (on day 14 and 28 after SCI; P<0.05).. The combined administration of VCE was clearly capable of modulating the antioxidant effects, and of reducing apoptosis and increasing autophagy at the lesion epicenter leading to an improved functional outcome. Use of such clinically ready drugs could help earlier clinical trials in selected cases of human SCIs.

Topics: Animals; Antioxidants; Apoptosis; Ascorbic Acid; Blotting, Western; Disease Models, Animal; Female; Oxidative Stress; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord Injuries; Vitamin E

Mitochondria actively participate in neurotransmission by providing energy (ATP) and maintaining normative concentrations of reactive oxygen species (ROS) in both presynaptic and postsynaptic elements. In human and animal epilepsies, ATP-producing respiratory rates driven by mitochondrial respiratory complex (MRC) I are reduced, antioxidant systems are attenuated and oxidative damage is increased. We report that MRCI-driven respiration and functional uncoupling (an inducible antioxidant mechanism) are reduced and levels of H2O2 are elevated in mitochondria isolated from KO mice. Experimental impairment of MRCI in WT hippocampal slices via rotenone reduces paired-pulse ratios (PPRs) at mossy fiber-CA3 synapses (resembling KO PPRs), and exacerbates seizure-like events in vitro. Daily treatment with AATP [a combination therapy composed of ascorbic acid (AA), alpha-tocopherol (T), sodium pyruvate (P) designed to synergistically target mitochondrial impairments] improved mitochondrial functions, mossy fiber PPRs, and reduced seizure burden index (SBI) scores and seizure incidence in KO mice. AATP pretreatment reduced severity of KA-induced seizures resulting in 100% protection from the severe tonic-clonic seizures in WT mice. These data suggest that restoration of bioenergetic homeostasis in the brain may represent a viable anti-seizure target for temporal lobe epilepsy.

Topics: Adenosine Triphosphate; alpha-Tocopherol; Animals; Ascorbic Acid; Disease Models, Animal; Electric Stimulation; Electroencephalography; Electron Transport Complex I; Epilepsy, Temporal Lobe; Hippocampus; Hydrogen Peroxide; In Vitro Techniques; Kainic Acid; Kv1.1 Potassium Channel; Mice; Mice, Knockout; Mitochondria; Pyruvic Acid; Reactive Oxygen Species; Respiration; Seizures

Since its discovery in 1982, the global importance of Helicobacter pylori-induced disease, particularly in developing countries, remains high. The use of rodent models, particularly mice, and the unanticipated usefulness of the gerbil to study H. pylori pathogenesis have been used extensively to study the interactions of the host, the pathogen, and the environmental conditions influencing the outcome of persistent H. pylori infection. Dietary factors in humans are increasingly recognized as being important factors in modulating progression and severity of H. pylori-induced gastric cancer. Studies using rodent models to verify and help explain mechanisms whereby various dietary ingredients impact disease outcome should continue to be extremely productive.

Topics: Animals; Ascorbic Acid; Developing Countries; Diet; Dietary Fats; Disease Models, Animal; Folic Acid; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Humans; Mice; Salts; Stomach Neoplasms

Traumatic brain injury (TBI) and hemorrhagic shock (HS) can be associated with coagulopathy and inflammation, but the mechanisms are poorly understood. We hypothesized that a combination of TBI and HS would disturb coagulation, damage the endothelium, and activate inflammatory and complement systems.. A total of 33 swine were allocated to either TBI + HS (n = 27, TBI and volume-controlled 40% blood loss) or controls (n = 6, anesthesia and instrumentation). TBI + HS animals were left hypotensive (mean arterial pressure, 30-35 mm Hg) for 2 hours. Blood samples were drawn at baseline, 3 minutes and 15 minutes after injury, as well as following 2 hours of hypotension. Markers of coagulation, anticoagulation, endothelial activation/glycocalyx shedding, inflammation, complement, and sympathoadrenal function were measured.. The TBI + HS group demonstrated an immediate (3 minutes after injury) activation of coagulation (prothrombin fragment 1 + 2, 289 ng/mL vs. 232 ng/mL, p = 0.03) and complement (C5a, 2.83 ng/mL vs. 2.05 ng/mL, p = 0.05). Shedding of the endothelial glycocalyx (syndecan 1) was evident 15 minutes after injury (851.0 ng/ml vs. 715.5 ng/ml, p = 0.03) while inflammation (tumor necrosis factor α [TNF-α], 81.1 pg/mL vs. 50.8 pg/mL, p = 0.03) and activation of the protein C system (activated protein C, 56.7 ng/mL vs. 26.1 ng/mL, p = 0.01) were evident following the 2-hour hypotension phase.. The combination of TBI and shock results in an immediate activation of coagulation and complement systems with subsequent endothelial shedding, protein C activation, and inflammation.

Topics: Animals; Ascorbic Acid; Blood Coagulation Disorders; Brain Injuries; Complement Activation; Disease Models, Animal; Endothelium; Female; Fibrinolysis; Hemorrhage; Inflammation; Shock, Hemorrhagic; Swine

The tear film comprises a major mechanism for protection of the ocular surface against harmful external agents. Disruption of tear production can lead to dry eye syndrome, causing damage ranging from mild discomfort to scarring of the ocular surface with irreversible vision impairment. The production of tears by the lacrimal gland is influenced by neuroendocrine, hormonal, and immunological factors. Reactive oxygen and nitrogen species play an important role in its regulation. We assessed the effects of oxidative stress on antioxidant defenses in the lacrimal gland and ocular surface in ovariectomized rats supplemented with n-3 polyunsaturated fatty acids (n-3 PUFA) and alpha-lipoic acid (ALP). We found that n-3 PUFA did not measurably influence oxidative stress, but ALP had site-specific pro-oxidant and antioxidant effects, and was an important influence on ocular surface dry eye improvement. As an index of oxidative damage to proteins and lipids, we measured levels of carbonyl and malondialdehyde (MDA), respectively. Enzymatic antioxidant defenses were measured as total superoxide dismutase (tSOD) and glutathione peroxidase (GPx), and non-enzymatic defenses were estimated by vitamin C, total glutathione, and indirect oxide nitric levels. PUFA and ALP treatment restored lacrimal production with resulting improvement in the dry eye Schirmer test in all supplemented groups. The results indicated that reactive oxygen species resulting from oxidative stress in the lacrimal gland did not play an important role in dry eye through reactive oxygen species; however, alpha-lipoic acid altered the metabolism of reactive nitrogen species, causing increased activity of lacrimal peroxidase and improved lacrimal production.

Topics: Animals; Antioxidants; Ascorbic Acid; Chromatography, High Pressure Liquid; Conjunctiva; Cornea; Dietary Supplements; Disease Models, Animal; Dry Eye Syndromes; Epithelium, Corneal; Estradiol; Fatty Acids, Omega-3; Female; Glutathione; Lacrimal Apparatus; Malondialdehyde; Microscopy, Electron, Scanning; Nitrates; Nitrites; Ovariectomy; Oxidative Stress; Progesterone; Radioimmunoassay; Rats; Rats, Wistar; Tears; Thioctic Acid

Cell sheet technology has emerged as an important tissue engineering approach. Adipose-derived stem cells (ASCs) have valuable applications in regenerative medicine, but their stemness and differentiation capabilities in the cell sheet format have not been well investigated. In this study, we found that l-ascorbate 2-phosphate (A2-P), a stable form of ascorbic acid, significantly enhanced ASC proliferation and induced ASC sheet fabrication in 7 days with abundant extracellular matrix deposition. Importantly, A2-P treatment significantly enhanced expression of pluripotent markers Sox-2, Oct-4 and Nanog, but treating ASCs with antioxidants other than A2-P revealed no stemness enhancement. Moreover, ASC treatment with A2-P and a collagen synthesis inhibitor, L-2-azetidine carboxylic acid or cis-4-hydroxy-d-proline, significantly inhibited the A2-P-enhanced expression of stemness markers. These findings demonstrated that A2-P enhances stemness of ASCs through collagen synthesis and cell sheet formation. We also showed that A2-P-stimulated collagen synthesis in ASCs may be mediated through ERK1/2 pathway. By culturing the ASC sheets in proper induction media, ASC transdifferentiation capabilities into neuron and hepatocyte-like cells were significantly enhanced after cell sheet formation, while adipogenic and osteogenic differentiation capacities were still maintained. Using a murine model of healing-impaired cutaneous wound, faster wound healing was noted in the group that received ASC sheet treatment, and we observed significantly more engrafted ASCs with evidence of differentiation toward endothelial and epidermal lineages in the cutaneous wound tissue. Therefore, A2-P-mediated ASC sheet formation enhanced ASC stemness and transdifferentiation capabilities, thereby representing a promising approach for applications in regenerative medicine.

Topics: Adipose Tissue; Adult; Animals; Antioxidants; Ascorbic Acid; Biomarkers; Cell Culture Techniques; Cell Proliferation; Cell Transdifferentiation; Collagen; Disease Models, Animal; Female; Humans; Mice; Mice, Nude; Middle Aged; Neurogenesis; Phenotype; Stem Cells; Wound Healing

We investigated the hypothesis that an antioxidant, Vitamin C, could attenuate abdominal aortic aneurysm (AAA) development in a rat model.. An AAA model induced by intraluminal infusion was created in 36 male Sprague Dawley rats, which were randomly distributed into three groups: Sham (saline infused, placebo treated), Control (elastase infused, placebo treated), and Vitamin C (elastase infused, vitamin C treated). Vitamin C and placebo were intraperitoneally injected, initiating 1 wk before the infusion and continuing throughout the study. The aortic dilatation ratio was measured, and aortic tissues were further examined using biochemical and histologic techniques.. Vitamin C attenuated the development of AAA, decreasing maximal aortic diameter by 25.8% (P < 0.05) and preserving elastin lamellae (P < 0.05). Vitamin C also decreased 8-hydroxyguanine (a marker of oxidative damage to DNA) and 8-isoprostane content (a marker of oxidative stress) in aortic tissues (P < 0.05, respectively). The proteins of matrix metalloproteinase (MMP)-2, MMP-9, and interleukin 6 were markedly downregulated (P < 0.05, respectively), accompanied with notably reduced messenger RNA expression of tumor necrosis factor-α, MMP-2/9, and interleukin 1β (P < 0.05, respectively). However, messenger RNA of tissue inhibitors of metalloproteinase-1 and tissue inhibitors of metalloproteinase-2 were both significantly upregulated in Vitamin C group. Vitamin C treatment had no significant effect on systolic blood pressure (P > 0.05).. Vitamin C attenuated AAA development in an elastase-induced rat model via crucial protective effect, which was mediated by an increased level of antioxidant in cooperation with preserving elastin lamellae, inhibiting matrix-degrading proteinases and suppressing inflammatory responses.

Topics: Animals; Antioxidants; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Ascorbic Acid; Blood Pressure; Disease Models, Animal; Drug Evaluation, Preclinical; Inflammation; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Oxidative Stress; Pancreatic Elastase; Random Allocation; Rats

The present study investigated the effects of a single intravenous (i.v.) dose of Vitamin C (ascorbate, ASC) on spatial memory in APP/PSEN1 mice, an Alzheimer's disease model. First, we confirmed the uptake time course in ASC-depleted gulo (-/-) mice, which cannot synthesize ASC. Differential tissue uptake was seen based on ASC transporter distribution. Liver (SVCT1 and SVCT2) ASC was elevated at 30, 60 and 120 min post-treatment (125 mg/kg, i.v.), whereas spleen (SVCT2) ASC increased at 60 and 120 min. There was no detectable change in cortical (SVCT2 at choroid plexus, and neurons) ASC within the 2-h interval, although the cortex preferentially retained ASC. APP/PSEN1 and wild type (WT) mice at three ages (3, 9, or 20 months) were treated with ASC (125 mg/kg, i.v.) or saline 45 min before testing on the Modified Y-maze, a two-trial task of spatial memory. Memory declined with age and ASC treatment improved performance in 9-month-old APP/PSEN1 and WT mice. APP/PSEN1 mice displayed no behavioral impairment relative to WT controls. Although dopamine and metabolite DOPAC decreased in the nucleus accumbens with age, and improved spatial memory was correlated with increased dopamine in saline treated mice, acute ASC treatment did not alter monoamine levels in the nucleus accumbens. These data show that the Modified Y-maze is sensitive to age-related deficits, but not additional memory deficits due to amyloid pathology in APP/PSEN1 mice. They also suggest improvements in short-term spatial memory were not due to changes in the neuropathological features of AD or monoamine signaling.

Topics: Administration, Intravenous; Age Factors; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Hippocampus; Humans; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurotransmitter Agents; Peptide Fragments; Presenilin-1; Space Perception; Time Factors

Blood-brain barrier (BBB) breakdown and mitochondrial dysfunction have been implicated in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disease characterized by cognitive deficits and neuronal loss. Besides vitamin C being as one of the important antioxidants, recently, it has also been reported as a modulator of BBB integrity and mitochondria morphology. Plasma levels of vitamin C are decreased in AD patients, which can affect disease progression. However, investigation using animal models on the role of vitamin C in the AD pathogenesis has been hampered because rodents produce with no dependence on external supply. Therefore, to identify the pathogenic importance of vitamin C in an AD mouse model, we cross-bred 5 familial Alzheimer's disease mutation (5XFAD) mice (AD mouse model) with ι-gulono-γ-lactone oxidase (Gulo) knockout (KO) mice, which are unable to synthesize their own vitamin C, and produced Gulo KO mice with 5XFAD mice background (KO-Tg). These mice were maintained on either low (0.66 g/l) or high (3.3 g/l) supplementation of vitamin C. We found that the higher supplementation of vitamin C had reduced amyloid plaque burden in the cortex and hippocampus in KO-Tg mice, resulting in amelioration of BBB disruption and mitochondrial alteration. These results suggest that intake of a larger amount of vitamin C could be protective against AD-like pathologies.

Topics: Alzheimer Disease; Animals; Ascorbic Acid; Blood-Brain Barrier; Capillaries; Cerebral Cortex; Dietary Supplements; Disease Models, Animal; Female; Gliosis; Hippocampus; L-Gulonolactone Oxidase; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Mitochondria; Plaque, Amyloid; Tight Junctions

Intravenous (IV) administration of ascorbic acid during cardiopulmonary resuscitation (CPR) was reported to facilitate defibrillation and improves survival in ventricular fibrillation (VF) cardiac arrest. We investigated whether IV administration of ascorbic acid after return of spontaneous circulation (ROSC) can improve outcomes in VF cardiac arrest in a rat model and its interaction with therapeutic hypothermia.. Ventricular fibrillation-induced cardiac arrest followed by CPR and defibrillation was performed in male Wistar rats. After ROSC, the animals were equally randomized to the normothermia (NormoT), hypothermia (HypoT), ascorbic acid (AA+NormoT), and ascorbic acid plus hypothermia (AA+HypoT) groups. The AA+NormoT and AA+HypoT groups received IV ascorbic acid (100 mg/kg). In the HypoT and AA+HypoT groups, therapeutic hypothermia was maintained at 32°C for 2 hours.. There were 12 rats in each group. Within 4 hours after ROSC, the HypoT, AA+NormoT, and AA+HypoT groups had significantly lower myocardial lipid peroxidation than the NormoT group. Within 4 hours following ROSC, the AA+NormoT group had a significantly better systolic function (dp/dt40 ) than the NormoT group (6887.9 mm Hg/sec, SD ± 1049.7 mm Hg/sec vs. 5953.6 mm Hg/sec, SD ± 1161.9 mm Hg/sec; p < 0.05). The AA+HypoT group also showed a significantly better diastolic function (-dp/dtmax ) than the HypoT group (dp/dt40 : 8524.8, SD ± 1166.7 mm Hg/sec vs. 7399.8 mm Hg/sec, SD ± 1114.5 mmHg/sec; dp/dtmax : -8183.4 mm Hg/sec, SD ± 1359.0 mm Hg/sec vs. -6573.7 mm Hg/sec, SD ± 1110.9 mm Hg/sec; p < 0.05) at the fourth hour following ROSC. Also at 4 hours, there was less myocytolysis in the HypoT, AA+NormoT, and AA+HypoT groups than the NormoT group. The HypoT, AA+NormoT, and AA+HypoT groups had significantly better survival rates and neurologic outcomes than the NormoT group. Compared with only five surviving animals in the NormoT group, there were nine, eight, and 10 in the HypoT, AA+NormoT, and AA+HypoT groups, respectively, with good neurologic outcomes at 72 hours.. Intravenous ascorbic acid administration after ROSC in normothermia may mitigate myocardial damage and improve systolic function, survival rate, and neurologic outcomes in VF cardiac arrest of rat. Combination of ascorbic acid and hypothermia showed an additive effect in improving both systolic and diastolic functions after ROSC.

Topics: Animals; Ascorbic Acid; Cardiopulmonary Resuscitation; Diastole; Disease Models, Animal; Electric Countershock; Heart Arrest; Hemodynamics; Hypothermia; Hypothermia, Induced; Infusions, Intravenous; Lipid Peroxidation; Male; Myocardial Contraction; Myocardium; Rats; Rats, Wistar; Survival Analysis; Systole; Ventricular Fibrillation

In response to sustained damage to a kidney, fibrosis that can be characterized as the deposition of a collagenous matrix occurs and consequently causes chronic kidney failure. Because most animals used in experiments synthesize ascorbic acid (AsA) from glucose, the roles of AsA in fibrotic kidney diseases are largely unknown. Unilateral ureteric obstruction (UUO) mimics the complex pathophysiology of chronic obstructive nephropathy and is an ideal model for the investigation of the roles of AsA in kidney failure. We examined the impact of a deficiency of Akr1a, a gene that encodes aldehyde reductase and is responsible for the production of AsA, on fibrotic damage caused by UUO in mice. Oxidatively modified DNA was elevated in wild-type and Akr1a-deficient kidneys as a result of UUO to a similar extent, and was only slightly suppressed by the administration of AsA. Even though Akrla-deficient mice could produce only about 10% of the AsA produced by wild-type mice, no difference was observed in collagen I synthesis under pathological conditions. The data implied either a low demand for AsA or the presence of another electron donor for collagen I production in the mouse kidney. Next, we attempted to elucidate the potential causes for oxidative damage in kidney cells during the fibrotic change. We found decreases in mitochondrial proteins, particularly in electron transport complexes, at the initial stage of the kidney fibrosis. The data imply that a dysfunction of the mitochondria leads to an elevation of ROS, which results in kidney fibrosis by stimulating cellular transformation to myofibroblasts.

Topics: Animals; Ascorbic Acid; Blotting, Western; Disease Models, Animal; Electron Transport Chain Complex Proteins; Fibrosis; Immunohistochemistry; Kidney Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Ureteral Obstruction

This study investigated the effects of ascorbic acid and N-acetyl cysteine (NAC) antioxidants on the development of myringosclerosis (MS) in an experimental model.. Myringotomies were performed in the ears of 15 guinea pigs, and Spongostan pieces were placed on the perforated regions of the tympanic membrane. The subjects were divided randomly into three groups and treated with three different solutions on the Spongostan-group 1: (control, 0.9% saline), group 2 (ascorbic acid), and group 3 (NAC). On day 15 after treatment, specimens from the tympanic membranes were obtained and examined via light microscopy. Sclerosis and inflammation scores and the tympanic membrane thicknesses were evaluated. Immunohistochemical methods were used to evaluate the expression of VEGF, TGF-β, iNOS, and IL1-β in all groups.. Lower sclerosis and inflammation scores and reduced tympanic membrane thicknesses were observed in groups treated with NAC or ascorbic acid compared with the control group. Immunohistochemical studies revealed significantly less expression of VEGF, TGF-β, and iNOS in groups 2 and 3 compared with group 1. Additionally, IL1-β expression was significantly less in group 3 than in group 1. Compared with group 1, group 2 animals exhibited reduced inflammation in the lamina propria, fewer active fibroblasts, less leukocyte infiltration, and decreased thickness of the vessels; group 3 animals exhibited decreased numbers of active fibroblasts and collagen fibers in the lamina propria.. Inflammation scores, cellular infiltration, and expression of VEGF, TGF-β, and iNOS were reduced by ascorbic acid and/or NAC treatments, thereby decreasing MS development. Decreased expression of IL1-β was observed only in animals treated with NAC.

Topics: Acetylcysteine; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Female; Fibrin Foam; Fibroblasts; Free Radical Scavengers; Guinea Pigs; Hemostatics; Immunohistochemistry; Inflammation; Leukocytes; Microscopy; Mucous Membrane; Myringosclerosis; Nitric Oxide Synthase; Random Allocation; Transforming Growth Factor beta; Tympanic Membrane; Vascular Endothelial Growth Factor A

The oxidative stress of placenta during fetal heart dysfunction (FHD) is lack of evaluation. So, we carried out an experiment to explore whether vitamin C (VitC) can be supplied for placental protection under FHD and its impacts on P-glycoprotein expression.. Fetal heart dysfunction was induced by two intra-amniotic injections of isoproterenol, then (VitC) was supplied. Hematoxylin-eosin (HE) staining was used to evaluate placental histology, and oxidative stress was measured by total antioxidant capacity, total superoxide dismutase and level of advanced oxidation protein products (AOPP), as well as apoptosis rate. Real-time polymerase chain reaction was adopted to measure the expressions of superoxide dismutase-1 (Sod-1), glutathione peroxidase-1 (Gpx-1) and endothelial nitric oxide synthase (eNOS) in placenta. Finally, western blot was performed to detect P-glycoprotein expression.. All isoproterenol twice-treated fetuses exhibited significant (P < 0.05) contractile dysfunction by fetal echocardiography compared to others. The HE staining showed severe placental hydrops in the FHD group, and that hydrops could be reduced by VitC treatment. Total antioxidant capacity and total Sod-1 decreased in FHD and elevated after VitC supplementation. Also, level of AOPP increased in FHD and dropped after VitC supplementation. Analysis of apoptosis demonstrated that there was a mild increase in apoptosis rate of FHD. Reductions of Sod-1 and eNOS mRNA expression were confirmed in FHD, but these could recovered after VitC supplementation, with the same tendency of the P-glycoprotein.. Severe oxidative injuries were identified in placentas of FHD with P-glycoprotein repression. VitC administration can reduce the oxidative stress and rebuild the protective mechanism of placenta.

Topics: Animals; Antioxidants; Ascorbic Acid; ATP Binding Cassette Transporter, Subfamily B, Member 1; Disease Models, Animal; Echocardiography; Female; Fetal Diseases; Heart Failure; Oxidative Stress; Placenta; Placenta Diseases; Polymerase Chain Reaction; Pregnancy; Rats, Sprague-Dawley

The aim of this study was to optimize reverse iontophoretic (RI) extraction of ferric/ferrous ions from the cornea.. Group I consisted of the right eye corneas from 20 normal rabbits. Corneal blood staining was induced in 60 right eyes. The corneal depths from the endothelium to the epithelium layers were divided into three groups by slit-lamp examination: Group II, one-third corneal thickness; Group III, one-half corneal thickness; Group IV, full corneal thickness. RI was performed using vertical diffusion cells. The lower chamber was loaded with glutathione bicarbonate Ringer's buffer (GBR; pH 7.0) or vitamin C (12.5 mg/mL) and GBR (pH 7.0), while the upper chamber was filled with 1 mL GBR. Progress of corneal blood staining removal was evaluated.. Application of 1.5 mA to the cornea increased flux by 1.72- and 2.19-fold in Groups III and IV, respectively, but not in Groups I or II, compared to the control. When vitamin C was included, we observed significant flux increases in the controls (1.5-, 2.06-, 2.60-, and 4.59-fold) for Groups I, II, III, and IV, and under RI conditions for Groups III and IV. Following RI, the corneal endothelia appeared similar to corneas from untreated control rabbits, while Draize scores were zero.. These results suggested that extracellular ferric/ferrous ions could be extracted from the cornea in vitro by RI, and that vitamin C reduced Fe(3+) to Fe(2+) in the cornea and altered its permselectivity, thus increasing the RI contribution to iron extraction.

Topics: Animals; Antioxidants; Ascorbic Acid; Cornea; Corneal Diseases; Disease Models, Animal; Female; Hemosiderosis; Iontophoresis; Iron Compounds; Male; Rabbits; Spectrophotometry, Atomic

Pre-induction of heme oxygenase (HO)-1, which is regarded as an effective method of "organ preconditioning", exerts beneficial effects during hemorrhagic shock (HS). However, the available HO-1 inducers exhibit disadvantages such as toxicity or complex technical requirements. Therefore, a safe and convenient HO-1 inducer would be promising and could be exploited in the treatment of foreseeable hemorrhaging, such as prior to major surgery. Here we investigated the effect of vitamin C (VitC), a common antioxidant, on intestinal HO-1 expression and examined whether VitC pretreatment prevented HS related intestinal tissue injuries after HO-1 induction. First, we conducted an in vitro study and found that HO-1 expression in rat intestinal epithelial cells (IEC-6) was induced by non-toxic VitC in a time and concentration dependent manner, and the mechanism was related to the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Next, we conducted an in vivo study and found that VitC induced intestinal HO-1 protein expression (mainly observed in the intestinal epithelial cells) and HO-1 activity in normal SD rats, and that these HO-1 levels were further enhanced by VitC in a rat model of HS. The HS related intestinal injuries, including histological damage, pro-inflammatory cytokine levels (tumor necrosis factor and interleukin-6), neutrophil infiltration and apoptosis decreased after VitC pretreatment, and this alleviating of organ injuries was abrogated after the inhibition of HO-1 activity by zinc protoporphyrin-IX. It was of note that VitC did little histological damage to the intestine of the sham rats. These data suggested that VitC might be applied as a safe inducer of intestinal HO-1 and that VitC pretreatment attenuated HS related intestinal injuries via the induction of HO-1.

Topics: Animals; Antioxidants; Apoptosis; Ascorbic Acid; Cells, Cultured; Disease Models, Animal; Gene Expression Regulation; Heme Oxygenase-1; Intestinal Diseases; Intestines; MAP Kinase Signaling System; Rats; Rats, Sprague-Dawley; Shock, Hemorrhagic

The aim of this study was to investigate the protective effect of vitamin C towards hyperhomocysteinemia (hHcy) induced oxidative DNA damage using the comet assay. The increase in plasma homocysteine levels is an important risk factor for vascular and cardiovascular diseases through free radical production. This study was also conducted to investigate the histopathological changes in the thoracic aorta and the oxidant/antioxidant status in heart, liver and kidney tissues. Twenty-four adult male Wistar rats were divided as control, hHcy and hHcy+vitamin C group. Chronic hHcy was induced by oral administration of l-methionine (1g/kg/day) for 28 days. Vitamin C was given 150mg/kg/day within the specified days. DNA damage was measured by use of the comet assay in lymphocytes. Levels of malondialdehyde (MDA) and glutathione (GSH) as well as catalase (CAT) and superoxide dismutase (SOD) activities were determined in heart, liver and renal tissues. Results show that l-methionine administration significantly increased % Tail DNA and Mean Tail Moment in hHcy group as compared with other groups. Vitamin C treatment significantly decreased the high MDA levels and increased activity of antioxidant enzymes in tissues. Aortic diameter and thickness of aortic elastic laminae were significantly lower in hHcy+vitamin C group. Comet assay can be used for the assessment of primary DNA damage caused by hHcy. Histopathological findings showed that vitamin C may have a preventive effect in alleviating the negative effects of hHcy. Vitamin C might be useful in the prevention of endothelial dysfunction caused by hHcy.

Topics: Animals; Antioxidants; Aorta; Ascorbic Acid; Comet Assay; Disease Models, Animal; DNA Damage; Hyperhomocysteinemia; Male; Oxidative Stress; Rats; Rats, Wistar

To investigate the potential role of oxidative stress and the possible therapeutic effects of N-acetyl cysteine (NAC), amifostine (AMF) and ascorbic acid (ASC) in methotrexate (MTX)-induced hepatotoxicity.. An MTX-induced hepatotoxicity model was established in 44 male Sprague Dawley rats by administration of a single intraperitoneal injection of 20 mg/kg MTX. Eleven of the rats were left untreated (Model group; n = 11), and the remaining rats were treated with a 7-d course of 50 mg/kg per day NAC (MTX + NAC group; n = 11), 50 mg/kg per single dose AMF (MTX + AMF group; n = 11), or 10 mg/kg per day ASC (MTX + ASC group; n = 11). Eleven rats that received no MTX and no treatments served as the negative control group. Structural and functional changes related to MTX- and the various treatments were assessed by histopathological analysis of liver tissues and biochemical assays of malondialdehyde (MDA), superoxide dismutase (SOD), catalase, glutathione (GSH) and xanthine oxidase activities and of serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and total bilirubin.. Exposure to MTX caused structural and functional hepatotoxicity, as evidenced by significantly worse histopathological scores [median (range) injury score: control group: 1 (0-3) vs 7 (6-9), P = 0.001] and significantly higher MDA activity [409 (352-466) nmol/g vs 455.5 (419-516) nmol/g, P < 0.05]. The extent of MTX-induced perturbation of both parameters was reduced by all three cytoprotective agents, but only the reduction in hepatotoxicity scores reached statistical significance [4 (3-6) for NAC, 4.5 (3-5) for AMF and 6 (5-6) for ASC; P = 0.001, P = 0.001 and P < 0.005 vs model group respectively]. Exposure to MTX also caused a significant reduction in the activities of GSH and SOD antioxidants in liver tissues [control group: 3.02 (2.85-3.43) μmol/g and 71.78 (61.88-97.81) U/g vs model group: 2.52 (2.07-3.34) μmol/g and 61.46 (58.27-67.75) U/g, P < 0.05]; however, only the NAC treatment provided significant increases in these antioxidant enzyme activities [3.22 (2.54-3.62) μmol/g and 69.22 (61.13-100.88) U/g, P < 0.05 and P < 0.01 vs model group respectively].. MTX-induced structural and functional damage to hepatic tissues in rats may involve oxidative stress, and cytoprotective agents (NAC > AMF > ASC) may alleviate MTX hepatotoxicity.

Topics: Acetylcysteine; Amifostine; Animals; Antioxidants; Ascorbic Acid; Biomarkers; Chemical and Drug Induced Liver Injury; Cytoprotection; Disease Models, Animal; Liver; Male; Methotrexate; Oxidative Stress; Rats, Sprague-Dawley; Time Factors

Recent studies showed that both sepsis and antibiotic therapy are associated with cell death and linked to reactive oxygen species generation. This study investigated the effects of intratracheal administration of combinations of antioxidants (n-acetyl cysteine (NAC), vitamins C and E) in the treatment of sepsis-induced lung injury.. Ninety-six male Wistar rats subjected to sepsis were treated with ceftriaxone plus NAC with or without vitamins C and E and compared to appropriate controls. As an index of oxidative damage protein carbonyls, sulfhydryl groups, lipid peroxidation and superoxide anion were measured, as well as superoxide dismutase and catalase. Histopathological alterations and mortality rate were also analyzed.. Twenty-four hours after sepsis induction, markers of oxidative stress increased in all lungs examined. Ceftriaxone plus intratracheal combination of NAC, vitamins C and E decreased lung injury in infected animals by reducing superoxide anion production (54%), lipid peroxidation (53%) and protein carbonyl (58%) and restored the redox status (7.5 times). This therapy also reduced the imbalance of antioxidant enzymes activities and attenuated the alveolar architectural disorganization, inflammatory cell infiltration and pulmonary oedema. Survival increased from 66.6% with ceftriaxone to 83.2% with ceftriaxone plus antioxidants.. Ceftriaxone plus intratracheal co-administration of antioxidants provides better protection, by decreasing pulmonary oxidative stress, limiting histophatological alterations and improving survival. Antioxidants should be explored as a co-adjuvant in the treatment of severe lung injury.

Topics: Acetylcysteine; Animals; Anti-Bacterial Agents; Antioxidants; Ascorbic Acid; Ceftriaxone; Disease Models, Animal; Drug Administration Routes; Drug Therapy, Combination; Lung Injury; Male; Rats; Rats, Wistar; Sepsis; Trachea; Vitamin E

To evaluate the effects of different doses of ascorbic acid (AA) on the functional performance of rats subjected to standardized spinal cord injury (SCI).. Thirty female Sprague-Dawley rats were divided into three groups (10 animals in each group): control group: rats were subjected to SCI injury and received intraperitoneal saline administration; normal-dose AA group: rats were subjected to SCI injury and received daily intraperitoneal administration of AA at 100 mg kg(-1) bodyweight; high-dose AA group: rats were subjected to SCI injury and received daily intraperitoneal administration of AA at 200 mg kg(-1) bodyweight. The Basso, Beattie, Bresnahan Locomotor Rating Score (BBB score) and footprint analysis were performed to evaluate the functional performance of the rats in each group, and hematoxylin and eosin staining was performed to evaluate necrosis at the injury site.. At days 14 and 28 after SCI, rats in the high-dose AA group, but not the normal-dose AA group, exhibited significantly better BBB score compared with the control group (P<0.05). Compared with the control and normal-dose AA group, the high-dose AA group also showed increased stride length, decreased stride width and reduced toe dragging (P<0.05). Histological analysis revealed that both the normal- and high-dose AA groups had reduced necrosis in the injury site compared with the control group (P<0.05).. High-dose AA administration during the acute phase post SCI significantly reduced secondary injury-induced tissue necrosis and improved functional performance in rats.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Injections, Intraperitoneal; Locomotion; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Recovery of Function; Severity of Illness Index; Spinal Cord Injuries; Time Factors

Cisplatin, a platinum-derived chemotherapeutic agent, produces antineoplastic effects coupled with toxic neuropathic pain and impaired general health status. These side-effects complicate long term studies of neuropathy or analgesic interventions in animals. We recently demonstrated that pretreatment with sodium bicarbonate (4% NaHCO3) prior to cisplatin (3 mg/kg i.p. weekly up to 5 weeks) was associated with improved health status (i.e. normal weight gain, body temperature, creatinine and ketone levels, and kidney weight ratio) in rats (Neurosci Lett 544:41-46, 2013). To reduce the nephrotoxic effects of cisplatin treatment in mice, we compared effects of sodium bicarbonate (4% NaHCO3 s.c.), vitamin C (25 mg/kg s.c.), resveratrol (25 mg/kg s.c.) and saline (0.9% NaCl) pretreatment on cisplatin-induced changes in animal health status, neuropathic pain and proinflammatory cytokine levels in spinal cord and kidney.. Cisplatin-treated mice receiving saline pretreatment exhibited elevated ketone, creatinine and kidney weight ratios, representative of nephrotoxicity. Vitamin C and sodium bicarbonate lowered creatinine/ketone levels and kidney weight ratio whereas resveratrol normalized creatinine levels and kidney weight ratios similar to saline pretreatment. All pretreatments were associated with decreased ketone levels compared to saline pretreatment. Cisplatin-induced neuropathy (i.e. mechanical and cold allodynia) developed equivalently in all pretreatment groups and was similarly reversed by either morphine (6 mg/kg i.p.) or ibuprofen (6 mg/kg i.p.) treatment. RT-PCR showed that mRNA levels for IL-1β were increased in lumbar spinal cord of cisplatin-treated groups pretreated with either saline, NaHCO3 or resveratrol/cisplatin-treated groups. However, IL-6 and TNF-alpha were elevated in the kidneys in all cisplatin-treated groups. Our studies also demonstrate that 60 days after the last cisplatin treatment, body weight, body temperature, kidney functions and mRNA levels have returned to baseline although the neuropathic pain (mechanical and cold) is maintained.. Studies employing cisplatin should include NaHCO3 or vitamin C pretreatment to improve animal health status and reduce nephrotoxicity (lower creatinine and kidney weight ratio) without affecting the development of chemotherapy-induced neuropathy or analgesic efficacy.

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Blood Glucose; Body Temperature; Body Weight; Cisplatin; Creatinine; Disease Models, Animal; Drug Administration Schedule; Health Status; Hyperalgesia; Ketones; Male; Mice; Mice, Inbred C57BL; Pain Threshold; Peripheral Nervous System Diseases; Sodium Bicarbonate; Vitamins

The objective of the present study was to prepare a stable iv injectable formulation of ascorbic acid and α-tocopherol in preventing the cerebral ischemia. Different niosomal formulations were prepared by Span and Tween mixed with cholesterol. The physicochemical characteristics of niosomal formulations were evaluated in vitro. For in vivo evaluation, the rats were made ischemic by middle cerebral artery occlusion model for 30 min and the selected formulation was used for determining its neuroprotective effect against cerebral ischemia. Neuronal damage was evaluated by optical microscopy and transmission electron microscopy. The encapsulation efficiency of ascorbic acid was increased to more than 84% by remote loading method. The cholesterol content of the niosomes, the hydrophilicity potential of the encapsulated compounds, and the preparation method of niosomes were the main factors affecting the mean volume diameter of the prepared vesicles. High physical stability of the niosomes prepared from Span 40 and Span 60 was demonstrated due to negligible size change of vesicles during 6 months storage at 4-8(°)C. In vivo studies showed that ST60/Chol 35 : 35 : 30 niosomes had more neuroprotective effects against cerebral ischemic injuries in male rats than free ascorbic acid.

Topics: alpha-Tocopherol; Animals; Ascorbic Acid; Brain Ischemia; Cerebral Cortex; Chemistry, Pharmaceutical; Disease Models, Animal; Infarction, Middle Cerebral Artery; Liposomes; Male; Neurons; Particle Size; Rats, Wistar; Reperfusion Injury

To analyze the protective activity of vitamin C on the lungs by assessing biochemical and histopathological analysi after performing an experimental isolated lung contusion model.. Fifty-four male Sprague-Dawley male rats were used. The rats were randomly separated into 4 groups Vitamin C (200 mg/kg) was injected intraperitoneally 30 min after trauma. Blood samples were obtained for myeloperoxidase (MPO) glutirthione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) activities and malondialdehyde (MDA) levels Blood gas analysis and bronchoalveolar lavage was performed. The lung tissue was also extracted for histopathological examination.. The lung contusion enhanced MDA, SOD, CAT, and MPO and diminished GSH-Px. Vitamin C administration after th pulmonary contusion was found to diminish the level of MDA and the activities of SOD, CAT, and MPO and to enhance the level of GSH-Px (P < 0.05). Contusion-induced disrupted gas analysis and leukocyte infiltration were both resolved by the vitamin C.. The present results indicate that vitamin C administration attenuated the oxidative damage and morphological change induced by pulmonary contusion in an experimental rat study.

Topics: Animals; Antioxidants; Ascorbic Acid; Bronchoalveolar Lavage; Catalase; Contusions; Disease Models, Animal; Glutathione Peroxidase; Lipid Peroxidation; Lung Injury; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley

The study was aimed at performing an experimental trial of the reparative osteogenesis stimulation by local injection of autologous plasma in combination with metabolically active substances such as L-ascorbic acid and D-glucose for management of pelvic fractures.. The experiment was carried out on twenty-six mongrel dog of both sexes aged 1.5 ± 0.09 years and with body weight of 17 ± 0.5kg. Transverse osteotomy was performed in the acetabulum (n = 20) and in the ilium body (n = 6). The fractures were stabilized with external fixators. On days two through 5 after the operation all dogs had intraarticular or intraosseous injections of the saline solution throughout 24 hours in the dose of 0.4 ml per day. Experimental animals were additionally injected once a day with 1 ml of a composition consisting of the ascorbic acid and glucose. The external apparatuses were dismounted on day 21 after the operation. The animals for histological study were euthanized on day 14 and 42 after the operation. The study used radiographic and histological methods of study as well as the method of radiographic electron probe microanalysis.. The control animals that had either intraosseous or intraarticular saline injections alone had fibro-cartilaginous union of the pelvic fragments. They developed bone deformity due to secondary displacement upon apparatus removal. The experimental animals had primary bone union on day 14. The bone was consolidated after the removal of the apparatus.. Autologous blood plasma in combination with active substances of ascorbic acid and glucose had a marked stimulating effect on pelvic fracture healing if applied locally in the posttraumatic period. The method of reparative osteogenesis stimulation that was developed is low traumatic. It does not hinder early functional loading and allows control of reparative process basing on the biological principles of tissue regeneration.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Dogs; Drug Administration Routes; Fracture Fixation, Internal; Fracture Healing; Fractures, Bone; Glucose; Pelvic Bones; Plasma; Treatment Outcome

Phenytoin is known to induce microsomal enzymes including xanthine oxidase which catalyzes uric acid synthesis with superoxides as byproducts, thus contributing to the oxidative stress of phenytoin hepatotoxicity. To investigate the role of antioxidant vitamins in ameliorating phenytoin induced hepatic changes through possible actions on xanthine oxidase activities as measured by urate concentration. Growing albino rats of Wistar strain were randomly divided into 8 groups of 7 rats each. Group 2, 3, 4, 5, 6, 7 and 8 were treated with phenytoin alone, phenytoin + folic acid, phenytoin + vitamin E, phenytoin + vitamin E + vitamin C, phenytoin + vitamin C, phenytoin + folic acid + vitamin E and phenytoin + vitamin E + vitamin C + folic acid respectively while animals in group 1 were given normal saline to serve as control. Serum concentrations of uric acid, albumin, total protein and the activities of aspartate and alanine aminotransferases (AST and ALT) and catalase were measured spectrophotometrically using appropriate commercial reagent kits. Result showed that administration of phenytoin alone caused significant (p < 0.05) increase in serum levels of globulin, uric acid, AST and ALT activities while the levels of albumin and catalase were reduced significantly (p < 0.05). Supplementation of phenytoin treatment with vitamins resulted in various degrees of protection. However, the elevated level of uric acid in serum was not significantly (p < 0.05) affected by any of the vitamins used and there was no significant correlation between the activities of aminotransferases and uric acid concentration in the vitamin treated animals as was observed between aminotransferases and catalase. The findings in this study suggest that antioxidant vitamins were able to ameliorate phenytoin hepatotoxic effects by improving oxidant radicals removal in the animals but would not inhibit further generation of the superoxides by xanthine oxidase activity and that xanthine oxidase may contribute significantly to the oxidative stress of phenytoin therapy.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Chemical and Drug Induced Liver Injury; Cytoprotection; Disease Models, Animal; Folic Acid; Liver; Oxidative Stress; Phenytoin; Rats, Wistar; Superoxides; Uric Acid; Vitamin E; Xanthine Oxidase

A series of novel (1S)-(-)-verbenone derivatives was synthesized bearing a 4-styryl scaffold. The synthesized compounds were tested for their anti-oxidant, anti-excitotoxic, and anti-ischemic activities. These derivatives significantly reduced oxygen-glucose deprivation-induced neuronal injury and N-methyl-D-aspartic acid-evoked excitotoxicity in cortical neurons. Furthermore, compound 3f was identified as a potent anti-ischemic agent in an in vitro ischemic model, potentially due to the inhibition of N-methyl-D-aspartic acid-evoked excitotoxicity and oxidative/nitrosative stress.

Topics: Animals; Antioxidants; Bicyclic Monoterpenes; Cells, Cultured; Disease Models, Animal; Drug Discovery; Ischemia; N-Methylaspartate; Neurons; Neuroprotective Agents; Oxidative Stress; Terpenes

Ozone is an environmentally reactive oxidant, and pycnogenol is a mixture of flavonoid compounds extracted from pine tree bark that have antioxidant activity. We investigated the effects of pycnogenol on reactive nitrogen species, antioxidant responses, and airway responsiveness in BALB/c mice exposed to ozone.. Antioxidant levels were determined using high performance liquid chromatography with electrochemical detection. Nitric oxide (NO) metabolites in bronchoalveolar lavage (BAL) fluid from BALB/c mice in filtered air and 2 ppm ozone with pycnogenol pretreatment before ozone exposure (n = 6) were quantified colorimetrically using the Griess reaction.. Uric acid and ascorbic acid concentrations were significantly higher in BAL fluid following pretreatment with pycnogenol, whereas γ-tocopherol concentrations were higher in the ozone exposed group but were similar in the ozone and pycnogenol pretreatment groups. Retinol and γ-tocopherol concentrations tended to increase in the ozone exposure group but were similar in the ozone and pycnogenol pretreatment groups following ozone exposure. Malonylaldehyde concentrations increased in the ozone exposure group but were similar in the ozone and pycnogenol plus ozone groups. The nitrite and total NO metabolite concentrations in BAL fluid, which parallel the in vivo generation of NO in the airways, were significantly greater in the ozone exposed group than the group exposed to filtered air, but decreased with pycnogenol pretreatment.. Pycnogenol may increase levels of antioxidant enzymes and decrease levels of nitrogen species, suggesting that antioxidants minimize the effects of acute ozone exposure via a protective mechanism.

Topics: alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Disease Models, Animal; Female; Flavonoids; Inhalation Exposure; Lung; Malondialdehyde; Mice; Mice, Inbred BALB C; Nitric Oxide; Oxidative Stress; Ozone; Plant Extracts; Uric Acid; Vitamin A

Adhesion formation is a complication of hand flexor tendon repair. Normal gliding function of flexor tendons can be impaired by an excessive fibrotic response, which may be caused by intraoperative and postoperative hemorrhage. As tissue damage and hemorrhage can disturb redox regulation, thereby favoring fibrotic responses, the purpose of this study was to investigate if antioxidants can reduce tendon adhesion by antagonizing oxidative stress.. Flexor digitorum profundus tendon injury was induced in fifty-seven chickens. In twelve chickens, oxidative stress preinjury, immediately after injury, and two and six weeks postinjury (n = 3 at each time period) was estimated by measuring tissue levels of the reduced form of glutathione (GSH) and oxidized glutathione (glutathione disulfide [GSSG]) in the proximal interphalangeal joint. In the remaining chickens, 50 μL of saline solution or vitamin-C solution (5 or 50 mg/mL) was injected into the wound immediately after closure of the tendon sheath. Samples were harvested at two weeks (n = 6 in each group) or six weeks (n = 6 in each group) postinjury for a gliding test, ultrasound imaging, and histological examination. Three chickens from each group were killed at two weeks postinjury for GSH and GSSG measurements to evaluate the treatment effects on postoperative oxidative stress.. The GSH level was significantly decreased at two and six weeks postinjury, and the GSSG level was significantly increased at six weeks postinjury. Both 5 and 50-mg/mL vitamin C led to higher tissue levels of GSH at two weeks postinjury, as compared with that in the saline solution group, but no significant change in the GSSG level was detected. Chickens with vitamin-C supplementation showed no significant improvement in gliding resistance and no significant reduction of the fibrotic size at two weeks postinjury, but they did show significant improvement in gliding resistance at six weeks postinjury and the 5-mg/mL vitamin-C group showed a significant reduction of the fibrotic size at six weeks. Histological examination showed less peritendinous adhesion in the vitamin-C groups.. Our results suggest that local injection of vitamin-C solution can reduce the extent of adhesion of healing tendons, probably by redox modulation, in a chicken model.

Topics: Animals; Ascorbic Acid; Chickens; Disease Models, Animal; Female; Glutathione; Glutathione Disulfide; Injections, Intra-Articular; Oxidative Stress; Statistics, Nonparametric; Tendon Injuries; Tissue Adhesions; Toes; Wound Healing

We examined the antileukemic effects of high concentrations of L-ascorbic acid (high AA) on human leukemic cells. In vitro, high AA markedly induced apoptosis in various leukemic cell lines by generating hydrogen peroxide (H2O2) but not in normal hematopoietic stem/progenitor cells. High AA significantly repressed leukemic cell proliferation as well as neoangiogenesis in immunodeficient mice. We then noted that in leukemic cells, HIF-1α transcription was strongly suppressed by high AA and correlated with the transcription of VEGF. Our data indicate that exposure to high AA markedly increased the intracellular AA content of leukemic cells and inhibited the nuclear translocation of NF-κB, which mediates expression of HIF-1α. We next generated K562 cells that overexpressed HIF-1α (K562-HIF1α cells) and assessed the mechanistic relationship between inhibition of HIF-1α transcription and the antileukemic effect of high AA. The ability of high AA to induce apoptosis was significantly lower in K562-HIF1α cells than in K562 cells in vitro. We found that expression of HIF-1α-regulated antiapoptotic proteins of the Bcl-2 family, such as Mcl-1, Bcl-xL, and Bcl-2, was significantly suppressed by high AA in K562 cells, but was sustained at higher levels in K562-HIF1α cells, regardless of high AA exposure. Moreover, repression of cell proliferation and neoangiogenesis by high AA was completely abrogated in mice receiving transplants of K562-HIF1α cells. These results indicate that, along with H2O2 generation, downregulation of HIF-1α transcription plays a crucial role in growth inhibition of human leukemic cells by high AA.

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Disease Progression; Gene Expression Regulation, Leukemic; Hematopoietic Stem Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; K562 Cells; Leukemia; Mice; Transcription, Genetic; Tumor Burden; Xenograft Model Antitumor Assays

Dysregulation of cortical and striatal neuronal processing plays a critical role in Huntington's disease (HD), a dominantly inherited condition that includes a progressive deterioration of cognitive and motor control. Growing evidence indicates that ascorbate (AA), an antioxidant vitamin, is released into striatal extracellular fluid when glutamate is cleared after its release from cortical afferents. Both AA release and glutamate uptake are impaired in the striatum of transgenic mouse models of HD owing to a downregulation of glutamate transporter 1 (GLT1), the protein primarily found on astrocytes and responsible for removing most extracellular glutamate. Improved understanding of an AA-glutamate interaction could lead to new therapeutic strategies for HD.. Increased expression of GLT1 following treatment with ceftriaxone, a beta-lactam antibiotic, increases striatal glutamate uptake and AA release and also improves the HD behavioral phenotype. In fact, treatment with AA alone restores striatal extracellular AA to wild-type levels in HD mice and not only improves behavior but also improves the firing pattern of neurons in HD striatum.. Although evidence is growing for an AA-glutamate interaction, several key issues require clarification: the site of action of AA on striatal neurons; the precise role of GLT1 in striatal AA release; and the mechanism by which HD interferes with this role.. Further assessment of how the HD mutation alters corticostriatal signaling is an important next step. A critical focus is the role of astrocytes, which express GLT1 and may be the primary source of extracellular AA.

Topics: Animals; Ascorbic Acid; Biological Transport; Cerebral Cortex; Corpus Striatum; Disease Models, Animal; Glutamic Acid; Humans; Huntington Disease; Mice; Mice, Transgenic

Both oxidative stress and inflammatory reactions play a major role in alcoholic liver fibrosis. We evaluated the efficacy of ascorbic acid (AA) and silymarin in the regression of alcohol-induced inflammation in hepatocytes of guinea pigs (Cavia porcellus). Animals were administered with ethanol at a daily dose of 4 g/kg body weight (b.wt) for 90 days. On the ninety-first day, ethanol administration was stopped and animals were divided into alcohol abstention group and silymarin- (25 mg/100 g b.wt) and AA- (25 mg/100 g b.wt) supplemented groups and maintained for 30 days. There was a significant increase in the activities of alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase in the serum of the ethanol group. The intracellular reactive oxygen species (ROS) and expressions of cytochrome P4502E1 and nuclear factor κB1, tumor necrosis factor-α, and transforming growth factor-β(1) in hepatocytes were significantly increased in ethanol group. The fibrotic markers α-smooth muscle actin and α(1)(I) collagen and activity of cytotoxicity marker caspase-3 were significantly increased and AA content was significantly reduced in hepatocytes of alcohol-treated guinea pigs. But the AA and silymarin supplementation significantly reduced these changes in comparison with alcohol abstention group. AA could induce greater reduction of inflammatory and fibrotic markers in hepatocytes than silymarin. This indicates that AA is superior to silymarin in inhibiting intracellular ROS generation and thereby reducing the ethanol-induced inflammation in hepatocytes.

Topics: Actins; Alanine Transaminase; Animals; Antioxidants; Aryl Hydrocarbon Hydroxylases; Ascorbic Acid; Aspartate Aminotransferases; Collagen Type I; Collagen Type I, alpha 1 Chain; Disease Models, Animal; Ethanol; gamma-Glutamyltransferase; Gene Expression; Guinea Pigs; Hepatocytes; Liver; Liver Cirrhosis, Alcoholic; Male; NF-kappa B; Oxidative Stress; Protective Agents; Reactive Oxygen Species; Silymarin; Steroid Hydroxylases; Transforming Growth Factor beta

Myelophil is composed of Astragali Radix and Salviae Miltiorrhizae Radix, according to the long traditional pharmacological practices, and it has been used for patients with chronic fatigue-associated symptoms including concentration problem or memory loss.. This study aimed to evaluate the clinical relevance of Myelophil on brain oxidative damage using a chronic cold stress mice model.. Balb/c mice were subjected to cold stress (4°C for 4h) six times per week for 2 weeks with or without oral administration of Myelophil (50, 100, or 200mg/kg), or ascorbic acid (50mg/kg).. Chronic cold stress induced histopathological hippocampal apoptosis with drastically increased serum levels of total reactive oxygen species and nitric oxide, as well as brain lipid peroxidation levels, protein carbonyl, and caspase-3/7 activity. These alterations were significantly ameliorated by Myelophil treatment. Myelophil administration significantly recovered the depleted glutathione and its enzymes, superoxide dismutase activity, and catalase protein and gene expression levels. Serum levels of corticosterone, dopamine, and adrenaline were notably altered by chronic cold stress but were significantly ameliorated by Myelophil treatment. Myelophil also normalized alterations in tumor necrosis factor-α, interleukin (IL)-1β, and IL-10 gene expression and protein levels. Chronic cold stress up-regulated gene expression levels of phenylethanolamine N-methyltransferase and monoamine oxidase-B, and glucocorticoid receptors in the hypothalamus and hippocampus, respectively, whereas Myelophil treatment completely normalized these levels.. These results suggest that Myelophil has potent pharmaceutical effects against chronic cold-stress-induced brain damage by relieving oxidative stress and inflammation and regulating stress hormones in mice.

Topics: Animals; Apoptosis; Ascorbic Acid; Brain Injuries; Caspase 3; Caspase 7; Corticosterone; Disease Models, Animal; Dopamine; Drugs, Chinese Herbal; Epinephrine; Glutathione; Hippocampus; Hypothalamo-Hypophyseal System; Interleukin-10; Interleukin-1beta; Lipid Peroxidation; Male; Mice; Mice, Inbred BALB C; Monoamine Oxidase; Nitric Oxide; Oxidative Stress; Phenylethanolamine N-Methyltransferase; Pituitary-Adrenal System; Reactive Oxygen Species; Receptors, Glucocorticoid; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the effect of vitamin C on the growth of experimental endometriotic cysts.. The endometrium of the uterine horn wall (diameter, 4 mm) was implanted onto the inner surface of the anterior abdominal wall of 40 Wistar albino adult female rats, by laparotomy. The day after the implantation, the rats were randomly assigned into four groups (control group and experimental groups [V1, V2, and V3]) comprising 10 rats each. For 6 weeks, the control group (Group C) received 1 mL distilled water, whereas the experimental groups (Groups V1, V2, and V3) received 0.5 mg, 1.25 mg, and 2.5 mg of vitamin C in 1 mL of distilled water, respectively. The doses were given via oral gavage once per day. At the end of the administration, a second laparotomy was performed and endometriotic cyst volumes and weights of rats among the groups were compared. In addition, the stromal and glandular tissue and the natural killer cell contents of the cysts were compared among the groups.. The cyst volume in Group V3 and the cyst weights in Groups V2 and V3 were significantly lower than those in Group C. The natural killer cell content in Groups V1, V2, and V3 was significantly lower than that in Group C. Stromal and glandular tissue contents of the groups were not significantly different.. The dose-dependent vitamin C supplementation significantly reduced the volumes and weights of the endometriotic cysts.

Topics: Abdominal Wall; Animals; Antioxidants; Ascorbic Acid; Cysts; Dietary Supplements; Disease Models, Animal; Disease Progression; Endometriosis; Female; Pilot Projects; Random Allocation; Rats; Rats, Wistar

Ageing is an important risk factor of cardiovascular diseases including heart failure. Senescence marker protein 30 (SMP30), which was originally identified as an important ageing marker protein, is assumed to act as a novel anti-ageing factor in various organs. However, the role of SMP30 in the heart has not been previously explored. In this study, our aim was to elucidate the functional role of SMP30 on cardiac remodelling.. SMP30 knockout (KO) mice and wild-type (WT) mice were subjected to continuous angiotensin II (Ang II) infusion. After 14 days, the extent of cardiac hypertrophy and myocardial fibrosis was significantly higher in SMP30-KO mice than in WT mice. Echocardiography revealed that SMP30-KO mice had more severely depressed systolic and diastolic function with left ventricular dilatation compared with WT mice. Generation of reactive oxygen species related with activation of nicotinamide adenine dinucleotide phosphate-oxidase was greater in SMP30-KO mice than in WT mice. The number of deoxynucleotidyl transferase-mediated dUTP nick end-labelling positive nuclei was markedly increased in SMP30-KO mice with activation of caspase-3, increases in the Bax to Bcl-2 ratio and phosphorylation of c-Jun N-terminal kinase compared with WT mice. Furthermore, the number of senescence-associated β-galactosidase-positive cells was significantly increased via up-regulation of p21 gene expression in SMP30-KO mice compared with WT mice.. This study demonstrated the first evidence that deficiency of SMP30 exacerbates Ang II-induced cardiac hypertrophy, dysfunction, and remodelling, suggesting that SMP30 has a cardio-protective role in cardiac remodelling with anti-oxidative and anti-apoptotic effects in response to Ang II.

Topics: Aging; Angiotensin II; Animals; Apoptosis; Ascorbic Acid; bcl-2-Associated X Protein; Biomarkers; Calcium-Binding Proteins; Cardiomegaly; Caspase 3; Disease Models, Animal; Fibrosis; Heart Failure; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Ventricular Remodeling

Cardiovascular disease is one of the most significant causes of mortality in humans and animals, and its etiology is usually unknown. The aim of this study was to investigate the cardiac pathology of endosulfan toxicity and the protective effect of vitamin C in rabbits. Twenty-four rabbits were divided into 4 groups: (1) the END group was given a daily sublethal dose of endosulfan in corn oil by oral gavage for 6 weeks; (2) the END + C group received the endosulfan as well as vitamin C over the same 6-week period; (3) the OIL + C group received corn oil daily and vitamin C every other day; and (4) the OIL group received only corn oil daily. We observed microscopic hemorrhages, single-cell necrosis, inflammatory reactions, and fibrotic changes in the myocardium in the END group. Small hemorrhages and single-cell necrosis also were seen in some hearts in the END + C group, but no inflammation was observed. Caspase-3 immunoreactivity was more significant in myocardial cells in the END group compared with the others. A protective effect of vitamin C on lesions was observed in the END + C group. These results showed that endosulfan resulted in toxic changes in the hearts of rabbits, but this toxicity could be decreased with vitamin C treatment.

Topics: Administration, Oral; Animals; Apoptosis; Ascorbic Acid; Cardiotoxins; Caspase 3; Disease Models, Animal; Dose-Response Relationship, Drug; Endosulfan; Fibrosis; Heart Diseases; Insecticides; Male; Myocytes, Cardiac; Necrosis; Rabbits

Ascorbic acid (AA) has long been described as an antiproliferative agent. However, the molecule has to be used at a very high concentrations, which necessitates i.v. injection, and the tight regulation of in-blood and in-cell AA concentrations making it impossible to hold very high concentrations for any substantial length of time. Here we report evidence that AA derivates are antiproliferative and cytotoxic molecules at an IC50 lower than AA itself. Among these new molecules, we selected K873 that has cytotoxic and antiproliferative effects on different human tumor cells at tenth micromolar concentration. In a further step, we demonstrated that K873 selectively to kills only cancer cells without being toxic for normal non-dividing (or poorly dividing) cells. Finally, we tested the effect of treatment with K873 (5-10 mg/kg/d by i.p. route) on tumor progression in xenografted immunodeficient mice (BALB/c Nude). Our data suggest that K873 administration strongly inhibits tumor progression. In a previous study using microarrays, we demonstrated that AA decreases the expression of two genes families involved in cell cycle progression, i.e. initiation factor of translation and tRNA synthetases. Here we show that K873 treatment also decreases the expression of four of these genes in xenografted tumors, in proportions similar to that previously observed with AA. Taken together, our data suggest that AA and K873 share similar action. Our findings suggest that AA derivatives could be a promising new class of anti-cancer drugs, either alone or in combination with other molecules.

Topics: Animals; Ascorbic Acid; Cell Line; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Female; Fibroblasts; HT29 Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Xenograft Model Antitumor Assays

To investigate the effects of an antioxidant cocktail (AC) on bleomycin, etoposide, and cisplatin (BEP)-induced testicular dysfunction.. In vivo study.. Research laboratory.. Adult male and female Sprague-Dawley rats.. The rats were treated with three cycles of 21 days each of therapeutically relevant dose levels of BEP (0.75, 7.5, and 1.5 mg/kg) with or without the AC (a mixture of α-tocopherol, L-ascorbic acid, Zn, and Se).. Sperm parameters, fertility, serum hormone levels (ELISA), testicular histopathology, and expression of proliferating cell nuclear antigen (PCNA), and transferrin (Western blotting and immunohistochemistry) were evaluated at the end of treatment and a 63-day recovery period.. At the end of treatment, the AC improved BEP-induced decrease in sperm motility and increase in abnormality but had no effect on reduced sperm count, fertility, and tubular atrophy, although it up-regulated germ cell proliferation. The AC normalized reduced inhibin B levels, but had no effect on decreased transferrin and testosterone and elevated LH levels. At the end of the recovery period, the AC enhanced the expression of PCNA and transferrin, repopulation of germ cells, LH-testosterone axis, and fertility, but had no effect on reduced FSH and elevated inhibin B levels.. The antioxidants protect and then enhance the recovery of testicular and reproductive endocrine functions when administered concomitantly with BEP therapy. The AC may be beneficial to regain testicular functions after chemotherapy.

Topics: alpha-Tocopherol; Animals; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Ascorbic Acid; Atrophy; Bleomycin; Blotting, Western; Cisplatin; Cytoprotection; Disease Models, Animal; Drug Combinations; Enzyme-Linked Immunosorbent Assay; Etoposide; Female; Fertility; Hormones; Immunohistochemistry; Male; Pituitary Gland; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Recovery of Function; Selenium; Sperm Count; Sperm Motility; Spermatogenesis; Testicular Diseases; Testis; Time Factors; Transferrin; Zinc

Disturbances in circadian rhythms are commonly observed in the development of several medical conditions and may also be involved in the pathophysiology of sepsis. Melatonin, with its antioxidative and anti-inflammatory effects, is known to modulate the response to endotoxemia. In this paper, we investigated the circadian variation with or without melatonin administration in an experimental endotoxemia model based on lipopolysaccharide (LPS). Sixty male Sprague-Dawley rats were assigned to six groups receiving an intraperitoneal injection of either LPS (5 mg/kg), LPS + melatonin (1 mg/kg), or LPS + melatonin (10 mg/kg) at either daytime or nighttime. Superoxide dismutase (SOD) was analyzed in liver samples collected after decapitation. Furthermore, inflammatory plasma markers (cytokines interleukin [IL]-6, IL-10) and oxidative plasma markers (ascorbic acid [AA], dehydroascorbic acid [DHA], and malondialdehyde [MDA]) were analyzed before and 5 h after the onset of endotoxemia. There were significant higher levels of SOD (p < 0.05), IL-6 (p < 0.01), and IL-10 (p < 0.05) during nighttime endotoxemia compared with daytime. At daytime, melatonin 1 and 10 mg reduced the levels of MDA and increased SOD, IL-6, IL-10, and DHA (p < 0.05). At nighttime, melatonin reduced the levels of MDA and increased DHA (p < 0.05). Additionally, 10 mg melatonin resulted in lower levels of AA during daytime (p < 0.05). No dose relationship of melatonin was observed. The results showed that the response induced by experimental endotoxemia was dependent on time of day. Melatonin administration modulated the inflammatory and oxidative stress responses induced by endotoxemia and also resulted in higher levels of antioxidants during daytime. The effect of circadian time on the endotoxemia response and possible modulatory effects of melatonin need further investigations in a human endotoxemia model.

Topics: Acute-Phase Reaction; Animals; Antioxidants; Ascorbic Acid; Circadian Rhythm; Darkness; Disease Models, Animal; Endotoxemia; Inflammation; Interleukin-10; Interleukin-6; Light; Lipopolysaccharides; Male; Malondialdehyde; Melatonin; Oxidative Stress; Oxygen; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Chemoprotection refers to the use of specific natural or synthetic chemical agents to suppress or prevent the progression to cancer. The purpose of this study is to assess the protective effect of aspirin, vitamin C or zinc in a dimethyl hydrazine (DMH) colon carcinoma model in rats and to investigate the effect of these supplements on changes associated with colonic zinc status. Rats were randomly divided into three groups, group 1 (aspirin), group 2 (vitamin C) and group 3 (zinc), each being subdivided into two groups and given subcutaneous injection of DMH (30 mg/kg body wt) twice a week for 3 months and sacrificed at 4 months (A-precancer model) and 6 months (B-cancer model). Groups 1, 2, 3 were simultaneously given aspirin, vitamin C, or zinc supplement respectively from the beginning till the end of the study. It was observed that 87.5% of rats co-treated with aspirin or vitamin C showed normal colonic histology, along with a significant decrease in colonic tissue zinc at both time points. Rats co-treated with zinc showed 100% reduction in tumor incidence with no significant change in colonic tissue zinc. Plasma zinc, colonic CuZnSOD (copper-zinc superoxide dismutase) and alkaline phosphatase activity showed no significant changes in all 3 cotreated groups. These results suggest that aspirin, vitamin C or zinc given separately, exert a chemoprotective effect against chemically induced DMH colonic preneoplastic progression and colonic carcinogenesis in rats. The inhibitory effects are associated with maintaining the colonic tissue zinc levels and zinc enzymes at near normal without significant changes.

Topics: 1,2-Dimethylhydrazine; Alkaline Phosphatase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Apoptosis; Ascorbic Acid; Aspirin; Blotting, Western; Carcinogens; Cell Proliferation; Colonic Neoplasms; Dietary Supplements; Disease Models, Animal; Precancerous Conditions; Rats; Rats, Wistar; Superoxide Dismutase; Trace Elements; Zinc

Pancreatic cancer cell lines with mutated ras underwent an alternative form of cell death (aponecrosis) when treated concomitantly with clinically achievable concentrations of arsenic trioxide, ascorbic acid, and disulfiram (Antabuse; AAA). AAA's major effects are mediated through generation of intracellular reactive oxygen species (ROS) and more than 50% decline in intracellular ATP. N-acetyl cysteine and a superoxide dismutase mimetic prevented aponecrosis and restored intracellular ATP levels. DIDS (4,4'-diisothiocyanatostilbene-2, 2' disulfonic acid), the pan- Voltage-Dependent Anion Channel (VDAC), -1, 2, 3 inhibitor and short hairpin RNA (shRNA) to VDAC-1 blocked cell death and ROS accumulation. In vivo exposure of AAA led to a 62% reduction in mean tumor size and eliminated tumors in 30% of nude mice with PANC-1 xenografts. We concluded that early caspase-independent apoptosis was shifted to VDAC-mediated "targeted" aponecrosis by the addition of disulfiram to arsenic trioxide and ascorbic acid. Conceptually, this work represents a paradigm shift where switching from apoptosis to aponecrosis death pathways, also known as targeted aponecrosis, could be utilized to selectively kill pancreatic cancer cells resistant to apoptosis.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Cell Line, Tumor; Disease Models, Animal; Disulfiram; Dose-Response Relationship, Drug; Heterografts; Humans; Male; Mice; Necrosis; Oxides; Pancreatic Neoplasms; Reactive Oxygen Species; Tumor Stem Cell Assay; Voltage-Dependent Anion Channels

The antioxidant role of tender cluster beans (Cyamopsis tetragonoloba, CB), a rich source of soluble fibre, was investigated in a hypercholesterolemia-induced oxidative stress situation in rats. In the context of dietary garlic (Allium sativa) potentiating the hypocholesterolemic influence of CB, we also examined if dietary garlic enhances the antioxidant potential of CB. Groups of Wistar rats were rendered hypercholesterolemic by feeding them a 0.5% cholesterol diet for 8 weeks. Dietary interventions were made by inclusion of 15% tender CB powder or 1% garlic powder or their combination in a high-cholesterol diet. Concentrations of antioxidant molecules and activities of antioxidant enzymes in blood and liver were examined. Dietary CB displayed an antioxidant influence in terms of elevating ascorbic acid and glutathione concentrations and stimulating the activities of antioxidant enzymes both in blood and liver. The antioxidant effect of dietary CB was generally potentiated by co-administration of garlic. Thus, consumption of tender CB and garlic together could form a strategy for improving the body's antioxidant status.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Antioxidants; Ascorbic Acid; Catalase; Cholesterol, Dietary; Cyamopsis; Diet; Disease Models, Animal; Garlic; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Hypercholesterolemia; Liver; Male; Phytotherapy; Plants, Medicinal; Rats; Rats, Wistar; Superoxide Dismutase

To investigate the effects of antihistamine treatment on immune function in rats with experimental hepatitis.. Thirty Wistar rats were randomly allocated into three groups:experimental hepatitis group (EH group), antihistamine treatment group (AH group) and normal control group (NC group). Rats in the EH group received the subcutaneous injection of 40% carbon tetrachloride oil solution and were fed on diet with low-protein, low-choline, high-fat and high-alcohol,while rats in the AH group received antihistamine treatment(ketotifen + vitamin C) additionally.They were sacrificed after 4 weeks, and the levels of serum alanine aminotransferase(ALT), total bilirubin (TBil), histamine(HA), IFNgamma, IL-12, IL-4 and IL-10 were determined. The levels of IL-12 mRNA and IFN-gamma mRNA in liver tissue were determined via real-time reverse transcriptional polymerase chain reaction(RT-PCR).. (1) Compared to the NC group, in the EH group, the levels of ALT, TBil, and circulating and intrahepatic HA were significantly increased(P less than 0.05); intrahepatic HA were significantly decreased(P less than 0.05) after antihistamine treatment. (2) Compared to the NC group, in the EH group, the levels of IL-4, IL-10 were significantly increased((0.504+/-0.202)ng/ml and (29.025+/-1.478) pg/ml vs (0.811+/-0.244)ng/ml and (33.72+/-4.293)pg/ml respectively, P less than 0.05), and the levels of IL-12 were decreased ((6.515+/-2.893)pg/ml vs (3.519+/-1.113)pg/ml, P less than 0.05); and after antihistamine treatment the levels of IL-4 and IL-10 were significantly decreased (were (0.423+/-0.168)ng/ml and (30.412+/-3.275)pg/ml, P less than 0.05), the levels of IL-12 were significantly increased (P less than 0.05), but the level of IFNgamma had no significance (P more than 0.05). The levels of intrahepatic IL-12 mRNA and IFNgamma mRNA had similar results.. Antihistamine treatment may improve liver function and correct Th1/Th2 unbalance.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Hepatitis; Histamine Antagonists; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-4; Ketotifen; Liver; Male; Rats; Rats, Wistar; Th1-Th2 Balance; Tumor Necrosis Factor-alpha

Huntington's disease has been associated with a failure in energy metabolism and oxidative damage. Ascorbic acid is a powerful antioxidant highly concentrated in the brain where it acts as a messenger, modulating neuronal metabolism. Using an electrophysiological approach in R6/2 HD slices, we observe an abnormal ascorbic acid flux from astrocytes to neurons, which is responsible for alterations in neuronal metabolic substrate preferences. Here using striatal neurons derived from knock-in mice expressing mutant huntingtin (STHdhQ cells), we study ascorbic acid transport. When extracellular ascorbic acid concentration increases, as occurs during synaptic activity, ascorbic acid transporter 2 (SVCT2) translocates to the plasma membrane, ensuring optimal ascorbic acid uptake for neurons. In contrast, SVCT2 from cells that mimic HD symptoms (dubbed HD cells) fails to reach the plasma membrane under the same conditions. We reason that an early impairment of ascorbic acid uptake in HD neurons could lead to early metabolic failure promoting neuronal death.

Topics: Animals; Ascorbic Acid; Astrocytes; Cell Line; Cell Membrane; Disease Models, Animal; Energy Metabolism; Female; Huntingtin Protein; Huntington Disease; Male; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neuroglia; Neurons; Protein Transport; Rats, Wistar; Sodium-Coupled Vitamin C Transporters

Clinically, chronic nephrotoxicity may lead to renal functional impairment and progress to end stage renal failure. The renoprotective effect of a flavonoid naringin (NG) against cyclosporine A (CsA)-induced nephrotoxicitywas investigated in this study.. Nephrotoxicity was induced in male albino Wistar rats by injecting 25 mg/kg body weight of CsAfor a period of 21 days. CsA-induced rats were also cotreated with 40 mg of NG/kg body weight, orally.. After the experimental period, the levels of lipid peroxides (TBARS) and hydroxyl radical (OH·) were found to be elevated, whereas the levels of SOD, catalase, glutathione, vitamin C, E and A were decreased in CsA-induced rats. NG co-treatment significantly decreased the levels of lipid peroxides and hydroxyl radicals and restored the levels of enzymic and non-enzymic antioxidants in renal tissues. Histological analysis revealed that CsA administration caused severe and widespread necrosis with dilatation of proximal tubules, vacuolization, tubular cell desquamation and intraluminal cast formation with massive infiltration of inflammatory cells. CsA-induced histopathological renal changes were minimal in animals which received NG treatment. The western blot and confocal microscopic expression of heme oxygenase-1 was restored by NG. In CsA-induced animals the expression was reduced compared to NG treated animals.. The present study reveals that NG can act as effective renoprotective drug against CsA-induced toxicity.

Topics: Animals; Antioxidants; Ascorbic Acid; Catalase; Cyclosporine; Cytoprotection; Disease Models, Animal; Flavanones; Heme Oxygenase (Decyclizing); Hydroxyl Radical; Kidney; Kidney Diseases; Male; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Time Factors; Vitamin A; Vitamin E

Ascorbic acid (AA) functions as an electron donor and scavenges reactive oxygen species such as superoxide, singlet oxygen, and hydroxyl radicals in vitro. However, little is known about the effect of an AA deficiency on protein and lipid oxidation levels in the liver. Therefore, we measured the levels of protein carbonyl and thiobarbituric acid reactive substances (TBARS) in livers from senescence marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice. These mice are deficient in AA, because they lack the SMP30/GNL gene, which is essential for the biosynthesis of AA in vivo. To track the effect of an AA deficiency, at 30 d of age, mice were divided into the following four groups: AA (-) SMP30/GNL KO, AA (+) SMP30/GNL KO, AA (-) wild type (WT), and AA (+) WT. The AA (+) groups were given water containing 1.5 g/L AA, whereas the AA (-) groups received water without AA for 57 d. All mice were fed an AA-free diet. Subsequently, protein carbonyl levels in livers from AA (-) SMP30/GNL KO mice were significantly higher than those from the other three groups; however, TBARS levels were not significantly different among the four groups. Therefore, AA must act as an anti-oxidant for proteins but might not directly protect lipid oxidation in the liver.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Disease Models, Animal; Lipid Metabolism; Liver; Mice; Mice, Knockout; Oxidation-Reduction; Protein Carbonylation; Proteins; Thiobarbituric Acid Reactive Substances

Angiogenesis plays a key role in post-ischaemic myocardial repair. We hypothesized that epicardial implantation of an ascorbic acid (AA)-enriched myocardial artificial graft (MAG), which has been prevascularized in the recipients' own body, promotes restoration of the ischaemic heart. Gelatin patches were seeded with GFP-luciferase-expressing rat cardiomyoblasts and enriched with 5 μm AA. Grafts were prevascularized in vivo for 3 days, using a renal pouch model in rats. The MAG patch was then implanted into the same rat's ischaemic heart following myocardial infarction (MI). MAG-treated animals (MAG group, n = 6) were compared to untreated infarcted animals as injury controls (MI group, n = 6) and sham-operated rats as healthy controls (healthy group, n = 7). In vivo bioluminescence imaging indicated a decrease in donor cell survival by 83% during the first week post-implantation. Echocardiographic and haemodynamic assessment 4 weeks after MI revealed that MAG treatment attenuated left ventricular (LV) remodelling (LV end-systolic volume, 0.31 ± 0.13 vs 0.81 ± 0.01 ml, p < 0.05; LV end-diastolic volume 0.79 ± 0.33 vs 1.83 ± 0.26 ml, p < 0.076) and preserved LV wall thickness (0.21 ± 0.03 vs 0.09 ± 0.005 cm, p < 0.05) compared to the MI group. Cardiac output was higher in MAG than MI (51.59 ± 6.5 vs 25.06 ± 4.24 ml/min, p < 0.01) and comparable to healthy rats (47.08 ± 1.9 ml/min). Histology showed decreased fibrosis, and a seven-fold increase in blood vessel density in the scar area of MAG compared to MI group (15.3 ± 1.1 vs 2.1 ± 0.3 blood vessels/hpf, p < 0.0001). Implantation of AA-enriched prevascularized grafts enhanced vascularity in ischaemic rat hearts, attenuated LV remodelling and preserved LV function.

Topics: Animals; Antigens; Ascorbic Acid; Cell Survival; Disease Models, Animal; Electrocardiography; Fibrosis; Heart Transplantation; Heart Ventricles; Hemodynamics; Male; Myocardial Ischemia; Myocardium; Neovascularization, Physiologic; Rats; Rats, Wistar; Ultrasonography; Ventricular Function, Left

There is a strong male predominance of oesophageal adenocarcinoma, which might be related to the higher prevalence of precursor lesions such as erosive reflux oesophagitis in men compared with women. This experiment investigated the gender difference in a reflux oesophagitis model of rats and explored the potential role of oestrogen in controlling oesophageal tissue damage.. An acid-reflux oesophagitis model was surgically produced in male and female rats, and ascorbic acid in the diet and sodium nitrite in the drinking water were administered to half of either group to provoke luminal exogenous nitric oxide (NO) as an exacerbating agent. Seven days after the surgery, the oesophagus was excised, and the injury area, myeloperoxidase activity and pro-inflammatory cytokine levels were measured. Furthermore, 17β-oestradiol was administered to ovariectomised female rats or male rats, which then underwent reflux oesophagitis surgery.. While there was no gender difference in oesophageal damage in the baseline model, oesophageal damage was more intensively observed in males than in females in the presence of exogenous NO administration. While oesophageal damage was increased in ovariectomised rats compared with sham ovariectomised, exacerbated oesophageal damage was attenuated by the replacement of 17β-oestradiol. In addition, exacerbated oesophageal damage in male rats was suppressed by 17β-oestradiol.. This is the first study showing the prominent gender difference in the severity of oesophageal tissue damage in a gastro-oesophageal reflux disease-related animal model, highlighting the critical involvement of oestrogen in controlling gastro-oesophageal reflux disease-related oesophageal epithelial injury.

Topics: Animals; Ascorbic Acid; Biomarkers; Chronic Disease; Cytokines; Disease Models, Animal; Esophagitis, Peptic; Esophagus; Estradiol; Estrogens; Female; Gastroesophageal Reflux; Male; Mucous Membrane; Nitric Oxide; Ovariectomy; Peroxidase; Random Allocation; Rats; Rats, Wistar; Severity of Illness Index; Sex Factors; Sodium Nitrite; Stomach

Oxidative stress is a critical route of damage in various physiological stress-induced disorders, including depression. Rose oil may be a useful treatment for depression because it contains flavonoids which include free radical antioxidant compounds such as rutin and quercetin. We investigated the effects of absolute rose oil (from Rosa × damascena Mill.) and experimental depression on lipid peroxidation and antioxidant levels in the cerebral cortex of rats. Thirty-two male rats were randomly divided into four groups. The first group was used as control, while depression was induced in the second group using chronic mild stress (CMS). Oral (1.5 ml/kg) and vapor (0.15 ml/kg) rose oil were given for 28 days to CMS depression-induced rats, constituting the third and fourth groups, respectively. The sucrose preference test was used weekly to identify depression-like phenotypes during the experiment. At the end of the experiment, cerebral cortex samples were taken from all groups. The lipid peroxidation levels in the cerebral cortex in the CMS group were higher than in control whereas their levels were decreased by rose oil vapor exposure. The vitamin A, vitamin E, vitamin C and β-carotene concentrations in the cerebral cortex were lower in the CMS group than in the control group whereas their concentrations were higher in the rose oil vapor plus CMS group. The CMS-induced antioxidant vitamin changes were not modulated by oral treatment. Glutathione peroxidase activity and reduced glutathione did not change statistically in the four groups following CMS or either treatment. In conclusion, experimental depression is associated with elevated oxidative stress while treatment with rose oil vapor induced protective effects on oxidative stress in depression.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain; Depression; Disease Models, Animal; Glutathione Peroxidase; Lipid Peroxidation; Male; Oxidative Stress; Plant Oils; Rats; Rats, Wistar; Rosa; Vitamin A; Vitamin E

Monosodium glutamate (MSG) is a commonly used food enhancer. Glutamate is used as food additive for enhancing the "meat flavor" of food and gives a particular taste named "umami". In this study, we evaluated the effect of vitamin C on monosodium glutamate induced rat liver injury. This study was divided into 3 groups: group 1 received a diet containing 0.9% NaCl; group 2 received diet containing MSG 6 mg/g/b.w.; and group 3 received a diet containing 6 mg/g/b.w. followed by vitamin C (500 mg/kg/b.w.) for 45 days. The resulting changes were detected using histological, histochemical, ultrastructural, and immuohistochemical analysis. Severe alterations were recorded including dilatations of the central veins; severe cyto-architectural distortions of the hepatocytes; marked reduction in both carbohydrates and proteins; vacuolated cytoplasm, swollen mitochondria and vesiculated rough endoplasmic reticulum with picknotic nuclei; in addition to significant variation in the expression of ki-67 and p53 proteins. The data obtained from this study showed the improvements in the pathological architecture of the liver after treatment with vitamin C. The present data point to the ameliorative effect of vitamin C against MSG induced liver injury.

Topics: Animals; Antioxidants; Ascorbic Acid; Chemical and Drug Induced Liver Injury; Collagen; Disease Models, Animal; Glycogen; Immunohistochemistry; Ki-67 Antigen; Liver; Male; Microscopy, Electron, Transmission; Rats; Sodium Glutamate; Tumor Suppressor Protein p53

The aim of our study was to analyze the effects of an antioxidant treatment on markers of oxidative and carbonyl stress in a rat model of obstructive sleep apnea.. Wistar rats were randomized into six groups-according to gender and intervention-sham, intermittent hypoxia, and intermittent hypoxia with treatment by vitamins C and E. Rats underwent tracheostomy. The tracheal cannula was closed for 12 s every minute for 1 h to simulate obstructive sleep apnea-related intermittent hypoxia. In the treatment group, rats received vitamin C and E 24 h prior to surgery.. The intervention had a significant effect on advanced oxidation protein products (p = 0.008) and advanced glycation end products-specific fluorescence (p = 0.006) but no effect on malondialdehyde. Oxidation and glycation protein products were higher in intermittent hypoxia groups than in sham and in treated groups.. Antioxidants alleviate oxidative and carbonyl stress in an experimental model of obstructive sleep apnea. Future studies will show whether such treatment has any clinical value regarding cardiovascular complications of sleep apnea syndrome, preferably in patients with low compliance to continuous positive airway pressure.

Topics: Advanced Oxidation Protein Products; Animals; Ascorbic Acid; Disease Models, Animal; Female; Male; Malondialdehyde; Oxidative Stress; Protein Carbonylation; Rats; Rats, Wistar; Sleep Apnea, Obstructive; Thiobarbituric Acid Reactive Substances; Vitamin E

Classic galactosemia is a genetic disorder that results from profound loss of galactose-1P-uridylyltransferase (GALT). Affected infants experience a rapid escalation of potentially lethal acute symptoms following exposure to milk. Dietary restriction of galactose prevents or resolves the acute sequelae; however, many patients experience profound long-term complications. Despite decades of research, the mechanisms that underlie pathophysiology in classic galactosemia remain unclear. Recently, we developed a Drosophila melanogaster model of classic galactosemia and demonstrated that, like patients, GALT-null Drosophila succumb in development if exposed to galactose but live if maintained on a galactose-restricted diet. Prior models of experimental galactosemia have implicated a possible association between galactose exposure and oxidative stress. Here we describe application of our fly genetic model of galactosemia to the question of whether oxidative stress contributes to the acute galactose sensitivity of GALT-null animals. Our first approach tested the impact of pro- and antioxidant food supplements on the survival of GALT-null and control larvae. We observed a clear pattern: the oxidants paraquat and DMSO each had a negative impact on the survival of mutant but not control animals exposed to galactose, and the antioxidants vitamin C and α-mangostin each had the opposite effect. Biochemical markers also confirmed that galactose and paraquat synergistically increased oxidative stress on all cohorts tested but, interestingly, the mutant animals showed a decreased response relative to controls. Finally, we tested the expression levels of two transcripts responsive to oxidative stress, GSTD6 and GSTE7, in mutant and control larvae exposed to galactose and found that both genes were induced, one by more than 40-fold. Combined, these results implicate oxidative stress and response as contributing factors in the acute galactose sensitivity of GALT-null Drosophila and, by extension, suggest that reactive oxygen species might also contribute to the acute pathophysiology in classic galactosemia.

Topics: Animals; Antioxidants; Ascorbic Acid; Cysteine; Dimethyl Sulfoxide; Disease Models, Animal; Drosophila melanogaster; Drosophila Proteins; Galactose; Galactosemias; Galactosephosphates; Gene Expression; Gene Knockout Techniques; Genes, Insect; Glutathione; Glutathione Transferase; Humans; Mutation; Oxidative Stress; Paraquat; Reactive Oxygen Species; UDPglucose-Hexose-1-Phosphate Uridylyltransferase; Xanthones

The goal of the present study is to establish the antioxidant status in the brain of a high pressure-induced rat model.. Ocular hypertension was induced in rats (n = 12) cauterizing two episcleral veins under a surgical microscope. A sham procedure (n = 12) was performed in the control group. The markers evaluated in the brain 7 days after surgery were as follows: spontaneous chemiluminescence, protein carbonylation, nitrite concentration, total reactive antioxidant potential (TRAP), ascorbic acid, glutathione, vitamin E and activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase.. Chemiluminescence in glaucoma was 55% higher than in controls (393 ± 20 cpm/mg protein, p < 0.001). Protein carbonylation in glaucoma was 93% higher than in controls (1.15 ± 0.18 nmol/mg protein, p < 0.001). Nitrite concentration was 5.30 ± 0.25 μM for glaucoma (controls 4.41 ± 0.24 μM, p < 0.05). Total reactive antioxidant potential decreased by 42% in glaucoma (controls 153 ± 14 μM Trolox, p < 0.001). Ascorbic acid was 67 ± 26 μM for glaucoma (controls 275 ± 22 μM, p < 0.001). Vitamin E was 0.58 ± 0.05 μmol/g organ for glaucoma (controls 1.10 ± 0.06 μmol/g organ, p < 0.01). Glutathione was 1.98 ± 0.13 μmol/g organ for glaucoma (controls 8.19 ± 0.71 μmol/g organ, p < 0.001). Superoxide dismutase and GPx were increased in glaucoma by 42 and 59%, respectively (p < 0.05).. Reactive oxygen and nitrogen species were increased in glaucoma, the increase in chemiluminescence, protein carbonylation and nitrite levels could be evidenced by this situation. The decrease in nonenzymatic antioxidants and a compensatory increase in SOD and GPx activity may have been a consequence of an increase in oxidative processes.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain; Catalase; Disease Models, Animal; Female; Glutathione; Glutathione Peroxidase; Intraocular Pressure; Luminescence; Ocular Hypertension; Oxidative Stress; Protein Carbonylation; Rats; Rats, Wistar; Reactive Nitrogen Species; Reactive Oxygen Species; Superoxide Dismutase; Vitamin E

Severe vitamin C deficiency (ascorbic acid; AA) was induced in gulo-/- mice incapable of synthesizing their own AA. A number of behavioral measures were studied before and during the deprivation period, including a scorbutic period, during which weight loss was observed in the mice. Mice were then resuscitated with AA supplements. During the scorbutic period, gulo-/- mice showed decreased voluntary locomotor activity, diminished physical strength, and increased preference for a highly palatable sucrose reward. These behaviors all returned to control levels following resuscitation. Altered trial times in subordinate mice in the tube test for social dominance in the AA-deprived mice persisted following resuscitation and may signify a depressive-like behavior in these mice. Biochemical analyses were undertaken following a second deprivation period. AA deficiency was accompanied by decreased blood glucose levels, oxidative damage to lipids and proteins in the cortex, and decreases in dopamine and serotonin metabolites in both the cortex and striatum. Given the reasonably high proportions of the population that do not consume sufficient AA in the diet, these data have important implications for physical and psychological function in the general population.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Behavior, Animal; Biogenic Monoamines; Disease Models, Animal; Female; L-Gulonolactone Oxidase; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Severity of Illness Index

Increased oxidative stress may contribute to cancer anorexia, which could be ameliorated by antioxidant supplementation. methylcholanthrene (MCA) sarcoma-bearing Fisher rats were studied. After tumour inoculation, rats were randomly assigned to standard diet (CTR group, n = 6), or to an antioxidant-enriched diet (AOX group, n = 8). Eight more rats (STD-AOX group) switched from standard to antioxidant diet when anorexia developed. At the end of the study, food intake (FI, g/d), body weight and tumour weight (g) were recorded, and plasma samples were obtained. On day 16, anorexia has appeared only in CTR and STD-AOX animals. At the end of the study, FI in AOX animals was still higher than in the other groups (p = 0.08). No differences in body and tumour weights were observed among groups. However, hydrogen peroxide and interleukin-1β levels were significantly reduced only in AOX rats. Data obtained suggest that early antioxidant supplementation improves cancer anorexia, ameliorates oxidative stress and reduces inflammation.

Topics: Animals; Anorexia; Antioxidants; Ascorbic Acid; Body Weight; Diet; Dietary Supplements; Disease Models, Animal; Drug Administration Schedule; Energy Intake; Hydrogen Peroxide; Interleukin-1beta; Male; Methylcholanthrene; Oxidative Stress; Random Allocation; Rats, Inbred F344; Sarcoma; Vitamin E

Key antioxidants, vitamins C and E, are necessary for normal brain development and neuronal function. In this study, we depleted both of these vitamins in two mouse models to determine if oxidative stress due to combined vitamin C and E dietary deficiency altered their neurological phenotype. The first model lacked both alleles for the Gulonolactone oxidase gene (Gulo(-/-)) and therefore was unable synthesize vitamin C. To obtain an additional cellular deficiency of vitamin C, the second model also lacked one allele for the cellular vitamin C transporter gene (Gulo(-/-)/SVCT2(+/-)).. The experimental treatment was 16 weeks of vitamin E deprivation followed by 3 weeks of vitamin C deprivation. Mice were assessed for motor coordination deficits, vitamin levels, and oxidative stress biomarkers.. In the first model, defects in motor performance were more apparent in both vitamin C-deficient groups (VE+VC-, VE-VC-) compared to vitamin C-supplemented groups (VE+VC+, VE-VC+) regardless of vitamin E level. Analysis of brain cortex and liver confirmed decreases of at least 80% for each vitamin in mice on deficient diets. Vitamin E deficiency doubled oxidative stress biomarkers (F2-isoprostanes and malondialdehyde). In the second model, Gulo(-/-)/SVCT2(+/-) mice on the doubly deficient diets showed deficits in locomotor activity, Rota-rod performance, and other motor tasks, with no concomitant change in anxiety or spatial memory.. Vitamin E deficiency alone caused a modest oxidative stress in brain that did not affect motor performance. Adding a cellular deficit in vitamin C to dietary deprivation of both vitamins significantly impaired motor performance.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Brain; Dietary Supplements; Disease Models, Animal; F2-Isoprostanes; Female; L-Gulonolactone Oxidase; Liver; Male; Malondialdehyde; Mice; Mice, Knockout; Oxidative Stress; Psychomotor Performance; Vitamin D Deficiency; Vitamin E; Vitamin E Deficiency

Chronic stress has been implicated as a contributing factor in liver injury. However, other factors that can contribute to the severity of stress effect in liver injury have not been well characterized. In this study, the combined effect of chronic psychosocial stress and variable dosing levels of vitamin C on liver injury, have been studied.. Stress was chronically induced using intruder method. Vitamin C was administered by oral gavage. Both biochemical and histopathological measures were undertaken.. The results showed that low (50mg/kg/day) and moderate (150 mg/kg/day) doses of vitamin C alone or in combination with chronic stress had no effect on liver. However, combination of high dose of vitamin C (500 mg/kg/day) and chronic stress induced various histopathological liver lesions in most of animals in the group that was stressed and supplemented with high dose vitamin C.. Results of this study show a dose-dependent effect for vitamin C in exacerbating stress contribution to liver injury.

Topics: Administration, Oral; Aggression; Animals; Ascorbic Acid; Chemical and Drug Induced Liver Injury; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Liver; Male; Precipitating Factors; Rats; Rats, Wistar; Stress, Psychological; Territoriality; Vitamins

Considerable evidence supports the presence of oxidative stress in cystic fibrosis (CF). The disease has long been associated with both increased production of reactive oxygen species and impaired antioxidant status, in particular during the chronic pulmonary infection with Pseudomonas aeruginosa, which is the main cause of morbidity and mortality in CF. Guinea pigs are unable to synthesize ascorbate (ASC) or vitamin C, a major antioxidant of the lung, and thus like human beings rely on its presence in the diet. On this basis, guinea pigs receiving ASC-deficient diet have been used as a model of oxidative stress. The aim of our study was to investigate the consequences of a 7-day biofilm-grown P. aeruginosa lung infection in 3-month-old guinea pigs receiving either ASC-sufficient or ASC-deficient diet for at least 2 months. The animals receiving ASC-deficient diet showed significantly higher mortality during infection and increased respiratory burst of peripheral polymorphonuclear neutrophils (PMNs) compared with the animals receiving ASC sufficient diet. The inflammatory response at the site of lung infection consisted of PMNs and mononuclear leucocytes (MN), and higher PMN/MN ratios were present in animals on ASC-deficient diet compared with animals on ASC sufficient diet. Measurements of the ASC levels in the lung were significantly decreased in infected compared with non-infected animals. Interestingly, the infection by itself decreased the antioxidant capacity of the plasma (measured as plasma oxidizability) more than the ASC-deficient diet, suggesting a high consumption of the antioxidants during infection. Our data show that poor antioxidant status exacerbates the outcome of biofilm-related infections.

Topics: Animals; Antioxidants; Ascorbic Acid; Ascorbic Acid Deficiency; Biofilms; Disease Models, Animal; Female; Guinea Pigs; Inflammation; Leukocytes, Mononuclear; Lung Diseases; Neutrophils; Oxidative Stress; Pseudomonas aeruginosa; Pseudomonas Infections

Glucocorticoid excess induces marked insulin resistance and glucose intolerance. A recent study has shown that antioxidants prevent dexamethasone (DEX)-induced insulin resistance in cultured adipocytes. The purpose of this investigation was to examine the effects of dietary vitamin E and C (Vit E/C) supplementation on DEX-induced glucose intolerance in rats. We hypothesized that feeding rats a diet supplemented with Vit E/C would improve glucose tolerance and restore insulin signaling in skeletal muscle, adipose, and liver and prevent alterations in AMPK signaling in these tissues. Male Wistar rats received either a control or Vit E/C-supplemented diet (0.5 g/kg diet each of L-ascorbate and DL-all rac-alpha-tocopherol) for 9 days prior to, and during, 5 days of daily DEX treatment (subcutaneous injections 0.8 mg/g body wt). DEX treatment resulted in increases in the glucose and insulin area under the curve (AUC) during an intraperitoneal glucose tolerance test. The glucose, but not insulin, AUC was lowered with Vit E/C supplementation. Improvements in glucose tolerance occurred independent of a restoration of PKB phosphorylation in tissues of rats stimulated with an intraperitoneal injection of insulin but were associated with increases in AMPK signaling in muscle and reductions in AMPK signaling and the expression of fatty acid oxidation enzymes in liver. There were no differences in mitochondrial enzymes in triceps muscles between groups. This study is the first to report that dietary Vit E/C supplementation can partially prevent DEX-induced glucose intolerance in rats.

Topics: Adipose Tissue; AMP-Activated Protein Kinases; Animals; Ascorbic Acid; Dexamethasone; Dietary Supplements; Disease Models, Animal; Glucose; Glucose Intolerance; Insulin; Liver; Male; Muscle, Skeletal; Rats; Rats, Wistar; Signal Transduction; Vitamin E

A total of 30 female Sprague-Dawley rats (180-220 g) subjected to spinal cord injury (SCI) were divided into three groups of ten rats each. Group 1 served as control (SCI + Saline), Group 2 received daily dose of ascorbic acid 2,000 mg/kg body weight and group 3 rats received alpha tocopherol daily with the dose of 2,000 mg/kg body weight for 14 days. The Spontaneous coordinate activity (SCA), Basso, Beattie, and Bresnahan (BBB) and Tarlov locomotor scores were used to assess functional recovery of SCI rats. Compared to group 1, group 2 showed statistically insignificant improvement in the SCA, BBB and Tarlov scores at the end of the study. Compared to group 1, group 3 showed statistically significant improvement in the SCA (P < 0.001), BBB (P < 0.001) and Tarlov (P < 0.01) scores at the end of the study. In conclusion, the administration of alpha-tocopherol enhances the reparative effects against SCI and it is more effective than ascorbic acid.

Topics: alpha-Tocopherol; Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Drug Administration Routes; Female; Locomotion; Rats; Rats, Sprague-Dawley; Recovery of Function; Severity of Illness Index; Spinal Cord Injuries; Time Factors

In this study, antidepressant-like activity of Emblica offcinalis Gaertn. fruits (Family: Euphorbiaceae) was evaluated in Swiss young male albino mice employing tail suspension test and forced swim test.. Aqueous extract (200 and 400 mg/kg) of the fruits was administered orally for 14 successive days to mice. On day 14, 60 min after extract administration, animals were subjected to tail suspension test and forced swim test.. The extract significantly decreased immobility period in both tail suspension test and forced swim test, indicating significant antidepressant-like activity. The lower dose (200 mg/kg) of the extract showed better antidepressant-like action. The efficacy of the extract was found to be comparable to fluoxetine (20 mg/kg), imipramine (15 mg/kg), and phenelzine (20 mg/kg). The extract did not show any significant effect on locomotor activity of the mice. Prazosin (alpha(1) -adrenoceptor antagonist), sulpiride (selective D(2) -receptor antagonist), baclofen (GABA(B) agonist), and p-CPA (tryptophan hydroxylase inhibitor) significantly attenuated the extract-induced antidepressant-like effect. The extract also significantly decreased brain MAO-A levels.. The aqueous extract might produce antidepressant-like effect by interaction with α(1)-adrenoceptors, dopamine D(2)- receptors, serotonergic, and GABA(B) receptors. In this study, aqueous extract was found to contain 2.94% of ascorbic acid. So ascorbic acid and other constituents like flavanoids, tannoid principles, and polyphenolic substances present in the aqueous extract of E. officinalis might be responsible for its antidepressant-like activity.. Thus, aqueous extract of E. officinalis showed antidepressant-like activity probably by inhibiting MAO-A and GABA; and also due to its antioxidant activity.

Topics: Animals; Antidepressive Agents; Ascorbic Acid; Biogenic Monoamines; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Fruit; gamma-Aminobutyric Acid; Hindlimb Suspension; Male; Mice; Monoamine Oxidase; Motor Activity; Phyllanthus emblica; Phytotherapy; Plant Preparations; Swimming; Time Factors

Reactive oxygen species (ROS) have been shown to play a role in the pathophysiology of depression. Taking into account that experimental chronic unpredictable stress (CUS) induces depressive-like behavior and that ascorbic acid has antidepressant-like effect in animals, the objective of this study was to investigate the influence of ascorbic acid on depressive-like behavior induced by CUS paradigm, serum corticosterone levels and markers of oxidative stress in cerebral cortex and hippocampus of mice. Animals were submitted to CUS procedure during 14 days. From the 8th to the 14th day mice received ascorbic acid (10 mg/kg) or fluoxetine (10 mg/kg, conventional antidepressant, positive control) once a day by oral route. On 15th day behavioral and biochemical parameters were analyzed. CUS exposure caused a depressive-like behavior evidenced by the increased immobility time in the tail suspension test and decreased time in which mice spent grooming in the splash test. Depressive-like behavior induced by CUS was accompanied by a significant increased lipid peroxidation (cerebral cortex and hippocampus), decreased catalase (CAT) (cerebral cortex and hippocampus) and glutathione reductase (GR) (hippocampus) activities and reduced levels of glutathione (cerebral cortex). Repeated ascorbic acid or fluoxetine administration significantly reversed CUS-induced depressive-like behavior and oxidative damage. No alteration was observed in locomotor activity, corticosterone levels and glutathione peroxidase (GPx) activity. These findings indicate a rapid and robust effect of ascorbic acid in reversing behavioral and biochemical alterations induced by CUS in mice, suggesting that this vitamin may be an alternative approach for the management of depressive symptoms.

Topics: Animals; Antidepressive Agents; Antioxidants; Ascorbic Acid; Catalase; Cerebral Cortex; Corticosterone; Depression; Disease Models, Animal; Fluoxetine; Glutathione; Glutathione Reductase; Hippocampus; Lipid Peroxidation; Mice; Motor Activity; Oxidative Stress; Stress, Psychological; Treatment Outcome

We investigated whether decreased vitamin C (VC) in a mouse model increases lens opacity (cataract) induced by in vivo exposure to ultraviolet radiation type B (UVR-B). Senescence marker protein-30 (SMP30) knockout (KO) mice, which cannot synthesize VC due to genetic disruption of the gluconolactonase (GNL) gene, were divided into 2 groups: VC sufficient (VC (+)) and VC deficient (VC (-)). Starting at 1 month of age, these groups had free access to water containing 0.0375 and 1.5 g/L of VC, respectively. SMP30 KO VC (-), SMP30 KO VC (+), and wild-type (WT) mice, all 14 weeks of age, were unilaterally exposed in vivo to UVR-B (200 mW/cm(2)) for 100 s twice a week for 3 weeks (total: 1200 mJ/cm(2)). At 48 h after the last UVR-B exposure, cataract morphology was documented, and the ratio of cataract induction was quantified as the cataract area ratio (opacity area/anterior capsule). UVR-B exposure induced cataract mainly at anterior sub-capsular in SMP30 KO VC (-), SMP30 KO VC (+), and WT mice. In SMP30 KO VC (-) lenses the opacities were more extensive than in SMP30 KO VC (+) or WT lenses (cataract area ratios: 59.3% ± 10% vs. 32.2% ± 11.7% or 29.0% ± 9.0%; P < 0.01). In conclusion, VC depletion may increase the susceptibility to develop UVR-B induced cataracts in mice unable to endogenously produce VC.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Calcium-Binding Proteins; Carboxylic Ester Hydrolases; Cataract; Disease Models, Animal; Intracellular Signaling Peptides and Proteins; Lens, Crystalline; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidative Stress; Radiation Injuries, Experimental; Ultraviolet Rays

The possible reason for elimination of myogenic cells after transplantation is inflammation at the injection site associated with oxidative stress. The aim of this study was to determine whether preconditioning of muscle-derived cells with an antioxidant, sodium ascorbate, can influence the fate of transplanted cells.. Autologous transplantation of muscle-derived cells was performed in rabbits. Isolated cells were identified, lipofected with β-galactosidase, preincubated or not with sodium ascorbate, and injected intramuscularly.. Two weeks after autologous transplantation in the edge of a previous muscle defect, donor cells formed multinucleated young myotubes. Pretreatment of cells with sodium ascorbate before injection resulted in a significant increase of donor cells at the injection site 2 weeks after transfer.. These results show that: (1) preincubation with antioxidant can increase the efficacy of myogenic cell transplantation; and (2) oxidative stress may play a role in elimination of cells after autologous transplantation.

Topics: Animals; Antioxidants; Ascorbic Acid; beta-Galactosidase; Cell Survival; Cell Transplantation; Cells, Cultured; Desmin; Disease Models, Animal; Green Fluorescent Proteins; Injections, Intramuscular; Muscle Fibers, Skeletal; Myositis; Oxidative Stress; Rabbits; Statistics, Nonparametric; Transfection; Transplantation, Autologous

Persistent, high-intensity noise is an environmental pollutant that plays a destructive role in daily life, especially in industrialized communities. Its effects may be reduced by Vitamin C supplementation. This study examined the possibility that pretreatment with vitamin C (100 mg or 200 mg/kg) could attenuate behavioural and anxiogenic effects of prolonged exposure to noise (100 dB for 2 months, 5 days/week, 4 h daily) on male laboratory mice, by using open-field and plus maze tests of emotionality, and by measuring the neutrophils-to-lymphocytes ratio, a physiological stress measure. The effects seen on behaviour in the open field and plus maze were consistent with the hypothesis that noise could be considered as a stressor as it significantly affected six measures of behaviour in the predicted directions. The neutrophil-to-lymphocyte ratio was also increased as a result of noise exposure. Furthermore, there was good evidence from all three procedures that vitamin C supplementation can attenuate the effects of noise. We conclude that vitamin C supplementation can attenuate or prevent the psychological and physiological damage induced by prolonged noise exposure in mice.

Topics: Animals; Anxiety; Ascorbic Acid; Cell Count; Disease Models, Animal; Lymphocytes; Male; Maze Learning; Mice; Mice, Inbred Strains; Motor Activity; Neutrophils; Noise; Stress, Psychological; Vitamins

Ca(v) 3.2 T-type calcium channels, targeted by H(2) S, are involved in neuropathic hyperalgesia in rats and ascorbic acid inhibits Ca(v) 3.2 channels. Therefore, we evaluated the effects of intraplantar (i.pl.) administration of ascorbic acid or topical application of disodium isostearyl 2-O-L-ascorbyl phosphate (DI-VCP), a skin-permeable ascorbate derivative on hyperalgesia induced by NaHS, an H(2) S donor, and on neuropathic hyperalgesia.. In rats mechanical hyperalgesia was evoked by i.pl. NaHS, and neuropathic hyperalgesia was induced by L5 spinal nerve cutting (L5SNC) or by repeated administration of paclitaxel, an anti-cancer drug. Dermal ascorbic acid levels were determined colorimetrically.. The NaHS-evoked Ca(v) 3.2 channel-dependent hyperalgesia was inhibited by co-administered ascorbic acid. Topical application of DI-VCP, but not ascorbic acid, prevented the NaHS-evoked hyperalgesia, and also increased dermal ascorbic acid levels. Neuropathic hyperalgesia induced by L5SNC or paclitaxel was reversed by i.pl. NNC 55-0396, a selective T-type calcium channel blocker, ascorbic acid or DI-VCP, and by topical DI-VCP, but not by topical ascorbic acid. The effects of i.pl. ascorbic acid and topical DI-VCP in the paclitaxel-treated rats were characterized by the faster onset and greater magnitude, compared with their effects in the L5SNC rats. Dermal ascorbic acid levels in the hindpaw significantly decreased after paclitaxel treatment, but not L5SNC, which was reversed by topical DI-VCP.. Ascorbic acid, known to inhibit Ca(v) 3.2 channels, suppressed neuropathic hyperalgesia. DI-VCP ointment for topical application may be of benefit in the treatment of neuropathic pain.

Topics: Administration, Topical; Animals; Ascorbic Acid; Calcium Channel Blockers; Calcium Channels, R-Type; Cation Transport Proteins; Disease Models, Animal; Hyperalgesia; Male; Neuralgia; Ointments; Pain Threshold; Patch-Clamp Techniques; Rats; Rats, Wistar; Sensory Receptor Cells; Skin; Skin Absorption

Photodynamic therapy (PDT) is a treatment modality that utilizes photosensitizers activated by light to induce cell death via the formation of singlet oxygen and other free radicals. Although this method has its advantages for tumor treatment, it cannot be well performed for involving so many therapeutic parameters during use. Tumor recurrence is common due to insufficient treatment. Therefore, a supplemental or complemental treatment is necessary for PDT.. L-ascorbate, commonly known as vitamin C, is an essential nutrient for humans. It is also a well-established pro-oxidant in the presence of certain transition metal ions. In our experiments, ascorbate was administered to tumor-bearing mice by intraperitoneal injection (i.p.) for 10 days after they were treated with PDT. We hypothesize that this supplement may improve the therapeutic outcome by as a result of the reactions between ascrobate and the metal ions induced by PDT.. The results demonstrate that PDT can cause Fe and Cu ions to be released from their protein complexes. The reactions between the ions and ascorbate resulted in a post-PDT surge in reactive oxygen species (ROS) as demonstrated in vitro with chemiluminescence detection. This ultimately leads to enhanced tumor cell death and, thus, an improved treatment outcome.. Based on the results that PDT induces metal ion release and ascorbate reacts with the metal ions producing subsequent ROS, an internal related, complementary and strengthened tumor treatment is established by combination of both PDT and ascorbate, as a low-toxicity and effective method.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Female; Mammary Neoplasms, Animal; Mice; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species; Sensitivity and Specificity; Tumor Cells, Cultured

The aim of this study was to investigate the preventive effects of melatonin and vitamin C as antioxidants on renal injury in chronic alcohol consumption.. A total of 24 adult male Wistar rats weighing 200-250 g were used in the study. Rats were divided into four equal groups. Group I (control): rats were not fed on alcohol; Group II: rats were fed on alcohol; Group III: rats were fed on alcohol and 40 mg/kg vitamin C; and Group IV: rats were fed on alcohol and 4 mg/kg melatonin.. Light microscopic examination revealed atrophic renal corpuscles, dilatation and congestion of the peritubular vessels, and renal corpuscles with obscure Bowman's space and a few foamy-appearing tubules due to alcohol consumption were observed. Expression of endothelial nitric oxide synthase (eNOS) was localized to glomerulus, distal, and collector tubules. eNOS staining decreased in alcohol treatment group and melatonin and vitamin C encore increased expression pattern of eNOS. Alcohol consumption increased malondialdehyde (MDA) level and superoxide dismutase (SOD) and catalase (CAT) activities significantly in the alcohol consumption groups compared with that in the control group, while in melatonin give group just MDA level was decreased statistically significant and SOD and CAT activities were also decreased numerically compared with the alcohol consumption groups.. These results indicated that chronic alcohol consumption caused renal damage by increased lipid peroxidation and melatonin and vitamin C administration produced in some degree protection against alcohol-induced damage.

Topics: Acute Kidney Injury; Alcoholic Intoxication; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Ethanol; Immunohistochemistry; Kidney; Lipid Peroxidation; Male; Melatonin; Nitric Oxide Synthase Type III; Oxidative Stress; Rats; Rats, Wistar; Vitamins

The present study was aimed to evaluate the antihypertensive effect of diosmin in deoxycorticosterone acetate (DOCA)-salt induced hypertension in male Wistar rats. Hypertension was induced in uninephrectomized rats by weekly twice subcutaneous injection of DOCA (25 mg/kg body weight) and 1% NaCl in the drinking water for six consecutive weeks. The important pathological events that occurred in DOCA-salt treated rats were significant increase in systolic, diastolic blood pressure, sodium and chloride in serum and lipid peroxidation products (thiobarbituric acid reactive substances, lipid hydroperoxides and conjugated dienes) in plasma and tissues (liver, kidney, heart and aorta) and significant decrease in serum potassium, total nitrite and nitrate levels in plasma. The activities of hepatic aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase and the levels of renal urea, uric acid, creatinine in serum, water intake, and organ weight (kidney and heart) were significantly increased in DOCA-salt hypertensive rats. DOCA-salt treated rats also showed a significant decrease in body weight, activities of superoxide dismutase, catalase and glutathione peroxidase in erythrocyte and tissues and the levels of reduced glutathione, vitamin C and vitamin E in plasma and tissues. Treatment with diosmin (25, 50 and 100 mg/kg body weight) brings back all the above parameters to near normal level, in which 50 mg/kg body weight showed the highest effect than that of other two doses. Histopathology of heart and kidney also confirmed the protective effect of diosmin. Thus the experiment clearly showed that diosmin acts as an antihypertensive agent against DOCA-salt induced hypertension.

Topics: Animals; Antihypertensive Agents; Aorta; Ascorbic Acid; Blood Pressure; Body Weight; Desoxycorticosterone; Diosmin; Disease Models, Animal; Flavonoids; Glutathione; Heart; Hypertension; Kidney; Lipid Peroxides; Liver; Male; Myocardium; Nitrates; Nitrites; Oxidoreductases; Potassium; Rats; Rats, Wistar; Sodium Chloride; Vitamin E

This study isolated the effects of maternal hypoxia independent of changes in maternal nutrition on maternal circulatory and placental molecular indices of oxidative stress and determined whether maternal antioxidant treatment conferred protection. Pregnant rats were subjected to normoxic pregnancy or 13% O2 chronic hypoxia for most of gestation with and without maternal treatment with vitamin C in the drinking water. Maternal hypoxia with and without vitamin C did not affect maternal food or water intake and led to a significant increase in maternal and fetal haematocrit. At gestational day 20, maternal plasma urate and L-cysteine concentrations, and placental levels of 4-hydroxynonenal and heat shock protein 70 were increased while placental heat shock protein 90 levels were decreased in hypoxic pregnancy. The induction of maternal circulatory and placental molecular indices of oxidative stress in hypoxic pregnancies was prevented by maternal treatment with vitamin C. Maternal hypoxia during pregnancy with or without vitamin C increased placental weight, but not total or compartmental volumes. Maternal treatment with vitamin C increased birth weight in both hypoxic and normoxic pregnancies. The data show that maternal hypoxia independent of maternal undernutrition promotes maternal and placental indices of oxidative stress, effects that can be prevented by maternal treatment with vitamin C in hypoxic pregnancy. While vitamin C may not be the ideal candidate of choice for therapy in pregnant women, and taking into consideration differences in ascorbic acid metabolism between rats and humans, the data do underlie that antioxidant treatment may provide a useful intervention to improve placental function and protect fetal growth in pregnancy complicated by fetal hypoxia.

Topics: Animals; Animals, Newborn; Antioxidants; Ascorbic Acid; Birth Weight; Catalase; Cysteine; Disease Models, Animal; Female; Hematocrit; Hypoxia; Oxidative Stress; Placenta; Pregnancy; Pregnancy Complications; Rats; Rats, Wistar; Superoxide Dismutase; Uric Acid

Organisms using oxygen for aerobic respiration require antioxidants to balance the production of reactive oxygen species during metabolic processes. Various species--including humans and other primates--suffer mutations in the GULO gene encoding L-gulono-γ-lactone oxidase; GULO is the rate-limiting enzyme in the biosynthesis of ascorbate, an important cellular antioxidant. Animals lacking the ability to synthesize vitamin C develop scurvy without dietary supplementation. The Gulo-/- knockout (KO) mouse requires oral supplemental vitamin C; without this supplementation the animal dies with a scorbutic condition within several weeks. Vitamin C is known to be most abundant in the brain, where it is believed to play important roles in neuroprotection, neurotransmission and neuromodulation. We therefore hypothesized that ascorbate deficiency in Gulo-/- KO mice might lead to an abnormal behavioral phenotype. We established the amount of ascorbate in the drinking water (220 ppm) necessary for generating a chronic low-ascorbate status in the brain, yet clinically the mice appeared healthy throughout 100 days postpartum at which time all behavioral-phenotyping tests were completed. Compared with Gulo+/+ wild-type littermates, ascorbate-deficient Gulo-/- mice were found to be less active in moving in their environment; when in water, these mice swam more slowly in some tests, consistent with a mild motor deficit. We found no evidence of cognitive, anxiety or sensorimotor-gating problems. Despite being less active, Gulo-/- mice exhibited exaggerated hyperactivity to the dopaminergic agonist methamphetamine. The subnormal movement, combined with hypersensitivity to a dopamine agonist, point to developmental ascorbate deficiency causing long-term striatal dysfunction.

Topics: Animals; Animals, Newborn; Ascorbic Acid; Ascorbic Acid Deficiency; Behavior, Animal; Disease Models, Animal; Female; L-Gulonolactone Oxidase; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Pregnancy

Ascorbic acid (Vitamin C) administration has been used to prevent infectious diseases in public or as a therapeutic agent by the physicians in treatment of several diseases. Ascorbic acid is also involved in immune cell functions and immune responses, although the mechanisms by which it exerts effects on immune cells against cancer cells are not fully understood at the normal plasma level. In this study, we used the mice lacking l-gulono-γ-lactone oxidase (Gulo), the enzyme required for the biosynthesis of ascorbic acid, to characterize the effects of ascorbic acid on NK cell cytotoxicity against ovarian cancer cells, MOSECs (murine ovarian surface epithelial cells). Gulo(-/-) mice depleted of ascorbic acid survived for a shorter time than the normal control or Gulo(-/-) mice supplemented with ascorbic acid after tumor challenge regardless of treatment with IL-2. CD69 and NKG2D expression was clearly reduced in NK cells isolated from mice depleted of ascorbic acid as compared to that in the normal control and the mice supplemented with ascorbic acid. We also observed that IFN-γ secretion by NK cells isolated from Gulo(-/-) mice depleted of ascorbic acid was decreased after NK cells were co-cultured with MOSECs. Furthermore, the mRNA expression of perforin and granzyme B genes was also significantly decreased in NK cells isolated from mice depleted of ascorbic acid. Taken together, our results suggest that ascorbic acid at the normal plasma concentration has an essential role in maintaining the NK cytotoxicity against cancer cells.

Topics: Animals; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Antioxidants; Apoptosis; Ascorbic Acid; Cell Line, Tumor; Cell Transformation, Neoplastic; Cytotoxicity, Immunologic; Disease Models, Animal; Female; Granzymes; Killer Cells, Natural; Lectins, C-Type; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Knockout; NK Cell Lectin-Like Receptor Subfamily K; Ovarian Neoplasms; Perforin

To evaluate the efficacy of vitamin C in reducing the consequences generated by the production of free radicals in the acute and chronic phases of Chagas disease, two different doses of ascorbic acid were administered orally to 60 mice infected by Trypanosoma cruzi QM2 strain.. The animals were divided into six groups: G1, G2, and G3 for the acute phase study, and G'1, G'2, and G'3 for the chronic stage. The groups G1 and G'1 received 8.6 x 10⁻⁴ mg/g of vitamin C daily, whereas G2 and G'2 received 7.14 x 10⁻³ mg/g daily. The other groups, G3 and G'3, were considered placebos and received 10 µL of mineral water.. The study of the acute phase showed statistically significant differences between G1 and the other groups at various count days of the parasitemia evolution. The multiplying parasite was slower in G1 until the 11th day, but on the 22nd day it had greater parasitemia than in G2 and G3, and from the 36th day on, parasitemia stabilized at higher levels. However, when the histopathology of acute and chronic phases is considered, one does not note significant differences.. The administration of two different doses of vitamin C was not able to protect mice and to contain the oxidative stress caused by free radicals formed by the metabolism of oxygen (reactive oxygen species) and nitrogen (reactive nitrogen species).

Topics: Acute Disease; Animals; Antioxidants; Ascorbic Acid; Chagas Disease; Chronic Disease; Disease Models, Animal; Male; Mice; Parasitemia

Nonalcoholic steatohepatitis (NASH), a progressive stage of nonalcoholic fatty liver disease (NAFLD), is characterized by steatosis (accumulation of triacylglycerols within hepatocytes) along with inflammation and ballooning degeneration. It has been suggested that oxidative stress may play an important role in the progress of NAFLD to NASH. The aim of present study was to determine whether antioxidant supplementations using EUK-8, EUK-134 and vitamin C could improve the biochemical and histological abnormalities associated with diet-induced NASH in rats.. NASH was induced in male N-Mary rats by feeding a methionine - choline deficient (MCD) diet. The rats were fed either normal chow or MCD diet for 10 weeks. After NASH development, the MCD-fed rats were randomly divided into four groups of six: the NASH group that received MCD diet, the EUK-8 group which was fed MCD diet plus EUK-8, the EUK-134 group which was fed MCD diet plus EUK-134 and the vitamin C group which received MCD diet plus vitamin C. EUK-8, EUK-134 and vitamin C (30 mg/kg body weight/day) were administered by gavage for eight weeks.. Treatment of MCD-fed rats with salens reduced the sera aminotransferases, cholesterol, low density lipoprotein contents, the extent of lipid peroxidation and protein carbonylation whereas the HDL-C cholesterol levels were significantly increased. In addition, EUK-8 and EUK-134 improved steatosis, ballooning degeneration and inflammation in liver of MCD-fed rats.. Antioxidant (EUK-8, EUK-134 and vitamin C) supplementation reduces NASH-induced biochemical and histological abnormalities, pointing out that antioxidant strategy could be beneficial in treatment of NASH.

Topics: Animals; Ascorbic Acid; Choline Deficiency; Diet; Disease Models, Animal; Ethylenediamines; Fatty Liver; Humans; Lipid Peroxidation; Methionine; Organometallic Compounds; Oxidative Stress; Rats; Salicylates

To evaluate the putative protective role of chrysin, an isoflavone, on D-galactose-induced aging in an experimental rat model.. Rats were divided into five groups of five each. Group I received 0.9% saline only. Groups II, III and IV received d-galactose (50 mg/kg bodyweight) intraperitoneally, additionally group III and group IV received chrysin (20 mg/kg bodyweight) and α-tocopherol acetate (200 mg/kg bodyweight), respectively. Group V received chrysin alone. The experiment period was for a period of 8 weeks. After the rats were killed, the tissue samples were analyzed for mean activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase, glucose-6-phosphate dehydrogenase, reduced glutathione, vitamin C, vitamin E, malondialdehyde and protein carbonyl. Histopathological studies were also carried out for morphological conformation.. Tissue samples from D-galactose-exposed untreated rats showed significantly (P < 0.05) lower levels of enzymatic and non-enzymatic anti-oxidants, and significantly (P < 0.05) higher levels of malondialdehyde and protein carbonyl when compared with group I and group III rats. Oral administration of chrysin for a period of 8 weeks, concomitant with the exposure to D-galactose, appeared to protect against oxidative damage and maintained all parameters at near normal levels. Histopathological studies confirmed the oxidative damage caused by D-galactose alone in tissues and also showed the tissue protective role of chrysin in rats receiving D-galactose and chrysin.. These results suggest that chrysin protects against oxidative stress-induced tissue damage in D-galactose-induced aging in an experimental rat model.

Topics: Aging; Analysis of Variance; Animals; Ascorbic Acid; Catalase; Disease Models, Animal; Flavonoids; Galactose; Glucosephosphate Dehydrogenase; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Male; Malondialdehyde; Oxidative Stress; Protein Carbonylation; Rats; Rats, Wistar; Superoxide Dismutase

The early antecedents of cerebral palsy (CP) are unknown but are suspected to be due to hypoxia-ischemia (H-I). In our rabbit model of CP, the MRI biomarker, apparent diffusion coefficient (ADC) on diffusion-weighted imaging, predicted which fetuses will develop postnatal hypertonia. Surviving H-I fetuses experience reperfusion-reoxygenation but a subpopulation manifested a continued decline of ADC during early reperfusion-reoxygenation, which possibly represented greater brain injury (RepReOx). We hypothesized that oxidative stress in reperfusion-reoxygenation is a critical trigger for postnatal hypertonia. We investigated whether RepReOx predicted postnatal neurobehavior, indicated oxidative stress, and whether targeting antioxidants at RepReOx ameliorated motor deficits, which included testing of a new superoxide dismutase mimic (MnTnHex-2-PyP). Rabbit dams, 79% gestation (E25), were subjected to 40 min uterine ischemia. Fetal brain ADC was followed during H-I, immediate reperfusion-reoxygenation, and 4-72 h after H-I. Endpoints were postnatal neurological outcome at E32, ADC at end of H-I, ADC nadir during H-I and reperfusion-reoxygenation, and area under ADC curve during the first 20 min of reperfusion-reoxygenation. Antioxidants targeting RepReOx were administered before and/or after uterine ischemia. The new MRI-ADC biomarker for RepReOx improved prediction of postnatal hypertonia. Greater superoxide production, mitochondrial injury, and oligodendroglial loss occurred in fetal brains exhibiting RepReOx than in those without. The antioxidants, MnTnHex-2-PyP and Ascorbate and Trolox combination, significantly decreased postnatal motor deficits and extent of RepReOx. The etiological link between early injury and later motor deficits can thus be investigated by MRI, and allows us to distinguish between critical oxidative stress that causes motor deficits and noncritical oxidative stress that does not.

Topics: Age Factors; Animals; Animals, Newborn; Antioxidants; Ascorbic Acid; Benzimidazoles; Blood Flow Velocity; Brain; Brain Mapping; Carbocyanines; Chromans; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Embryo, Mammalian; Female; Flow Cytometry; Hypoxia-Ischemia, Brain; Ionophores; Laser-Doppler Flowmetry; Membrane Potential, Mitochondrial; Metalloporphyrins; Microvessels; Mitochondria; Movement Disorders; Muscle Hypertonia; O Antigens; Pregnancy; Rabbits; Reperfusion Injury; Superoxides; Time Factors; Valinomycin

The Pringle maneuver is a surgical procedure to minimize hemorrhage during hepatectomy, which however, can induce production of reactive oxygen species causing remote organ injury. We sought to study the impact of the Pringle maneuver on cardiac function as well as the protective effects of L-ascorbic acid and α-tocopherol pretreatments.. Rats were divided into four study groups: L-ascorbic acid (60 mg/kg/d) or α-tocopherol (200 mg/kg/d), and surgical interventions (Sham-operated or liver ischemia-reperfusion [I/R]). Liver ischemia was performed by clamping the hepatic artery and portal vein for 30 minutes, followed by reperfusion by releasing the clamps for 2 hours. Cardiac function was evaluated by a high-fidelity pressure-volume catheter positioned in the left ventricle. Myocardial injury was assessed through plasma creatine kinase-MB (CKMB) and troponin I (cTnI). Cardiac lipid peroxidation and systemic hydroxyl radical levels were assessed by cardiac tissue malondialdehyde and plasma methylguanidine, respectively.. Cardiac function was significantly depressed in the I/R group, where plasma CKMB and cTnI were markedly increased (P < .05). L-ascorbic acid and α-tocopherol pretreatments improved cardiac function and significantly reduced cardiac injury (P < .05). L-ascorbic acid pretreatment demonstrated better heart protection than α-tocopherol, in terms of cTnI and CKMB (P < .05), but no significant difference in terms of cardiac functional improvement.. L-ascorbic acid and α-tocopherol pretreatment 3 days prior to the Pringle maneuver attenuated myocardial injury and protected cardiac function by scavenging hydroxyl radical and reducing lipid peroxidation. L-ascorbic acid demonstrated better protection than α-tocopherol.

Topics: alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; Biomarkers; Cardiac Catheterization; Creatine Kinase, MB Form; Disease Models, Animal; Heart Diseases; Hepatectomy; Hydroxyl Radical; Lipid Peroxidation; Liver Diseases; Malondialdehyde; Methylguanidine; Myocardial Contraction; Myocardium; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Time Factors; Troponin I; Ventricular Function, Left; Ventricular Pressure

Despite numerous advances and improvements in surgical techniques the incidence of incisional hernias after laparotomy remains high. The aim of this study was to investigate possible effects of single application of ascorbic acid, stanozolol, a synthetic anabolic steroid, copper peptide and transforming growth factor-β (TGF-β) on laparotomy wound healing in an incisional wound model in diabetic mice. After diabetes induction with streptozotozin in Balb-c mice, midline laparatomies were carried out. Closure of the linea alba was followed by single-dose application of the agents dissolved in a hydrogel before skin closure. The functional outcome was assessed in terms of maximum tensile strength. In addition, vessel densities, collagen contents and proliferation, were measured. The breaking strength of the skin 14 days after surgery was significantly higher in ascorbic acid (ΑΑ)-treated incisional wounds, whereas the other agents did not show a significantly better functional outcome. No significant differences were seen in vessel densities. Collagen type III contents was higher in the ΑΑ-treated animals, whereas the percentage of Ki67-positive nuclei was lower compared to the other groups. These data underline the positive effect of topically applied ascorbic acid in wound healing.

Topics: Animals; Ascorbic Acid; Cicatrix; Copper; Diabetes Mellitus, Experimental; Disease Models, Animal; Female; Fibrillar Collagens; Hydrogels; Laparotomy; Mice; Mice, Inbred BALB C; Peptides; Stanozolol; Tensile Strength; Transforming Growth Factor beta; Wound Healing

The concentration of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, is decreased in the lung in both fibrotic diseases and experimental fibrosis models. The underlying mechanisms and biological significance of GSH depletion, however, remain unclear. Transforming growth factor β (TGF-β) is the most potent and ubiquitous profibrogenic cytokine and its expression is increased in almost all fibrotic diseases. In this study, we show that increasing TGF-β1 expression in mouse lung to a level comparable to those found in lung fibrotic diseases by intranasal instillation of AdTGF-β1(223/225), an adenovirus expressing constitutively active TGF-β1, suppressed the expression of both catalytic and modifier subunits of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in de novo GSH synthesis, decreased GSH concentration, and increased protein and lipid peroxidation in mouse lung. Furthermore, we show that increasing TGF-β1 expression activated JNK and induced activating transcription factor 3, a transcriptional repressor involved in the regulation of the catalytic subunit of GCL, in mouse lung. Control virus (AdDL70-3) had no significant effect on any of these parameters, compared to saline-treated control. Concurrent with GSH depletion, TGF-β1 induced lung epithelial apoptosis and robust pulmonary fibrosis. Importantly, lung GSH levels returned to normal, whereas fibrosis persisted at least 21 days after TGF-β1 instillation. Together, the data suggest that increased TGF-β1 expression may contribute to the GSH depletion observed in pulmonary fibrosis diseases and that GSH depletion may be an early event in, rather than a consequence of, fibrosis development.

Topics: Activating Transcription Factor 3; Animals; Apoptosis; Ascorbic Acid; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Epithelial Cells; Gene Expression Regulation, Enzymologic; Glutamate-Cysteine Ligase; Glutathione Disulfide; JNK Mitogen-Activated Protein Kinases; Lipid Peroxidation; Lung; Mice; Oxidation-Reduction; Oxidative Stress; Pulmonary Fibrosis; Respiratory Mucosa; Transcription, Genetic; Transforming Growth Factor beta1; Tyrosine

Excessive concentrations of free radicals in the developing brain may lead to neurons maldevelopment and neurons damage and death. Thyroid hormones (THs) states play an important role in affecting the modulation of oxidative stress and antioxidant defense system. Thus, the objective of this study was to clarify the effect of hypothyroidism and hyperthyroidism in rat dams on the neurons development of different brain regions of their offspring at several postnatal weeks in relation to changes in the oxidative stress and antioxidant defense system. The adult female rats were administered methimazole (MMI) in drinking water (0.02% w/v) from gestation day 1 to lactation day 21 to induce hypothyroidism and exogenous thyroxine (T4) in drinking water (0.002% w/v) beside intragastric incubation of 50--200 T4 μg/kg body weight (b. wt.) to induce hyperthyroidism. In normal female rats, the sera total thyroxine (TT4) and total triiodothyronine (TT3) levels were detectably increased at day 10 post-partum than those at day 10 of pregnancy. Free thyroxine (FT4), free triiodothyronine (FT3), thyrotropin (TSH) and growth hormone (GH) concentrations in normal offspring were elevated at first, second and third postnatal weeks in an age-dependent manner. In hypothyroid group, a marked depression was observed in sera of dam TT3 and TT4 as well as offspring FT3, FT4 and GH, while there was a significant increase in TSH level with the age progress. The reverse pattern to latter state was recorded in hyperthyroid group. Concomitantly, in control offspring, the rate of neuron development in both cerebellar and cerebral cortex was increased in its density and complexity with age progress. This development may depend, largely, on THs state. Both maternal hypothyroidism and hyperthyroidism caused severe growth retardation in neurons of these regions of their offspring from the first to third weeks. Additionally, in normal offspring, seven antioxidant enzymes, four non-enzymatic antioxidants and one oxidative stress marker (lipid peroxidation, LPO) followed a synchronized course of alterations in cerebrum, cerebellum and medulla oblongata. In both thyroid states, the oxidative damage has been demonstrated by the increased LPO and inhibition of enzymatic and non-enzymatic antioxidants in most examined ages and brain regions. These disturbances in the antioxidant defense system led to deterioration in the neuronal maturation and development. In conclusion, it can be suggested that the

Topics: Age Factors; alpha-Tocopherol; Analysis of Variance; Animals; Animals, Newborn; Antioxidants; Ascorbic Acid; Aspirin; Brain; Catalase; Catechol Oxidase; Disease Models, Animal; Drug Combinations; Female; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Hyperthyroidism; Hypothyroidism; Lipid Peroxidation; Male; Neurons; Oxidative Stress; Peroxidase; Pregnancy; Pregnancy Complications; Radioimmunoassay; Rats; Silver Staining; Superoxide Dismutase; Thyrotropin; Thyroxine; Triiodothyronine

Therapeutic angiogenesis has emerged as an attractive approach for the management of peripheral arterial disease in diabetic patients. Oxidative stress generated and aggravated by prolonged hyperglycemia may interfere with and destroy the newly formed blood vessels. Angiogenic effect of simvastatin has been reported; however, its exact mechanism is yet to be evaluated. In addition, the exact role of antioxidant vitamins in diabetic peripheral arterial disease is still controversial. The present study was undertaken to investigate the therapeutic potential of simvastatin and antioxidant vitamins (E and C) and their combined effects on angiogenesis in diabetic hind-limb ischemia. Streptozotocin diabetic rats were treated for 6 weeks with simvastatin either alone or in combination with vitamin E or vitamin C. Parameters of angiogenesis, nitric oxide, heme oxygenase-1 (HO-1), and oxidative stress markers were evaluated. CD31 immunostaining revealed an increased capillary density in ischemic gastrocnemious tissue of diabetic rats treated with either simvastatin or its combination with vitamin C. This effect was accompanied by up-regulated plasma levels of HO-1, nitric oxide, vascular endothelial growth factor (VEGF) and its intra-muscular receptor type-2 (Flk-1). Tissue reduced glutathione and antioxidant enzymes activities were normalized in groups treated with antioxidant vitamins or their combination with simvastatin with concomitant blunting of lipid peroxidation. Vitamins E and C, through their antioxidant effects, evidently enhanced the angiogenic effect of simvastatin in ischemic diabetic muscle. Hence, the use of antioxidant vitamins combined with statins to induce therapeutic angiogenesis is a promising strategy in the management of diabetes-associated peripheral arterial disease.

Topics: Angiogenesis Inducing Agents; Animals; Antioxidants; Ascorbic Acid; Biomarkers; Capillaries; Diabetes Complications; Disease Models, Animal; Heme Oxygenase-1; Hindlimb; Ischemia; Male; Neovascularization, Physiologic; Nitric Oxide; Oxidative Stress; Rats; Rats, Wistar; Simvastatin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Vitamin E; Vitamins

The aim of the study was to delineate the protective effect of ascorbic acid with plausible mechanism after single and repetitive cadmium administration to Swiss mice. The effects of single high dose administration of CdCl(2) (6 mg/kg) or ascorbic acid (AsA) (50 mg/kg) and chronic (three times) administration of Cd at low dose (2 mg/kg) or AsA at same dose (50 mg/kg) were compared in Swiss albino mice. Changes of lipid peroxidation [determined by the malonyldialdehyde (MDA) concentration] were taken as a measure of the oxidative stress intensity. Lipid fatty acid's unsaturation related to the permeability of cell membranes was also examined. Mobilization of the immune system was determined by analyzing changes in antioxidant concentrations of AsA and glutathione (GSH), and by measuring the activation of antioxidant enzymes SOD, GPx and CAT. In addition, the level of free polyamines and variation in their proportions were examined. In conclusion, exposure to higher levels of cadmium will have more deleterious effects on the body rather than chronic exposure at lower levels with this toxic metal, while this study clearly demonstrated the protective effects of AsA in a mouse model.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain; Brain Chemistry; Cadmium Chloride; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Environmental Pollutants; Fatty Acids; Immune System; Kidney; Lipid Peroxidation; Liver; Male; Malondialdehyde; Mice; Oxidative Stress; Oxidoreductases; Time Factors

In the present study, the effect of l-ascorbic acid (AA) was studied on the climbing ability of the Parkinson's disease (PD) model Drosophila expressing normal human alpha synuclein (h-αs) in the neurons. These flies show locomotor dysfunction as the age progresses. AA at final concentration of 11.35 × 10(-5) M, 22.71 × 10(-5) M, 45.42 × 10(-5) M, and 68.13 × 10(-5) M was added to the diet, and the flies were allowed to feed for 21 days. AA at 11.35 × 10(-5) M did not show any significant delay in the loss of climbing ability of PD model flies. However, AA at 22.71 × 10(-5) M, 45.42 × 10(-5) M, and 68.13 × 10(-5) M showed a dose dependent significant (p < .05) delay in the loss of climbing ability of PD model flies as compared to the untreated PD flies. The total protein concentration in brain homogenate was measured in treated as well as control groups after 21 days, no significant difference was obtained between treated as well as control (PD flies and l-dopa) groups. The results suggest that AA is potent in delaying the climbing disability of the PD model flies expressing h-αs in the neurons.

Topics: Age Factors; alpha-Synuclein; Animals; Animals, Genetically Modified; Antioxidants; Antiparkinson Agents; Ascorbic Acid; Brain; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Drosophila; Drosophila Proteins; Gait Disorders, Neurologic; Humans; Levodopa; Membrane Proteins; Neurons; Parkinson Disease; Transcription Factors

Stress is a potent risk factor for depression, yet the underlying mechanism is not clearly understood. In the present study, we explored the mechanism of development and maintenance of depression in a stress-induced animal model. Mice restrained for 2 h daily for 14 d showed distinct depressive behavior, and the altered behavior persisted for >3 months in the absence of intervention. Acute restraint induced a surge of oxidative stress in the brain, and stress-induced oxidative stress progressively increased with repetition of stress. In vitro, the stress hormone glucocorticoid generated superoxide via upregulation of NADPH oxidase. Consistently, repeated restraints increased the expression of the key subunits of NADPH oxidase, p47phox and p67phox, in the brain. Moreover, stressed brains markedly upregulated the expression of p47phox to weak restress evoked in the poststress period, and this molecular response was reminiscent of amplified ROS surge to restress. Pharmacological inhibition of NADPH oxidase by the NADPH oxidase inhibitor apocynin during the stress or poststress period completely blocked depressive behavior. Consistently, heterozygous p47phox knock-out mice (p47phox(+/-)) or molecular inhibition of p47phox with Lenti shRNA-p47phox in the hippocampus suppressed depressive behavior. These results suggest that repeated stress promotes depressive behavior through the upregulation of NADPH oxidase and the resultant metabolic oxidative stress, and that the inhibition of NADPH oxidase provides beneficial antidepression effects.

Topics: Acetophenones; Analysis of Variance; Animals; Antidepressive Agents, Tricyclic; Antioxidants; Ascorbic Acid; Brain; Cell Line; Corticosterone; Depressive Disorder; Disease Models, Animal; Drug Administration Schedule; Gene Expression Regulation, Enzymologic; Green Fluorescent Proteins; Hindlimb Suspension; Hippocampus; Humans; Hydrogen Peroxide; Imipramine; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; NADPH Oxidases; Neuroblastoma; Neurons; Phosphoproteins; Reactive Oxygen Species; Restraint, Physical; RNA, Messenger; RNA, Small Interfering; Social Behavior; Superoxides; Swimming; Time Factors

To determine the efficacy of the topical application of ascorbic acid for the treatment of corneal neovascularization.. Corneal neovascularization was induced in 16 rabbits with a silk suture in the corneal stroma (32 eyes). At 1 week after suturing, 15 rabbits were divided into 3 groups and were treated with topical ascorbic acid at 3 different concentrations: 10 mg/mL (group 1), 1 mg/mL (group 2), and 0.5 mg/mL (group 3). All treatments were added in the right eye twice a day. All left eyes (15 eyes) and both eyes of the 16th rabbit were used as experimental controls and a normal control, respectively. The area of corneal neovascularization was measured using light microscopy. The concentrations of vascular endothelial growth factor and matrix metalloproteinase-9 in the corneal tissue were measured.. The neovascularized area was decreased in the treated groups compared with the control group. There was a significant difference in the neovascularized areas between the control and groups 1 and 2. No significant difference was observed between the control and group 3. The concentration of vascular endothelial growth factor was significantly lower in the treated groups than in the control group, but there was no difference between the treated groups. The concentration of matrix metalloproteinase-9 showed a significant difference between the control and treated groups, but no difference between the treated groups.. Topical administration of ascorbic acid may be useful for the treatment of corneal neovascularization.

Topics: Administration, Topical; Animals; Antioxidants; Ascorbic Acid; Corneal Neovascularization; Disease Models, Animal; Female; Male; Matrix Metalloproteinase 9; Ophthalmic Solutions; Rabbits; Treatment Outcome; Vascular Endothelial Growth Factor A

This study investigated the effectiveness of pirfenidone compared with antioxidants, in the prevention of pulmonary fibrosis and increasing the survival in acutely paraquat poisoned rats.. Five groups of ten rats were included in this study. Three groups were poisoned with intraperitoneal injection of 15 mg/kg paraquat. Among these poisoned groups, one group was treated with vitamin C (500 mg/kg, intraperitoneal), vitamin E (200 mg/kg, intraperitoneal) and N-acetylcysteine (250 mg/kg, intravenous); two others were treated with either normal saline or pirfenidone (200 mg/kg, intravenous); two groups were not poisoned and received normal saline or pirfenidone (200 mg/kg, intravenous). All injections except paraquat were repeated in four consecutive days. On the 15th day of study a semi-quantitative determination of lung fibrosis was done using Ashcroft staging criteria on the lung sections.. Pirfenidone decreased paraquat induced lung fibrosis (p < 0.001) while antioxidants did not decrease the lung fibrosis (p = 0.413). Life expectancy decreased in paraquat + normal saline (11 days, 95% CI 7.94-14.05) and paraquat + antioxidant (11 days, 95% CI 7.77-14.23) groups. The increase in the survival of rats in paraquat/pirfenidone group was insignificant (13.4 days, 95% CI 11.13-15.67).. This study showed that pirfenidone is able to decrease pulmonary fibrosis following paraquat poisoning in a rat model.

Topics: Acetylcysteine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Ascorbic Acid; Disease Models, Animal; Herbicides; Injections, Intraperitoneal; Injections, Intravenous; Life Expectancy; Male; Paraquat; Pulmonary Fibrosis; Pyridones; Rats; Rats, Wistar; Survival Rate; Vitamin E

Thermal injuries with more than 20% of burned body surface area (BSA) lead to systemic shock with generalised oedema in addition to local tissue destruction. This condition, known as burn injury, is caused by immunmodulative mediators whose individual significance is not known in detail. We present an experimental model where plasma of burned animals (burn plasma) is transmitted to healthy animals, to trigger burn iniury without performing direct burn trauma.. The systemic oedema is measured by extravasation of fluorescent albumin in mesenterial venules of Wistar rats. In addition, leukocyte-endothelial interactions ("leukocyte rolling and sticking") is examined.. The systemic capillary leak is induced by both direct thermal trauma as well as by infusion of burn plasma. This is evident even after plasma dilution (1% in Ringer's lactate) of the burn plasma. In addition, topical therapy for burned animals (donors) with cerium nitrate led to a significant reduction of plasma extravasation in receiver animals. In addition, systemic antioxidant therapy with high-dose vitamin C of receiver animals, led to a significant reduction of the capillary leak. Leukocyte-endothelial interactions are not significantly affected in either case.. In summary, for the first time a reliable model of burn injury has been established, which eliminates mediator-independent effects. In addition, our studies show that antioxidant therapy with high doses of vitamin C and topical treatment with cerium nitrate both reduce the systemic capillary leak in receiver animals. Their positive influence could therefore soon be integrated in clinical treatment algorithms.

Topics: Animals; Anti-Infective Agents, Local; Antioxidants; Ascorbic Acid; Blood Flow Velocity; Burns; Capillary Leak Syndrome; Cell Adhesion; Cerium; Cytokines; Disease Models, Animal; Edema; Extravasation of Diagnostic and Therapeutic Materials; Leukocytes; Male; Mesenteric Veins; Microcirculation; Plasma; Rats; Rats, Wistar; Shock; Venules

The nephroprotective effect of co-administration of vitamin C and losartan as prophylaxis against cisplatin-induced nephrotoxicity (CIN) was evaluated.. Co-administration of vitamin C and losartan was compared with losartan (10 mg/kg), vitamin C (250 mg/kg), and placebo in 4 groups of rats with CIN. The prophylactic agents were injected daily for a period of 4 days, and on day 3, a single dose (6 mg/kg) of cisplatin was administrated. The animals were sacrificed 7 days later for pathological examination of the kidneys.. Cisplatin prevented the animals' weight gain. The serum levels of creatinine and blood urea nitrogen increased within the groups with CIN, but no significant difference was observed between the groups. The prophylaxis has no effect on serum osmolality, total protein, or nitrite concentrations. The kidney tissue damage was scored, and losartan provided a lower damage score than vitamin C and a combination of vitamin C and losartan.. We concluded that co-administration of vitamin C and losartan was not more effective than the administration of vitamin C or losartan alone.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antioxidants; Ascorbic Acid; Biomarkers; Blood Proteins; Blood Urea Nitrogen; Cisplatin; Creatinine; Cytoprotection; Disease Models, Animal; Drug Therapy, Combination; Kidney; Kidney Diseases; Losartan; Male; Nitrites; Rats; Rats, Wistar; Time Factors; Weight Gain

Endoplasmic reticulum (ER) thiol oxidases initiate a disulfide relay to oxidatively fold secreted proteins. We found that combined loss-of-function mutations in genes encoding the ER thiol oxidases ERO1α, ERO1β, and PRDX4 compromised the extracellular matrix in mice and interfered with the intracellular maturation of procollagen. These severe abnormalities were associated with an unexpectedly modest delay in disulfide bond formation in secreted proteins but a profound, 5-fold lower procollagen 4-hydroxyproline content and enhanced cysteinyl sulfenic acid modification of ER proteins. Tissue ascorbic acid content was lower in mutant mice, and ascorbic acid supplementation improved procollagen maturation and lowered sulfenic acid content in vivo. In vitro, the presence of a sulfenic acid donor accelerated the oxidative inactivation of ascorbate by an H(2)O(2)-generating system. Compromised ER disulfide relay thus exposes protein thiols to competing oxidation to sulfenic acid, resulting in depletion of ascorbic acid, impaired procollagen proline 4-hydroxylation, and a noncanonical form of scurvy.

Topics: Animals; Ascorbic Acid; Cells, Cultured; Connective Tissue; Disease Models, Animal; Disulfides; Endoplasmic Reticulum; Female; Glycoproteins; Male; Mice; Mice, Mutant Strains; Mutation; Oxidation-Reduction; Oxidoreductases; Peroxiredoxins; Procollagen; Protein Folding; Protein Processing, Post-Translational; Scurvy; Sulfenic Acids; Transforming Growth Factor beta

Oxidative stress causes the generation of reactive oxygen species (ROS) that lead to nephrotoxicity. An aminoglycoside, gentamicin, has pronounced nephrotoxic effect in humans and animals and this study was planned to observe the nephro-protective effect of antioxidants, vitamin C and Nigella sativa oil. Serum creatinine, blood urea nitrogen, and antioxidant activity were measured as indicators of nephrotoxicity for all the groups of rabbits. Results showed that vitamin C and Nigella sativa oil both had nephro-protective effect as they lowered the values of nephrotoxicity indicators (serum creatinine, blood urea nitrogen, and antioxidant activity) as compared to gentamicin control group values. When these two antioxidants were given as combination, they proved to have synergistic nephro-protective effect.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Blood Urea Nitrogen; Creatinine; Cytoprotection; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Gentamicins; Kidney Diseases; Male; Nephrons; Oxidative Stress; Plant Oils; Rabbits; Time Factors

The goal of our study is to evaluate the effects of antioxidant vitamins (vitamin C and E), Coenzyme Q10 (CoQ10) and dexamethasone (Dxm) in experimental rat models with pulmonary contusion (PC).. Rats were randomly divided into six groups. Except for the control, all subgroups had a moderate pulmonary contusion. Animals in the group I and group II received intraperitoneal saline, group III received 10mg.kg-1 CoQ10 group IV received 100mg.kg-1 vitamin C, group V received 150 mg.kg-1 vitamin E, and group VI received 10mg.kg-1 Dxm. Blood gas analysis, serum nitric oxide (NO) and malondialdehyde (MDA) levels as well as superoxide dismutase (SOD) activity assays, bronchoalveolar lavage (BAL) fluid and histopathological examination were performed.. Administration of CoQ10 resulted in a significant increase in PaO2 values compared with the group I (p = 0.004). Levels of plasma MDA in group II were significantly higher than those in the group I (p = 0.01). Early administration of vitamin C, CoQ10, and Dxm significantly decreased the levels of MDA (p = 0.01). Lung contusion due to blunt trauma significantly decreased SOD activities in rat lung tissue compared with group I (p = 0.01). SOD levels were significantly elevated in animals treated with CoQ10, Vitamin E, or Dxm compared with group II (p = 0.01).. In our study, CoQ10, vitamin C, vitamin E and Dxm had a protective effect on the biochemical and histopathological outcome of PC after experimental blunt thorax trauma.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Blood Gas Analysis; Bronchoalveolar Lavage Fluid; Dexamethasone; Disease Models, Animal; Histocytochemistry; Lung Injury; Male; Neutrophils; Rats; Rats, Wistar; Statistics, Nonparametric; Ubiquinone; Vitamin E; Vitamins

The aim of this study was to investigate a new flavone triglycoside, together with eleven phenolic metabolites from 80% aqueous methanol extract of S. splendens leaves (AME) and assessment of its hypoglycemic and antiinflammatory activities along with in vitro antioxidant effect.. The phenolic composition of S. splendens leaves was analyzed using UV, 1D and 2D NMR and negative ESI-MS spectroscopy. Hypoglycemic activity of AME was assessed by measuring blood glucose in streptozotocin induced-diabetic rats. Antiinflammatory activity was evaluated using the carrageenan-induced paw oedema test. Antioxidant activity was evaluated in vitro using DPPH test..  Twelve phenolic metabolites including three phenolic acids, namely caffeic acid 1, rosmarinic acid 2 and methyl rosmarinate 3; four flavone glycosides viz the new compound luteolin 7-O-(4″,6″-di-O-α-L-rhamnopyranosyl)-β-D-glucopyranoside 4, apigenin 7-O-β-D-rutinoside 5, cosmosiin 6 and cinaroside 7, together with four flavones aglycone, luteolin 8, apigenin 9, pedalitin 10 and crisiliol 11 in addition to one coumarin, 6,7-dihydroxycoumarin 12 were isolated from the leaves of S. splendens Sellow ex Roem & Schult. The AME of S. splendens was non toxic to mice up to 5 g/kg b.wt. it exhibited a significant hypoglycemic activity at 250 and 500 mg/kg as compared with control pre-drug (zero time) for each group as well as the diabetic control. Moreover, AME exhibited a significant antiinflammatory activity only at 1000 mg/kg in comparison to indomethacin. Finally, AME exhibited a marked significant scavenging activity against DPPH; the maximum reactive reaction rate after 5 min was 62.9, 82.5, 83.7, 84.3 and 85.1% for the concentrations 10, 20, 30, 40 and 50 mg/ml, respectively in comparison to L-ascorbic acid (86.8%)..  This is the first study reporting the identification of a new flavone triglycoside, along with eleven known phenolic metabolites from AME of S. splendens. It showed significant hypoglycemic and antiinflammatory effects in dose dependant manner. Moreover it showed an in vitro antioxidant activity.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Female; Hypoglycemic Agents; Indomethacin; Inflammation; Magnetic Resonance Spectroscopy; Male; Mice; Plant Extracts; Plant Leaves; Polyphenols; Rats; Rats, Sprague-Dawley; Salvia; Spectrometry, Mass, Electrospray Ionization

The tissue changes that occur in Chagas disease are related to the degree of oxidative stress and antioxidant capacity of affected tissue. Studies with vitamin C supplementation did not develop oxidative damage caused by Chagas disease in the host, but other studies cite the use of peroxiredoxins ascorbate - dependent on T. cruzi to offer protection against immune reaction. Based on these propositions, thirty "Swiss" mice were infected with T. cruzi QM1 strain and treated with two different vitamin C doses in order to study the parasitemia evolution, histopathological changes and lipid peroxidation biomarkers during the acute phase of Chagas disease. The results showed that the parasite clearance was greater in animals fed with vitamin C overdose. There were no significant differences regarding the biomarkers of lipid peroxidation and inflammatory process or the increase of myocardium in animals treated with the recommended dosage. The largest amount of parasite growth towards the end of the acute phase suggests the benefit of high doses of vitamin C for trypomastigotes. The supplementation doesn't influence the production of free radicals or the number of amastigote nests in the acute phase of Chagas disease.

Topics: Acute Disease; Animals; Antioxidants; Ascorbic Acid; Chagas Disease; Dietary Supplements; Disease Models, Animal; Dose-Response Relationship, Drug; Lipid Peroxidation; Male; Mice; Parasitemia; Time Factors; Trypanosoma cruzi

Before induced pluripotent stem cells (iPSCs) can be used to treat neurologic diseases, human iPSC-derived neural cells must be analyzed in the primate brain. In fact, although mouse and human iPSCs have been used to generate dopaminergic (DA) neurons that are beneficial in rat models of Parkinson's disease (PD), human iPSC-derived neural progenitor cells (NPCs) have not been examined in primate brains. Here, we generated NPCs at different stages of predifferentiation using a feeder-free culture method, and grafted them into the brains of a monkey PD model and NOD-SCID mice. Magnetic resonance imaging (MRI), positron emission tomography (PET), immunocytochemistry, and behavioral analyses revealed that NPCs pretreated with Sonic hedgehog and fibroblast growth factor-8 followed by glial cell-derived neurotrophic factor, brain-derived neurotrophic factor, ascorbic acid, and dibutyryl cyclic AMP resulted in smaller grafts than those without these treatments, and survived as DA neurons in a monkey brain as long as six months. Thus, for the first time, we describe a feeder-free neural differentiation method from human iPSCs and an evaluation system that can be used to assess monkey PD models.

Topics: Animals; Ascorbic Acid; Carrier Proteins; Cell Differentiation; Cyclic AMP; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Humans; Induced Pluripotent Stem Cells; Intercellular Signaling Peptides and Proteins; Macaca fascicularis; Male; Mesencephalon; Mice; Nerve Tissue Proteins; Neural Cell Adhesion Molecule L1; Parkinson Disease; Radionuclide Imaging; Sialic Acids; Time Factors

Phosphate ester of vitamin C and vitamin E (EPCK1), a strong antioxidant, is a water- and lipid-soluble phosphate ester of vitamin C and vitamin E. In the current study, we tested whether EPCK1 inhibits oxidative stress and prevents systemic inflammation.. Mice were randomly divided into a negative control group, a lipopolysaccharide (LPS)-induced sepsis group, and a group treated with an intraperitoneal infusion of EPCK1 (10 mg/kg) prior to or following LPS administration. In addition, RAW 264.7 cells were treated with LPS in the presence or absence of EPCK1. We examined levels of high mobility group box 1 (HMGB1) protein and inducible nitric oxide synthase (iNOS) in both in vivo and in vitro experiments, and liver histopathology in the in vivo experiment.. Liver histopathology significantly improved in the EPCK1 group compared with the LPS group. Although LPS administration increased HMGB1 and nitric oxide (NO) secretion, EPCK1 decreased the secretion of these mediators in vitro and in vivo.. Our findings suggest that EPCK1 may inhibit inflammation and potentially function as a novel anti-inflammatory therapeutic agent.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Cell Line; Disease Models, Animal; Esters; HMGB1 Protein; Inflammation; Lipopolysaccharides; Liver; Macrophages; Male; Mice; Mice, Inbred BALB C; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Phosphates; Sepsis; Survival Rate; Vitamin E

Cadmium (Cd) is one of the most important environmental pollutants that cause a number of adverse health effects in humans and animals. Recent studies have shown that Cd-induced oxidative damage within the vascular tissues results in vascular dysfunction. The current study was aimed to investigate whether ascorbic acid could protect against Cd-induced vascular dysfunction in mice. Male ICR mice were received CdCl(2) (100 mg/l) via drinking water for 8 weeks alone or received ascorbic acid supplementation at doses of 50 and 100 mg/kg/day for every other day. Results showed that Cd administration increased arterial blood pressure and blunted the vascular responses to vasoactive agents. These alterations were related to increased superoxide production in thoracic aorta, increased urinary nitrate/nitrite, increased plasma protein carbonyl, elevated malondialdehyde (MDA) concentrations in plasma and tissues, decreased blood glutathione (GSH), and increased Cd contents in blood and tissues. Ascorbic acid dose-dependently normalized the blood pressure, improved vascular reactivities to acetylcholine (ACh), phenylephrine (Phe) and sodium nitroprusside (SNP). These improvements were associated with significant suppression of oxidant formation, prevention of GSH depletion, and partial reduction of Cd contents in blood and tissues. The findings in this study provide the first evidence in pharmacological effects of ascorbic acid on alleviation of oxidative damage and improvement of vascular function in a mouse model of Cd-induced hypertension and vascular dysfunction. Moreover, our study suggests that dietary supplementation of ascorbic acid may provide beneficial effects by reversing the oxidative stress and vascular dysfunction in Cd-induced toxicity.

Topics: Animals; Ascorbic Acid; Cadmium; Disease Models, Animal; Hypertension; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Testis; Vascular Diseases

Vitamin C deficiency - or hypovitaminosis C defined as a plasma concentration below 23 μm - is estimated to affect hundreds of millions of people in the Western world, in particular subpopulations of low socio-economic status that tend to eat diets of poor nutritional value. Recent studies by us have shown that vitamin C deficiency may result in impaired brain development. Thus, the aim of the present study was to investigate if a poor diet high in fat and cholesterol affects the vitamin C status of guinea pigs kept on either sufficient or deficient levels of dietary ascorbate (Asc) for up to 6 months with particular emphasis on the brain. The present results show that a high-fat and cholesterol diet significantly decreased the vitamin C concentrations in the brain, irrespective of the vitamin C status of the animal (P < 0·001). The brain Asc oxidation ratio only depended on vitamin C status (P < 0·0001) and not on the dietary lipid content. In plasma, the levels of Asc significantly decreased when vitamin C in the diet was low or when the fat/cholesterol content was high (P < 0·0001 for both). The Asc oxidation ratio increased both with low vitamin C and with high fat and cholesterol content (P < 0·0001 for both). We show here for the first time that vitamin C homoeostasis of brain is affected by a diet rich in fat and cholesterol. The present findings suggest that this type of diet increases the turnover of Asc; hence, individuals consuming high-lipid diets may be at increased risk of vitamin C deficiency.

Topics: Animals; Antioxidants; Ascorbic Acid; Ascorbic Acid Deficiency; Brain; Cholesterol, Dietary; Chronic Disease; Dietary Fats; Disease Models, Animal; Guinea Pigs; Homeostasis; Oxidation-Reduction; Oxidative Stress

Alcoholic liver disease (ALD) is a major medical complication of drinking alcohol, and commonly accompanied with hepatic iron overload and liver injuries. Oxidative stress plays an important role in pathogenesis of ALD and also leads to iron-metabolic disorders. In this study, the effects of vitamin C (Vc) on iron metabolism-related genes expression and liver protection from drinking in mice were investigated. Twenty-four male kunming mice were divided into four groups (six mice per group): control (water drinking); alcohol group (20% alcohol drinking), alcohol + low Vc group (adding 50 mg/kg Vc daily) and alcohol + high Vc group (adding 100 mg/kg Vc daily). All these mice were sacrificed after 7 days. Vc can ameliorate the increase of sera alanine aminotransferase (ALT) activity and hepatic iron overload of drinking alcohol in mice. Vc increases the expression of the iron-regulated hormone hepcidin and decreases transferrin receptor 1 (TfR1) expression in liver. Vc also down-regulates the expression of ferroportin 1 (Fpn1) in the intestine and decreases the iron release to blood. In conclusion, Vc ameliorated the alcoholic liver injuries through regulating the iron metabolism-related genes expression.

Topics: Alanine Transaminase; Animals; Antimicrobial Cationic Peptides; Antioxidants; Ascorbic Acid; Blotting, Western; Disease Models, Animal; Ethanol; Gene Expression Regulation; Hepcidins; Iron; Iron Overload; Liver; Liver Diseases, Alcoholic; Male; Mice; Mice, Inbred Strains; Receptors, Transferrin; RNA, Messenger

Humans acquire vitamin C (ascorbate) from their diet, and optimal tissue concentrations are required to maintain its enzyme cofactor and antioxidant activities. How dietary intake affects tissue concentrations is difficult to monitor and has generally been based on the measurement of plasma concentrations.. We aimed to determine the effect of various ascorbate intakes on tissue concentrations in the Gulo mouse model of vitamin C deficiency and to compare the effectiveness of delivery when ascorbate was added to the drinking water or obtained through a fruit source (kiwifruit).. Gulo(-/-) mice were fed various amounts of ascorbate for 1 mo, either in their drinking water or as a kiwifruit gel. Tissue vitamin C content was measured and compared with concentrations in wild-type mice.. Ascorbate concentrations in serum, liver, kidney, heart, and white blood cells were extremely labile and were well below concentrations observed in the wild-type mice when serum concentrations were below saturation. All tissues except for brain were rapidly depleted when intake was stopped. Consumption of a preparation of fresh kiwifruit (either green or gold varieties) resulted in up to 5 times more effective delivery to tissues than when ascorbate was administered via the drinking water.. Subsaturation concentrations of plasma ascorbate resulted in severe deficiency in many tissues, and saturating amounts were required to achieve tissue concentrations similar to those found in wild-type animals. It is possible that the bioavailability of ascorbate is superior from some foods, such as kiwifruit. These results have important implications for human nutrition.

Topics: Actinidia; Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Biological Availability; Diet; Disease Models, Animal; Drinking; Fruit; Mice; Mice, Inbred C57BL; Mice, Knockout; Plant Extracts; Tissue Distribution; Water

The present study investigates the potential ability of selenium, considered as an antioxidant with pharmacological property to alleviate oxidative stress and hematological parameter disorders induced by methimazole, an antithyroid drug. Pregnant Wistar rats were randomly divided into four groups of six each: group I served as negative control and received a standard diet; group II received 250 mg/L of methimazole in drinking water and a standard diet; group III received both methimazole (250 mg/L, orally) and selenium (0.5 mg/kg of diet) supplemented to the standard diet; group IV served as positive control and received a supplement of selenium in the diet (0.5 mg/kg of diet) as sodium selenite (Na(2)SeO(3)). Treatment was started from the 14th day of pregnancy until day 14 after delivery. Methimazole reduced the number of red blood cells, hemoglobin concentration and hematocrit in mothers and their pups. Besides, plasma iron, vitamins B(9), B(12), C and E levels were reduced. Lipid peroxidation increased, objectified by high malondialdehyde levels and lactate dehydrogenase activity in plasma, while glutathione, glutathione peroxidase, superoxide dismutase and catalase activities showed a significant decline. Co-administration of selenium through diet improved all the parameters cited above. It can be concluded that the administration of selenium alleviates methimazole-induced toxicity, thus demonstrating its antioxidant efficacy.

Topics: Anemia; Animals; Animals, Newborn; Animals, Suckling; Antioxidants; Antithyroid Agents; Ascorbic Acid; Disease Models, Animal; Female; Folic Acid; Glutathione; Hematologic Tests; Iron; Lipid Peroxidation; Male; Malondialdehyde; Methimazole; Oxidative Stress; Oxidoreductases; Pregnancy; Pregnancy Complications, Hematologic; Protective Agents; Rats; Rats, Wistar; Selenium; Vitamin B 12; Vitamin E

Memory impairment induced by streptozotocin in rats is a consequence of changes in CNS that are secondary to chronic hyperglycemia, impaired oxidative stress, cholinergic dysfunction, and changes in glucagon-like peptide (GLP). Treatment with antihyperglycemics, antioxidants, and cholinergic agonists are reported to produce beneficial effect in this model. Berberine, an isoquinoline alkaloid is reported to exhibit anti-diabetic and antioxidant effect, acetylcholinesterase (AChE) inhibitor, and increases GLP release. However, no report is available on influence of berberine on streptozotocin-induced memory impairment. Therefore, we tested its influence against cognitive dysfunction in streptozotocin-induced diabetic rats using Morris water maze paradigm. Lipid peroxidation and glutathione levels as parameters of oxidative stress and choline esterase (ChE) activity as marker of cholinergic function were assessed in the cerebral cortex and hippocampus. Thirty days after diabetes induction rats showed a severe deficit in learning and memory associated with increased lipid peroxidation, decreased reduced glutathione, and elevated ChE activity. In contrast, chronic treatment with berberine (25-100mg/kg, p.o., twice daily, 30 days) improved cognitive performance, lowered hyperglycemia, oxidative stress, and ChE activity in diabetic rats. In another set of experiment, berberine (100mg/kg) treatment during training trials also improved learning and memory, lowered hyperglycemia, oxidative stress, and ChE activity. Chronic treatment (30 days) with vitamin C or metformin, and donepezil during training trials also improved diabetes-induced memory impairment and reduced oxidative stress and/or choline esterase activity. In conclusion, the present study demonstrates treatment with berberine prevents the changes in oxidative stress and ChE activity, and consequently memory impairment in diabetic rats.

Topics: Acetylcholine; Administration, Oral; Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; Berberine; Blood Glucose; Body Weight; Brain; Cholinesterase Inhibitors; Cholinesterases; Diabetes Mellitus, Experimental; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Drug Interactions; Exploratory Behavior; Glutathione; Hypoglycemic Agents; Indans; Lipid Peroxidation; Male; Maze Learning; Memory Disorders; Metformin; Piperidines; Rats; Rats, Wistar

Sepsis-induced lung injury is a persisting clinical problem with no direct therapy. Recent work suggests that intravenously infused ascorbic acid improves the circulatory dysfunction of sepsis. We used a model of endotoxin-induced acute lung injury to determine whether parenteral ascorbic acid modulates the dysregulated proinflammatory, procoagulant state that leads to lung injury.. C57BL/6 mice were exposed to lethal lipopolysaccharide doses (10 μg/g of body weight) to induce acute lung injury.. Laboratory investigation.. Wild-type C57BL/6 mice.. Ascorbic acid or its oxidized form (dehydroascorbic acid) was administered intraperitoneally at 200 mg/kg 30 mins after the lethal lipopolysaccharide dose.. We quantified survival, lung capillary leak, proinflammatory chemokine expression, and lung microvascular thrombosis. Lipopolysaccharide induced 100% lethality in mice within 28 hrs of exposure and in lung we observed intense neutrophil sequestration, loss of capillary barrier function, exuberant pulmonary inflammation, and extensive microthrombus formation. A time-delayed infusion protocol of both ascorbic acid and dehydroascorbic acid significantly prolonged survival. Both ascorbic acid and dehydroascorbic acid preserved lung architecture and barrier function while attenuating proinflammatory chemokine expression and microvascular thrombosis. Ascorbic acid and dehydroascorbic acid attenuated nuclear factor kappa B activation and normalized coagulation parameters.. Ascorbic acid administered in an interventional manner following lipopolysaccharide infusion attenuates proinflammatory, procoagulant states that induce lung vascular injury in an animal model of sepsis.

Topics: Acute Lung Injury; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Escherichia coli; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Sepsis

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Calcium-Binding Proteins; Dehydroascorbic Acid; Disease Models, Animal; Glucose Transporter Type 1; Humans; Intracellular Signaling Peptides and Proteins; Liver Cirrhosis; Mice; Mice, Knockout; PPAR gamma

Considering that Na(+),K(+)-ATPase is an embedded-membrane enzyme and that experimental chronic hyperprolinemia decreases the activity of this enzyme in brain synaptic plasma membranes, the present study investigated the effect of chronic proline administration on thiobarbituric acid-reactive substances, as well as the influence of antioxidant vitamins E plus C on the effects mediated by proline on Na(+),K(+)-ATPase activity in cerebral cortex of rats. The expression of Na(+),K(+)-ATPase catalytic subunits was also evaluated. Results showed that proline increased thiobarbituric acid-reactive substances, suggesting an increase of lipid peroxidation. Furthermore, concomitant administration of vitamins E plus C significantly prevented the increase of lipid peroxidation, as well as the inhibition of Na(+),K(+)-ATPase activity caused by proline. We did not observe any change in levels of Na(+),K(+)-ATPase mRNA transcripts after chronic exposure to proline and vitamins E plus C. These findings provide insights into the mechanisms through which proline exerts its effects on brain function and suggest that treatment with antioxidants may be beneficial to treat neurological dysfunctions present in hyperprolinemic patients.

Topics: 1-Pyrroline-5-Carboxylate Dehydrogenase; Amino Acid Metabolism, Inborn Errors; Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; Cerebral Cortex; Disease Models, Animal; Drug Synergism; Gene Expression; Humans; Lipid Peroxidation; Oxidative Stress; Proline; Proline Oxidase; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase; Synaptic Membranes; Thiobarbituric Acid Reactive Substances; Vitamin E

Chrysin, a natural flavonoid has been reported to possess potent anti-inflammatory, anti-cancer and antioxidation properties. In the present study, we aimed to evaluate the putative protective effect of chrysin, an isoflavone, on carbon tetrachloride (CCl(4))-induced toxicity in male Wistar rats. Intraperitoneal administration of CCl(4) (2 ml/kg) to rats for 4 days resulted in significantly elevated (p < 0.05) serum levels of glutamic oxaloacetic transaminase (SGOT), glutamic pyruvate transaminase (SGPT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), when compared to normal rats. In addition, the tissues (liver, kidney and brain) and haemolysate samples showed considerable increase in levels (p < 0.05) of malondialdehyde (MDA) and lowered levels (p < 0.05) of reduced glutathione (GSH), vitamin C and E when compared to values in normal rats. Quantitative analysis of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (Gpx) exhibited lower activities of these antioxidant enzymes in the tissues and haemolysate of CCl(4)-administered rats. The protective action of chrysin on CCl(4)-induced rat was demonstrated with SGPT, SGOT, ALP and LDH resuming to near normal levels, while the mean levels of GSH and of vitamin C and E were elevated, the mean activities of CAT, SOD and Gpx were enhanced and the mean level of MDA was lowered in the tissue and haemolysate samples when compared to the CCl(4)-exposed untreated rats. The expression of the iNOS gene appeared to be up-regulated in the liver and kidney samples of CCl(4)-exposed untreated rats, whereas in CCl(4)-exposed chrysin-treated rats, the mRNA transcript levels of iNOS approximated normal levels. These results strongly suggest that chrysin is able to prevent the oxidative damage induced by CCl(4) in the liver, brain, kidney and haemolysate of male Wistar rats.

Topics: Animals; Antioxidants; Ascorbic Acid; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Flavonoids; Kidney; Liver; Liver Function Tests; Male; Malondialdehyde; Nitric Oxide Synthase Type II; Oxidoreductases; Rats; Rats, Wistar; RNA, Messenger; Up-Regulation; Vitamin E

Striatal cholinergic interneurons show tonic spiking activity in the intact and sliced brain, which stems from intrinsic mechanisms. Because of it, they are also known as "tonically active neurons" (TANs). Another hallmark of TAN electrophysiology is a pause response to appetitive and aversive events and to environmental cues that have predicted these events during learning. Notably, the pause response is lost after the degeneration of dopaminergic neurons in animal models of Parkinson's disease. Moreover, Parkinson's disease patients are in a hypercholinergic state and find some clinical benefit in anticholinergic drugs. Current theories propose that excitatory thalamic inputs conveying information about salient sensory stimuli trigger an intrinsic hyperpolarizing response in the striatal cholinergic interneurons. Moreover, it has been postulated that the loss of the pause response in Parkinson's disease is related to a diminution of I(sAHP), a slow outward current that mediates an afterhyperpolarization following a train of action potentials. Here we report that I(sAHP) induces a marked spike-frequency adaptation in adult rat striatal cholinergic interneurons, inducing an abrupt end of firing during sustained excitation. Chronic loss of dopaminergic neurons markedly reduces I(sAHP) and spike-frequency adaptation in cholinergic interneurons, allowing them to fire continuously and at higher rates during sustained excitation. These findings provide a plausible explanation for the hypercholinergic state in Parkinson's disease. Moreover, a reduction of I(sAHP) may alter synchronization of cholinergic interneurons with afferent inputs, thus contributing to the loss of the pause response in Parkinson's disease.

Topics: Acetylcholine; Action Potentials; Analysis of Variance; Animals; Anthracenes; Apamin; Ascorbic Acid; Barium; Computer Simulation; Corpus Striatum; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; In Vitro Techniques; Indoles; Interneurons; Male; Models, Neurological; Neuroprotective Agents; Oxidopamine; Parkinsonian Disorders; Pyridines; Rats; Rats, Sprague-Dawley; Substantia Nigra

Inhaled nitric oxide (NO) has the capacity to selectively dilate pulmonary blood vessels, and thus enhance the matching of ventilation and perfusion, improve oxygenation and decrease pulmonary hypertension. However, existing approaches for the administration of inhaled NO are associated with the co-delivery of potentially toxic concentrations of nitrogen dioxide (NO2) due to the oxidation of NO in oxygen rich environments. We tested the ability of a novel methodology for generating highly purified NO through the reduction of NO2 by ascorbic acid to reverse pulmonary hypertension. In vitro testing demonstrated that the NO output of the novel device is ultrapure and free of NO2. An in vivo hypoxemic swine model of pulmonary hypertension was used to examine the dose response to NO in terms of pulmonary pressures and pulmonary vascular resistance. Pulmonary hypertension was induced by lowering inspired oxygen to 15% prior to treatment with inhaled ultra purified NO (1, 5, 20, and 80PPM). Hypoxemia increased mean pulmonary artery pressures and pulmonary vascular resistance. Inhaled ultra purified NO doses (down to 1PPM) show a marked reduction of hypoxemia-induced pulmonary vascular resistance. These experiments demonstrate a simple and robust method to generate purified inhaled NO that is devoid of NO2 and capable of reversing hypoxemia induced pulmonary hypertension.

Topics: Administration, Inhalation; Animals; Ascorbic Acid; Disease Models, Animal; Hypertension, Pulmonary; Hypoxia; Nitric Oxide; Nitrogen; Nitrogen Dioxide; Oxygen; Pulmonary Artery; Swine; Vascular Resistance

Acute kidney injury (AKI) occurs frequently in the intensive care unit. A primary cause is renal ischemia/reperfusion (I/R) injury, during which excess reactive oxygen species (ROS) are produced. ROS subsequently damage renal cells, leading to the development of AKI. Here, we investigated whether renal I/R injury could be attenuated by the antioxidant EPC-K1.. We divided male Wistar rats into the following three groups: (1) a renal I/R group, (2) an EPC-K1 + renal I/R group and (3) a control group. Rats were sacrificed 24 h after treatment (I/R or sham). To measure oxidative stress in renal tissue, histological examinations were performed and serum levels of blood urea nitrogen (BUN) and creatinine were measured. The antioxidant action of EPC-K1 was also evaluated in RAW264.7 cells stimulated with antimycin A.. Serum BUN and creatinine levels were elevated in the I/R group; however, this increase was significantly attenuated by EPC-K1 in the EPC-K1 + I/R group. Renal tissue injury was also significantly lower in the EPC-K1 + I/R group compared with the I/R group. In vitro experiments showed that EPC-K1 significantly attenuated the generation of ROS induced by antimycin A.. In our study, EPC-K1 was able to attenuate AKI due to renal I/R by reducing oxidative stress. These results suggest that EPC-K1 may be effective against various types of I/R injury.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Cell Line; Disease Models, Animal; Kidney; Kidney Diseases; Kidney Function Tests; Male; Malondialdehyde; Mice; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Vitamin E

Oxidative stress is related to the pathogenesis of Alzheimer's disease (AD) characterized by progressive memory impairment. Soluble amyloid-β (Aβ) oligomers cause cognitive loss and synaptic dysfunction rather than senile plaques in AD. The decline of the antioxidant status is associated with dementia in AD patients, especially low levels of vitamin C. Our group previously reported a relationship between anti-aging and supplementation of vitamin C derivatives. Here we report that vitamin C mitigated Aβ oligomer formation and behavioral decline in an AD mouse model treated with a vitamin C solution for 6 months. The attenuation of Aβ oligomerization was accompanied with a marked decrease in brain oxidative damage and in the ratio of soluble Aβ₄₂ to Aβ₄₀, a typical indicator of AD progression. Furthermore, the intake of vitamin C restored the declined synaptophysin and the phosphorylation of tau at Ser396. On the other hand, brain plaque deposition was not altered by the dietary intake of vitamin C. These results support that vitamin C is a useful functional nutrient for the prevention of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Glial Fibrillary Acidic Protein; Glutathione; Maze Learning; Mental Disorders; Mice; Mice, Transgenic; Oxidative Stress; Peptide Fragments; Plaque, Amyloid; Protein Carbonylation; Synaptophysin; Time Factors

Phytotherapy has played an important role in the management of diabetes and related complications. In the present study different fractions of Catharanthus roseus L. (Apocynaceae), Ocimum sanctum L. (Labiatae), Tinospora cordifolia Willd. (Menispermaceae), Aegle marmelos L. (Rutaceae), Ficus golmerata L. (Moraceae), Psoralea corlifolia L. (Fabaceae), Tribulus terrestris L. (Zygophyllaceae), and Morinda cetrifolia L. (Rubiaceae) were evaluated as possible inhibitors of aldose reductase (AR: a key enzyme implicated in cataractogenesis) and antioxidant agents. Anti-cataract activity of the selected plants was demonstrated using 'sugar induced lens opacity model' and the cytotoxicity studies were carried out using MTT assay. Among the tested plants, water extract of M. cetrifolia (IC50 0.132 mg/ml) exhibited maximum AR inhibitory activity as compared to other phytofractions which showed the activity in an IC50 range of 0.176-0.0.82 mg/ml. All the plant fractions showed considerable antioxidant potential. Sugar induced lens opacity studies revealed that, M. cetrifolia possess significant anti-cataract potential to maintain lens opacity as compared to glucose induced lens opacity in bovine lens model. The extract of the selected plants showed moderate cytotoxicity against HeLa cell line. Results of the present studies may find useful in converting botanicals into therapeutic modalities.

Topics: Aegle; Aldehyde Reductase; Animals; Ascorbic Acid; Cataract; Catharanthus; Cattle; Diabetes Complications; Disease Models, Animal; Enzyme Inhibitors; Ficus; Flavonoids; Free Radical Scavengers; HeLa Cells; Humans; Hypoglycemic Agents; Male; Menispermaceae; Morinda; Ocimum; Phenols; Phytotherapy; Plant Extracts; Plants, Medicinal; Psoralea; Rats; Tinospora; Tribulus

Spice bioactive compounds, capsaicin and curcumin, were both individually and in combination examined for antilithogenic potential during experimental induction of cholesterol gallstones in mice. Cholesterol gallstones were induced by feeding mice a high-cholesterol (0.5%) diet for 10 weeks. Groups of mice were maintained on a lithogenic diet that was supplemented with 0.015% capsaicin/0.2% curcumin/0.015% capsaicin + 0.2% curcumin. The lithogenic diet that contained capsaicin, curcumin, or their combination reduced the incidence of cholesterol gallstones by 50%, 66%, and 56%, respectively, compared with lithogenic control. This was accompanied by reduced biliary cholesterol and a marginal increase in phospholipid in these spice-fed groups. Increased cholesterol saturation index and cholesterol : phospholipid ratio in the bile caused by the lithogenic diet was countered by the dietary spice compounds. The antilithogenic influence of spice compounds was attributable to the cholesterol-lowering effect of these dietary spices in blood and liver, as well as a moderate increase in phospholipids. Decreased activities of hepatic glutathione reductase and glutathione-S-transferase caused by the lithogenic diet were countered by the combination of capsaicin and curcumin. The increased lipid peroxidation and the decreased concentration of ascorbic acid in the liver that was caused by the lithogenic diet was countered by the dietary spice compounds, individually or in combination. Thus, while the capsaicin and curcumin combination did not have an additive influence in reducing the incidence of cholesterol gallstones in mice, their combination nevertheless was more beneficial in enhancing the activity of hepatic antioxidant enzyme ─ glutathione reductase in the lithogenic situation. The antioxidant effects of dietary spice compounds are consistent with the observed reduction in cholesterol gallstones formed under lithogenic condition.

Topics: Animals; Antioxidants; Ascorbic Acid; Capsaicin; Cholesterol; Curcumin; Diet; Disease Models, Animal; Gallstones; Glutathione Reductase; Glutathione Transferase; Lipid Peroxidation; Liver; Male; Mice

Cuminum cyminum Linn. (Apiaceae), cumin, is a popular spice with a long history of medicinal use to treat various symptoms such as diarrhea, flatulence, gynecological, and respiratory diseases.. To date, no scientific investigation was reported regarding memory-enhancing and antistress activity of cumin fruits. The present study deals with the memory-enhancing and antistress activities and further the antioxidant status via lipid peroxidation inhibition.. Antistress activity was evaluated by inducing stress via forced swimming and the urinary vanillylmandelic acid (VMA) and ascorbic acid were estimated as biomarkers. Memory-enhancing activity was studied by conditioned avoidance response using Cook's pole climbing apparatus in normal and scopolamine-induced amnestic rats. Thiobarbituric acid reactive substances (TBARS) assay was used to evaluate the lipid peroxidation.. Daily administration of cumin at doses of 100, 200, and 300 mg/kg body weight 1 h prior to induction of stress inhibited the stress-induced urinary biochemical changes in a dose-dependent manner without altering the levels in normal control groups. The cognition, as determined by the acquisition, retention, and recovery in rats, was observed to be dose-dependent. The extract also produced significant lipid peroxidation inhibition in comparison with known antioxidant ascorbic acid in both rat liver and brain.. This study provides scientific support for the antistress, antioxidant, and memory-enhancing activities of cumin extract and substantiates that its traditional use as a culinary spice in foods is beneficial and scientific in combating stress and related disorders.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain; Cuminum; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Lipid Peroxidation; Liver; Male; Medicine, Traditional; Memory Disorders; Plant Extracts; Rats; Rats, Wistar; Scopolamine; Stress, Psychological

We compared ascorbic acid (AA) levels in the blood and TPA- and fMLP-stimulated superoxide (O(2)(•-)) production in neutrophils of pre-, early, and late hypertensive stroke-prone spontaneously hypertensive rats (SHRSP) with those of age-matched Wistar Kyoto rats (WKY), or two other normotensive strains of rats. Plasma and lymphocyte AA levels were about two-fold higher in SHRSP as early as 4 weeks old compared to WKY, and also higher than those of Wistar and Sprague-Dawley (SD) rats. Levels of AA were high in the liver and adrenal glands of SHRSP, indicating congenitally high AA levels. The production of O(2)(•-) in neutrophils was about two-fold higher in SHRSP than in WKY even at 4 weeks of age, and increased with age in both strains. Among SHRSP, AA levels in lymphocytes decreased at the late hypertensive stages with a decrease in hepatic l-gulono-γ-lactone oxidase (GLO) activities. These data suggest that bi-phasic AA levels in the blood of SHRSP comprise congenitally high levels and a decrease after persistent hypertension due to enhanced O(2)(•-) production and a decrease in de novo AA synthesis through GLO.

Topics: Adrenal Glands; Aging; Animals; Ascorbic Acid; Disease Models, Animal; Glucose; Hypertension; L-Gulonolactone Oxidase; Liver; Male; Neutrophils; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Risk Factors; Stroke; Superoxides

Tumor necrosis factor-α-converting enzyme (TACE; also known as ADAM17) is a proteolytic sheddase that is responsible for the cleavage of several membrane-bound molecules. We report that TACE cleaves neuregulin-1 (NRG1) type III in the epidermal growth factor domain, probably inactivating it (as assessed by deficient activation of the phosphatidylinositol-3-OH kinase pathway), and thereby negatively regulating peripheral nervous system (PNS) myelination. Lentivirus-mediated knockdown of TACE in vitro in dorsal root ganglia neurons accelerates the onset of myelination and results in hypermyelination. In agreement, motor neurons of conditional knockout mice lacking TACE specifically in these cells are significantly hypermyelinated, and small-caliber fibers are aberrantly myelinated. Further, reduced TACE activity rescues hypomyelination in NRG1 type III haploinsufficient mice in vivo. We also show that the inhibitory effect of TACE is neuron-autonomous, as Schwann cells lacking TACE elaborate myelin of normal thickness. Thus, TACE is a modulator of NRG1 type III activity and is a negative regulator of myelination in the PNS.

Topics: ADAM Proteins; ADAM17 Protein; Age Factors; Amyloid Precursor Protein Secretases; Animals; Animals, Newborn; Antioxidants; Ascorbic Acid; Aspartic Acid Endopeptidases; Axons; Cells, Cultured; Coculture Techniques; Disease Models, Animal; Embryo, Mammalian; Femoral Nerve; Ganglia, Spinal; Gene Expression Regulation, Developmental; Homeodomain Proteins; Humans; Mice; Mice, Knockout; Microscopy, Electron, Transmission; Motor Neurons; Myelin Basic Protein; Myelin Sheath; Neuregulin-1; Neurofilament Proteins; Polyradiculoneuropathy; Rats; RNA, Small Interfering; Schwann Cells; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Transcription Factors; Transfection

Ascorbic acid, a potential antioxidant, is known to inhibit melanogenesis. However, there are conflicting findings that ascorbic acid has very low stability and acts as a pro-oxidant, eventually increasing proliferation and melanin content in melanoma cells. In the present study, we explored the effects of ascorbic acid on the activity and expression of tyrosinase and melanin pigmentation in the presence and absence of α-melanocyte-stimulating hormone (α-MSH) using B16F10 melanoma cells. The mechanism by which ascorbic acid stimulated the expression of tyrosinase was also investigated. No inhibitory effect on melanin content was observed in ascorbic acid-treated cells, regardless of the presence of α-MSH. Ascorbic acid stimulated the activity and expression of tyrosinase and increased the expression of melanogenic regulatory factors, such as tyrosinase-related protein-1 (TRP-1), dihydroxyphenylalaminechrome tautomerase (TRP-2), and microphthalmia-associated transcription factor (MITF). Ascorbic acid also induced phosphorylation of p38 mitogen-activated protein kinase (MAPK). The inhibition of p38 MAPK pathway by SB203580 led to the suppression of tyrosinase, TRP-1, and TRP-2 expression in cells treated with ascorbic acid. Combined treatment with N-acetyl-L: -cysteine and/or desferrioxamine mesylate attenuated the stimulating effect of ascorbic acid on tyrosinase activation in the cells. Collectively, ascorbic acid stimulates tyrosinase activity and expression in B16F10 cells via activation of p38 MAPK signaling and subsequent up-regulation of MITF, tyrosinase, and TRP expression.

Topics: alpha-MSH; Animals; Anti-Inflammatory Agents, Non-Steroidal; Ascorbic Acid; Deferoxamine; Disease Models, Animal; Enzyme Activation; Humans; Imidazoles; Intramolecular Oxidoreductases; MAP Kinase Signaling System; Melanins; Melanoma; Melanoma, Experimental; Mice; Microphthalmia-Associated Transcription Factor; Monophenol Monooxygenase; Oxidoreductases; Pyridines

The insulinomimetic activity of a Zn(ii) complex is reported. The effects of the Zn(ii) complex with ascorbic acid (Vitamin C; VC), methylmethionine sulfonium chloride (Vitamin U; VU) and l-carnitine were assessed in diet-induced metabolic syndrome model rats. Zn(VU)(2)Cl(2) and Zn(VC)Cl(2) were suggested to be useful supplementary materials for preventing metabolic syndrome by reducing visceral adipose tissues or accelerating blood fluidity.

Topics: Adipocytes; Adipose Tissue; Animals; Ascorbic Acid; Body Weight; Carnitine; Cell Separation; Diet; Disease Models, Animal; Fatty Acids; Feeding Behavior; Glucose; Inhibitory Concentration 50; Insulin; Metabolic Syndrome; Rats; Vitamin U; Zinc

The present study was designed to observe the effect of PTZ on expression of caspsae-3, and to evaluate the neuroprotective role of vitamin C (vit-C) against PTZ-induced apoptotic neurodegeneration in adult rat brain. We observed that administration of a single conclusive dose of pentylenetetrazol (PTZ 50mg/kg) in adults rats induced epileptic seizure and increased activation of caspase-3 and caused neuronal death. Further, rats were injected with vit-C (250 mg/kg) 30 min before PTZ injection. The protective effect of vit-C against PTZ-induced apoptotic neurodegeneration in adult rat brain was observed using Western blot analysis and Nissl staining. The results showed that conclusive dose of PTZ-induced seizure, increased expression of caspase-3 and neuronal apoptosis in adult rat brain. Whereas, the pretreatment of vit-C along with PTZ showed significantly decreased expression of caspase-3 as compare to control group. Finally, our results indicated that vit-C can prevent some of the deleterious effect of seizure and neuronal degeneration induced by PTZ in adult rat brain.

Topics: Animals; Apoptosis; Ascorbic Acid; Brain; Caspase 3; Disease Models, Animal; Epilepsy; Male; Nerve Degeneration; Neuroprotective Agents; Pentylenetetrazole; Rats; Rats, Sprague-Dawley

Lactate has been identified as an alternative fuel for the brain in situations of increased energy demand, as following a traumatic brain injury (TBI). This study investigates the effect of treatment with sodium lactate (NaLac) on the changes in brain energy state induced by a severe diffuse TBI. Rats were assigned to one of the eight groups (n=10 per group): 1-sham, normal saline; 2-TBI, normal saline; 3-TBI, hypertonic saline; 4-TBI, 100mM NaLac, 5-TBI, 500 mM NaLac; 6-TBI, 1280 mM NaLac; 7-TBI, 2000 mM NaLac and 8-TBI-500 mM NaLac+magnesium sulfate. Cerebrums were removed 6h after trauma. Metabolites representative of the energy state (ATP, ATP-catabolites), N-acetylaspartate (NAA), antioxidant defenses (ascorbic acid, glutathione), markers of oxidative stress (malondialdehyde, ADP-ribose) and nicotinic coenzymes (NAD(+)) were measured by HPLC. TBI induced a marked decrease in the cerebral levels of ATP, NAA, ascorbic acid, glutathione and NAD(+) and a significant rise in the content of ATP-catabolites, malondialdehyde and ADP-ribose. These alterations were not ameliorated with NaLac infusion. We observed a significant reduction in cerebral NAD(+), an essential co-enzyme for mitochondrial lactate-dehydrogenase that converts lactate into pyruvate and thus replenishes the tricarboxylic acid cycle. These results suggest that the metabolic pathway necessary to consume lactate may be compromised following a severe diffuse TBI in rats.

Topics: Adenosine Triphosphate; Animals; Ascorbic Acid; Aspartic Acid; Blood Gas Analysis; Blood Pressure; Brain Chemistry; Brain Injuries; Cerebral Cortex; Chromatography, High Pressure Liquid; Disease Models, Animal; Energy Metabolism; Glutathione; Male; Models, Biological; NAD; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Sodium Lactate

Oxidative stress may cause a loss of tetrahydrobiopterin (BH4), a co-factor of nitric oxide synthase (NOS), decrease the bioavailability of NO and aggravate ischemia/reperfusion (I/R) injury in diabetic heart. We hypothesized that ascorbic acid (AA) and N-acetyl cysteine (NAC) protect the diabetic heart from I/R injury by increasing BH4/dihydrobiopterin (BH2) ratio and inhibiting uncoupling of NOS. Diabetes mellitus was induced in rats by streptozotocin treatment, and the hearts were isolated and perfused. BH4 and BH4/BH2 ratio decreased in the diabetic heart associated with increased production of superoxide and nitrotyrosine (NT). Treatment with AA or NAC significantly increased BH4/BH2 ratio in the diabetic heart associated with decreased production of superoxide and NT and increased generation of nitrate plus nitrite (NOx). Pre-treatment with AA or NAC before 30 min ischemia followed by 120 min reperfusion improved left ventricular (LV) function and reduced infarct size in the diabetic but not non-diabetic hearts. The NOS inhibitor, L-NAME, inhibited the increase in the generation of superoxide, NT and NOx, but aggravated LV function and increased infarct size in the diabetic heart. L-NAME also abrogated the increase in NOx and improvement of LV function and the infarct size-limiting effect induced by AA or NAC in the diabetic heart. These results suggest that AA and NAC increase BH4/BH2 ratio and prevent NOS uncoupling in the diabetic heart. Resultant increase in the bioavailability of NO renders the diabetic heart toleratant to I/R injury.

Topics: Acetylcysteine; Animals; Ascorbic Acid; Biopterins; Diabetes Mellitus, Experimental; Disease Models, Animal; Male; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide Synthase; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the nigrostriatal system and dopamine (DA) depletion in the striatum. The most popular therapeutic medicine for treating PD, 3-(3,4-Dihydroxyphenyl)-L-alanine (L-DOPA), has adverse effects, such as dyskinesia and disease acceleration. As superoxide (·O(2)(-)) and hydroxyl radical (·OH) have been implicated in the pathogenesis of PD, free radical scavenging and antioxidants have attracted attention as agents to prevent disease progression. Rodents injected with 6-hydroxydopamine (6-OHDA) intracerebroventricularly are considered to be a good animal model of PD. Zingerone and eugenol, essential oils extracted from ginger and cloves, are known to have free radical scavenging and antioxidant effects. Therefore, we examined the effects of zingerone and eugenol on the behavioral problems in mouse model and on the DA concentration and antioxidant activities in the striatum after 6-OHDA administration and L-DOPA treatment. Daily oral administration of eugenol/zingerone and injection of L-DOPA intraperitoneally for 4 weeks following a single 6-OHDA injection did not improve abnormal behaviors induced by L-DOPA treatment. 6-OHDA reduced the DA level in the striatum; surprisingly, zingerone and eugenol enhanced the reduction of striatal DA and its metabolites. Zingerone decreased catalase activity, and increased glutathione peroxidase activity and the oxidized L-ascorbate level in the striatum. We previously reported that pre-treatment with zingerone or eugenol prevents 6-OHDA-induced DA depression by preventing lipid peroxidation. However, the present study shows that post-treatment with these substances enhanced the DA decrease. These substances had adverse effects dependent on the time of administration relative to model PD onset. These results suggest that we should be wary of ingesting these spice elements after the onset of PD symptoms.

Topics: Animals; Antioxidants; Ascorbic Acid; Catalase; Corpus Striatum; Disease Models, Animal; Dopamine; Eugenol; Free Radical Scavengers; Glutathione; Glutathione Peroxidase; Guaiacol; Levodopa; Male; Mice; Oxidopamine; Parkinson Disease; Parkinson Disease, Secondary; Superoxide Dismutase

Cerebral vasospasm (CVS) is a common serious complication after the spontaneous subarachnoid hemorrhage (SAH). Despite recent advances in medical and surgical treatments, the 30-day mortality rate of SAH remains high, and there is lack of especially effective clinical treatment to alleviate and improve CVS. The present study has investigated the therapeutic effect of insulin and vitamin C on CVS after SAH.. Five days after SAH, there is obvious basilar artery spasm in SAH group, whose average vascular cross-sectional area (233,099 ± 16,750 μm²) is significantly smaller than that in control group (462,128 ± 74,756 μm²), which is also significantly different from those in SAH + insulin group (221,114 ± 43,457 μm²) and SAH + vitamin C group (237,820 ± 21,703 μm²). SAH + insulin + vitamin C group shows no evident vasospasm and maintains a vascular cross-sectional area of 425,530 ± 45,503 μm², which is significantly different from that in SAH group. Insulin receptor α (InRα) expression is significantly downregulated in the vascular endothelial cells of SAH, SAH + insulin, and SAH + vitamin C groups (P < 0.01) but remains unchanged in vascular endothelial cells of SAH + insulin + vitamin C group (P > 0.05). Five days after SAH, serum and cerebrospinal fluid NO levels in SAH, SAH + insulin, and SAH + vitamin C groups decrease significantly (P < 0.01) compared to that in control group, whereas the reduction is not evident in SAH + insulin + vitamin C group (P > 0.05).. Combinatorial treatment with insulin and vitamin C has effectively relieved the CVS after SAH in rabbit, possibly through increasing the InRα expression and NO level, whereas treatment with insulin or vitamin C alone fails to do so.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Drug Therapy, Combination; Hypoglycemic Agents; Insulin; Rabbits; Subarachnoid Hemorrhage; Vasospasm, Intracranial; Vitamins

Clinical and preclinical data reported that ascorbic acid has antidepressant properties. The present study was designed to investigate the participation of l-arginine-NO-cGMP pathway in the antidepressant-like effect of ascorbic acid in the tail suspension test (TST) in mice. The antidepressant-like effect of ascorbic acid (1mg/kg, p.o.) in the TST was prevented by the pre-treatment of mice with NMDA (0.1pmol/site, i.c.v.), l-arginine (750mg/kg, i.p., a substrate for nitric oxide synthase) or sildenafil (5mg/kg, i.p., a phosphodiesterase 5 inhibitor). The administration of MK-801 (0.001mg/kg, i.p), 7-nitroindazole (25mg/kg, i.p., a neuronal nitric oxide synthase inhibitor) or ODQ (30pmol/site i.c.v., a soluble guanylate cyclase inhibitor) in combination with a sub-effective dose of ascorbic acid (0.1mg/kg, p.o.) reduced the immobility time in the TST test when compared with either drug alone. None of the results in the TST appears to be due to a nonspecific locomotor effect. Our findings provide evidence that the effect of ascorbic acid in the TST involve an interaction with NMDA receptors and l-arginine-NO-cGMP pathway, contributing to the understanding of the mechanisms underlying the antidepressant-like effect of this vitamin.

Topics: Animals; Antidepressive Agents; Arginine; Ascorbic Acid; Cyclic GMP; Depression; Disease Models, Animal; Dizocilpine Maleate; Enzyme Inhibitors; Exploratory Behavior; Female; Hindlimb Suspension; Indazoles; Mice; N-Methylaspartate; Nitric Oxide; Oxadiazoles; Piperazines; Purines; Quinoxalines; Signal Transduction; Sildenafil Citrate; Sulfones

Lyophilized plasma (LP) has been shown to be as effective as fresh frozen plasma (FFP) for resuscitation in polytrauma and hemorrhagic shock. LP reconstituted with ascorbic acid is associated with suppression of cytokines when compared with fresh frozen plasma. We aimed to determine the effect of using alternate LP reconstitution acids on physiologic parameters, blood loss, coagulation, oxidative DNA damage, and proinflammatory cytokines in a polytrauma and hemorrhagic shock model.. Thirty swine were anesthetized, subjected to polytrauma, hemorrhagic shock, and randomized to resuscitation with LP-ascorbic acid (AA), LP-citric acid (CA), or LP-hydrochloric acid (HCL). Physiologic data were continuously monitored, blood loss measured, and serum collected at baseline, 2 hours, and 4 hours for enzyme-linked immunosorbent assays. Measured 8-OH-2'-deoxyguanosine (8-OHdG) was a biomarker of oxidative DNA damage.. No differences were observed in physiologic measures, blood loss, or coagulation parameters. Interleukin-6 increased over time for all groups, but at 2 hours, the concentration in AA (median [minimum, maximum]: 113 ng/mL [0, 244]) was lower compared with CA (181 ng/mL [69, 314], p = 0.01) and HCL (192 ng/mL [41, 310], p = 0.03). Comparing 4 hours to baseline, a significant increase in oxidative DNA damage was observed in CA (22.9 ng/mL [16.3, 34.3] vs. 15.6 ng/mL [13.6, 26.7], p = 0.03) and HCL (19.6 ng/mL [15.7, 56.7] vs. 15.8 ng/mL [11.6, 21.4], p = 0.01) but not in AA (17.9 ng/mL [12.6, 26.9] vs. 17.1 ng/mL [11.8, 18.4], p = 0.24).. Resuscitation with AA results in decreased interleukin-6 expression and oxidative DNA damage compared with CA and HCL.

Topics: Animals; Antioxidants; Ascorbic Acid; Cytokines; Disease Models, Animal; DNA Damage; Enzyme-Linked Immunosorbent Assay; Inflammation; Multiple Trauma; Oxidative Stress; Plasma; Resuscitation; Shock, Hemorrhagic; Swine; Treatment Outcome

Delivery of a high ratio of plasma to packed red blood cells to patients who require massive transfusion is associated with improved survival. Hemorrhagic shock causes increased production of pro-inflammatory cytokines. These are associated with late morbidity and mortality. The use of fresh frozen plasma makes high ratio resuscitation logistically difficult and does not address dysfunctional inflammation. Lyophilized plasma (LP) is a stable powdered form of plasma that is both safe and easily reconstituted. Previous work demonstrated that LP reconstituted with ascorbic acid (AA) decreased inflammation. Whether the reduction of inflammation was associated with LP or the AA is unknown.. Thirty female swine were anesthetized and subjected to a multisystem combat relevant model consisting of femur fracture, controlled hemorrhage, and hypothermia. A standardized grade V liver injury was made and the animals were randomly assigned to receive LP reconstituted with AA, citric acid (CA), or hydrochloric acid (HCl). Blood was drawn at baseline and at 2 hours and 4 hours for interleukin (IL)-6, IL-8, and tumor necrosis factor-α serum concentrations measured by enzyme-linked immunosorbent assay. Lung tissue was harvested and processed for gene expression before euthanizing the animals.. No differences were observed in mortality, baseline cytokine serum concentration, or gene expression. Enzyme-linked immunosorbent assay demonstrated that IL-6 concentration increased over time for all groups (p < 0.05), but less so at 2 hours in the AA group compared with CA and HCl.. In this animal model of trauma, hemorrhage and resuscitation, AA decreases IL-6 expression relative to CA and HCl. These findings confirm previous work from our laboratory and suggest that AA is responsible for suppression of dysfunctional inflammation in this model.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Female; Freeze Drying; Inflammation; Interleukin-6; Plasma; Polymerase Chain Reaction; Shock, Hemorrhagic; Swine; Tumor Necrosis Factor-alpha

We investigated the effect of Vitamin C (Vit C) on the changes of activity of the enzymes of NO-synthase system, nitric oxide content, lipoperoxidation processes, activity of SOD and catalase in gastric mucosa (GM), and concentrations of L-arginine, Vit C and Vit E in the blood of rats under conditions of experimental ulcer of the stomach caused by adrenaline injection. Vit C displayed a pronounced antioxidant action, reduced the degree of destructive affections, diminished the activity of iNOS and lipoperoxidation processes, decreased the NO content and SOD activity. Furthermore, the concentration of L-arginine and Vit C in the blood was increased. Combined action of Vit C with L-arginine reduced the degree of GM lesions, activity of eNOS and the content of NO in GM whereas the concentration of L-arginine in blood was increased. Under conditions of Vit C action and iNOS and COX-2 blockage, the activity of NO-synthases and lipoperoxidation processes were slightly decreased, indicating on dominant action of Vit C.

Topics: Animals; Antioxidants; Arginine; Ascorbic Acid; Disease Models, Animal; Gastric Mucosa; Lipid Peroxidation; Nitric Oxide; Nitric Oxide Synthase Type II; Rats; Stomach Ulcer; Superoxide Dismutase

Osteogenic disorder shionogi (ODS) rats carry a hereditary defect in ascorbic acid synthesis, mimicking human scurvy when fed with an ascorbic acid-deficient (aa-def) diet. As aa-def ODS rats were shown to feature disordered bone formation, we have examined the bone mineralization in this rat model. A fibrous tissue layer surrounding the trabeculae of tibial metaphyses was found in aa-def ODS rats, and this layer showed intense alkaline phosphatase activity and proliferating cell nuclear antigen-immunopositivity. Many osteoblasts detached from the bone surfaces and were characterized by round-shaped rough endoplasmic reticulum (rER), suggesting accumulation of malformed collagen inside the rER. Accordingly, fine, fragile fibrillar collagenous structures without evident striation were found in aa-def bones, which may result from misassembling of the triple helices of collagenous α-chains. Despite a marked reduction in bone formation, ascorbic acid deprivation seemed to have no effect on mineralization: while reduced in number, normal matrix vesicles and mineralized nodules could be seen in aa-def bones. Fine needle-like mineral crystals extended from these mineralized nodules, and were apparently bound to collagenous fibrillar structures. In summary, collagen mineralization seems unaffected by ascorbic acid deficiency in spite of the fine, fragile collagenous fibrils identified in the bones of our animal model.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Bone Diseases; Calcification, Physiologic; Collagen; Disease Models, Animal; Humans; Male; Osteoblasts; Rats; Rats, Mutant Strains; Tibia

The incidence of esophageal adenocarcinoma in humans is increasing more rapidly than any other malignancy in the United States. Animal studies have demonstrated the efficacy of freeze-dried berry supplementation on carcinogen-induced esophageal squamous cell carcinoma in rats; however, no such studies have been done in esophagoduodenal anastomosis (EDA), an animal model for reflux-induced esophageal adenocarcinoma (EAC) development. Eight-week-old male Sprague-Dawley rats were randomized into 3 groups: EDA + control diet (EDA-CD; n = 10); EDA + 2.5% black raspberry diet (EDA-BRB; n = 11) and EDA + 2.5% blueberry diet (EDA-BB; n = 12). After 2 wk of feeding the respective diets, the rats underwent EDA surgery to induce gastroesophageal reflux and then continued the diet. Measurement of feed intake suggested that all EDA-operated animals had lower feed intake starting at 10 wk after surgery and this was significant close to termination at 24 wk. There were no significant differences in either reflux esophagitis (RE), intestinal metaplasia (IM) (70% in CD, 64% in BRB, and 66% in BB; P = 0.1) or EAC incidence (30% for CD, 34% for BRB, and 25% for BB; P = 0.2) with supplementation. Berry diets did not alter COX-2 levels, but BB diet significantly reduced MnSOD levels (1.23 ± 0.2) compared to control diet (2.05 ± 0.14; P < 0.05). We conclude that a dietary supplementation of freeze-dried BRB and BB at 2.5% (w/w) was not effective in the prevention of reflux-induced esophageal adenocarcinoma in this EDA animal model.

Topics: Adenocarcinoma; Anastomosis, Surgical; Animals; Anthocyanins; Ascorbic Acid; Biomarkers; Blueberry Plants; Cyclooxygenase 2; Dietary Supplements; Disease Models, Animal; Disease Progression; Esophageal Neoplasms; Esophagitis, Peptic; Esophagus; Food Handling; Freeze Drying; Fruit; Linear Models; Male; Plant Preparations; Rats; Rats, Sprague-Dawley; Selenium; Superoxide Dismutase; Weight Gain

Here we report structure-activity relationship study of a novel hybrid series of compounds where structural alteration of aromatic hydrophobic moieties connected to the piperazine ring and bioisosteric replacement of the aromatic tetralin moieties were carried out. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors with tritiated spiperone to evaluate inhibition constants (K(i)). Functional activity of selected compounds in stimulating GTPgammaS binding was assessed with CHO cells expressing human D2 receptors and AtT-20 cells expressing human D3 receptors. SAR results identified compound (-)-24c (D-301) as one of the lead molecules with preferential agonist activity for D3 receptor (EC(50) (GTP gamma S); D3 = 0.52 nM; D2/D3 (EC(50)): 223). Compounds (-)-24b and (-)-24c exhibited potent radical scavenging activity. The two lead compounds, (-)-24b and (-)-24c, exhibited high in vivo activity in two Parkinson's disease (PD) animal models, reserpinized rat model and 6-OHDA induced unilaterally lesioned rat model. Future studies will explore potential use of these compounds in the neuroprotective therapy for PD.

Topics: Animals; Antiparkinson Agents; Benzothiazoles; CHO Cells; Cricetinae; Cricetulus; Disease Models, Animal; Free Radical Scavengers; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Isoquinolines; Locomotion; Mice; Parkinson Disease; Radioligand Assay; Rats; Receptors, Dopamine D2; Receptors, Dopamine D3; Reserpine; Structure-Activity Relationship; Thiazoles

The aim of the present study was to investigate the effect of different doses of vitamin C on oxidative liver injury due to isoniazid (INH) in rats.. Rats were divided into four subgroups, each containing 10 rats. Group 1 was the control group; group 2, INH 50 mg/kg per day; group 3, INH 50 mg/kg per day + low-dose vitamin C (100 mg/kg per day); group 4, INH 50 mg/kg per day + high-dose vitamin C (1000 mg/kg per day). INH and vitamin C were administered into their stomachs through an oral tube. After 21 days, measurements were made in both serum and homogenized liver tissues. The levels of glutathione (GSH), superoxide dismutase (SOD) and other biochemical variables were measured. Malondialdehyde (MDA), glutathione peroxidase (GSH-px) and vitamin C were measured using commercial kits.. Aspartate amino transferase and alanine aminotransferase in group 2 were higher than those in groups 1, 3 and 4 (P < 0.008 for both). Serum and tissue levels of MDA in group 2 were higher than that in groups 1 and 3 (P < 0.008 for both). There was no difference in the SOD levels between the four groups (P= 0.095). Erythrocyte and tissue GSH in group 2 were higher than that in groups 1 and 3 (P < 0.008 for both). Interestingly, erythrocyte and tissue GSH in group 4 were lower than those in group 1 (P < 0.008 for both). Erythrocyte level of GSH-px in group 2 was higher than that in groups 1 and 3 (P < 0.008 for both).. INH-induced liver injury is associated with oxidative stress, and co-administration of low-dose vitamin C may reduce this damage effectively in a rat model. The antioxidant effect of high-dose vitamin C does not seem more potent compared to the low dose.

Topics: Animals; Antioxidants; Antitubercular Agents; Ascorbic Acid; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione; Glutathione Peroxidase; Isoniazid; Liver Function Tests; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Wistar; Superoxide Dismutase

Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many phenotypic features of WS, including a prooxidant status and a shorter mean life span compared to wild-type animals. Here, we show that Wrn mutant mice also develop premature liver sinusoidal endothelial defenestration along with inflammation and metabolic syndrome. Vitamin C supplementation rescued the shorter mean life span of Wrn mutant mice and reversed several age-related abnormalities in adipose tissues and liver endothelial defenestration, genomic integrity, and inflammatory status. At the molecular level, phosphorylation of age-related stress markers like Akt kinase-specific substrates and the transcription factor NF-kappaB, as well as protein kinase Cdelta and Hif-1alpha transcription factor levels, which are increased in the liver of Wrn mutants, were normalized by vitamin C. Vitamin C also increased the transcriptional regulator of lipid metabolism PPARalpha. Finally, microarray and gene set enrichment analyses on liver tissues revealed that vitamin C decreased genes normally up-regulated in human WS fibroblasts and cancers, and it increased genes involved in tissue injury response and adipocyte dedifferentiation in obese mice. Vitamin C did not have such effect on wild-type mice. These results indicate that vitamin C supplementation could be beneficial for patients with WS.

Topics: Adipose Tissue; Aging; Animals; Ascorbic Acid; Base Sequence; Disease Models, Animal; DNA, Mitochondrial; Gene Expression Profiling; Glutathione; Humans; Liver; Longevity; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microscopy, Electron, Scanning; Oxidative Stress; PPAR alpha; RecQ Helicases; Werner Syndrome; Werner Syndrome Helicase

This experiment was designed to assess the protective effect of betacyanins from Portulaca oleracea L. against the D-galactose (D-gal)-induced neurotoxicity in mice. Betacyanins from Portulaca oleracea markedly reversed the D-gal-induced learning and memory impairments, as measured by behavioral tests. The activities of superoxide dismutases (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) in D-gal-treated mice were enhanced, while the content of the lipid peroxidation product malondialdehyde (MDA) was decreased by betacyanin administration. Furthermore, significant negative correlations were found between mouse latency in finding the platform and the activities of SOD, CAT GR and GPx in the mouse brain, but the level of MDA correlated positively with the latency. These results suggest that the neuroprotective effect of betacyanins against D-gal-induced neurotoxicity might be caused, at least in part, by an increase in the activities of antioxidant enzymes with a reduction in lipid peroxidation. In comparison with vitamin C (VC), the betacyanins had a more pronounced effect on ameliorating cognition deficits in mice.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain; Carbocyanines; Cognition Disorders; Disease Models, Animal; Enzymes; Galactose; Lipid Peroxidation; Male; Malondialdehyde; Maze Learning; Memory; Mice; Mice, Inbred Strains; Neurotoxins; Oxidative Stress; Phytotherapy; Plant Extracts; Portulaca

Recent studies demonstrate that rehabilitation ameliorates physical and cognitive impairments of patients with stroke, spinal cord injury, and other neurological diseases and that rehabilitation also has potencies to modulate brain plasticity. Here we examined the effects of compulsive exercise on Parkinson's disease model of rats. Before 6-hydroxydopamine (6-OHDA, 20 microg) lesion into the right striatum of female SD rats, bromodeoxyuridine (BrdU) was injected to label the proliferating cells. Subsequently, at 24 h after the lesion, the rats were forced to run on the treadmill (5 days/week, 30 min/day, 11 m/min). As behavioral evaluations, cylinder test was performed at 1, 2, 3, and 4 weeks and amphetamine-induced rotational test was performed at 2 and 4 weeks with consequent euthanasia for immunohistochemical investigations. The exercise group showed better behavioral recovery in cylinder test and significant decrease in the number of amphetamine-induced rotations, compared to the non-exercise group. Correspondingly, significant preservation of tyrosine hydroxylase (TH)-positive fibers in the striatum and TH-positive neurons in the substantia nigra pars compacta (SNc) was demonstrated, compared to the non-exercise group. Additionally, the number of migrated BrdU- and Doublecortin-positive cells toward the lesioned striatum was increased in the exercise group. Furthermore, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor increased in the striatum by exercise. The results suggest that exercise exerts neuroprotective effects or enhances the neuronal differentiation in Parkinson's disease model of rats with subsequent improvement in deteriorated motor function.

Topics: Amphetamine; Animals; Ascorbic Acid; Behavior, Animal; Brain-Derived Neurotrophic Factor; Bromodeoxyuridine; Cell Proliferation; Corpus Striatum; Disease Models, Animal; Doublecortin Domain Proteins; Doublecortin Protein; Exercise Test; Female; Glial Cell Line-Derived Neurotrophic Factors; Microtubule-Associated Proteins; Movement; Neuropeptides; Oxidopamine; Parkinson Disease, Secondary; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Rotation; Substantia Nigra; Time Factors; Tyrosine 3-Monooxygenase

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Tolerance; Endothelium, Vascular; Heme Oxygenase-1; Humans; Ischemic Preconditioning; Nitrates; Nitroglycerin; Reperfusion Injury; Vasodilator Agents

Ascorbic acid and nitric oxide are known to play important roles in epilepsy. The aim of present study was to identify the involvement of nitric oxide (NO) in the anticonvulsant effects of ascorbic acid on penicillin-induced epileptiform activity in rats. Intracortical injection of penicillin (500, International Units (IU)) into the left sensorimotor cortex induced epileptiform activity within 2-5 min. Thirty minutes after penicillin injection, nitric oxide synthase (NOS) inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME, 100mg/kg), neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI, 40 mg/kg), NO substrate, l-arginine (500 mg/kg) were administered with the most effective dose of ascorbic acid (100 mg/kg) intraperitoneally (i.p.). The administration of l-arginine significantly decreased the frequency of epileptiform activity while administration of l-NAME did not influence the mean frequency of epileptiform activity. Injection of 7-NI decreased the mean frequency of epileptiform activity but did not influence amplitude. Ascorbic acid decreased both the mean frequency and amplitude of penicillin-induced epileptiform activity in rats. The application of l-NAME partially and temporarily reversed the anticonvulsant effects of ascorbic acid. The results support the hypothesis of neuro-protective role for NO and ascorbic acid. The protective effect of ascorbic acid against epileptiform activity was partially and temporarily reversed by nonspecific nitric oxide synthase inhibitor l-NAME, but not selective neuronal nitric oxide synthase inhibitor 7-NI, indicating that ascorbic acid needs endothelial-NOS/NO route to decrease penicillin-induced epileptiform activity.

Topics: Analysis of Variance; Animals; Antioxidants; Arginine; Ascorbic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Electroencephalography; Enzyme Inhibitors; Epilepsy; Free Radical Scavengers; Indazoles; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type III; Penicillins; Rats; Rats, Wistar

Excess hepatic iron generates reactive oxygen species that result in oxidative stress and oxidative damage to the liver. Vitamins have hitherto been considered to be a possible remedy. The aim of this study was to determine if high doses of delta-alpha-tocopherol supplementation in iron overload would ameliorate the oxidative stress. Four groups of 20 male Wistar albino rats were studied: group 1 (control) was fed normal diet, group 2 (Fe) 0.75% Ferrocene iron, group 3 (FV gp) 0.75% Ferrocene/delta-alpha-tocopherol (10x RDA), group 4 (V gp) normal diet/delta-alpha-tocopherol. After 12 months, serum iron, reduced glutathione, catalase, vitamin C, Oxygen Radical Absorbance Capacity, lipid peroxidation, 8-hydroxy-2'-deoxyguanosine (8-OHdG), aspartate transaminase (AST), and alanine transaminase (ALT) were measured. Vitamin C levels were: F gp = 5.04 +/- 0.09; FV gp = 5.85 +/- 0.13 (micromol/l) (p < 0.05). 8-hydroxy-2'-deoxyguanosine levels were: F gp = 143.6 +/- 6.4; FV gp = 179.2 +/- 18.2 (ng/ml) (p < 0.05). Oxidative liver damage, as determined by serum AST and ALT levels, was not attenuated by alpha-tocopherol. A positive correlation existed between vitamin C and 8-OHdG, suggesting possible delta-alpha-tocopherol toxicity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Alanine Transaminase; alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; Aspartate Aminotransferases; Biomarkers; Catalase; Deoxyguanosine; Disease Models, Animal; Ferrous Compounds; Glutathione; Iron; Iron Overload; Lipid Peroxidation; Liver; Male; Metallocenes; Oxidative Stress; Rats; Rats, Wistar; Time Factors; Up-Regulation; Vitamins

The aim of this study was to determine the effects of enrofloxacin (ENR), flunixin meglumine (FM) and dexamethasone (DEX) on antioxidant status and organ damage markers in experimentally-induced endotoxemia. Rats were divided into three groups. To induce endotoxemia, lipopolysaccharide (LPS) was injected into all groups, including the positive control. The two other groups received the following drugs (simultaneously with LPS): ENR + FM + low-dose DEX and ENR + FM + high-dose DEX. After the treatments, blood samples were collected at 0, 1, 2, 4, 6, 8, 12, 24 and 48 h. Oxidative stress parameters were determined by ELISA, while serum organ damage markers were measured by autoanalyser. LSP increased (p < 0.05) malondialdehyde, 13,14-dihydro-15-keto-prostaglandin F(2 alpha) and nitric oxide, while LPS reduced vitamin C. These changes were especially inhibited (p < 0.05) by ENR + FM + high-dose DEX. LPS increased organ damages markers. Cardiac and hepatic damage was not completely inhibited by any treatment, whereas renal damage was inhibited by two treatments. This study suggested that ENR + FM + high-dose DEX is most effective in the LPS-caused oxidative stress and organ damages.

Topics: Animals; Ascorbic Acid; Autoanalysis; Biomarkers; Clonixin; Dexamethasone; Dinoprost; Disease Models, Animal; Drug Therapy, Combination; Enrofloxacin; Enzyme-Linked Immunosorbent Assay; Female; Fluoroquinolones; Heart Diseases; Kidney Diseases; Lipopolysaccharides; Liver Diseases; Male; Malondialdehyde; Multiple Organ Failure; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Shock, Septic; Superoxide Dismutase; Time Factors

Ascorbic acid is a sugar acid and an essential vital food nutrient found mainly in fruits and vegetables. The purpose of this study was to investigate the effects of ascorbic acid against arsenic induced oxidative stress in blood of rat. In rat, treatment with ascorbic acid prevented the increased serum enzymatic activity of AST, ALT, ALP, ACP and LDH. In addition, treatment with ascorbic acid prevented elevated production of LPO, PC and NO and restored the depletion of reduced SOD and CAT activities. Interestingly, ascorbic acid markedly upregulated lymphocytes relative mRNA expression of lymphocytes SOD2 gene corresponding to GAPDH, house keeping candidate gene in arsenic-treated rat, which might provide anti-oxidative activity in the blood.

Topics: Animals; Antioxidants; Arsenic Poisoning; Ascorbic Acid; Biomarkers; Catalase; Chronic Disease; Disease Models, Animal; Enzymes; Gene Expression Regulation, Enzymologic; Glyceraldehyde-3-Phosphate Dehydrogenases; Lipid Peroxidation; Lymphocytes; Male; Nitric Oxide; Oxidative Stress; Rats; Rats, Wistar; RNA, Messenger; Superoxide Dismutase; Up-Regulation

Many studies suggest a role for antioxidants in the prevention of lung hypoplasia in nitrofen-induced rat models with congenital diaphragmatic hernia (CDH). This study investigates the oxidative status and the histological outcome of prenatal administration of vitamins E and C with synergistic effect, and effect of N-acetylcysteine (NAC) to improve lung maturation of nitrofen-induced rats.. CDH was induced by maternal administration of a single oral dose of nitrofen on day 9.5 of gestation, and the Sprague-Dawley rats were randomly divided into five groups: nitrofen (N), nitrofen + vitamin C (NC), nitrofen + vitamin E (NE), nitrofen + vitamin C + vitamin E (NCE) and nitrofen + NAC (NNAC). A control group in which only vehicle was administered was included. Cesarean section was performed on day 21. Body weight (BW) and total lung weight (LW) of all fetuses with CDH were recorded; lung histological evaluation was performed, and protein content of lungs, determination of thiobarbituric acid reactive substances, and the protein carbonyls in tissue samples were determined.. A total of 133 rat fetuses with CDH were investigated. The body weight and the lung weight of fetuses of all groups that were exposed to nitrofen were significantly decreased than of the control group (P < 0.05). The animals exposed to nitrofen with different antioxidants showed increased protein levels in lung tissue. However, in the NCE and the NNAC groups, protein levels were significantly increased than in the others. Malondialdehyde levels significantly decreased in the NCE and the NNAC groups when compared with the NC and the NE groups. In addition, the NCE and NNAC groups decreased protein oxidation to control levels, and no significant difference was observed between control and these two antioxidants groups. The N, NC, NE and NNAC groups showed minimal improvement in lung histology; the NCE groups showed the most improvement in lung histology when compared with the other nitrofen plus antioxidant groups.. Prenatal administration of NAC and vitamin E in combination with vitamin C represented the best effects to avoid oxidative damage and protein content of the lungs in rat pups with CDH at birth.

Topics: Acetylcysteine; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Drug Synergism; Female; Fetus; Free Radical Scavengers; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Lipid Peroxidation; Lung; Lung Diseases; Male; Maternal-Fetal Exchange; Pesticides; Phenyl Ethers; Pregnancy; Proteins; Rats; Rats, Sprague-Dawley; Thiobarbituric Acid Reactive Substances; Vitamin E

The aim of the following study was to evaluate the effect of a purified saponin mixture (PSM), isolated from Astragalus corniculatus Bieb. (Fabaceae), on enzyme-induced and non-enzyme-induced lipid peroxidation (LPO), in liver microsomes from spontaneously hypertensive rats (SHRs) - strain Okamoto Aoki, as compared to normotensive Wistar rats (NTRs). The enzyme-induced lipid peroxidation was performed by incubating rat liver microsomes with carbonetetrachloride (CCl(4)) in the presence of NADPH. In nonenzyme-induced LPO, the microsomes were incubated with a solution of iron sulphate and ascorbinic acid (Fe(2+)/AA). The effect of PSM (196.5 microg/ml) was assessed at 20 minutes' incubation time. MDA, a product of LPO, was measured spectrophotometrically. The results of our study showed that the initial MDA quantity in SHRs was significantly higher, than in NTRs. The incubation of the microsomes from both strains with PSM (196.5 microg/ml), resulted in significant reduction of MDA level, by 25% in SHRs. In NTRs, the formation of MDA was unchanged. In enzyme-induced LPO model, PSM significantly decreased the formation of MDA, by 55% in NTRs and by 35% in SHRs, compared to the respective control groups. In the model of non-enzyme induced LPO, PSM significantly decreased the formation of MDA by 95% in NTRs and practically restored it to the control level. The MDA quantity in SHR's microsomes was reduced by 25%. According to the results of this experiment we could conclude that PSM, isolated from Astragalus corniculatus, shows antioxidant activity both in SHRs and NTRs and the effect in NTRs is more pronounced.

Topics: Animals; Antioxidants; Ascorbic Acid; Astragalus Plant; Carbon Tetrachloride; Disease Models, Animal; Iron Compounds; Lipid Peroxidation; Malondialdehyde; Microsomes, Liver; NADP; Oxidative Stress; Plant Extracts; Rats; Rats, Inbred SHR; Rats, Wistar; Saponins; Spectrophotometry

Exposure of the esophageal mucosa to refluxed gastroduodenal contents is recognized to be an important risk factor for Barrett's esophagus (BE). At the human gastroesophageal junction, nitric oxide is generated luminally through the enterosalivary recirculation of dietary nitrate, and in cases with gastroesophageal reflux, the site of luminal nitric oxide generation could shift to the distal esophagus. The aim of this study is to investigate whether exogenous luminal nitric oxide could promote the development of BE in rats. Sodium nitrite plus ascorbic acid were administered to a rat surgical model of BE, in which the gastroduodenal contents were refluxed into the esophagus to generate exogenous luminal nitric oxide in the esophagus by the acid-catalyzed chemical reaction between the 2 reagents. The emergence of BE was evaluated histologically in the early phase (several weeks) after the surgery with or without exogenous nitric oxide administration. To elucidate the histogenesis of BE, CDX2, MUC2 and MUC6 expressions were investigated immunohistochemically. Coadministration of sodium nitrite plus ascorbic acid significantly accelerated the timing of emergence and increased the area of BE compared with controls. Administration of either reagent alone did not show any promotive effects on BE formation. Immunohistochemically, the columnar epithelium thus induced was similar to the specialized intestinal metaplasia in human BE. The results of this animal model study suggest that exogenous luminal nitric oxide could be involved in the pathogenesis of the columnar transformation of the esophagus. Further studies in human are warranted.

Topics: Animals; Ascorbic Acid; Barrett Esophagus; Disease Models, Animal; Esophagitis; Gastroesophageal Reflux; Nitric Oxide; Random Allocation; Rats; Sodium Nitrite

The present study was aimed at investigating the possible antioxidant potential of curcumin at a dose of 75 mg/kg body weight on selenite-induced cataract in experimental rat pups.. Group I: Control rat pups receiving physiological saline; Group II: Selenite-induced group (15 microM/kg body wt); Group III: Selenite-induced group co-treated with curcumin (single dose of curcumin orally 75 mg/kg body wt); Group IV: Selenite-induced animals post-treated (after 24 hrs) with curcumin at a dose mentioned for group III; Group V: Rat pups were pretreated with curcumin (dose as mentioned in Group III), 24 hrs before the administration of selenite. Encapsulated lenses liver, kidney, and serum were analyzed for antioxidant enzymes and malondialdehyde, a marker of lipid peroxidation.. Intraperitoneal injection of sodium selenite (15 microM/kg body wt) to 8-10-day-old rat pups led to severe oxidative stress in eye lens as evidenced by enhanced LPO levels that led to cataract formation. Sodium selenite also led to decrease in activities of SOD, GST, GPx, CAT with simultaneous decrease in the levels of GSH, vitamin C, and vitamin E. Treatment with curcumin (75 mg/kg body wt) led to a significant decrease in the levels of LPO, enzymic antioxidants, and nonenzymic antioxidants, which were similar to that of control.. Curcumin suppressed selenite-induced oxidative stress and cataract formation in rat pups. The presence of oxidative stress in selenite cataract development and its prevention by curcumin support the possibility that the natural consumption of curcumin in food can help prevent the onset of senile cataract.

Topics: Animals; Animals, Newborn; Antioxidants; Ascorbic Acid; Cataract; Curcumin; Disease Models, Animal; Glutathione; Injections, Intraperitoneal; Lens, Crystalline; Lipid Peroxidation; Male; Oxidative Stress; Oxidoreductases; Rats; Rats, Wistar; Sodium Selenite; Vitamin E

Sympathetic vasomotor hyperactivity and baroreflex dysfunction are involved in the development and maintenance of renovascular arterial hypertension. We hypothesized that angiotensin (Ang) II-dependent oxidative stress contributes to the pathophysiology of the two-kidney, one-clip (2K-1C) model.. The mean arterial pressure (MAP), baroreflex, and renal sympathetic nerve activity (rSNA) were evaluated after chronic administration of an antioxidant, vitamin C (vitC 150 mg/kg/day) in male Wistar 2K-1C rats. Additionally, the mRNA levels of Ang II subtype 1 receptor (AT(1)R), NAD(P)H oxidase subunits (p47phox and gp91phox), and major antioxidant enzymes were evaluated in the renal cortex.. After vitC treatment, the MAP (170 +/- 4 vs. 133 +/- 6 mm Hg; P < 0.05) and rSNA (161 +/- 5 vs. 118 +/- 12 spikes/s; P < 0.05) were significantly reduced only in the 2K-1C group. VitC improved the baroreflex control of heart rate (HR) and rSNA. The expression of AT(1)R, p47phox, and gp91phox was elevated (51, 184, and 132%, respectively) in the clipped kidney of 2K-1C group. VitC downregulated AT(1)R in the clipped kidney (31%). Catalase (CAT) expression was reduced in clipped (70%) and nonclipped (83%) kidneys of 2K-1C rats. VitC treatment augmented the expression of glutathione peroxidase (GPx) in both clipped (185%) and nonclipped (212%) kidneys of the 2K-1C group.. The present study suggests a role for oxidative stress in the cardiovascular and sympathetic alterations in renovascular hypertension, associated with changes in the expression of AT(1)R, NAD(P)H oxidase subunits, and antioxidant enzymes in the kidney.

Topics: Animals; Antioxidants; Ascorbic Acid; Baroreflex; Biomarkers; Blood Pressure; Catalase; Disease Models, Animal; Glutathione Peroxidase; Hypertension, Renovascular; Kidney; Male; NADPH Oxidases; Oxidative Stress; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Superoxide Dismutase; Sympathetic Nervous System

Underlying cardiovascular disease (CVD) is a risk factor for the exacerbation of air pollution health effects. Pulmonary oxidative stress, inflammation, and altered iron (Fe) homeostasis secondary to CVD may influence mammalian susceptibility to air pollutants. Rodent models of CVD are increasingly used to examine mechanisms of variation in susceptibility. Baseline cardiac and pulmonary disease was characterized in healthy normotensive Wistar Kyoto (WKY) rats, cardiovascular compromised spontaneously hypertensive rats (SHR), and spontaneously hypertensive heart failure (SHHF) rats. Blood pressure, heart rate, and breathing frequencies were measured in rats 11 to 12 wk of age, followed by necropsy at 14 to 15 wk of age. Blood pressure and heart rate were increased in SHR and SHHF relative to WKY rats (SHR > SHHF > WKY). Increased breathing frequency in SHHF and SHR (SHR > SHHF > WKY) resulted in greater minute volume relative to WKY. Bronchoalveolar lavage fluid (BALF) protein and neutrophils were higher in SHHF and SHR relative to WKY (SHHF >> SHR > WKY). Lung ascorbate and glutathione levels were low in SHHF rats. BALF Fe-binding capacity was decreased in SHHF relative to WKY rats and was associated with increased transferrin (Trf) and ferritin. However, lung ferritin was lower and Trf was higher in SHHF relative to WKY or SHR rats. mRNA for markers of inflammation and oxidative stress (macrophage inflammatory protein [MIP]-2, interleukin [IL]-1alpha, and heme oxygenase [HO]-1) were greater in SHHF and SHR relative to WKY rats. Trf mRNA rose in SHR but not SHHF relative to WKY rats, whereas transferrin receptors 1 and 2 mRNA was lower in SHHF rats. Four of 12 WKY rats exhibited cardiac hypertrophy despite normal blood pressure, while demonstrating some of the pulmonary complications noted earlier. This study demonstrates that SHHF rats display greater underlying pulmonary complications such as oxidative stress, inflammation, and impaired Fe homeostasis than WKY or SHR rats, which may play a role in SHHF rats' increased susceptibility to air pollution.

Topics: Animals; Ascorbic Acid; Biomarkers; Bronchoalveolar Lavage Fluid; Cardiovascular Diseases; Disease Models, Animal; Ferritins; Gene Expression; Glutathione; Heart Failure; Hemodynamics; Homeostasis; Hypertension; Inflammation; Iron; Lung; Lung Diseases; Male; Obesity; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Respiratory Function Tests; Stroke; Transferrin

In the present study we investigated the effect of acute hyperprolinemia on some parameters of energy metabolism, including the activities of succinate dehydrogenase and cytocrome c oxidase and (14)CO(2) production from glucose and acetate in cerebral cortex of young rats. Lipid peroxidation determined by the levels of thiobarbituric acid-reactive substances, as well as the influence of the antioxidants alpha-tocopherol plus ascorbic acid on the effects elicited by Pro on enzyme activities and on the lipid peroxidation were also evaluated. Wistar rats of 12 and 29 days of life received one subcutaneous injection of saline or proline (12.8 or 18.2 micromol/g body weight, respectively) and were sacrificed 1 h later. In another set of experiments, 5- and 22-day-old rats were pretreated for a week with daily intraperitoneal administration of alpha-tocopherol (40 mg/kg) plus ascorbic acid (100 mg/kg) or saline. Twelve hours after the last injection, rats received one injection of proline or saline and were sacrificed 1 h later. Results showed that acute administration of proline significantly reduced cytochrome c oxidase activity and increased succinate dehydrogenase activity and (14)CO(2) production in cerebral cortex, suggesting that Pro might disrupt energy metabolism in brain of young rats. In addition, proline administration increased the thiobarbituric acid-reactive substances levels, which were prevented by antioxidants. These findings suggest that mitochondrial dysfunction and oxidative stress may be important contributors to the neurological dysfunction observed in some hyperprolinemic patients and that treatment with antioxidants may be beneficial in this pathology.

Topics: Age Factors; Aging; alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; Brain Diseases, Metabolic; Cerebral Cortex; Disease Models, Animal; Drug Synergism; Energy Metabolism; Lipid Peroxidation; Oxidative Stress; Proline; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances

Nitric oxide synthase (NOS) depletion or inhibition reduces ventilator-induced lung injury (VILI), but the responsible mechanisms remain incompletely defined. The aim of this study was to elucidate the role of endothelial NOS, NOS3, in the pathogenesis of VILI in an in vivo mouse model. Wild-type and NOS3-deficient mice were ventilated with high-tidal volume (HV(T); 40 ml/kg) for 4 h, with and without adding NO to the inhaled gas. Additional wild-type mice were pretreated with tetrahydrobiopterin and ascorbic acid, agents that can prevent NOS-generated superoxide production. Arterial blood gas tensions, histology, and lung mechanics were evaluated after 4 h of HV(T) ventilation. The concentration of protein, IgM, cytokines, malondialdehyde, and 8-isoprostane were measured in bronchoalveolar lavage fluid (BALF). Myeloperoxidase activity, total and oxidized glutathione levels, and NOS-derived superoxide production were measured in lung tissue homogenates. HV(T) ventilation induced VILI in wild-type mice, as reflected by decreased lung compliance, increased concentrations of protein and cytokines in BALF, and oxidative stress. All indices of VILI were ameliorated in NOS3-deficient mice. Augmenting pulmonary NO levels by breathing NO during mechanical ventilation did not increase lung injury in NOS3-deficient mice. HV(T) ventilation increased NOS-inhibitable superoxide production in lung extracts from wild-type mice but not in those from NOS3-deficient mice. Administration of tetrahydrobiopterin and ascorbic acid ameliorated VILI in wild-type mice. Our results indicate that NOS3 contributes to ventilator-induced lung injury via increased production of superoxide.

Topics: Animals; Ascorbic Acid; Biopterins; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Immunoglobulin M; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Superoxides; Ventilator-Induced Lung Injury

Cigarette smoking is a major risk for developing atherosclerosis; however, the underlying mechanism is poorly understood. This paucity of knowledge is largely attributed to the lack of an animal model; therefore, our efforts were targeted towards establishing cigarette smoke (CS)-induced atherosclerosis in guinea pig. To understand the mechanism, we investigated apoptosis, an event implicated in atherosclerosis, in the aorta of CS-exposed animals. Since a major deleterious effect of CS is oxidative stress, we also examined the effect of vitamin C, an antioxidant, on CS- induced atherosclerosis.. Guinea pigs on a diet with or without vitamin C supplement were exposed to CS for different time periods. Aortal sections from these animals were examined for atherosclerotic changes by staining with H&E and Oil red O. Atherogenic changes were observed in sections obtained from CS-exposed guinea pigs only. TUNEL assay showed the occurrence of apoptosis in CS-exposed guinea pig aorta. Our results revealed that CS-induced apoptosis could contribute to the progression but not to the initiation of the disease. Immunohistochemical analysis documents that CS-induced apoptosis in aortal sections is mediated at least in part by an increased Bax/Bcl2 ratio. In contrast, CS-exposed guinea pigs fed with vitamin C-supplemented diet exhibit little or no atherogenic changes. This anti-atherosclerotic activity of vitamin C can be attributed partly to its ability to inhibit CS-induced apoptosis and platelet activation.. Exposure of guinea pigs to cigarette smoke causes the development of atherosclerosis, which can be prevented by vitamin C supplement.

Topics: Animals; Antioxidants; Aorta; Apoptosis; Ascorbic Acid; Atherosclerosis; Dietary Supplements; Disease Models, Animal; Guinea Pigs; Immunoenzyme Techniques; In Situ Nick-End Labeling; Male; Oxidative Stress; Platelet Activation; Smoking

Since chronic stress has been used widely for studying clinical depression and that brain energy metabolism and oxidative stress might be involved in the pathophysiology of this illness, the objective of this study was investigate the activities of pyruvate kinase, complex II and IV (cytocrome c oxidase) in hippocampus and prefrontal cortex of rats submitted to chronic variable stress. We also evaluated if vitamins E and C administration could prevent such effects. During 40 days adult rats from the stressed group were subjected to one stressor per day, at a different time each day, in order to minimize predictability. The stressed group had gained less weight while its immobilization time in the forced swimming test was greater than that of the control group. Results showed that stressed group presented an inhibition in the activities of complex II and cytochrome c oxidase in prefrontal cortex, while in hippocampus just complex IV was inhibited. Pyruvate kinase activity was not altered in stressed group when compared to control. Vitamins E and C administration prevented the alterations on respiratory chain caused by stress. These data suggest that the impairment of energy metabolism and oxidative stress could be related with the pathogenic pathways in stress related disorders.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain Diseases, Metabolic; Chronic Disease; Disease Models, Animal; Electron Transport; Electron Transport Complex IV; Energy Metabolism; Hippocampus; Oxidative Stress; Prefrontal Cortex; Pyruvate Kinase; Rats; Rats, Wistar; Stress, Psychological; Vitamin E

P90Gylation refers to the modification of lipid molecules by one or more phospholipid chains. Phospholipon 90G (P90G) contains about 94.0% of phosphatidylcholine stabilized with 0.1% ascorbyl palmitate and is a safe (GRAS) FDA-approved parenteral excipient with wide applications in drug delivery. P90Gylated-Softisan 142 conjugate, otherwise referred to as (SRMS142), has numerous advantages: wetting, solubilization, drug stabilization, emulsification, and modified release. Here, we report an evaluation of solid lipid microparticles (SLMs) formulated from SRMS142 systems as an alternative carrier system for oral glibenclamide administration in diabetic rats. The result of our findings showed that SRMS142 generated an imperfect matrix with numerous spaces that accommodated glibenclamide in a concentration-dependent manner up to 60.58%. The blood glucose-lowering effect of the SLMs was higher than that of a commercial sample.

Topics: Administration, Oral; Animals; Ascorbic Acid; Blood Glucose; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Delayed-Action Preparations; Diabetes Mellitus, Experimental; Disease Models, Animal; Drug Carriers; Drug Compounding; Glyburide; Hypoglycemic Agents; Male; Particle Size; Phosphatidylcholines; Rats; Rats, Wistar; Solubility; Technology, Pharmaceutical

To assess the role of combined deficiencies of vitamins C and E on the earliest stages of atherosclerosis (an inflammatory condition associated with oxidative stress), 4 combinations of vitamin supplementation (low C/low E, low C/high E, high C/low E, and high C/high E) were studied in atherosclerosis-prone apolipoprotein E-deficient mice also unable to synthesize their own vitamin C (gulonolactone oxidase(-/-)); and to evaluate the effect of a more severe depletion of vitamin C alone in a second experiment using gulonolactone oxidase(-/-) mice carrying the hemizygous deletion of SVCT2 (the vitamin C transporter).. After 8 weeks of a high-fat diet (16% lard and 0.2% cholesterol), atherosclerosis developed in the aortic sinus areas of mice in all diet groups. Each vitamin-deficient diet significantly decreased liver and brain contents of the corresponding vitamin. Combined deficiency of both vitamins increased lipid peroxidation, doubled plaque size, and increased plaque macrophage content by 2- to 3-fold in male mice, although only plaque macrophage content was increased in female mice. A more severe deficiency of vitamin C in gulonolactone oxidase(-/-) mice with defective cellular uptake of vitamin C increased both oxidative stress and atherosclerosis in apolipoprotein E(-/-) mice compared with littermates receiving a diet replete in vitamin C, again most clearly in males.. Combined deficiencies of vitamins E and C are required to worsen early atherosclerosis in an apolipoprotein E-deficient mouse model. However, a more severe cellular deficiency of vitamin C alone promotes atherosclerosis when vitamin E is replete.

Topics: Animals; Aortic Diseases; Apolipoproteins E; Ascorbic Acid; Ascorbic Acid Deficiency; Atherosclerosis; Brain; Dietary Supplements; Disease Models, Animal; Disease Progression; Female; L-Gulonolactone Oxidase; Lipid Peroxidation; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Organic Anion Transporters, Sodium-Dependent; Oxidative Stress; Severity of Illness Index; Sex Factors; Sodium-Coupled Vitamin C Transporters; Symporters; Time Factors; Vitamin E; Vitamin E Deficiency; Vitamins

Vitamin C (VC) is a crucial antioxidant in the brain. To assess whether different brain regions vary in their sensitivity to oxidative stress induced by VC depletion, we used the gulonolactone oxidase (gulo) knockout mouse. This mouse, like humans, cannot synthesize VC and thus its tissue VC levels can be varied by dietary VC intake. Gulo knockout mice were fed drinking water containing standard (0.33g/L), low (0.033g/L) or zero (0g/L) VC supplementation levels. After 4weeks, mice were sacrificed and different brain regions removed for assay of VC and malondialdehyde, a marker of lipid peroxidation. Compared to age-matched wild-type controls, the cerebellum, olfactory bulbs and frontal cortex had the highest VC content, whereas the pons and spinal chord had the lowest. However, in mice that did not receive VC, area differences were no longer significant as all values trended towards zero. Malondialdehyde increased in the cortex as VC supplementation was decreased. The same changes were not observed in the cerebellum or pons, suggesting that cortex is more susceptible to oxidative damage from low VC. These results suggest enhanced susceptibility of the cortex to oxidative stress induced by low VC compared to other brain regions.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Brain; Disease Models, Animal; L-Gulonolactone Oxidase; Malondialdehyde; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidative Stress; Statistics, Nonparametric; Tissue Distribution

The formation of reactive oxygen species (ROS) is increased in heart failure (HF). However, the causal and mechanistic relationship of ROS formation with contractile dysfunction is not clear in detail. Therefore, ROS formation, myofibrillar protein oxidation and p38 MAP kinase activation were related to contractile function in failing rabbit hearts.. Three weeks of rapid left ventricular (LV) pacing reduced LV shortening fraction (SF, echocardiography) from 32 +/- 1% to 13 +/- 1%. ROS formation, as assessed by dihydroethidine staining, increased by 36 +/- 8% and was associated with increased tropomyosin oxidation, as reflected by dimer formation (dimer to monomer ratio increased 2.28 +/- 0.66-fold in HF vs. sham, P < 0.05). Apoptosis (TdT-mediated dUTP nick end labelling staining) increased more than 12-fold after 3 weeks of pacing when a significant increase in the phosphorylation of p38 MAP kinase and HSP27 was detected (Western blotting). Vitamins C and E abolished the increases in ROS formation and tropomyosin oxidation along with an improvement of LVSF (19 +/- 1%, P < 0.05 vs. untreated HF) and prevention of apoptosis, but without modifying p38 MAP kinase activation. Inhibition of p38 MAP kinase by SB281832 counteracted ROS formation, tropomyosin oxidation and contractile failure, without affecting apoptosis.. Thus, p38 MAP kinase activation appears to be upstream rather than downstream of ROS, which impacts on LV function through myofibrillar oxidation. p38 MAP kinase inhibition is a potential target to prevent or treat HF.

Topics: Actin Cytoskeleton; Animals; Antioxidants; Apoptosis; Ascorbic Acid; Disease Models, Animal; Disease Progression; Drug Delivery Systems; Heart Failure; Imidazoles; Male; Myocardial Contraction; Oxidation-Reduction; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pyrimidines; Rabbits; Reactive Oxygen Species; Ventricular Function, Left; Vitamin E

Age-related hearing loss (ARHL) is characterized by gradual, progressive sensorineural hearing loss, which impairs communication, lending to clinical depression and social withdrawal. There are currently no effective treatments for ARHL. The purpose of this study is to evaluate the potential of a combination antioxidant therapy in preventing ARHL.. Randomized controlled trial.. Animal study.. C57BL/6 mice, a recognized animal model of ARHL, were assigned to one of three groups: early treatment (n = 12), late treatment (n = 9), or control group (n = 9). Treatment groups of mice were fed with a combination agent comprising six antioxidant agents that target four sites within the oxidative pathway: L-cysteine-glutathione mixed disulfide, ribose-cysteine, NW-nitro-L-arginine methyl ester, vitamin B12, folate, and ascorbic acid. Auditory brainstem response (ABR) thresholds were recorded at baseline and every three months following initiation of treatment.. Threshold shifts from baseline were decreased in the treatment groups when compared to the control group at all tested frequencies (P < 0.001). The ABR threshold shift at 12 months of age for the control group was 34.7 dB with a 95% confidence interval (CI) of +/-1.6. The mean threshold shifts for the early and late treatment groups were 7.5 dB (+/-0.87, 95% CI) and 9.2 dB (+/-1.6, 95% CI).. Combination antioxidant therapy effectively decreased threshold shifts on ABR within an animal model of ARHL. Combination antioxidant therapy, with further research and investigation, may provide a safe and cost-effective method of preventing presbycusis in the growing elderly population.

Topics: Aging; Animals; Antioxidants; Ascorbic Acid; Auditory Threshold; Cysteine; Disease Models, Animal; Drug Therapy, Combination; Evoked Potentials, Auditory, Brain Stem; Glutathione; Mice; Mice, Inbred C57BL; NG-Nitroarginine Methyl Ester; Presbycusis; Vitamin B Complex

Ascorbic acid has important antioxidant properties, and may play a role in the protective effects of ischemic preconditioning on later ischemia-reperfusion. Herein, we examined the role of endogenous extracellular ascorbic acid in ischemic preconditioning in the kidney.. We developed a solitary rabbit kidney model where animals received ischemia-reperfusion only (ischemia-reperfusion group, n = 15) or ischemic preconditioning followed by ischemia-reperfusion (ischemic preconditioning group, n = 15). Ischemia-reperfusion was induced by occluding and loosening of the renal pedicle. The process of ischemic preconditioning included 15-minute brief ischemia and 10-minute reperfusion. In vivo microdialysis coupled with online electrochemical detection was used to determine levels of endogenous extracellular ascorbic acid in both groups. The extent of tissue damage was determined in kidney sections stained with hematoxylin and eosin. Serum creatinine and urea nitrogen were also detected to assess renal function.. During ischemia-reperfusion, the extracellular ascorbic acid concentration during ischemia increased rapidly to the peak level ((130.01 +/- 9.98)%), and then decreased slowly to near basal levels. Similar changes were observed during reperfusion (peak level, (126.78 +/- 18.24)%). In the ischemic preconditioning group there was a similar pattern of extracellular ascorbic acid concentration during ischemic preconditioning. However, the ascorbic acid level was significantly lower during the ischemia and early reperfusion stage compared to the ischemia-reperfusion group. Additionally, the extent of glomerular ischemic collapse, tubular dilation, tubular denudation, and loss of brush border were markedly attenuated in the ischemic preconditioning group. Levels of serum creatinine and urea nitrogen were also decreased significantly in the ischemic preconditioning group.. Ischemic preconditioning may protect renal tissue against ischemia-reperfusion injury via use of extracellular ascorbic acid. In vivo microdialysis coupled with online electrochemical detection is effective for continuous monitoring extracellular ascorbic acid in the renal cortex.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Ischemic Preconditioning; Kidney; Rabbits; Reperfusion Injury

Some studies have made use of the antioxidative capabilities of high doses of vitamins C and E with the aim of neutralizing the noxious effects of free radicals following spinal cord lesion.. To evaluate the effects of vitamins C and E, separately and together, on the functional performance of rats that were subjected to standardized spinal cord contusion.. Forty male Wistar rats were used, divided into four groups of 10 animals each. Group 3 received vitamin C 100 mg kg(-1) day(-1) intraperitoneally; Group 2 received vitamin E 100 mg kg(-1) day(-1) orally; Group 1 received vitamins C and E, at the same dosages; and Group 4 was the control. The vitamin therapy was administered for 1 month and then the animals were killed. A direct contusional injury was caused and functional evaluation was performed using the Basso, Beattie and Bresnahan rating scale. The rats were evaluated on the second postoperative day and weekly thereafter, until the end of the experiment.. The results were evaluated by means of the one-tailed, non-paired and non-parametric Mann-Whitney test, comparing the groups two by two. No significant difference in functional performance was observed between the groups.. The use of vitamins C and E in these rats did not improve their neurological performance. However, histopathological examination showed that the inflammatory response was less intense following administration of the combination of vitamins C and E.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Laminectomy; Male; Rats; Rats, Wistar; Spinal Cord Injuries; Vitamin E

Cytotoxic concentrations of nitric oxide are generated luminally at the gastroesophageal junction through the entero-salivary recirculation of dietary nitrate in humans. The site of luminal nitric oxide generation shifts to the lower esophagus when gastric acid is refluxed into the esophagus. The aim of this study was to investigate the influence of persistent administration of exogenous nitric oxide on esophageal damage.. 0.1% sodium nitrite and/or 1% ascorbic acid was administered in an established rat acid-refluxed esophagitis model. Co-administration of both reactants in this model is thought to induce high concentrations of nitric oxide luminally in the esophagus by an acid-catalyzed chemical reaction when refluxed gastric acid is present. The tissue damage was evaluated by a macroscopic lesion index and myeloperoxidase activity. Nitrotyrosin was assessed immunohistochemically as a footprint of peroxynitrite formation.. Co-administration of sodium nitrite and ascorbic acid induced a 4- to 5-fold increase in the esophageal damage compared with baseline reflux esophagitis, while the damage was unchanged when either of the reagents alone was given. Nitrotyrosine was strongly stained in the tissue from the co-administration. Treatment of superoxide scavengers efficiently prevented the exacerbation of esophageal damage by exogenous nitric oxide exposure, suggesting an essential role of superoxide in esophageal damage.. Exogenous luminal nitric oxide greatly exacerbated the tissue damage of reflux esophagitis. Diffusion of the luminal nitric oxide into the adjacent superoxide-enriched inflamed tissue of the esophagus could lead to the production of the highly toxic agent peroxynitrite, thus causing exacerbation of the esophageal damage.

Topics: Analysis of Variance; Animals; Ascorbic Acid; Biopsy, Needle; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Esophagitis, Peptic; Esophagogastric Junction; Immunohistochemistry; Male; Nitric Oxide; Omeprazole; Peroxidase; Probability; Random Allocation; Rats; Rats, Wistar; Sensitivity and Specificity

Vascular tolerance to nitroglycerin (GTN) may be caused by impaired GTN bioactivation due to inactivation of mitochondrial aldehyde dehydrogenase (ALDH2). As relaxation to GTN is reduced but still sensitive to ALDH2 inhibitors in ascorbate deficiency, we compared the contribution of ALDH2 inactivation to GTN hyposensitivity in ascorbate deficiency and classical in vivo nitrate tolerance.. Guinea pigs were fed standard or ascorbate-free diet for 2 weeks. Reversibility was tested by feeding ascorbate-deficient animals standard diet for 1 week. Nitrate tolerance was induced by subcutaneous injection of 50 mg x kg(-1) GTN 4 times daily for 3 days. Ascorbate levels were determined in plasma, blood vessels, heart and liver. GTN-induced relaxation was measured as isometric tension of aortic rings; vascular GTN biotransformation was assayed as formation of 1,2- and 1,3-glyceryl dinitrate (GDN).. Two weeks of ascorbate deprivation had no effect on relaxation to nitric oxide but reduced the potency of GTN approximately 10-fold in a fully reversible manner. GTN-induced relaxation was similarly reduced in nitrate tolerance but not further attenuated by ALDH inhibitors. Nitrate tolerance reduced ascorbate plasma levels without affecting ascorbate in blood vessels, liver and heart. GTN denitration was significantly diminished in nitrate-tolerant and ascorbate-deficient rings. However, while the approximately 10-fold preferential 1,2-GDN formation, indicative for active ALDH2, had been retained in ascorbate deficiency, selectivity was largely lost in nitrate tolerance.. These results indicate that nitrate tolerance is associated with ALDH2 inactivation, whereas ascorbate deficiency possibly results in down-regulation of ALDH2 expression.

Topics: Aldehyde Dehydrogenase; Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Biotransformation; Chloral Hydrate; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Drug Tolerance; Enzyme Activation; Enzyme Inhibitors; Female; Guinea Pigs; Hydrazines; Injections, Subcutaneous; Isoflavones; Male; Nitric Oxide; Nitric Oxide Donors; Nitroglycerin; Time Factors; Vasodilation; Vasodilator Agents

The ultrastructural changes on capillaries of the dermis in diabetic and benfluorex-vitamin C treated diabetic rats have been investigated. Three groups of 21 Wistar albino rats were used in the examination: control, diabetes, and benfluorex-vitamin C treated diabetic rats. Diabetes was induced by injection of streptozotocin. The streptozotocin-induced group was treated for 21 days with vitamin C and benfluorex, of which antidiabetic and antihyperlipidemic effects were experimentally proved. Samples taken from the skin of rats' legs were examined under transmission electron microscopy. Swollen endothelial cells, narrowed capillary lumens, a thickened basement membrane, and fusion of mitochondrial cristae in the capillaries of diabetic rat dermis were seen. In the benfluorex-vitamin C treated group, contrary to the diabetic group, neither signs of degeneration in endothelial cells nor a significant difference with the control group with regard to capillary structure were observed. Amelioration in capillaries appears to be due to benfluorex and vitamin C treatment in diabetes.

Topics: Animals; Ascorbic Acid; Capillaries; Dermis; Diabetes Mellitus, Experimental; Dietary Supplements; Disease Models, Animal; Endothelial Cells; Fenfluramine; Hypolipidemic Agents; Rats; Rats, Wistar

Ceramide is a biologically active lipid causing apoptosis in a variety of cells. In this study, we examined the effect of CCl4 on the ceramide metabolism and indicators of oxidative stress. After 12 h of oral administration of CCl4 (4 ml/kg body weight as a 1:1 mixture of CCl4 and mineral oil) to rats, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were increased. Antioxidants such as vitamins C and E were decreased in the liver and kidney. In addition, the ratio of GSH/GSSG in the liver, plasma, kidney, and brain decreased at 2h. The total ceramide in the liver significantly increased as early as 2h after CCl4 administration. After 24 and 36 h, the total ceramide in plasma and the kidney was also augmented. In the brain, the total ceramide dramatically increased at 36 h. These results suggested that the increased ceramide in plasma was transferred to the kidney and the brain. The activity of neutral sphingomyelinase (SMase), which was reported to be enhanced by the decrease of GSH, was significantly increased after CCl4 treatment in the liver, kidney, and brain. However, acid SMase activities were not increased in the liver and kidney. Thus, the activation of neutral SMase via oxidative stress induced the increase of ceramide during CCl4 intoxication in not only the liver but also other tissues. These results suggested that the excess accumulation of ceramide causes damage in other organs including the kidney and brain during fulminant hepatic failure.

Topics: Alanine Transaminase; Animals; Ascorbic Acid; Aspartate Aminotransferases; Blood Urea Nitrogen; Brain; Carbon Tetrachloride; Ceramides; Disease Models, Animal; Glutathione; Glutathione Disulfide; Kidney; Liver; Liver Failure, Acute; Male; Oxidative Stress; Rats; Rats, Wistar; Sphingomyelin Phosphodiesterase; Time Factors; Up-Regulation; Vitamin E

1. The aim of the present study was to investigate the effects of ascorbic acid (AA) on the antifungal activity of fluconazole (FCZ) in a systemic murine candidiasis model as well as in vitro. 2. The murine model was established by infusion of Candida albicans via the tail vein. Control mice received no further treatment. Other groups of mice were injected with FCZ (0.5 mg/kg, i.p.) and then treated or not with 50 or 500 mg/kg AA intragastrically (i.g.) or i.p. In all groups, FCZ was administered i.p. 2 h after fungal inoculation, whereas AA was administered 6 h after fungal inoculation. Survival rate, kidney fungal burden and renal pathological changes were evaluated. 3. The in vitro effects of AA (5, 1 and 0.2 mmol/L) on the growth of various Candida strains in the presence of FCZ (0.125-64 microg/mL) were also investigated. The in vitro effects of two anti-oxidants, namely N-acetylcysteine (NAC; 5, 1 and 0.2 mmol/L) and reduced glutathione (GSH; 5, 1 and 0.2 mmol/L), on FCZ activity were evaluated to determine the mechanism of action of AA. 4. Intragastric administration of AA (50 or 500 mg/kg) significantly decreased the antifungal effect of 0.5 mg/kg FCZ. Although i.p. administration of AA (50 or 500 mg/kg) had no significant effect on the survival of mice, it dose-dependently inhibited the activity of FCZ, with significant inhibition observed with 500 mg/kg AA. 5. In vitro, AA decreased the activity of FCZ against various Candida strains. Both NAC and GSH dose-dependently decreased the activity of FCZ. 6. The results of the present study indicate that AA inhibits the antifungal activity of FCZ, suggesting that the two should not be used together clinically for the treatment of candidiasis.

Topics: Animals; Antifungal Agents; Antioxidants; Ascorbic Acid; Candida albicans; Candidiasis; Disease Models, Animal; Drug Antagonism; Drug Evaluation, Preclinical; Drug Resistance, Fungal; Fluconazole; Mice; Microbial Sensitivity Tests

Ascorbic acid is highly concentrated in the brain, being considered as a neuromodulator. This study investigated the effect of ascorbic acid in the tail suspension test (TST) and in the forced swimming test (FST) in mice and the contribution of the monoaminergic system to its antidepressant-like effect. Moreover, the effects of fluoxetine, imipramine and bupropion in combination with ascorbic acid in the TST were investigated. Ascorbic acid (0.1-10 mg/kg, i.p., 1-10 mg/kg p.o. or 0.1 nmol/mice i.c.v.) produced an antidepressant-like effect in the TST, but not in the FST, without altering the locomotor activity. The effect of ascorbic acid (0.1 mg/kg, i.p.) in the TST was prevented by i.p. pre-treatment with NAN-190 (0.5 mg/kg), ketanserin (5 mg/kg), MDL72222 (0.1 mg/kg), prazosin (62.5 microg/kg), yohimbine (1 mg/kg), propranolol (2 mg/kg), haloperidol (0.2 mg/kg), sulpiride (50 mg/kg), but not with SCH23390 (0.05 mg/kg, s.c.). Additionally, ascorbic acid (1 mg/kg, p.o.) potentiated the effect of subeffective doses (p.o. route) of fluoxetine (1 mg/kg), imipramine (0.1 mg/kg), or bupropion (1 mg/kg) in the TST. The combined treatment of ascorbic acid with antidepressants produced no alteration in the locomotion in the open-field test. In conclusion, our results show that administration of ascorbic acid produces an antidepressant-like effect in TST, which is dependent on its interaction with the monoaminergic system. Moreover, ascorbic acid caused a synergistic antidepressant-like effect with conventional antidepressants. Therefore, the present findings warrant further studies to evaluate the therapeutical relevance of ascorbic acid for the treatment of depression and as a co-adjuvant treatment with antidepressants.

Topics: Analysis of Variance; Animals; Antidepressive Agents; Ascorbic Acid; Behavior, Animal; Biogenic Monoamines; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Female; Hindlimb Suspension; Male; Mice; Motor Activity; Neurotransmitter Agents; Swimming; Synaptic Transmission

Oxidative stress and inflammation have been linked to bone loss. We evaluated the effects of feeding orange pulp (OP), a source of vitamin C and flavonoids, on bone quality in a rat model of male osteoporosis. One-year-old retired breeder rats (n = 43) were orchidectomized (ORX) or sham-operated (SHAM). Three days postsurgery, ORX rats were randomly assigned to treatments: ORX or ORX with 2.5% OP, 5% OP, or 10% OP. Diets were isonitrogenous, isocaloric, modified AIN-93M diets with equal fiber content. All ORX rats were fed for 4 months to the mean food intake of the SHAM group. At the end of the study blood, urine and bone samples were collected. Plasma antioxidant capacity and urinary deoxypyridinoline (DPD) were determined. Bone density, structure, and strength were assessed using dual energy X-ray absorptiometry, microcomputed tomography, and finite element analyses. ORX decreased (P < .05) antioxidant status, while OP as low as 2.5% maintained the antioxidant capacity of ORX rats comparable to that of the SHAM group. Cortical thickness at the tibial midshaft was significantly decreased by ORX and increased by OP, and urinary DPD was significantly increased by ORX and decreased by OP. In fourth lumbar trabecular cores, ORX rats had significantly reduced bone volume fraction, connectivity density, and trabecular number and increased trabecular separation. OP significantly increased bone volume fraction and trabecular number and decreased trabecular separation in ORX rats. Improvements due to OP in microarchitectural properties of vertebral bones and in cortical thickness of long bones were subtle but significant. The consistently negative impacts of ORX on bone density, structure, and strength parameters confirm the previously reported importance of testosterone for bone.

Topics: Animals; Ascorbic Acid; Bone and Bones; Bone Density; Bone Density Conservation Agents; Citrus sinensis; Disease Models, Animal; Flavonoids; Fruit; Male; Orchiectomy; Osteoporosis; Plant Preparations; Rats; Rats, Sprague-Dawley; Spine; Tibia; Vitamins

In the present study, we tested whether or not acute antioxidant treatment with vitamin C is able to protect the heart during myocardial infarction. The effects of vitamin C on the autonomic balancing of the heart and on the histopathological and immunohistochemical changes in response to isoproterenol administration (ISO) were evaluated.. Four groups of male Wistar rats (n = 32) were studied: control; ISO treated; vitamin C treated; ISO + vitamin C treated. ISO 150 mg/kg was administered for 2 consecutive days. Vitamin C (250 mg/kg, oral) was administered 30 min before each ISO treatment. Phenylephrine and sodium nitroprusside were administrated to increase or decrease blood pressure in conscious rats.. The baroreceptor reflex index for bradycardia was significantly reduced in the ISO group (control, -3.4 +/- 0.3 beats/mm Hg; ISO -2 +/- 0.4 beats/mm Hg) and vitamin C treatment significantly improved the reflex index (-2.9 +/- 0.7 beats/mm Hg). Treatment with vitamin C showed mild degenerative changes in the myocardial tissue of the ISO group. The antioxidant was able to decrease the inducible nitric oxide (iNOS) expression in rats treated with vitamin C.. Vitamin C administration proved to be effective in reducing the extent of myocardial damage during ISO-induced myocardial infarction in rats associated with an iNOS downregulation and improving the autonomic balancing of the heart.

Topics: Animals; Antioxidants; Ascorbic Acid; Blood Pressure; Cardiotonic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Isoproterenol; Male; Myocardial Infarction; Myocardium; Nitric Oxide Synthase Type II; Nitroprusside; Phenylephrine; Rats; Rats, Wistar

The present study was conducted to investigate whether the conditionally essential amino acid, taurine, could play any protective role against the potent neurotoxin arsenic (As)-induced oxidative impairment in the rat brain. Administration in the form of NaAsO(2) (at a dose of 10 mg/kg body weight for 2 days, orally), As increased the intracellular accumulation of metallic As, reactive oxygen species, and super oxide radicals. The toxin also augmented the extent of lipid peroxidation, protein carbonylation, and the levels of glutathione disulphide. Activities of the antioxidant enzymes, membrane-bound enzymes, acetylcholinesterase, and the levels of reduced glutathione, as well as total thiols, have been significantly decreased due to As exposure. Oral administration of taurine (at a dose of 100 mg/kg/body weight for 5 days) was found to be very effective in the prevention of As-induced oxidative impairment in the brain tissue of the experimental rats. To validate the experimental results, a well-known water-soluble antioxidant, vitamin C, was used as the positive control in the study. Combining all, results suggest that taurine plays a beneficial role against As-induced cerebral oxidative stress.

Topics: Acetylcholinesterase; Adenosine Triphosphatases; Amino Acids, Essential; Animals; Antioxidants; Apoptosis; Arsenic; Arsenic Poisoning; Ascorbic Acid; Brain; Catalase; Disease Models, Animal; Dose-Response Relationship, Drug; Free Radical Scavengers; Glutathione; Glutathione Transferase; Lipid Peroxidation; Male; Oxidants; Oxidative Stress; Rats; Reactive Oxygen Species; Sulfhydryl Compounds; Taurine

Oxidative stress has been implicated in the pathogenesis of many neurodegenerative diseases including Alzheimer's disease (AD). We investigated the effect of a truncated form of the human tau protein in the neurons of transgenic rats. Using electron paramagnetic resonance we observed significantly increased accumulation of ascorbyl free radicals in brains of transgenic animals (up to 1.5-fold increase; P < 0.01). Examination of an in vitro model of cultured rat corticohippocampal neurons revealed that even relatively low level expression of human truncated tau protein (equal to 50% of endogenous tau) induced oxidative stress that resulted in increased depolarization of mitochondria (approximately 1.2-fold above control, P < 0.01) and increases in reactive oxygen species (approximately 1.3-fold above control, P < 0.001). We show that mitochondrial damage-associated oxidative stress is an early event in neurodegeneration. Furthermore, using two common antioxidants (vitamin C and E), we were able significantly eliminate tau-induced elevation of reactive oxygen species. Interestingly, vitamin C was found to be selective in the scavenging activity, suggesting that expression of truncated tau protein preferentially leads to increases in aqueous phase oxidants and free radicals such as hydrogen peroxide and hydroxyl and superoxide radicals. Our results suggest that antioxidant strategies designed to treat AD should focus on elimination of aqueous phase oxidants and free radicals.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain; Cells, Cultured; Cerebral Cortex; Dehydroascorbic Acid; Disease Models, Animal; Electron Spin Resonance Spectroscopy; Free Radicals; Hippocampus; Humans; Mitochondria; Neurons; Oxidative Stress; Rats; Rats, Transgenic; Reactive Oxygen Species; tau Proteins; Tauopathies; Vitamin E

Allograft safety is a great concern owing to the risk of disease transmission from nonsterile tissues. Radiation sterilization is not used routinely because of deleterious effects on the mechanical integrity and stability of allograft collagen. We previously reported several individual cross-linking or free radical scavenging treatments provided some radioprotective effects for tendons. We therefore asked whether a combination of treatments would provide an improved protective effect after radiation exposure regarding mechanical properties and enzyme resistance. To address this question we treated 90 rabbit Achilles tendons with a combination of cross-linking (1-ethyl-3-[3-dimethyl aminopropyl] carbodiimide [EDC]) and one of three scavenging regimens (mannitol, ascorbate, or riboflavin). Tendons then were exposed to one of three radiation conditions (gamma or electron beam irradiation at 50 kGy or unsterilized). Combination-treated tendons (10 per group) had increases in mechanical properties and higher resistance to collagenase digestion compared with EDC-only and untreated tendons. Irradiated tendons treated with EDC-mannitol, -ascorbate, and -riboflavin combinations had comparable strength to native tendon and had averages of 26%, 39%, and 37% greater, respectively, than those treated with EDC-only. Optimization of a cross-linking protocol and free radical scavenging cocktail is ongoing with the goal of ensuring sterile allografts through irradiation while maintaining their structure and mechanical properties.

Topics: Achilles Tendon; Animals; Ascorbic Acid; Biomechanical Phenomena; Cross-Linking Reagents; Disease Models, Animal; Free Radical Scavengers; Mannitol; Materials Testing; Rabbits; Radiation Dosage; Radiation Injuries; Random Allocation; Reference Values; Riboflavin; Sensitivity and Specificity; Tendon Transfer; Tensile Strength; Tissue and Organ Harvesting; Transplantation, Homologous

A behavior-related deficit in the release of ascorbate (AA), an antioxidant vitamin, occurs in the striatum of R6/2 mice expressing the human mutation for Huntington's disease (HD), a dominantly inherited condition characterized by striatal dysfunction. To determine the role of corticostriatal fibers in AA release, we combined slow-scan voltammetry with electrical stimulation of cortical afferents to measure evoked fluctuations in extracellular AA in wild-type (WT) and R6/2 striatum. Although cortical stimulation evoked a rapid increase in AA release in both groups, the R6/2 response had a significantly shorter duration and smaller magnitude than WT. To determine if corticostriatal dysfunction also underlies the behavior-related AA deficit in R6/2s, we measured striatal AA release in separate groups of mice treated with d-amphetamine (5 mg/kg), a psychomotor stimulant known to release AA from corticostriatal terminals independently of dopamine. Relative to WT, both AA release and behavioral activation were diminished in R6/2 mice. Collectively, our results show that the corticostriatal pathway is directly involved in AA release and that this system is dysfunctional in HD. Moreover, because AA release requires glutamate uptake, a failure of striatal AA release in HD is consistent with an overactive glutamate system and diminished glutamate transport, both of which are thought to be central to HD pathogenesis.

Topics: Amphetamine; Analysis of Variance; Animals; Ascorbic Acid; Cerebral Cortex; Corpus Striatum; Disease Models, Animal; Electrochemistry; Huntington Disease; Male; Mice; Mice, Transgenic; Motor Activity; Mutation; Neural Pathways; Reverse Transcriptase Polymerase Chain Reaction; Trinucleotide Repeat Expansion

Niemann-Pick disease type C1 (NPC1) is a neurodegenerative lysosomal disorder characterized by sphingolipid and cholesterol storage in the late endocytic system. In common with other neurodegenerative diseases, activation of the innate immune system occurs in the brain resulting in neuro-inflammation. Targeting inflammation in the brain therefore represents a potential clinical intervention strategy that aims to slow the rate of disease progression and improve quality of life. We evaluated non-steroidal anti-inflammatory drugs (NSAIDs) and an anti-oxidant to determine whether these agents are disease modifying in an acute mouse model of NPC1. NSAIDs significantly prolonged the lifespan of NPC1 mice and slowed the onset of clinical signs. However, anti-oxidant therapy was of no significant benefit. Combining NSAID therapy with substrate reduction therapy (SRT) resulted in additive benefit. These data suggest that anti-inflammatory therapy may be a useful adjunctive treatment in the clinical management of NPC1, alone or combined with SRT.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Ascorbic Acid; Brain; Disease Models, Animal; Inflammation; Mice; Mice, Inbred BALB C; Mice, Knockout; Niemann-Pick Disease, Type C

The aim of this research was to investigate differential gene expression of cyclin-dependent kinase inhibitors (CKIs) in white adipose tissue (WAT) and liver from high-fat fed male Wistar rats with or without vitamin C (VC) supplementation (750 mg/kg of body weight). After 56 d of experimentation, animals fed on a cafeteria diet increased significantly body weights and total body fat. Reverse transcription-polymerase chain reaction (RT-PCR) studies showed that cafeteria diet decreased p21 and p57 mRNA expression in subcutaneous WAT and increased p21 mRNA in liver. Overall, these data provide new information about the role of high fat intake on mRNA levels of several CKIs with implications in adipogenesis, cell metabolism and weight homeostasis. Interestingly, VC supplementation partially prevented diet-induced adiposity and increased p27 mRNA in liver without any changes in the other tissues and genes analyzed. Thus, hepatic mRNA changes induced by ascorbic acid indicate a possible role of these genes in diet-induced oxidative stress processes.

Topics: Adipogenesis; Adipose Tissue, White; Animals; Antioxidants; Ascorbic Acid; Body Weight; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinase Inhibitor p57; Cyclin-Dependent Kinase Inhibitor Proteins; Dietary Fats; Disease Models, Animal; Energy Intake; Gene Expression Regulation; Leptin; Liver; Male; Malondialdehyde; Obesity; Organ Size; Oxidative Stress; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The aim of this study was to investigate the effects of melatonin and vitamin C on expression of endothelial nitric oxide synthase (NOS) in heart tissue of chronic alcoholic rats. Twenty-four adult male Wistar rats weighing 200-250 g were used in this study. Rats were divided into four groups. The first group served as control (n = 6). The second group was treated with ethanol (%7.2) for 28 days (n = 6), which was administered in artificial isocaloric diets. The third group was given ethanol and supplemented with 40 mg/kg vitamin C [intraperitoneally (i.p.)] (n = 6). The fourth group was given ethanol and supplemented with 4 mg/kg melatonin (i.p.) (n = 6). At the end of the experiment, rats were sacrificed and heart tissues were processed for immunohistochemistry analysis to endothelial NOS (eNOS). eNOS immunoreactivity showed heterogeneous distribution in control group. eNOS immunoreactivity was (+) in some myocytes and (++) in some others. Expression of eNOS in alcohol group was heterogeneous like control group but also stronger than that. Immunoreactivity was (+++) in myocytes near the epicardial zone and (++) in myocytes near the endocardium border. In melatonin and vitamin C-treated groups, eNOS immunoreactivity was diffuse and the intensity of reaction was (+++) in subepicardial region. However, eNOS immunoreactivity scores were weaker in these groups when compared with the alcohol group. Our results indicate that alleviation of oxidative stress by antioxidant therapy reduces reactive oxygen species-mediated nitric oxide inactivation.

Topics: Alcohol-Induced Disorders; Animals; Antioxidants; Ascorbic Acid; Catalase; Central Nervous System Depressants; Chronic Disease; Disease Models, Animal; Ethanol; Heart; Immunoenzyme Techniques; Male; Malondialdehyde; Melatonin; Myocardium; Myocytes, Cardiac; Nitric Oxide Synthase Type III; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species

The aim of the present investigation was to study the effects of olive oil (OO), corn oil (CO), and flaxseed oil (FO), with or without supplementation of vitamins E and C, on food intake, body weight gain %, liver weight to body weight %, total lipids, liver functions, and liver histology in male rats intoxicated with carbon tetrachloride (CCl(4)). Forty-two rats were divided into two main groups. The first main group was fed on basal diet (BD) as a negative control group (NC). The second main group received subcutaneous injections of CCl(4) in paraffin oil (50% v/v 2 ml/kg) twice a week to induce chronic damage in the liver. The group was then divided into six subgroups, three of which were fed on 4% unsupplemented oils (CO, FO, and OO) as positive control for the three oils used. The rest of the groups were fed on 4% of the same oils supplemented with vitamins E and C. The results of the flaxseed oil rat group indicate that supplementing vitamin E and C led to a significant reduction in the mean values of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and liver alanine amino transferase enzyme (ALT). Moreover, it caused an increase of the mean value of high-density lipoprotein cholesterol (HDL-C) as compared to the negative control group (NC). The olive oil group supplemented with the same vitamins showed a significant decrease in the mean value of serum TC and significant (P<0.05) increase in the mean value of serum HDL-C as compared to NC. The results of the corn oil group supplemented with vitamins showed a significant increase in the mean value of serum HDL-C as compared to the negative control group. The histology results confirmed that the group hepatically injured with CCl(4) treatment and fed on supplemented FO or OO showed apparently normal hepatocytes.. The most effective treatment was observed with oils supplemented with vitamins E and C. Hierarchically FO achieved the best results compared to other additives, followed by OO and finally CO showing the least effective treatment among the observed groups.

Topics: Animals; Ascorbic Acid; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury, Chronic; Dietary Supplements; Disease Models, Animal; Drug Combinations; Lipids; Liver Function Tests; Male; Nutritional Status; Oils; Rats; Rats, Sprague-Dawley; Treatment Outcome; Vitamin E

The present study investigated the relationships among oxidative stress, beta-amyloid and cognitive abilities in the APP/PSEN1 double-transgenic mouse model of Alzheimer's disease. In two experiments, long-term dietary supplements were given to aged APP/PSEN1 mice containing vitamin C alone (1 g/kg diet; Experiment 1) or in combination with a high (750 IU/kg diet, Experiments 1 and 2) or lower (400 IU/kg diet, Experiment 2) dose of vitamin E. Oxidative stress, measured by F(4)-neuroprostanes or malondialdehyde, was elevated in cortex of control-fed APP/PSEN1 mice and reduced to wild-type levels by vitamin supplementation. High-dose vitamin E with C was less effective at reducing oxidative stress than vitamin C alone or the low vitamin E+C diet combination. The high-dose combination also impaired water maze performance in mice of both genotypes. In Experiment 2, the lower vitamin E+C treatment attenuated spatial memory deficits in APP/PSEN1 mice and improved performance in wild-type mice in the water maze. Amyloid deposition was not reduced by antioxidant supplementation in either experiment.

Topics: Aging; Alzheimer Disease; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; Behavior, Animal; Brain Chemistry; Cognition; Diet; Disease Models, Animal; Female; Liver; Male; Memory; Mice; Mice, Transgenic; Oxidative Stress; Plaque, Amyloid; Presenilin-1; Vitamin E

The present study was designed to investigate the antioxidant, anti-inflammatory and analgesic potential of Citrus decumana peel extract. Antioxidant activity of Citrus decumana peel extract in four solvent systems was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH(.)) and hydrogen peroxide (H(2)O(2)) radical scavenging methods. Ethyl acetate peel extract of Citrus decumana (EtCD) was studied for its anti-inflammatory and analgesic activities at a dose level of 100, 200 and 300 mg/kg. Anti-inflammatory activity was performed using carrageenan-induced paw edema in rats. Analgesic activity was evaluated for its central and peripheral pharmacological actions in mice. EtCD showed significant antioxidant activity in a dose-dependent manner when compared with ascorbic acid. EtCD at the dose of 300 mg/kg produced significant decrease in paw volume and pain when compared with reference drug diclofenac and morphine, respectively. The Citrus decumana peel extract may be useful as a natural antioxidant in the treatment of inflammation and pain.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Citrus; Diclofenac; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Inflammation; Male; Mice; Morphine; Pain; Plant Extracts; Rats; Rats, Wistar; Solvents

Lyophilized plasma (LP) is as safe and effective as fresh frozen plasma (FFP) for resuscitation after severe trauma.. Multicenter animal study.. Animal laboratories, 2 level I trauma centers.. Thirty-two Yorkshire crossbred swine.. Lyophilized plasma was analyzed for factor levels and clotting activity before lyophilization and after reconstitution. Swine were subjected to complex multiple trauma including extremity fracture, hemorrhage, severe liver injury, acidosis, and hypothermia. They were then resuscitated with FFP, LP, FFP and packed red blood cells (PRBCs) in a ratio of 1:1, or 1:1 LP and PRBCs.. Residual clotting activity of LP after reconstitution, swine mortality, hemodynamic measures, total blood loss, coagulation profiles, and inflammatory measures.. Lyophilization decreased clotting factor activity by an average of 14%. Survival and heart rate were similar between all groups. Swine resuscitated with LP had equivalent or higher mean arterial pressures. Swine treated with LP had similar coagulation profiles, plasma lactate levels, and postinjury blood loss compared with those treated with FFP. Swine treated with 1:1 FFP-PRBCs were similar to those treated with 1:1 LP-PRBCs. Resuscitation with LP resulted in a reduction in postresuscitation interleukin 6 expression compared with resuscitation with FFP.. The process of lyophilization and reconstitution of plasma reduces coagulation factor activity by 14%, without acute differences in blood loss. Lyophilized plasma can be used for resuscitation in a severe multiple trauma and hemorrhagic shock swine model with efficacy equal to that of FFP and with decreased interleukin 6 production.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Disseminated Intravascular Coagulation; Fluid Therapy; Freeze Drying; Plasma; Plasma Substitutes; Resuscitation; Shock, Hemorrhagic; Swine; Wounds and Injuries

The female sex has been associated with increased resistance to acute myocardial ischemia-reperfusion (I/R) injury. While enhanced antioxidant capacity has been implicated in female cardioprotection, there is little evidence to support this assumption. Previous studies have shown an important role of cellular glutathione peroxidase (GPx1) in protection of the myocardium from I/R injury. Whether GPx1 is mechanistic in the protection of female myocardium, post-I/R, has not been examined. We utilized a murine model with homozygous deletion of GPx1 and examined its impact on postischemic myocardial recovery in male and female mice. Following I/R, male GPx1(-/-) hearts were more susceptible to contractile and diastolic dysfunction, and this was associated with increased protein carbonyls, a marker of oxidative stress. In contrast, GPx1 deficiency in female hearts did not exacerbate dysfunction or oxidative stress post-I/R. Both wild-type and GPx1(-/-) female hearts exhibited reduced creatine kinase leakage and a more favorable ascorbate redox status compared with males. Following I/R, female GPx1(-/-) hearts showed a comparable decrease in glutathione redox status as their male counterparts; however, they exhibited a greater decrease in nitrate-to-nitrite ratio, suggesting a higher consumption of nitrate in female GPx1(-/-) hearts. Our findings demonstrate that GPx1 is critical for cardioprotection during I/R in male, but not female, mice. The maintenance of cardioprotection in female mice lacking GPx1 post-I/R may be due to an improved ascorbate redox homeostasis and enhanced nitrate-to-nitrite conversion, which would predictably be accompanied by enhanced production of cardioprotective nitric oxide.

Topics: Animals; Antioxidants; Ascorbic Acid; Creatine Kinase; Disease Models, Animal; Female; Glutathione; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Male; Mice; Mice, Knockout; Myocardial Contraction; Myocardial Reperfusion Injury; Myocardium; Nitrates; Nitric Oxide; Nitrites; Oxidation-Reduction; Oxidative Stress; Recovery of Function; Sex Factors; Time Factors; Ventricular Function, Left

Coronary heart disease and in particular its most serious form - acute myocardial infarction (AMI) - represents the most common cause of mortality in developed countries. Better prognosis may be achieved by understanding the etiopathogenetic mechanisms of AMI. Therefore, a catecholamine model of myocardial injury, which has appeared to be very similar to AMI in human in some aspect, was used. Male Wistar:Han rats were randomly divided into two groups: control group (saline) and isoprenaline group (ISO; synthetic catecholamine, 100 mg.kg(- 1) subcutaneously [s.c.]). After 24 hours, functional parameters were measured, biochemical markers in the blood and metals content in the heart tissue were analysed and histological examination was performed. ISO caused marked myocardial injury that was associated with myocardial calcium overload. Close correlation between myocardial impairment (i.e. serum TnT, stroke volume index and wet ventricles weight) and the levels of myocardial calcium was observed. Direct reactive oxygen species (ROS) involvement was documented only by non-significant increase in malonyldialdehyde 24 hours after ISO injury. Moreover, myocardial element analysis revealed no significant changes as for the content of zinc and iron while selenium and copper increased in the ISO group although it reached statistical significance only for the latter.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Blood Pressure; Calcium; Catecholamines; Disease Models, Animal; Heart Function Tests; Heart Rate; Heart Ventricles; Iron; Isoproterenol; Male; Myocardial Infarction; Myocardium; Organ Size; Rats; Rats, Wistar; Reactive Oxygen Species; Troponin T; Vitamin E; Zinc

The aim was to study the effect of naringenin, a biologically active compound, on tissue antioxidant status and lipid peroxidation in ethanol-induced hepatotoxicity in rats.. Rats were divided into four groups: Groups 1 and 2 received isocaloric glucose and 0.5% carboxymethyl cellulose; groups 3 and 4 received 20% ethanol equivalent to 6 g/kg daily for 60 days. In addition, groups 2 and 4 were given naringenin (50 mg/kg) daily for the last 30 days of the experiment.. The results showed significantly elevated levels of serum aspartate and alanine transaminases, gamma-glutamyl transpeptidase, tissue thiobarbituric acid reactive substances, conjugated dienes, lipid hydroperoxides and protein carbonyl content, and significantly lowered activities/levels of antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, reduced glutathione and vitamins C and E in ethanol-treated rats compared with control rats. Administration of naringenin to rats with ethanol-induced liver injury significantly decreased the levels of serum aspartate and alanine transaminases, gamma-glutamyl transpeptidase, tissue thiobarbituric acid reactive substances, conjugated dienes, lipid hydroperoxides and protein carbonyl content and significantly elevated the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase, and the levels of reduced glutathione and vitamins C and E in the tissues compared with unsupplemented ethanol-treated rats. Histological changes observed in the liver correlated with the biochemical findings.. Taken together these findings suggest that naringenin has a therapeutic potential in the abatement of ethanol-induced hepatotoxicity.

Topics: Animals; Antioxidants; Ascorbic Acid; Biological Products; Disease Models, Animal; Flavanones; Heart; Kidney; Lipid Peroxidation; Liver Cirrhosis, Alcoholic; Male; Myocardium; Oxidative Stress; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Time Factors; Vitamin E

Vitamin C is traditionally regarded to be beneficial for asthma, however the benefit is still controversial. In the present study, high dose vitamin C was supplemented to ovalbumin (OVA)-sensitized and challenged mice to evaluate the effects of dietary vitamin C on allergic asthma. In this study, the experimental mice were divided into four groups, including nonsensitized control, dietary control, positive control (cured ip with dexamethasone), and high dose vitamin C supplementation (130 mg of vitamin C/kg bw/day by gavage for 5 weeks). Differential leukocyte counts, levels of inflammatory mediators, as well as type 1 T-helper lymphocytes (Th1)-type and type 2 T-helper lymphocytes (Th2)-type cytokines in the bronchoalveolar lavage fluid (BALF) were determined. The results showed that both high dose vitamin C supplementation and dexamethasone treatments significantly (P < 0.05) decreased eosinophilic infiltration into BALF. High dose vitamin C supplementation significantly increased the secretion ratio of interferon (IFN)-gamma/interleukin (IL)-5 cytokines. This study suggests that high dose vitamin C supplementation might attenuate allergic inflammation in vivo via modulating the Th1/Th2 balance toward the Th1 pole during the Th2-skewed allergic airway inflammation and decreasing eosinophilic infiltration into BALF.

Topics: Animals; Ascorbic Acid; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Dietary Supplements; Disease Models, Animal; Dose-Response Relationship, Drug; Eosinophils; Female; Humans; Leukemic Infiltration; Mice; Mice, Inbred BALB C; Ovalbumin; Random Allocation; T-Lymphocytes, Helper-Inducer; Th1 Cells; Th2 Cells

We assessed whether co-supplementation of vitamins C and E has additive beneficial effects on reducing the kidney damage and attenuation of the arterial pressure elevation compared to administration of either vitamin C or vitamin E alone in deoxycorticosterone acetate-salt-induced hypertension.. Forty rats were divided into 4 study groups and 1 sham-operated group. Unilateral nephrectomy was carried out in the study groups and hypertension was induced by deoxycorticosterone injection and 1% sodium chloride and 0.2% potassium chloride added to the drinking water. Vitamins C and E (200 mg/kg/day) or combination of them were administered with DOCA-salt for 4 weeks in 3 study groups. The effects of DOCA and salt and treatment with vitamins were compared in terms of blood pressure, urinary protein excretion, antioxidant activity of the kidneys, and renal histological changes.. Four weeks of supplementations of vitamins C, vitamin E, and both in the DOCA-salt-treated rats had comparable significant effects in decreasing systolic blood pressure. Urinary protein excretion and histological damage did not significantly change with the combination therapy of vitamins C and E compared to the vitamin C or E alone. The renal levels of glutathione and ferric reducing/antioxidant power in combination therapy group were similar to the two other treatment groups and were significantly higher than non-treated group.. Co-administration of vitamin C and E does not have an additive beneficial effect on reducing the kidney damage and hypertension compared to either vitamin C or E alone in DOCA-salt-induced hypertension.

Topics: Animals; Antioxidants; Ascorbic Acid; Calcium Chloride; Desoxycorticosterone; Dietary Supplements; Disease Models, Animal; Drug Therapy, Combination; Hypertension; Kidney Diseases; Male; Potassium Chloride; Rats; Rats, Sprague-Dawley; Vitamin E

The objective of this study was to determine if prolonged hyperoxia exposure would deplete antioxidants, resulting in excessive oxidative stress that would lead to oxidation of pulmonary surfactant and contribute to lung dysfunction. Rats were exposed to either hyperoxic (> 95% O(2)) or normoxic (21% O(2)) oxygen concentrations for 48 or 60 hours. Pulmonary compliance, inflammatory cells, and total protein levels were measured as indicators of lung injury. Bronchoalveolar lavage (BAL) samples were analyzed for surfactant composition, antioxidant content, and markers of oxidative stress. Antioxidants were also measured in lung tissue and plasma samples. Hyperoxia exposure for 60 hours resulted in increased protein and inflammatory cells in BAL, and lower pulmonary compliance, compared to all other groups. Total surfactant and surfactant large aggregates were increased following 48 hours of hyperoxia exposure, with a further increase following 60 hours. Animals exposed to 60 hours of hyperoxia also demonstrated lower ascorbate levels in lung tissue, increased lipid peroxides in BAL, and increased oxidation of phosphatidylglycerol species in surfactant. This study demonstrates that the balance of oxidant/antioxidant components is disrupted within the lung during periods of hyperoxia, and that although surfactant lipids may be susceptible to oxidative damage, they do not likely represent a major mechanism for the lung dysfunction observed.

Topics: Acute Lung Injury; Animals; Antioxidants; Ascorbic Acid; Biomarkers; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Hyperoxia; Lipid Peroxides; Lung; Lung Compliance; Male; Oxidative Stress; Phosphatidylcholines; Phosphatidylglycerols; Pulmonary Surfactants; Rats; Rats, Sprague-Dawley; Time Factors; Uric Acid

This experimental study was performed to assess, whether or not, vitamin C, required during the collagen synthesis, would influence the Achilles tendon healing in a healthy rat model.. The right Achilles tendons of 42 healthy female Wistar Albino rats were completely ruptured. The rats were randomly divided into the vitamin C and control groups and both groups included third, tenth and twenty-first day subgroups. One hundred and fifty milligrams (1.5 cc) of vitamin C and 1.5 cc % 0.9 NaCl were injected once for every 2 days for the vitamin C and control groups, respectively. Qualitative and quantitative microscopic comparisons of the repair tissues of both groups were made on the mentioned days.. Angiogenesis was more evident on the third day in the vitamin C group. There was a significant difference between the control and vitamin C groups regarding the type I collagen production on the tenth day. The structure of the repair tissue was almost in the form of regular dense connective tissue at the end of twenty-first day in the vitamin C group. Mean collagen fiber diameter was considerably higher, and the number of active fibroblasts in the repair tissue was slightly elevated in the vitamin C group during the entire healing process.. High-dose vitamin C supplementation once for every 2 days has stimulating effects on the Achilles tendon healing because of early angiogenesis and increased collagen synthesis in a healthy rat model. Further studies are needed to make clear the mentioned encouraging effects of the vitamin C on the Achilles tendon healing.

Topics: Achilles Tendon; Animals; Ascorbic Acid; Collagen; Disease Models, Animal; Female; Rats; Rats, Wistar; Tendon Injuries; Vitamins; Wound Healing

The antioxidant effects of exogenous salicylic acid (SA) and vitamin C (Vit C) on the oxidative stress induced by 56 mg/m(3) of sulfur dioxide (SO2) in mouse livers and brains were investigated. The exposure of SO2 caused significant elevation of thiobarbituric acid-reactive substance (TBARS) levels and reduction of enzyme activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) in brain and liver, accompanied by a decrease in relative growth rate, when compared with controls. Application of moderate concentrations of SA and Vit C markedly reduced the SO2-induced elevation of TBARS levels, with 5.5 mg/kg SA or 200 mg/kg Vit C being most effective. In contrast to the decrease of TBARS levels, the levels of SOD, POD, and CAT in liver and brain were significantly increased in comparison with controls. The polyacrylamide gel electrophoresis (PAGE) of total liver proteins showed that the SO2 inhalation caused a 30-kD protein band disappearance compared with the control. However, the band remained unchanged in the samples treated with 5.5 and 8.25 mg/kg SA or 100, 200, and 400 mg/kg Vit C. Therefore, this protein band may serve as a marker for the damage induced by SO2 and an additional basis for drug screening and selection.

Topics: Administration, Inhalation; Air Pollutants; Animals; Antioxidants; Ascorbic Acid; Body Weight; Brain; Catalase; Disease Models, Animal; Lipid Peroxidation; Liver; Male; Malondialdehyde; Mice; Oxidative Stress; Peroxidase; Salicylic Acid; Sulfur Dioxide; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Previous experiments in rats with chemically induced colitis have shown that the antioxidant N-acetylcysteine plus mesalamine (5-ASA) exerted a significantly greater therapeutic effect in promoting mucosal healing when compared to either agent alone. The aims of the present study were to compare the effects of three antioxidants plus mesalamine vs. 5-ASA alone in treatment of colitis induced by trinitrobenzene sulfonic acid (TNBS) in rats.. Three days following induction of TNBS colitis, rats received 8 days of rectal therapy with 5-ASA, or 5-ASA plus vitamin C (ascorbic acid), 5-ASA plus phenyl butylnitrone (PBN) and 5-ASA plus vitamin E (alpha-tocopherol). Distal colonic tissues were examined for microscopic colitis and myeloperoxidase (MPO) activity.. Global assessments of microscopic colitis induced by TNBS indicated that 5-ASA alone significantly changed colonic injury by -31%. Combination therapy with ascorbic acid plus 5-ASA or alpha-tocopherol plus 5-ASA caused further significant change in TNBS colitis by -65 and -82%, respectively. Each of these values was significantly below scores observed with 5-ASA as monotherapy. Reduction in colitis with PBN plus 5-ASA was not different from 5-ASA alone. MPO activity was decreased significantly in response to monotherapy with 5-ASA and each of the antioxidants plus 5-ASA when compared to TNBS. alpha-Tocopherol plus 5-ASA, however, was the only treatment strategy that reduced significantly MPO activity below that recorded for 5-ASA alone. In conclusion, our results indicate that antioxidants other than N-acetylcysteine significantly enhance the therapeutic effectiveness of 5-ASA in the treatment of TNBS colitis. alpha-Tocopherol plus 5-ASA exerted profound anti-inflammatory and reparative effects upon colitis induced by TNBS.

Topics: Animals; Antioxidants; Ascorbic Acid; Colitis; Cyclic N-Oxides; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Intestinal Mucosa; Male; Mesalamine; Rats; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid; Vitamin E

During times of war and natural disasters, rhabdomyolysis-induced myoglobinuric acute renal failure (ARF) can assume epidemic proportions. Free radicals play an important role in the pathogenesis of myoglobinuric ARF. Vitamin C is a major antioxidant, scavenging free radicals. We have not found any studies on the effect of vitamin C on myoglobinuric ARF. Thus, we aimed to investigate the effects of vitamin C on the myoglobinuric ARF formed by glycerol in rats. Three groups of rats were employed in this study. Group 1 served as control, group 2 was given 50% glycerol (10 mL/kg, i.m.), and group 3 was given glycerol plus vitamin C (20 mg/kg, i.p. for four days). Ninety-six hours after glycerol injections, blood samples and kidney tissues were taken from the anesthetized rats. Urea and creatinine levels in plasma; N-acetyl-beta-D-glucosaminidase activity in urine; malondialdehyde levels, superoxide dismutase and catalase enzyme activity in kidney tissue were determined. Histopathological changes and iron accumulation in the kidney tissue were evaluated. In this study, glycerol administration led to marked renal oxidative stress and severe renal functional and morphological deterioration. The treatment of animals with vitamin C partially corrected the renal dysfunction and morphological impairment. In this respect, vitamin C appears to be a promising candidate for the prevention of rhabdomyolysis-induced ARF. Higher dosages of vitamin C than in 20 mg/kg may be beneficial for better functional and morphological recovery in this model ARF.

Topics: Acute Kidney Injury; Animals; Ascorbic Acid; Biopsy, Needle; Disease Models, Animal; Glycerol; Immunohistochemistry; Kidney Function Tests; Kidney Tubular Necrosis, Acute; Male; Malondialdehyde; Myoglobinuria; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Rhabdomyolysis; Sensitivity and Specificity; Severity of Illness Index; Statistics, Nonparametric

Many studies have shown that hexavalent chromium (Cr(6+)) compounds cause variety of toxicity, such as carcinogenic effects and pulmonary fibrosis. The aim of this study was to investigate the effect of vitamins C and E on hexavalent chromium-induced lung fibrosis in animal model. Rats weighing 180-210 g were used during the study. The negative control group received a single dose of 0.2 ml intratracheal normal saline. Other groups were given single intratracheal instillation of 50 mg/kg sodium dichromate in saline vehicle and then treated with either vitamin C or E orally. Vit C group treated with 75 mg/kg/day vit C. Vit E group treated with 20 mg/kg/day vit E. Vit C+E group treated with 75 mg/kg/day vit C + 20 mg/kg/day vit E. Three weeks after such treatments animals were killed, lungs were removed for histology and biochemical investigation. Collagen and hydroxyproline content of lung tissue were determined using spectrophotometric methods. Hexavalent chromium caused marked alveolar thickening associated with fibroblasts and myofibroblasts proliferation and collagen production in interstitial tissue leading to pulmonary fibrosis. Administration of vitamins C and E reduced the fibrotic damage in lung tissue. The combination of vit E and C had more pronounced effect. From this study it can be concluded that co-administration of vit C & E may significantly diminish the toxic effects of hexavalent chromium on lung.

Topics: Administration, Oral; Air Pollutants, Occupational; Animals; Antioxidants; Ascorbic Acid; Chromium; Collagen; Disease Models, Animal; Drug Therapy, Combination; Female; Fibroblasts; Male; Pulmonary Alveoli; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Vitamin E

This study was conducted to test whether oxidative stress activates the intracellular protein kinase B (AKT1) signaling pathway, which culminates with cardiac hypertrophy in experimental hyperthyroidism. Male Wistar rats were divided into four groups: control, vitamin E, thyroxine (T(4)), and T(4)+vitamin E. Hyperthyroidism was induced by T(4) administration (12 mg/l in drinking water for 28 days). Vitamin E treatment was given during the same period via s.c. injections (20 mg/kg per day). Morphometric and hemodynamic parameters were evaluated at the end of the 4-week treatment period. Protein oxidation, redox state (reduced glutathione, GSH/glutathione dissulfide, GSSG), vitamin C, total radical-trapping antioxidant potential (TRAP), hydrogen peroxide (H2O2), and nitric oxide metabolites (NO(X)) were measured in heart homogenates. The p-AKT1/AKT1 ratio, p-glycogen-synthase kinase (GSK)3B/GSK3B ratio, FOS, and JUN myocardial protein expression were also quantified by western blot after 4 weeks. Increases in biochemical parameters, such as protein oxidation (41%), H2O2 (62%), and NO(X) (218%), and increase in the left ventricular end-diastolic pressure were observed in the T(4) group. T(4) treatment also caused a decrease in GSH/GSSG ratio (83%), vitamin C (34%), and TRAP (55%). These alterations were attenuated by vitamin E administration to the hyperthyroid rats. Expression of p-AKT1/AKT1, p-GSK3B/GSK3B, FOS, and JUN were elevated in the T(4) group (by 69, 37, 130, and 33% respectively), whereas vitamin E administration promoted a significant reduction in their expression. These results indicate that oxidative stress plays an important role in cardiac hypertrophy, and suggest redox activation of AKT1 and JUN/FOS signaling pathways with H2O2 acting as a possible intracellular mediator in this adaptive response to experimental hyperthyroidism.

Topics: Animals; Ascorbic Acid; Blotting, Western; Cardiomegaly; Disease Models, Animal; Glutathione; Hydrogen Peroxide; Hyperthyroidism; Male; Oxidation-Reduction; Rats; Rats, Wistar; Signal Transduction; Thyroxine

We examined the effect of a nutrient mixture (NM) that contains lysine, proline, ascorbic acid, and green tea extract in mice treated with carbon tetrachloride (CCl4), a model of liver injury in which free radical, oxidative stress, and cytokine production are closely linked. Seven-week-old male Imprinting Control Region (ICR) mice were divided into four groups (A-D) of five animals each. Groups A and C mice were fed a regular diet for 2 weeks, whereas groups B and D mice were supplemented with 0.5% NM (w/w) during that period. Groups A and B received corn oil i.p., whereas groups C and D received CCl4 (25 microL/kg, in corn oil, i.p.). All animals were killed 24 h after CCl4 administration, serum was collected to assess liver and kidney functions, and livers and kidneys were excised for histology. Mean serum aspartate aminotransferase and alanine aminotransferase were comparable in groups A and B, increased markedly in group C, and significantly lowered in group D compared with group C. CCl4 had no significant effect on renal markers (blood urea nitrogen [BUN], creatinine, and BUN/creatinine ratio). CCl4 administration caused an intense degree of liver necrosis that was less severe in the NM fed group D. These results indicate that NM could be a useful supplement in preventing acute chemical-induced liver toxicity.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Ascorbic Acid; Aspartate Aminotransferases; Camellia sinensis; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Drug Combinations; Food; Kidney; Liver; Lysine; Male; Mice; Mice, Inbred ICR; Organ Size; Plant Extracts; Proline

The aim of this study was to determine whether vitamin C, vitamin E, and selenium have protective effects against cadmium-induced renal toxicity of rats. Vitamin C (250 mg/kg/day), vitamin E (250 mg/kg/day), and sodium selenate (0.25 mg/kg/day) were given to rats orally for 8 days. Cadmium (2 mg/kg/day CdCl2) was given to rats intraperitoneally. Vitamin C, vitamin E, and selenium (in the same dose and time) were given 1 h prior to the administration of cadmium every day. The tissue and blood samples were taken from the rats for histological evaluation and biochemical analyses on the Day 9. Lipid peroxidation (LPO) and glutathione (GSH) determination were made in kidney tissue. In addition, urea and creatinine levels were determined in serum. The damage to the kidney tissue was moderate in the rats given cadmium. In this group, the distinctive changes in the proximal tubules were observed. Degenerative changes in kidney tissue were also observed in rats given vitamin C, vitamin E, selenium, and cadmium. LPO levels significantly increased and GSH levels decreased in kidney tissues following cadmium administration. Serum urea and creatinine levels were also increased in rats given cadmium. The administration of vitamin C, vitamin E, and selenium caused a significant decrease in LPO levels and an increase in GSH levels in the kidney of rats given cadmium. Serum urea and creatinine levels were decreased in rats given both the antioxidant and cadmium. It is concluded that vitamin C, vitamin E, and selenium showed some protective effect on the rat kidney.

Topics: Administration, Oral; Animals; Antioxidants; Ascorbic Acid; Cadmium Chloride; Creatinine; Cytoprotection; Disease Models, Animal; Glutathione; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Rats; Rats, Sprague-Dawley; Selenic Acid; Selenium Compounds; Urea; Vitamin E

The replacement of established evidence-based cancer therapy protocols (mainstream therapy) by unevaluated complementary and alternative medicine (CAM) is a challenge in pediatric oncology. We tested the hypothesis that oral application of L-lysine and ascorbic acid (Lysin C Drink) in combination with epigallocatechin-gallate (EGCG) and amino-acids (Epican forte) is effective in a preclinical model of neuroblastoma.. Primary tumors and spontaneous metastases were induced in A/J mice by injection of NXS2 neuroblastoma cells. Mice were treated by daily oral gavage with L-lysine and ascorbic acid (Lysin C Drink) (equivalent to 150 mg ascorbic acid/day/mouse) (treatment A) or with EGCG plus ascorbic- and amino-acids (Epican forte) (9.2 mg/mouse) (treatment B). Treatment A was started in the prophylactic setting (7 days before tumor cell injection) as well as in the therapeutic setting (1 day after tumor cell inoculation). Finally, treatment B was evaluated alone and in combination with treatment A in the therapeutic setting. The effect on primary tumor growth and the development of spontaneous liver metastases was evaluated.. L-lysine and ascorbic acid (Lysin C Drink) and EGCG plus ascorbic- and amino-acids (Epican forte) are ineffective in reduction of primary tumor growth and prevention of spontaneous liver metastases in this model.. Neither a formal clinical development nor the use of these substances can be recommended for neuroblastoma.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Catechin; Dietary Supplements; Disease Models, Animal; Female; Liver Neoplasms, Experimental; Lysine; Mice; Mice, Inbred A; Neuroblastoma; Proline

This study was designed to examine if ebselen, an organoselenium compound with antioxidant and glutathione peroxidase-mimetic properties, attenuates testicular injury caused by intraperitoneal administration of CdCl(2). A number of toxicological parameters were evaluated in the testes of mice, such as delta-aminolevulinic acid dehydratase (delta-ALA-D) activity, lipid peroxidation, ascorbic acid levels and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Ebselen attenuated lipid peroxidation levels altered by CdCl(2). delta-ALA-D activity inhibited by the highest dose of CdCl(2) was attenuated by ebselen. A significant negative correlation between lipid peroxidation levels and delta-ALA-D activity was observed. Ebselen restored ascorbic acid levels reduced by CdCl(2). A significant negative correlation between ascorbic acid levels and delta-ALA-D activity reinforces the idea that ebselen attenuated the damage induced by CdCl(2) via its antioxidant property. The significant correlation between ALT and delta-ALA-D activity supports the assumption that ebselen prevented damage caused by CdCl(2). The results show that ebselen attenuated oxidative stress, a process important for CdCl(2) toxicity.

Topics: Alanine Transaminase; Animals; Antioxidants; Ascorbic Acid; Aspartate Aminotransferases; Azoles; Biomarkers; Cadmium Chloride; Disease Models, Animal; Drug Antagonism; Injections, Intraperitoneal; Isoindoles; Lipid Peroxidation; Male; Mice; Organoselenium Compounds; Porphobilinogen Synthase; Testicular Diseases; Testis; Thiobarbituric Acid Reactive Substances

Reflux-induced injury and oxidative stress result in esophageal inflammation and the potential for progression to intestinal metaplasia and adenocarcinoma. Proton-pump inhibitors represent the standard medical approach, but anti-inflammatories and antioxidants offer novel therapeutic possibilities.. Six weeks after an esophagojejunostomy reflux procedure, female Wistar rats (n = 100) were randomized to receive either an antioxidant (vitamin C, 8 mg or 28 mg/day), a cyclooxygenase-2 (COX-2) inhibitor (rofecoxib, 1 mg/day), or no therapy. After sacrifice 16 weeks later, esophageal injury was scored using pathologic and image analysis scoring.. Esophagitis was present in all 63 animals completing the study and was severe in 27 (43%). No animal developed metaplasia or tumor. The extent of inflammation and esophageal ulceration were not significantly different between experimental groups.. In this model of reflux injury, antioxidants and COX-2 inhibitors failed to ameliorate the severe inflammation induced. Further experimental designs should evaluate these novel approaches in less severe experimental models.

Topics: Animals; Antioxidants; Ascorbic Acid; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Esophagitis, Peptic; Esophagus; Female; Jejunum; Lactones; Random Allocation; Rats; Rats, Wistar; Sulfones

Cochlear implant surgery is currently the therapy of choice for profoundly deaf patients. However, the functionality of cochlear implants depends on the integrity of the auditory spiral ganglion neurons. This study assesses the combined efficacy of two classes of agents found effective in preventing degeneration of the auditory nerve following deafness, neurotrophic factors, and antioxidants. Guinea pigs were deafened and treated for 4 weeks with either local administration of GDNF or a combination of GDNF and systemic injections of the antioxidants ascorbic acid and Trolox. The density of surviving spiral ganglion cells was significantly enhanced and the thresholds for eliciting an electrically evoked brain stem response were significantly reduced in GDNF treated animals compared to deafened-untreated. The addition of antioxidants significantly enhanced the evoked responsiveness over that observed with GDNF alone. The results suggest multiple sites of intervention in the rescue of these cells from deafferentation-induced cell death.

Topics: Acoustic Stimulation; Animals; Antioxidants; Ascorbic Acid; Auditory Threshold; Chromans; Deafness; Disease Models, Animal; Dose-Response Relationship, Radiation; Drug Administration Routes; Electric Stimulation; Evoked Potentials, Auditory, Brain Stem; Glial Cell Line-Derived Neurotrophic Factor; Guinea Pigs; Neurons; Spiral Ganglion; Statistics, Nonparametric

The field of oxidative stress, free radicals, cellular defense and antioxidants is a burgeoning field of research. An important biomarker of oxidative stress is ascorbate and alterations in ascorbate have been shown to be a reliable measure of oxidative stress mechanisms. The purpose of this pharmacological study was to assess changes in ascorbate in a morphine/ascorbate animal model using novel sensors which selectively detect electrochemical signals for ascorbate, dopamine (DA) and serotonin (5-HT). Studies were also performed to show reversal of morphine-induced effects by the opioid antagonist, naloxone. In vivo studies were modeled after (Enrico et al. 1997, 1998) in which the oxidative biomarker, ascorbate, was reported to compensate for free radicals produced by morphine-induced increases in DA and 5-HT. In vivo studies consisted of inserting the Laurate sensor in ventrolateral nucleus accumbens (vlNAcc), in anesthetized male, Sprague-Dawley rats. In separate studies, laboratory rats were injected with (1) ascorbate, (5-35 mg/kg, ip) or (2) dehydroascorbate (DHA) (20-100 mg/kg, ip). In another study, (3) morphine sulfate (10-20 mg/kg, sc) was injected followed by a single injection of naloxone (5 mg/kg, ip) in the same animal. Results showed that in vlNAcc, (1) neither ascorbate nor DHA injections produced ascorbate release, (2) morphine significantly increased DA and 5-HT release, but did not alter ascorbate release, and (3) naloxone significantly reversed the increased DA and 5-HT release produced by morphine. Moreover, the sensors, N-stearoyl cerebroside and laurate were studied in vitro, in separate studies, in order to assess selective and separate electrochemical detection of ascorbate, DA and 5-HT, neuromolecules involved in oxidative stress mechanisms. In vitro studies consisted of pretreatment of each sensor with a solution of phosphotidylethanolamine (PEA) and bovine serum albumin (BSA) which simulates the lipid/protein composition of brain. Each new sensor was tested for stability, sensitivity and selectivity by pipetting graduated increases in concentration of ascorbate, DA and 5-HT into an electrochemical cell containing saline/phosphate buffer. Multiple and repetitive images of electrochemical signals from ascorbate, DA and 5-HT were recorded. Results showed that both sensors produced three well-defined cathodic, selective and separate electrochemical signals for ascorbate, DA and 5-HT at characteristic oxidation potentials. Dopamine

Topics: Animals; Antioxidants; Ascorbic Acid; Cerebrosides; Disease Models, Animal; Dopamine; Electrochemistry; Laurates; Male; Microdialysis; Morphine; Narcotics; Nucleus Accumbens; Oxidative Stress; Rats; Rats, Sprague-Dawley; Serotonin

Combined treatment with sodium nitrite (NaNO2) and ascorbic acid (AsA) has already been shown to promote rat forestomach carcinogenesis, possibly due to nitric oxide generation under acidic conditions. We hypothesized that a similar effect might occur in the esophagus when the luminal pH is decreased by acid reflux. To clarify this possibility, reflux esophagitis model rats (F344 male) were coadministered 0.2% NaNO2 in the drinking water and 1% AsA in the diet. After 32 weeks of the combined treatment, a significant increase in the incidence of epithelial hyperplasias of the lower-middle and lowest parts of the esophagus were observed compared with the basal-diet group, along with exacerbation of dysplasia and extension of the lesions. Additionally, one squamous cell papilloma was found only in the combined-treatment group. Subsequently, we confirmed the enhancing effects of NaNO2 and AsA cotreatment in the rat N-bis(2-hydroxypropyl)nitrosamine-initiated esophageal tumorigenesis model. The incidence of hyperplasia was enhanced in all segments, along with the incidence and multiplicity of squamous cell papillomas in the lowest segment of the esophagus. Thus, the data demonstrate that combined treatment with NaNO2 and AsA exerts promoting effects on rat esophageal carcinogenesis under acid reflux conditions, as in the forestomach. These findings suggest that the risk of excessive intake of a combination of nitrite and antioxidants for esophageal carcinogenesis is appreciable, particularly in patients with reflux esophagitis.

Topics: Animals; Antioxidants; Ascorbic Acid; Carcinoma, Squamous Cell; Cocarcinogenesis; Disease Models, Animal; Esophageal Neoplasms; Esophagitis, Peptic; Food Preservatives; Male; Rats; Rats, Inbred F344; Sodium Nitrite

Hereditary tyrosinemia type 1 (HT1) is a recessive disease caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH) that catalyzes the conversion of fumarylacetoacetate (FAA) into fumarate and acetoacetate. In mice models of HT1, FAH deficiency causes death within the first 24h after birth. Administration of 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3 cyclohexanedione (NTBC) prevents neonatal death in HT1 mice, ameliorates the HT1 phenotype but does not prevent development of hepatocellular carcinoma later on. FAA has been shown to deplete cells of glutathione by forming adducts. We tested whether a combination of a cell membrane permeable derivative of glutathione, glutathione monoethylester (GSH-MEE) and vitamin C could provide an alternative effective treatment for HT1. GSH-MEE (10 mmol/kg/j)/vitamin C (0.5 mmol/kg/j) treatment was given orally to pregnant/nursing female mice. While FAH-/- pups died in absence of treatment, all FAH-/- pups survived the critical first 24h of life when the mothers were on the GSH-MEE/vitamin C treatment and showed normal growth until postnatal day 10 (P10). However, after P10, pups showed failure to thrive, lethargy and died around P17. Thus, GSH-MEE/vitamin C supplementation could rescue the mice model of HT1 from neonatal death but it did not prevent the appearance of a HT1 phenotype in the second week after birth.

Topics: Animals; Animals, Newborn; Antioxidants; Ascorbic Acid; Carcinoma, Hepatocellular; Cyclohexanones; Disease Models, Animal; Drug Therapy, Combination; Female; Glutathione; Hydrolases; Liver Neoplasms; Mice; Mice, Knockout; Nitrobenzoates; Oxidative Stress; Pregnancy; Tyrosinemias

Oxidative stress is a state in which excess reactive oxygen species (ROS) overwhelm endogenous antioxidant systems. It is known that this state has been involved in the development of hypertension. On the basis of previous data, we hypothesized that overactivity of NAD(P)H oxidase-derived ROS and the lowered activity of CuZnSOD, an endogenous antioxidant within the rostral ventrolateral medulla (RVLM), could contribute to 2K-1C (two-kidney one-clip) hypertension. Moreover, to test the functional significance of whether oxidative stress was involved in the maintenance of sympathetic vasomotor tone and blood pressure in 2K-1C hypertension, we administered Ascorbic Acid (Vit C), an antioxidant, into the RVLM or systemically.. Experiments were performed in male Wistar rats (6 weeks after renal surgery--Goldblatt hypertension model--2K-1C). The mRNA expression of NAD(P)H oxidase subunits (p47phox and gp91phox) and CuZnSOD were analyzed in the RVLM using real-time PCR technique. The mean arterial blood pressure, heart rate, and renal sympathetic nerve activity were analyzed. Blood samples were collected and measured using thiobarbituric acid-reactive substances (TBARS).. The mRNA expression of NAD(P)H oxidase subnits (p47phox and gp91pox) was greater in 2K-1C compared to the control group in the RVLM, and CuZnSOD expression was similar in both groups. In the RVLM, Vit C resulted in a fall in arterial pressure and in the sympathetic activity only in the 2K-1C rats. Thiobarbituric acid-reactive substances (TBARS) were significantly greater in 2K-1C rats and the acute infusion of Vit C significantly decreased arterial pressure and renal sympathetic activity in 2K-1C.. The results support the idea that an increase in oxidative stress within the RVLM and systemically plays a major role in maintaining high arterial blood pressure and sympathetic drive in 2K-1C hypertension.

Topics: Animals; Antihypertensive Agents; Antioxidants; Ascorbic Acid; Blood Pressure; Disease Models, Animal; Heart Rate; Hypertension, Renovascular; Infusions, Intravenous; Kidney; Ligation; Male; Medulla Oblongata; Membrane Glycoproteins; Microinjections; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Rats; Rats, Wistar; Renal Artery; RNA, Messenger; Superoxide Dismutase; Sympathetic Nervous System; Thiobarbituric Acid Reactive Substances; Time Factors

We have previously demonstrated that acute arginine administration induces oxidative stress and compromises energy metabolism in rat hippocampus. In the present study, we initially investigated the effect of intracerebroventricular infusion of arginine (0.1, 0.5 and 1.5 mM solution) on Na(+),K(+)-ATPase activity and on some parameters of oxidative stress, namely thiobarbituric acid-reactive substances (TBA-RS) and total radical-trapping antioxidant parameter (TRAP) in the hippocampus of rats. Results showed that 1.5 mM arginine solution significantly increases TBA-RS and reduces Na(+),K(+)-ATPase activity and TRAP in the rat hippocampus. We also evaluated the influence of the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), and antioxidants, namely alpha-tocopherol plus ascorbic acid, on the effects elicited by arginine on Na(+),K(+)-ATPase activity, TBA-RS and TRAP. Results showed that treatment with alpha-tocopherol plus ascorbic acid per se did not alter these parameters but prevented these effects. Furthermore, intracerebroventricular infusion of L-NAME prevented the inhibition caused by arginine on Na(+),K(+)-ATPase activity, as well as the increased of TBA-RS. Our findings indicate that intracerebroventricular infusion of arginine induces oxidative stress in rat hippocampus and that the inhibition of Na(+),K(+)-ATPase activity caused by this amino acid was probably mediated by NO and/or its derivatives ONOO(-) and/or other free radicals. Finally, we suggest that the administration of antioxidants should be considered as an adjuvant therapy to specific diets in hyperargininemia.

Topics: alpha-Tocopherol; Amidines; Analysis of Variance; Animals; Antioxidants; Arginine; Ascorbic Acid; Brain Injuries; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Hippocampus; Injections, Intraventricular; Male; NG-Nitroarginine Methyl Ester; Oxidative Stress; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase; Thiobarbituric Acid Reactive Substances

Impaired relaxation induced by the new nitric oxide (NO) donor [Ru(NH.NHq)(terpy)NO(+)](3+) (TERPY) has been observed in the aortic rings from renal hypertensive rats (2K-1C). An increased production of reactive oxygen species (ROS) in the aortas from 2K-1C rats are capable of reducing NO bioavailability. Therefore, this study aimed at investigating the effects of an antioxidant (vitamin C) on the relaxant effect of NO released from TERPY on the 2K-1C rat aorta. As for vascular reactivity, the potency of TERPY is greater in the control rats (2K) than in 2K-1C whereas the maximum relaxation (ME) is not significantly different between the 2K and 2K-1C rat aortas. The relaxation of TERPY is potentiated only in the 2K-1C aortic ring treated with vitamin C. TERPY has a lower effect in decreasing cytosolic Ca(2+) concentration ([Ca(2+)]c) in vascular smooth muscle cells (VSMCs) from 2K-1C rats. This effect is also potentiated in 2K-1C aortic cells treated with vitamin C, but it is not altered in 2K cells. The basal cytosolic NO concentration ([NO]c) is lower in 2K-1C than in 2K cells, and the bioavailability of the NO released from TERPY is larger in 2K than in 2K-1C VSMCs. The superoxide radical concentration ([O(2)(*-)]) is higher in the 2K-1C aorta, and vitamin C reduces the [O(2)(*-)] in the 2K-1C aorta. Taken together, these results show that in the aortas of renal hypertensive 2K-1C rats, released NO from the new NO donor is not available to produce a similar effect in 2K aorta due to increased [O(2)(*-)].

Topics: Animals; Aorta; Ascorbic Acid; Calcium; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Hypertension, Renal; Kidney; Male; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Donors; Organ Culture Techniques; Organometallic Compounds; Phenylephrine; Rats; Rats, Wistar; Ruthenium; Superoxides; Time Factors; Vasodilation

We have previously shown oxidative stress and oedema, caused by both xanthine oxidase-derived oxidants and infiltrating neutrophils, within skeletal muscle after contractile-induced claudication. The purpose of this study was to determine whether supplementation with antioxidant vitamins attenuates the oxidative stress, neutrophil infiltration and oedema associated with an acute bout of contractile-induced claudication. Rats received vehicle, vitamin C, vitamin E or vitamin C + E for 5 days prior to contractile-induced claudication. Force production was significantly reduced in the claudicant limbs of all groups compared with the control (sham) limb of control animals. Contractile-induced claudication caused a significant increase in protein oxidation, lipid peroxidation, neutrophil infiltration and oedema compared with sham muscles. Supplementation with vitamin C, E or C + E prevented the increases in each of these, and there were no differences between groups. These findings suggest that, in an animal model of exercise-induced claudication, neutrophil chemotaxis is caused by oxidizing species and that antioxidant supplementation can prevent oxidative damage, neutrophil infiltration and oedema following an acute bout of contractile-induced claudication.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Edema; Electric Stimulation; Intermittent Claudication; Ischemia; Lipid Peroxidation; Male; Muscle Contraction; Muscle, Skeletal; Neutrophil Infiltration; Neutrophils; Oxidative Stress; Peroxidase; Protein Carbonylation; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Vitamin E

The aim of the current study was to investigate the biochemical changes in the plasma and retina of apolipoprotein E deficient (apoE-/-) mice supplemented with various antioxidants. Ten wild type (WT-Con, C57BL/6) and 10 apoE-/- (AE-Con) mice received drinking water. Another 40 apoE-/- animals were divided into four groups of 10 mice each and received either chromocarbe diethylamine (AE-CD, 50mg/kg), cyaninosides chloride (AE-CC, 50mg/kg), multivitamin complex (AE-MC, 50mg/kg), or vitamins C and E (AE-CE, 100mg/kg and 200IU/kg). Cholesterol, triglycerides, and lipid peroxidation (thiobarbituric acid reactive substances [TBARS]) were measured in plasma, and TBARS and nitric oxide metabolites (NOx) concentration were determined in retinal homogenates. Transmission electron microscopy was performed to examine the retinal ultrastructure. AE-Con mice had significantly (P<0.05) increased oxidative stress in the plasma and retina with augmented production of retinal NOx compared with WT-Con mice. Retinal TBARS decreased in the AE-MC and AE-CE animals compared with the AE-Con group (P<0.05 and P<0.01, respectively). Only AE-CE treatment significantly (P<0.01) lowered retinal NOx. Morphologic retinal changes in the AE-Con group decreased in the AE-CE and AE-MC groups. There were no significant changes in the biochemical and structural parameters in the AE-CD and AE-CC groups. AE-Con mice had increased systemic and retinal oxidative stress compared with WT-Con animals. Vitamins C and E and the multivitamin-mineral complex reduced oxidative stress and ultrastructural retinal changes in this murine model of hypercholesterolemia.

Topics: Animals; Antioxidants; Apolipoproteins E; Ascorbic Acid; Disease Models, Animal; Drug Evaluation, Preclinical; Flavonoids; Hyperlipoproteinemia Type III; Lipid Peroxidation; Lipids; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron; Nitric Oxide; Oxidative Stress; Pigment Epithelium of Eye; Retina; Vitamin E; Vitamins

Indirect observations are compatible with cardiac vitamin C deficiency as one contributory factor to oxidative stress in heart failure, but data on ventricular vitamin C content are lacking. Here, we used the well established model of aortic-banded rats at the stage of compensated hypertrophy (6 weeks after banding) and at the transition to cardiac failure (22 weeks after banding) to analyze vitamin C, vitamin E, protein carbonyls and malondialdehyde tissue content together with the respective plasma concentrations. Furthermore, we investigated the expression of the vitamin C transporters SVCT1 and SVCT2 in the left ventricle (LV). Aortic-banded rats, independently from their age, had higher malondialdehyde and protein carbonyl levels in plasma and LV tissue compared to sham-operated animals indicating increased oxidative stress. Plasma vitamin C remained unaffected from cardiac overload, while LV vitamin C was elevated in both stages of hypertrophy together with an increased expression of the vitamin C transporter SVCT2 suggesting increased vitamin C uptake. The levels of antioxidants and lipid peroxides were similar 6 and 22 weeks after aortic banding. Therefore, the accumulation of vitamin C in compensated hypertrophy and in decompensated failure excludes cardiac vitamin C deficiency as a primary factor to oxidative stress in this model.

Topics: Animals; Ascorbic Acid; Blotting, Western; Disease Models, Animal; Heart Failure; Hemodynamics; Hypertrophy, Left Ventricular; Lipid Peroxidation; Male; Malondialdehyde; Matrix Metalloproteinase 2; Myocardium; Organic Anion Transporters, Sodium-Dependent; Oxidative Stress; Protein Carbonylation; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Sodium-Coupled Vitamin C Transporters; Symporters; Tissue Inhibitor of Metalloproteinase-1; Vitamin E

Information on the change in extracellular ascorbic acid (AA) during the acute period of cerebral ischemia is of great importance in the early therapeutic intervention of the cerebral ischemic injury since AA is known to be involved into most kinds of neurochemical changes in the cerebral ischemia. This study describes a fast and efficient method through integration of in vivo microdialysis with on-line electrochemical detection for continuous monitoring cerebral AA, allowing comparative study of the change in the extracellular AA level in different brain ischemia/reperfusion models. The method exhibits a high specificity for AA measurements, bearing a good tolerance against the fluctuation in the brain anoxia and acidity induced by cerebral ischemia/reperfusion. In the global two-vessel occlusion (2-VO) ischemia model, the striatum AA did not change with statistic significance until 60 min after occlusion and was decreased to be 91+/-3% (n=5, P<0.05) of the basal level (8.05+/-0.23 microM) at the time point of 60 min after occlusion. In the 2-VO ischemia/reperfusion model, AA remained unchanged during the 10 min of ischemia, and was sharply increased to be 267+/-74% (n=5, P<0.05) of the basal level after the initial 15 min of reperfusion, and then decreased to be 122+/-33% (n=5, P<0.05) of the basal level after 50 min of reperfusion. Extracellular AA was largely increased after 5 min of left middle cerebral artery occlusion (LMCAO) and was then gradually increased to be 257+/-49% (n=5, P<0.05) of the basal level after 60 min of LMCAO ischemia. In the LMCAO ischemia/reperfusion model, AA was greatly increased during 10 min of ischemia and then gradually increased to be 309+/-69% (n=5, P<0.05) of the basal level after the consecutive 50 min of reperfusion. The results demonstrated here may be useful for understanding the neurochemical processes in the acute period of cerebral ischemia and could thus be important for neuroprotective therapeutics for cerebral ischemic injury.

Topics: Animals; Ascorbic Acid; Brain; Corpus Striatum; Disease Models, Animal; Electrochemistry; Extracellular Fluid; Hydrogen-Ion Concentration; Hypoxia-Ischemia, Brain; Infarction, Middle Cerebral Artery; Male; Microdialysis; Neurochemistry; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Processing, Computer-Assisted; Time Factors

Arazyme is a novel protease produced by the HY-3 strain of Aranicola proteolyticus, which is a Gram-negative aerobic bacterium that has been isolated from the intestine of the spider Nephila clavata. This study focused on the hepatoprotective effect of Arazyme on carbon tetrachloride (CCl4)-induced acute hepatic injury in senescence marker protein 30 (SMP30) knock-out (KO) mice and SMP30 wild-type (WT) mice. WT mice and SMP30 KO mice were divided into eight groups as follows: (i) two negative control groups (G1, G5) which were treated with a single intraperitoneal (i.p.) olive oil injection. (ii) Two positive control groups (G2, G6) which received a single i.p. CCl4 (0.4mL/kg) injection. (iii) Two vitamin C-treated groups (G3, G7) which received a single oral administration of vitamin C (100mg/kg) and were injected with a single i.p. CCl4 (0.4mL/kg). (iv) Two Arazyme-treated groups (G4, G8) which received a single oral administration of Arazyme (500mg/kg) and were injected with a single i.p. CCl4 (0.4mL/kg). Through present study, we could find that Arazyme-treated groups showed decreased degree of liver injury, increased expression of SMP30, decreased expression of phospho-Smad3 (p-Smad3), elevated expression of antioxidant proteins including sorbitol dehydrogenase, dihydropteridine reductase (DHPR), dehydrofolate reductase (DHFR), NADH dehydrogenase, glutathione S-transferase kappa 1 (GSTK1) and phospholipid hydroperoxide glutathione peroxidase (PHGPx) compared with non-Arazyme-treated groups. Therefore, it is concluded that Arazyme plays a significant role in protecting injured hepatocytes by increasing the expression of SMP30, inhibiting the transforming growth factor-beta (TGF-beta)/Smad pathway and elevating the expression of antioxidant proteins.

Topics: Animals; Antioxidants; Ascorbic Acid; Calcium-Binding Proteins; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Chemoprevention; Disease Models, Animal; Female; Fluorescent Antibody Technique, Indirect; Immunoenzyme Techniques; Intracellular Signaling Peptides and Proteins; Liver; Male; Metalloproteases; Mice; Mice, Knockout; Oxidoreductases; Proteomics; Serratia; Smad3 Protein; Specific Pathogen-Free Organisms; Transforming Growth Factor beta; Up-Regulation

Combination treatment with sodium nitrite (NaNO(2)) and ascorbic acid (AsA) is well known to promote forestomach carcinogenesis in rats and weakly enhance esophageal carcinogenesis under acid reflux conditions. Nitric oxide generation and oxidative DNA damage are considered to be related to the enhancement of carcinogenesis. The purpose of the present study was to investigate whether oxidative DNA damage-associated genotoxicity and tumor initiating potential are involved in the carcinogenesis. In the bacterial reverse mutation assay using Escherichia coli deficient in the mutM gene encoding 8-hydroxydeoxyguanosine (8-OHdG) DNA glycosylase, the combination with NaNO(2) and AsA increased the mutation frequency dramatically, slight increase being evident in the parental strain. In vivo, a significant increase in 8-OHdG levels in the rat forestomach epithelium occurred at 24 h after combined treatment. Six-week-old F344 male rats were given drinking water containing 0.2% NaNO(2) and a diet supplemented with 1% AsA in combination, or the chemicals individually or basal diet alone for 12 weeks. After an interval of 2 weeks, they received 1% butylated hydroxyanisole in the diet for promotion until the end of weeks 52 and 78. Although one squamous cell carcinoma was observed in the combined group, there was no significant variation in tumor development among the groups. The study indicated that the combination of NaNO(2) with AsA induces genotoxicity due to oxidative DNA damage in vitro, and elevates 8-OHdG levels in the forestomach epithelium, but lacks initiating activity in the rat two-stage carcinogenesis model.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Ascorbic Acid; Butylated Hydroxyanisole; Carcinogens; Cocarcinogenesis; Deoxyguanosine; Disease Models, Animal; DNA Damage; DNA, Bacterial; Drug Therapy, Combination; Escherichia coli; Gastric Mucosa; Male; Methylnitronitrosoguanidine; Mutagens; Organisms, Genetically Modified; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach Neoplasms

Nitroglycerin (GTN) acts through release of a nitric oxide (NO)-related activator of soluble guanylate cyclase in vascular smooth muscle. Besides enzymatic GTN bioactivation catalysed by aldehyde dehydrogenase, non-enzymatic reaction of GTN with ascorbate also results in the formation of a bioactive product. Using an established guinea pig model of ascorbate deficiency, we investigated whether endogenous ascorbate contributes to GTN-induced vasodilation.. Guinea pigs were fed either standard or ascorbate-free diet for 2 or 4 weeks prior to measuring the GTN response of aortic rings and isolated hearts. The effects of ascorbate on GTN metabolism were studied with purified mitochondrial aldehyde dehydrogenase (ALDH2) and isolated mitochondria. Ascorbate deprivation led to severe scorbutic symptoms and loss of body weight, but had no (2 weeks) or only slight (4 weeks) effects on aortic relaxations to a direct NO donor. The EC(50) of GTN was increased from 0.058 +/- 0.018 to 0.46 +/- 0.066 and 5.5 +/- 0.9 microM after 2 and 4 weeks of ascorbate-free diet, respectively. Similarly, coronary vasodilation to GTN was severely impaired in ascorbate deficiency. The potency of GTN was reduced to a similar extent by ALDH inhibitors in control and ascorbate-deficient blood vessels. Up to 10 mM ascorbate had no effect on GTN metabolism catalysed by purified ALDH2 or liver mitochondria isolated from ascorbate-deficient guinea pigs.. Our results indicate that prolonged ascorbate deficiency causes tolerance to GTN without affecting NO/cyclic GMP-mediated vasorelaxation.

Topics: Aldehyde Dehydrogenase; Animals; Aorta; Ascorbic Acid; Ascorbic Acid Deficiency; Disease Models, Animal; Female; Guinea Pigs; Heart; Heart Rate; Male; Mitochondria, Liver; Nitroglycerin; Regional Blood Flow; Scurvy; Vasodilation; Vasodilator Agents

A series of new tetrasubstituted thiophenes (4a-4i, 5a-5i and 6a-6f) have been synthesized as novel anti-inflammatory agents and were evaluated for their anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at the doses of 10, 20 and 40mg/kg body weight. Among ester series, the best compound 4c showed 71% protection at 10mg/kg, 72% at 20mg/kg, and 76% at 40mg/kg to inflamed paw; while in acid series 5a showed 79% protection at 10mg/kg, 80% at 20mg/kg, and 70% at 40mg/kg, and 5c showed 72% protection at 10mg/kg, 75% at 20mg/kg, and 69% at 40mg/kg, to inflamed paw. In case of oxime series 6a-6f, the anti-inflammatory activities of the candidates were found to be poor as compared to acid and ester series. It was found on the basis of SAR studies of target compounds, that the presence of OCH(3) at R(2) position and H, OCH(3) at R(1) are one of the requirements for eliciting comparable anti-inflammatory activity in both tetrasubstituted thiophenes' ester and acid series. Compounds 4a-4i, 5a-5i were investigated for their analgesic activity in acetic acid induced writhing response model at 10mg/kg dose. Among the ester series compound 4e showed maximum protection of 60%, while 4a, 4b, and 4i exhibited 55%, 45%, and 43% protection, respectively. The result showed that presence of H, Cl at R(1) and OCH(3), CH(3) at R(2) in tetrasubstituted thiophene ester series enhances their analgesic activity. The candidates of acid series 5a-5i showed poor analgesic activity as compared to the standard drug ibuprofen. Compounds 4a-4i, 5a-5i were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay. Among the ester series 4a showed maximum in vitro nitric oxide radical scavenging activity having IC(50) value 30.08microg/ml while in acid series 5a has IC(50) value 25.20microg/ml. The results showed that the presence of R(1)=H, R(2)=OCH(3) and R(1)=R(2)=OCH(3) enhances nitric oxide radical scavenging property in tetrasubstituted thiophenes' acid series.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Rats; Structure-Activity Relationship; Thiophenes

To evaluate changes in the reducing power of aqueous humor (AH) with cyclic voltammetry (CV) and HPLC-EC.. NZW Rabbits exhibiting a sporadic mutation causing bilaterally buphthalmus eyes were set for intra ocular pressure (IOP) and eye size measurements. AH was obtained under anesthesia, from congenital glaucomatic rabbits (CGR, n=6) and age-matched controls (CON; n=6). The AH samples were analysed by CV and HPLC-EC.. CGR IOP was found to be significantly higher than in CON (33.5+/-1.1 and 14.2+/-1.0 mmHg, respectively), eye size was 18.25 and 13.9 cm, respectively. CV analysis revealed two anodic currents representing two groups of low molecular weight antioxidant (LMWA). The two anodic potentials were equal for the two tested groups, indicating the same components of LMWA. The first anodic current of CGR was only 30% of the CON rabbits (2.11 vs7.17 microA/mg protein, t-test: P<0.05). As the main hydrophilic components of the first anodic current are known to be uric acid (UA) and ascorbic acid (AA), they were analysed for exact content by HPLC-EC. UA and AA levels were significantly lower in the CGR group (UA: 17.1+/-3.2 and 189.1+/-75.70 microM/mg, AA: 1.1+/-0.3 and 4.8+/-2.0 microM/mg protein respectively).. Changes in the reducing power, as indicated by CV analysis, of CGR AH, is probably a result of chronic oxidative stress caused by the pathology. The differences in the first anodic wave are mainly due to a fall in the concentration of UA and AA.

Topics: Animals; Aqueous Humor; Ascorbic Acid; Chromatography, High Pressure Liquid; Disease Models, Animal; Eye; Female; Glaucoma; Intraocular Pressure; Male; Oxidation-Reduction; Rabbits; Uric Acid

Excess hepatic iron is known to enhance both porphyria cutanea tarda (PCT) and experimental uroporphyria. Since previous studies have suggested a role for ascorbate (AA) in suppressing uroporphyria in AA-requiring rats (in the absence of excess iron), the present study investigated whether AA could suppress uroporphyria produced by excess hepatic iron. Hepatic URO accumulation was produced in AA-requiring Gulo(-/-) mice by treatment with 3,3',4,4',5-pentachlorbiphenyl, an inducer of CYP1A2, and 5-aminolevulinic acid. Mice were administered either sufficient AA (1000 ppm) in the drinking water to maintain near normal hepatic AA levels or a lower intake (75 ppm) that resulted in 70 % lower hepatic AA levels. The higher AA intake suppressed hepatic URO accumulation in the absence of administered iron, but not when iron dextran (300-500 mg Fe/kg) was administered. This effect of iron was not due to hepatic AA depletion since hepatic AA content was not decreased. The effect of iron to prevent AA suppression of hepatic URO accumulation was not observed until a high hepatic iron threshold was exceeded. At both low and high AA intakes, hepatic malondialdehyde (MDA), an indicator of oxidative stress, was increased three-fold by high doses of iron dextran. MDA was considerably increased even at low iron dextran doses, but without any increase in URO accumulation. The level of hepatic CYP1A2 was unaffected by either AA intake.. In this mouse model of PCT, AA suppresses hepatic URO accumulation at low, but not high hepatic iron levels. These results may have implications for the management of PCT.

Topics: Aminolevulinic Acid; Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Cytochrome P-450 CYP1A2; Dietary Supplements; Disease Models, Animal; Dose-Response Relationship, Drug; Iron; Iron-Dextran Complex; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidative Stress; Polychlorinated Biphenyls; Porphyria Cutanea Tarda; Uroporphyrins

Ethological assessment of murine models of Huntington's disease (HD), an inherited neurodegenerative disorder, enables correlation between phenotype and pathophysiology. Currently, the most characterized model is the R6/2 line that develops a progressive behavioral and neurological phenotype by 6 weeks of age. A recently developed knock-in model with 140 CAG repeats (KI) exhibits a subtle phenotype with a longer progressive course, more typical of adult-onset HD in humans. We evaluated rotarod performance, open-field behavior, and motor activity across the diurnal cycle in KI mice during early to mid-adulthood. Although we did not observe any effects of age, relative to wild-type (WT) mice, KI mice showed significant deficits in both open-field climbing behavior and home-cage running wheel activity during the light phase of the diurnal cycle. An interesting sex difference also emerged. KI females spent more time in the open-field grooming and more time running during the diurnal dark phase than KI males and WT mice of both sexes. In striatum, the primary site of HD pathology, we measured behavior-related changes in extracellular ascorbate (AA), which is abnormally low in the R6/2 line, consistent with a loss of antioxidant protection in HD. KI males exhibited a 20-40% decrease in striatal AA from anesthesia baseline to behavioral activation that was not observed in other groups. Collectively, our results indicate behavioral deficits in KI mice that may be specific to the diurnal cycle. Furthermore, sex differences observed in behavior and striatal AA release suggest sex-dependent variation in the phenotype and neuropathology of HD.

Topics: Analysis of Variance; Animals; Ascorbic Acid; Behavior, Animal; Body Weight; Circadian Rhythm; Disease Models, Animal; Exploratory Behavior; Female; Huntingtin Protein; Huntington Disease; Male; Mice; Mice, Transgenic; Motor Activity; Neostriatum; Nerve Tissue Proteins; Nuclear Proteins; Rotarod Performance Test; Sex Factors; Trinucleotide Repeat Expansion

Insulin-like growth factor 1 (IGF-1) and its major binding protein, IGF binding protein 3 (IGFBP-3) are implicated in lung cancer and other malignancies. We have previously shown that the combination of three major antioxidants [beta-carotene (BC), alpha-tocopherol (AT) and ascorbic acid (AA)] can prevent lung carcinogenesis in a 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-treated and smoke-exposed (SM) ferret model, which is highly analogous to humans. The present study is aimed at determining the effect of the combination of BC, AT and AA on antioxidant capacity, lymphocyte DNA damage, plasma IGF-1 and IGFBP-3 concentrations, as well as on IGF-1/IGFBP-3 mRNA expression in the tissues (lung and liver) of the ferrets. Ferrets were treated with or without combined antioxidant (BC, AT and AA) supplementation (AOX) for 6 months in the following 4 groups: (i) control; (ii) SM+NNK; (iii) AOX; and (iv) SM+NNK+AOX. Combined AOX supplementation significantly attenuated SM+NNK induced lymphocyte DNA damage in the ferret, while increasing resistance to oxidative damage when challenged with H(2)O(2) in vitro. Ferrets treated with SM+NNK had significantly lower IGFBP-3 mRNA expression in lungs, whereas there was significantly higher IGFBP-3 mRNA expression in the liver, as well as higher circulating IGFBP-3 concentrations. Combined AOX supplementation did not affect the plasma or tissue (lung and liver) ratio of IGF-1/IGFBP-3. Combined antioxidant supplementation provides protection against smoke-induced oxidative DNA damage, but does not affect the IGF-1/IGFBP-3 system. Differential expression of IGFBP-3 in different tissues indicates that caution should be taken when using plasma IGFBP-3 as a biomarker of tissue status.

Topics: Animals; Antioxidants; Ascorbic Acid; beta Carotene; Disease Models, Animal; DNA Breaks, Single-Stranded; Ferrets; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Liver; Lung; Lung Neoplasms; Male; Nitrosamines; Smoke; Vitamin E

Carbon tetrachloride (CCl(4): 4 ml/kg body weight as a 1:1 mixture of CCl(4) and mineral oil) was orally administered to rats. After 12 h the activity of plasma AST (aspartate aminotransferase) and ALT (alanine aminotransferase) was significantly higher than that of the control group and plasma AST and ALT activities increased thereafter. These results indicated that the necrotic process was active at about 12 h and developed thereafter. After 2-24 h of CCl(4) administration, the hepatic level of vitamin C, the most sensitive indicator of oxidative stress, decreased significantly, indicating that oxidative stress was significantly enhanced as early as 2 h after CCl(4) intoxication and thereafter. Phosphorylated JNK (c-Jun NH(2)-terminal kinase) and phospho-ERK1/2 (extracellular signal-regulated kinase1/2) were significantly increased transiently 1-3 h after treatment with CCl(4), while phosphorylated p38 decreased significantly 1-24 h after CCl(4) treatment. These results indicated that the change in MAPKs (mitogen activated protein kinases) slightly preceded that in vitamin C, the most sensitive chemical indicator of oxidative stress.

Topics: Animals; Ascorbic Acid; Carbon Tetrachloride Poisoning; Disease Models, Animal; Enzyme Activation; JNK Mitogen-Activated Protein Kinases; Liver; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Necrosis; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; Rats, Wistar; Time Factors

Recently, many antioxidants have been tested in cardiovascular disease. The effect of antioxidants on alleviation of coronary vasospasm, however, remains unclear. We investigated whether chronic administration of ascorbic acid and glutathione prevents coronary vasospasm in pigs.. Balloon-induced endothelial injury in the left anterior descending coronary artery was performed every 2 weeks until 6 weeks (0, 2, 4, 6 weeks). Ten micrograms per kilogram serotonin-induced vasoconstriction was assessed before each endothelial injury and at eighth week by coronary angiography.. In endothelial injury without antioxidant group (ED group, n=12), serotonin-induced left anterior descending coronary artery vasoconstriction was augmented from 7+/-4% (0 week) to 88+/-8% (8th week, P<0.01) with electrocardiogram-ST elevation, and an increase of cyclooxygenase-2 expression and a decrease of endothelial nitric oxide synthase expression was observed at the spasm portion removed from the endothelial denuded site. In the endothelial injury group with oral administration of ascorbic acid 3 g/day and glutathione 1 g/day after the first endothelial injury (ASC+GSH group, n=12), serotonin-induced vasoconstriction was suppressed (8th week, 60+/-6%, P<0.01 vs. ED group) and endothelial nitric oxide synthase expression was fairly well maintained. Intimal thickening was observed at the left anterior descending artery spasm portion in the endothelial injury without antioxidant group but not at the corresponding portion in the ASC+GSH group.. Antioxidant therapy was partially effective to prevent coronary vasospasm, whereas intimal thickening after endothelial injury was nearly restored. From these results, chronic antioxidant therapy may well be a useful supportive therapy for the treatment of coronary vasospasm, although it has limited availability despite amelioration of endothelial dysfunction.

Topics: Animals; Antioxidants; Ascorbic Acid; Coronary Vasospasm; Cyclooxygenase 2; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Glutathione; Heart Rate; Nitric Oxide Synthase Type III; Swine; Tunica Intima

To evaluate the effect of topically administered ascorbic acid on experimentally induced corneal neovascularization in the rat model.. Corneal chemical cauterization of 72 eyes in Long-Evans male rats was performed using silver nitrate/potassium nitrate sticks. Nine groups of eight eyes were used to evaluate eight concentrations of ascorbic acid with one group of eight eyes serving as a control. Topical instillation of 100 mg/ml non-pH-neutralized ascorbic acid was performed in one group while the remaining seven groups were evaluated using pH-neutralized ascorbic acid in concentrations of 100 mg/ml, 50 mg/ml, 10 mg/ml, 5 mg/ml, 1 mg/ml, 500 microg/ml, and 250 microg/ml.. The percentage of corneal neovascularization and burn stimulus score was determined for all the eyes. The means of percent of corneal neovascularization in ascorbic acid 100 mg/ml (non-neutralized), 100 mg/ml, 50 mg/ml, 10 mg/ml, 5 mg/ml, 1 mg/ml, 500 microg/ml, 250 microg/ml, and control group were 17.50 +/- 12.80 (p = 0.001), 17.00 +/- 19.30 (p = 0.001), 15.25 +/- 13.26 (p = 0.001), 17.62 +/- 11.89 (p = 0.001), 28.87 +/- 23.08 (p = 0.001), 29.62 +/- 16.91 (p = 0.001), 60.12 +/- 8.50 (p = 0.04), 65.62 +/- 2.26 (p = 0.185), and 68.25 +/- 4.06, respectively (Tables 1 and 2). All animals had a burn score of 2+ or higher (Table 1).. Ascorbic acid applied in a topical solution appears to inhibit corneal neovascularization in the rat model of inflammatory neovascularization in concentrations in a dose-dependent manner. The optimal dose-effect relation was in our model found in concentrations between 1 mg and 500 microg/ml. At concentrations below 500 microg/ml there was no statistically significant inhibition in the degree of corneal neovascularization compared to control.

Topics: Administration, Topical; Angiogenesis Inhibitors; Animals; Antioxidants; Ascorbic Acid; Corneal Neovascularization; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Hydrogen-Ion Concentration; Nitrates; Potassium Compounds; Rats; Rats, Long-Evans; Silver Nitrate

Angiogenesis requires the deposition of type IV collagen by endothelial cells into the basement membrane of new blood vessels. Stabilization of type IV collagen triple helix depends on the hydroxylation of proline, which is catalyzed by the iron-containing enzyme prolyl hydroxylase. This enzyme, in turn, requires ascorbic acid to maintain the enzyme-bound iron in its reduced state. We hypothesized that dietary ascorbic acid might be required for tumor angiogenesis and, therefore, tumor growth. Here, we show that, not surprisingly, ascorbic acid is necessary for the synthesis of collagen type IV by human endothelial cells and for their effective migration and tube formation on a basement membrane matrix. Furthermore, ascorbic acid depletion in mice incapable of synthesizing ascorbic acid (Gulo(-/-)) dramatically restricts the in vivo growth of implanted Lewis lung carcinoma tumors. Histopathological analyses of these tumors reveal poorly formed blood vessels, extensive hemorrhagic foci, and decreased collagen and von Willebrand factor expression. Our data indicate that ascorbic acid plays an essential role in tumor angiogenesis and growth, and that restriction of ascorbic acid or pharmacological inhibition of prolyl hydroxylase may prove to be novel therapeutic approaches to the treatment of cancer.

Topics: Animals; Ascorbic Acid; Carcinoma, Lewis Lung; Cell Movement; Cells, Cultured; Collagen Type IV; Disease Models, Animal; Endothelial Cells; Humans; L-Gulonolactone Oxidase; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Procollagen-Proline Dioxygenase

We studied the effect of vitamin C on fracture healing in the elderly. A total of 80 elderly Osteogenic Disorder Shionogi rats were divided into four groups with different rates of vitamin C intake. A closed bilateral fracture was made in the middle third of the femur of each rat. Five weeks after fracture the femora were analysed by mechanical and histological testing. The groups with the lower vitamin C intake demonstrated a lower mechanical resistance of the healing callus and a lower histological grade. The vitamin C levels in blood during healing correlated with the torque resistance of the callus formed (r = 0.525). Therefore, the supplementary vitamin C improved the mechanical resistance of the fracture callus in elderly rats. If these results are similar in humans, vitamin C supplementation should be recommended during fracture healing in the elderly.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Biomechanical Phenomena; Dietary Supplements; Disease Models, Animal; Female; Femoral Fractures; Femur; Fracture Healing; Rats; Rats, Mutant Strains; Stress, Mechanical; Vitamins

Epileptic seizure results from excessive discharge in a population of hyperexcitable neurons. A number of studies help to document the effects of active oxygen free radical scavengers such as alpha-tocopherol or ascorbic acid (vitamin C). In the present study, we examined the effects of ascorbic acid, at the six different doses, on penicillin-induced epileptiform activity.. A single microinjection of penicillin (2.5 microl, 500 units, intracortically) into the left sensorimotor cortex induced epileptiform activity within 2-5 min, progressing to full seizure activity lasting approximately 3-5 h. In the first set of experiments, 30 min after penicillin injection, six different doses of ascorbic acid (25, 50, 100, 200, 400, or 800 mg/kg) were administered intraperitoneally (IP). The other group of animals received the effective dose of ascorbic acid (100 mg/kg, IP) for 7 days. Ascorbic acid administration was stopped 24 h before penicillin treatment. Another group of rats received the effective dose of ascorbic acid (100 mg/kg, IP) 30 min before penicillin treatment. In the second set of experiments, the lipid peroxidation (MDA) and reduced glutathione (GSH) levels of brain were measured in the control, control + ascorbic acid, penicillin, and penicillin + ascorbic acid groups.. Ascorbic acid, at the low dose (50, 100 mg/kg, 30 min after penicillin injection), decreased both the frequency and amplitude of penicillin-induced epileptiform activity in rats. Ascorbic acid, at intermediate doses (200, 400 mg/kg, 30 min after penicillin injection), decreased the frequency of epileptiform activity without changing the amplitude. Ascorbic acid, at the lowest dose (25 mg/kg) and highest dose (800 mg/kg) (30 min after penicillin injection), did not change either the frequency or amplitude of epileptiform activity. Ascorbic acid, at the low dose (100 mg/kg) was the most effective dose in changing the frequency and amplitude of penicillin-induced epileptiform activity. Pretreatment with ascorbic acid (100 mg/kg) 30 min before penicillin treatment caused a significant delay in the onset of penicillin-induced epileptiform activity. Pretreatment with ascorbic acid (100 mg/kg) for 7 days did not change the latency of epileptiform activity. The most effective dose of ascorbic acid (100 mg/kg) prevented both the decrease in GSH level and the increase in lipid peroxidation level (MDA) occurring after penicillin-induced epileptiform activity.. These data indicate that ascorbic acid has neuroprotective activity against penicillin-induced epileptiform electrocorticogram activity.

Topics: Animals; Ascorbic Acid; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Free Radical Scavengers; Glutathione; Injections, Intraperitoneal; Lipid Peroxidation; Male; Penicillins; Rats; Rats, Wistar

The objective of this study was to compare the beneficial effects of caffeic acid phenethyl ester (CAPE), vitamin C, vitamin E and N-acetylcysteine on vancomycin-induced nephrotoxicity. Thirty rats were randomly devided into six groups: (i) control; (ii) vancomycin, 200 mg/kg administrated via intraperitoneal route; (iii) vancomycin plus CAPE-vancomycin with 10 micromol/kg CAPE; (iv) vancomycin plus vitamin C-vancomycin (intraperitoneally) with 200 mg/dl vitamin C in drinking water; (v) vancomycin plus vitamin E-vancomycin with 1000 mg/kg body weight vitamin E (intramuscularly); and (vi) vancomycin plus N-acetylcysteine-vancomycin with 10 mg/kg body weight (intraperitoneally) of N-acetylcysteine. Vancomycin treatments were started 1 day after the first administrations of these agents and continued for 7 days. At the end of the experiments, catalase activity was significantly decreased by vancomycin in kidney homogenates (P < 0.05). Vitamin E, vitamin C, N-acetylcysteine and CAPE administrations decreased the blood urea nitrogen levels increased by vancomycin, although significant differences were detected only in the vitamins E and C groups (P < 0.05). Increased renal malondialdehyde and nitric oxide levels by vancomycin were significantly suppressed by agents used in the study (P < 0.05). Histopathological examination demonstrated prominent damages in the vancomycin-treated group. Vitamin E was the most beneficial agent on vancomycin-induced tubular damage, followed by vitamin C, N-acetylcysteine and CAPE treatments, respectively. The data suggest that vitamin E, as well as vitamin C, N-acetylcysteine and CAPE, could be useful for reducing the detrimental effects on vancomycin-induced toxicity in kidneys.

Topics: Acetylcysteine; Animals; Anti-Bacterial Agents; Antioxidants; Ascorbic Acid; Blood Urea Nitrogen; Caffeic Acids; Catalase; Disease Models, Animal; Drinking; Drug Combinations; Injections, Intramuscular; Injections, Intraperitoneal; Kidney; Kidney Diseases; Male; Phenylethyl Alcohol; Rats; Rats, Wistar; Vancomycin; Vitamin E; Water Supply

Glutathione (GSH) metabolism dysfunction is one risk factor in schizophrenia. A transitory brain GSH deficit was induced in Wistar (WIS) and mutant (ODS; lacking ascorbic acid synthesis) rats using BSO (l-buthionine-(S,R)-sulfoximine) from post-natal days 5-16. When GSH was re-established to physiological levels, juvenile BSO-ODS rats were impaired in the water maze task. Long after treatment cessation, adult BSO-WIS/-ODS rats showed impaired place discrimination in the homing board with distributed visual or olfactory cues. Their accuracy was restored when a single cue marked the trained position. Similarly, more working memory errors were made by adult BSO-WIS in the radial maze when several olfactory cues were present. These results reveal that BSO rats did not suffer simple sensory impairment. They were selectively impaired in spatial memory when the task required the integration of multimodal or olfactory cues. These results, in part, resemble some of the reported olfactory discrimination and cognitive impairment in schizophrenia.

Topics: Aging; Animals; Animals, Newborn; Ascorbic Acid; Brain; Cognition Disorders; Cues; Disease Models, Animal; Female; Glutathione; Male; Maze Learning; Memory Disorders; Nerve Degeneration; Olfaction Disorders; Orientation; Oxidative Stress; Rats; Rats, Mutant Strains; Rats, Wistar; Schizophrenia; Sex Characteristics; Smell

When the availability of tetrahydrobiopterin (BH4) is deficient, endothelial nitric oxide synthase (eNOS) produces superoxide rather than NO (uncoupled eNOS). We have shown that the atherosclerotic lesion size was augmented in apolipoprotein E-deficient (ApoE-KO) mice overexpressing eNOS because of the enhanced superoxide production. In this study, we addressed the specific importance of uncoupled eNOS in atherosclerosis, and the potential mechanistic role for specific versus nonspecific antioxidant strategies in restoring eNOS coupling.. We crossed mice overexpressing eNOS in the endothelium (eNOS-Tg) with mice overexpressing GTP-cyclohydrolase I (GCH), the rate-limiting enzyme in BH4 synthesis, to generate ApoE-KO/eNOS-Tg/GCH-Tg mice. As a comparison, ApoE-KO/eNOS-Tg mice were treated with vitamin C. Atherosclerotic lesion formation was increased in ApoE-KO/eNOS-Tg mice compared with ApoE-KO mice. GCH overexpression in ApoE-KO/eNOS-Tg/GCH-Tg mice increased vascular BH4 levels and reduced plaque area. This reduction was associated with decreased superoxide production from uncoupled eNOS. Vitamin C treatment failed to reduce atherosclerotic lesion size in ApoE-KO/eNOS-Tg mice, despite reducing overall vascular superoxide production.. In contrast to vitamin C treatment, augmenting BH4 levels in the endothelium by GCH overexpression reduced the accelerated atherosclerotic lesion formation in ApoE-KO/eNOS-Tg mice, associated with a reduction of superoxide production from uncoupled eNOS.

Topics: Analysis of Variance; Animals; Antioxidants; Apolipoproteins E; Ascorbic Acid; Atherosclerosis; Biopterins; Disease Models, Animal; Endothelium, Vascular; Female; GTP Cyclohydrolase; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type III; Probability; Reactive Oxygen Species; Sensitivity and Specificity; Superoxides

Hyperglycemia worsens outcome of stroke either in the clinical setting or in animal models. In the present study, two focal cerebral ischemia models, permanent middle cerebral artery occlusion (MCAO, 3-4 h) and reversible MCAO (1 h ischemia + 3 h reperfusion), under hyperglycemic conditions were compared. Using 2,3,5-triphenyltetrazolium chloride staining to define viable tissue, this resulted in the infarction area being confined primarily to the cerebral cortex in the permanent MCAO group, while it extended to the subcortical area in the reversible MCAO group, and the lesion areas were respectively 27.7 +/- 5.3% and 46.8 +/- 12.0% of the ipsilateral hemisphere (P = 0.012). Hyperglycemia accelerated the cerebral damage compared to normoglycemia and ascorbic acid pre-treatment maintained tissue viability during the acute phase of hyperglycemic MCAO. In conclusion, hyperglycemia combined with either of the two MCAO models resulted in rapid infarction associated with increased oxidative stress. The hyperglycemic models are suitable for pharmaceutical therapeutic studies of antioxidant efficacy.

Topics: Animals; Antioxidants; Ascorbic Acid; Blood Glucose; Disease Models, Animal; Hyperglycemia; Infarction, Middle Cerebral Artery; Male; Rats; Rats, Sprague-Dawley

Retinitis pigmentosa (RP) is a heterogeneous group of diseases in which one of a wide variety of mutations selectively causes rod photoreceptor cell death. After rods die, cone photoreceptors gradually die resulting in blindness. Antioxidants reduce cone cell death in rd1/rd1 mice indicating that cones die from oxidative damage in that model of rapidly progressive RP. In this study, we sought to determine if this observation could be generalized to models of other types of RP, rd10/rd10 mice, a model of more slowly progressive recessive RP, and Q344ter mice, a model of rapidly progressive dominant RP. Compared to appropriate vehicle-treated controls, rd10/rd10 and Q344ter mice treated between P18 and P35 with a mixture of antioxidants previously found to be effective in rd1/rd1 mice showed significantly greater cone survival. Antioxidant-treated rd10/rd10 mice showed preservation of cone function as shown by a significant increase in photopic ERG b-wave amplitudes, and surprisingly showed temporary preservation of scotopic a-wave amplitudes, prolonged rod survival, and slowed depletion of rhodopsin mRNA. These data suggest that oxidative damage contributes to cone cell death regardless of the disease causing mutation that leads to the demise of rods, and that in more slowly progressive rod degenerations, oxidative damage may also contribute to rod cell death. Protection from oxidative damage may be a broadly applicable treatment strategy in RP.

Topics: alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; Cell Death; Codon, Nonsense; Cyclic Nucleotide Phosphodiesterases, Type 6; Disease Models, Animal; Drug Administration Schedule; Electroretinography; Exons; Heterozygote; Homozygote; Injections, Intraperitoneal; Kinetics; Mice; Mice, Mutant Strains; Mutation, Missense; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Rhodopsin; RNA, Messenger; Thioctic Acid

Ascorbic acid has shown promise in attenuation of intestinal ischemia-reperfusion (I/R) injury. The aim of this study was to determine the protective effects of ascorbic acid on intestinal morphology during IR injury in rats.. We examined morphological changes in the small intestine of Wistar rats after (i) 40 minutes of ischemia (I), (ii) ischemia followed by 30 min of reperfusion (IR), (iii) ischemia with ascorbic acid (IA), (iv) ischemia followed by reperfusion and ascorbic acid (IRA) and (v) in a sham group (S). We used morphometry to evaluate the amount of villous architecture, crypts, necrosis, hemorrhagic infarcts and inflammatory cells at the mesenteric and antimesenteric borders of the small intestine.. Ascorbic acid caused a significant reduction of antimesenteric villous hemorrhagic infarction (p<0.05) of the small intestine after ischemia followed by reperfusion as well as villous necrosis reduction at both borders after ischemia (p<0.05). The lesions found in the small intestine were more prominent along the antimesenteric margin.. Ascorbic acid pretreatment has a protective effect against the intestinal morphological lesions induced by ischemia-reperfusion injury in rats.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Intestine, Small; Male; Rats; Rats, Wistar; Reperfusion Injury; Time Factors

D-Galactosamine (D-Galn: 300 mg/kg) was intraperitoneally administered to rats. After 6 h the activity of plasma GOT and GPT was significantly higher than that of the control group and plasma GOT and GPT activities increased thereafter. These results indicated that the necrotic process was initiated at about 6 h and developed thereafter. With coadministration of DMSO (1 h before administration of D-Galn: 2.5 mL/kg, oral), plasma GOT and GPT were significantly lower, showing that DMSO inhibited the necrotic action of D-Galn. After 6-24 h of D-Galn administration, the hepatic level of vitamin C, the most sensitive indicator of oxidative stress, decreased significantly, indicating that oxidative stress was significantly enhanced 6 h after D-Galn intoxication and thereafter. DMSO significantly restored the liver vitamin C level 24 h after D-Galn injection, demonstrating that DMSO effectively ameliorated the oxidative stress caused by D-Galn, resulting in the prevention of necrosis of the liver. Phosphorylated JNK and phospho-ERK were significantly increased transiently 6-12 h after treatment with D-Galn. These results indicated that oxidative stress and the activation of JNK took place almost simultaneously. Phosphorylated p38 MAPK was not changed and DMSO treatment did not affect the change of these MAPKs by D-Galn.

Topics: Alanine Transaminase; Analysis of Variance; Animals; Ascorbic Acid; Aspartate Aminotransferases; Blotting, Western; Dimethyl Sulfoxide; Disease Models, Animal; Free Radical Scavengers; Galactosamine; Liver; Male; Mitogen-Activated Protein Kinases; Necrosis; Oxidative Stress; Rats; Rats, Wistar; Time Factors

Cisplatin is a widely used antineoplastic agent that exhibits dose limiting nephrotoxicity. We have previously shown that the administration of cisplatin results in decrease in the activities of renal brush border membrane (BBM) enzymes and transport of inorganic phosphate (Pi) across BBM vesicles. In the present study we have investigated the effect of pre-treatment with vitamin C (ascorbic acid) on cisplatin-induced nephrotoxicity and changes in BBM enzymes and Pi transport. Administration of a single dose of cisplatin (6 mg/kg body weight) caused nephrotoxicity in rats that manifested biochemically as an elevation of serum urea nitrogen and creatinine levels. Treatment of rats with a single dose of vitamin C, six hours prior to administration of cisplatin, protected the kidney from the damaging effect of cisplatin. Vitamin C pre-treatment significantly decreased the urea nitrogen and creatinine levels. It attenuated the cisplatin-induced reduction in the activities of BBM and anti-oxidant enzymes and also Pi transport. These results suggest that vitamin C is an effective chemoprotectant against cisplatin-induced acute renal failure and dysfunction of the renal BBM in rats.

Topics: Acute Kidney Injury; Alkaline Phosphatase; alpha-Glucosidases; Animals; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Blood Urea Nitrogen; Catalase; Cisplatin; Creatinine; Disease Models, Animal; Dose-Response Relationship, Drug; Enzymes; gamma-Glutamyltransferase; Kidney; Kidney Cortex; Leucyl Aminopeptidase; Lipid Peroxidation; Male; Microvilli; Phosphates; Rats; Rats, Wistar; Sulfhydryl Compounds; Superoxide Dismutase

To investigate the effects of free oxygen radicals and various antioxidants on bone healing after experimental formation of fracture.. Fifty male rats were used and divided into five groups (ten rats in each). The right forelimbs of the rats were broken by bimanual compression method. One hour before this procedure, 5 ml/kg of intraperitoneal (i.p.) physiologic saline were given to the control Group 1. All 40 rats in the experimental Groups 2, 3, 4 and 5 were treated with i.p. zymosan at a dosage of 100 mg/kg to induce the production of free radicals by stimulating NADPH oxidase in polymorphonuclear leukocytes. Zymosan induction was stopped on the fifth post-fracture day. In addition to the zymosan, i.p. 1 g/kg/day of dimethyl sulfoxide were given to the animals in Group 3, 50 mg/kg/d of Ginko biloba Extract (EGb 761) in Group 4 and 500 mg/kg/day of vitamin C in Group 5. Radiographs of the fractures of all animals were obtained to assess callus formation, remodeling and bridging bone formation under ether anesthetics on postfracture day 7, 14 and 21. All rats were euthanized on day 22, and sections of the radius and ulna were examined both histologically with light and electron microscopy and ultrastructurally. Statistical analysis was made with Kruskal-Wallis variance analyze test and comparison between groups was performed by Dunn's multiple comparison test.. An impairment of bone healing was observed in Group 2 inducted with purely zymosan. Variable results were obtained for bone healing in the groups treated with various antioxidants. There was very significant difference of fracture healing between Groups 1 and 2 both histologically and radiologically (P < 0.001). There was significant difference between Groups 2 and 5 radiologically (P < 0.05).. Free oxygen radicals demonstrate a negative effect on fracture healing and vitamin C (an antioxidant) partially prevents the negative effect of zymosan on fracture healing.

Topics: Animals; Antioxidants; Ascorbic Acid; Dimethyl Sulfoxide; Disease Models, Animal; Fracture Healing; Free Radical Scavengers; Free Radicals; Ginkgo biloba; Male; Plant Extracts; Radius Fractures; Random Allocation; Rats; Rats, Wistar; Research Design; Statistics, Nonparametric; Time Factors; Ulna Fractures; Zymosan

This study was designed to examine if diphenyl diselenide (PhSe)(2), an organoselenium compound, attenuates pulmonar and cerebral oxidative stress caused by sub-chronic exposure to CdCl(2). Male adult Swiss albino mice received CdCl(2) (10 micromol/kg, subcutaneously), 5 times/week, for 4 weeks. (PhSe)(2) (10 micromol/kg or 20 micromol/kg, orally) was given concomitantly with CdCl(2) to mice. A number of toxicological parameters in lung and brain of mice were examined including delta-aminolevulinic acid dehydratase (delta-ALA-D), superoxide dismutase (SOD) and catalase activities, lipid peroxidation, non-protein thiols (NPSH) and ascorbic acid content. Na(+),K(+)-ATPase activity, acetylcholinesterase (AChE) activity, [(3)H]glutamate uptake and [(3)H]glutamate release were also carried out in brain. Cadmium concentration and histopathological analysis were carried out in lung tissue. (PhSe)(2) at the dose of 20 micromol/kg protected the inhibition of delta-ALA-D, SOD and CAT activities, the reduction of vitamin C content and the increase of lipid peroxidation levels caused by CdCl(2) in lungs. At 10 micromol/kg, (PhSe)(2) protected cerebral AChE and CAT activities inhibited by CdCl(2). There were no histopathological alterations in the lung of mice after CdCl(2) exposure. The pulmonary cadmium concentration was higher (2.8-fold) in the group exposed to CdCl(2) than in control mice. (PhSe)(2) at dose of 20 micromol/kg reduced cadmium concentration towards the control level. The results suggest that oral administration of (PhSe)(2) attenuated the oxidative damage induced by CdCl(2) in lung and brain of mice.

Topics: Acetylcholinesterase; Animals; Antioxidants; Ascorbic Acid; Benzene Derivatives; Brain; Brain Diseases; Cadmium Chloride; Catalase; Disease Models, Animal; Dose-Response Relationship, Drug; Glutamic Acid; Lipid Peroxidation; Lung; Lung Diseases; Male; Mice; Organoselenium Compounds; Oxidative Stress; Porphobilinogen Synthase; Sodium-Potassium-Exchanging ATPase; Sulfhydryl Compounds; Superoxide Dismutase

The study evaluates the inhibitory activity of ethanolic root extract of Hemidesmus indicus (H. indicus) and its active principle 2-hydroxy 4-methoxy benzoic acid (HMBA) on liver fibrotic markers and characteristics such as collagen content, matrix metalloproteinases (MMPs) 2 and 9 in ethanol-fed rats. Experimental groups were control, H. indicus (500 mg/kg body weight every day during the last 30 days), HMBA (200 microg/kg body weight every day during the last 30 days), alcohol (5 g/kg body weight by intragastric intubation everyday, i.e. throughout the experimental period of 60 days), alcohol plus H. indicus and alcohol plus HMBA. Ethanol administration significantly increased the levels of liver collagen and hydroxy proline content, cross-linked fluorescence, shrinkage temperature and lipid peroxidation and significantly decreased the solubility of liver collagen and the ascorbic acid content when compared with control rats. On treatment with H. indicus and HMBA the ethanol-fed rats showed significantly reduced levels of liver collagen and hydroxyproline content, cross-linked fluorescence, shrinkage temperature and lipid peroxidation and enhanced solubility of liver collagen and ascorbic acid levels when compared with untreated ethanol-fed rats. MMPs were extracted from the liver of control, H. indicus-treated, HMBA-treated, ethanol-administered, ethanol with H. indicus-coadministered and ethanol with HMBA-coadministered rats. The inhibition was analyzed by gelatin zymography and the percentage of expression was determined by a gel documentation system. The activities of MMPs 2 and 9 were significantly increased in ethanol-supplemented rats. Cotreatment of H. indicus/HMBA with ethanol showed significantly decreased activities of these enzymes when compared with those of the untreated rats. H. indicus/HMBA alone treatment showed no such significant alterations. Thus, our present study reveals the strong inhibitory activity of H. indicus and HMBA on the quantitative and qualitative properties of hepatic collagen and also MMPs involved in the extracellular matrix degradation during ethanol intoxication.

Topics: Animals; Ascorbic Acid; Benzoates; Central Nervous System Depressants; Collagen; Disease Models, Animal; Ethanol; Fluorescence; Hemidesmus; Hydroxyproline; Lipid Peroxidation; Liver; Liver Diseases, Alcoholic; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Plant Roots; Rats; Rats, Wistar

The aim of this study is to determine the relation between diabetes and vaginal candidiasis in terms of oxidative biomarker levels in a vaginal candidiasis model of the diabetic rats by evaluating malondialdehyde (MDA), sulphydrile groups or glutathione (RSH), and ascorbic acid (C vit) levels. All rats were randomly divided into five groups. All of the groups were observed for 21 days. In the treated diabetes groups, MDA (0.90, 0.68 nmol/ml and 3.78, 3.79 nmol/g tissue, plasma and vaginal tissue, respectively) and RSH (227, 171 nmol/100 ml 0.38, 0.37 micromol/g tissue, plasma and vaginal tissue, respectively) levels were found to be decreased while the levels of C vit were found to be increased (0.49, 0.37 micromol/l 2.39, 2.01 nmol/g tissue plasma, and vaginal tissue, respectively) (P < 0.05). In the groups of untreated diabetes, vaginal candidiasis were found to be more serious and oxidative biomarkers were found to be increased (MDA 1.30, 1.26 nmol/ml and 7.82, 2.37 nmol/g tissue and RSH 258, 145 nmol/100 ml and 0.31, 0.46 micromol/g tissue) while the antioxidant C vit levels were found to be decreased (0.24, 0.17 micromol/l 1.33, 2.66 nmol/g tissue) (P < 0.05). RSH, plasma MDA, blood glucose, and tissue MDA levels of vaginal candidiasis embedeled diabetic rats, were found to be higher than those in untreated diabetic and untreated vaginitis enbedeled rats 'P < 0.05'. Vaginal candidiasis caused oxidative stress in diabetic rats working together. Systemic oxidative stress biomarkers were found to be affected from vaginal candidiasis although it was a local mucosal infection.

Topics: Animals; Ascorbic Acid; Biomarkers; Blood Glucose; Candidiasis; Diabetes Mellitus, Experimental; Disease Models, Animal; Female; Glutathione; Lipid Peroxides; Malondialdehyde; Oxidative Stress; Random Allocation; Rats; Rats, Wistar; Streptozocin; Vaginal Diseases

The goal of this study was to test the hypothesis that increases in oxidative stress in Dahl S rats on a high-salt diet help to stimulate renal nuclear factor-kappaB (NF-kappaB), renal proinflammatory cytokines, and chemokines, thus contributing to hypertension, renal damage, and dysfunction. We specifically studied whether antioxidant treatment of Dahl S rats on high Na intake would decrease renal inflammation and thus attenuate the hypertensive and adverse renal responses. Sixty-four 7- to 8-wk-old Dahl S or R/Rapp strain rats were maintained for 5 wk on high Na (8%) or high Na + vitamins C (1 g/l in drinking water) and E (5,000 IU/kg in food). Arterial and venous catheters were implanted at day 21. By day 35 in the high-Na S rats, antioxidant treatment significantly increased the renal reduced-to-oxidized glutathione ratio and decreased renal cortical H(2)O(2) and O(2)(*-) release and renal NF-kappaB. Antioxidant treatment with vitamins C and E in high-Na S rats also decreased renal monocytes/macrophages in the glomeruli, cortex, and medulla, decreased tumor necrosis factor-alpha by 39%, and decreased monocyte chemoattractant protein-1 by 38%. Vitamin-treated, high-Na S rats also experienced decreases in arterial pressure, urinary protein excretion, renal tubulointerstitial damage, and glomerular necrosis and increases in glomerular filtration rate and renal plasma flow. In conclusion, antioxidant treatment of high-Na Dahl S rats decreased renal inflammatory cytokines and chemokines, renal immune cells, NF-kappaB, and arterial pressure and improved renal function and damage.

Topics: Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Antioxidants; Ascorbic Acid; Blood Pressure; Chemokine CCL2; Disease Models, Animal; Glomerular Filtration Rate; Glutathione; Heart Rate; Hydrogen Peroxide; Hypertension; Inflammation; Interleukin-6; Kidney; Macrophages; Monocytes; NF-kappa B; Oxidative Stress; Proteinuria; Rats; Rats, Inbred Dahl; Renal Circulation; Sodium Chloride, Dietary; Superoxides; Time Factors; Tumor Necrosis Factor-alpha; Vitamin E

Lead is a neurotoxin that affects the developing central nervous system and may potentially induce apoptotic cell death. We investigated the effect of ascorbic acid against lead-induced neurotoxicity in the developing rat hippocampus. Female Sprague-Dawley rats were divided into three groups: control group, lead-treated group and lead plus ascorbic acid-treated group. Lead (0.2% lead acetate) was administered to female rats during pregnancy and lactation, in their drinking water. During this period, rats in the lead plus ascorbic acid-treated group received 100 mg/kg/day ascorbic acid, orally. At the end of the treatment, neuronal damage, apoptosis and blood lead levels were determined and the levels of Bax and Bcl-2 were immunodetected in the hippocampus of 21-day-old male pups. Histopathological evaluation demonstrated that ascorbic acid significantly attenuates apoptosis in the developing hippocampus and also spares hippocampal CA1, CA3 and dentate gyrus (DG) neurons. Simultaneous administration of ascorbic acid and lead lowered the level of Bax protein and increased Bcl-2 in pup hippocampus and reduced lead level in blood of dams compared with lead-treated only. Based on these results, it seems that ascorbic acid may potentially be beneficial in treating lead-induced brain injury in the developing rat brain.

Topics: Animals; Animals, Newborn; Apoptosis; Ascorbic Acid; bcl-2-Associated X Protein; Disease Models, Animal; Drug Interactions; Female; Gene Expression Regulation, Developmental; Hippocampus; In Situ Nick-End Labeling; Lead; Lead Poisoning; Male; Nerve Degeneration; Neuroprotective Agents; Pregnancy; Proto-Oncogene Proteins c-bcl-2; Rats

This study examined whether the anti-oxidants ascorbic acid, alpha- or gamma-tocopherol, could modify adrenocorticotrophic hormone (ACTH)-hypertension in Sprague-Dawley rats, a model associated with increased oxidative stress. Systolic blood pressure (SBP) was measured by the tail-cuff method. After four days of ascorbic acid (AA) (200 mg/kg/day drinking) or alpha-tocopherol (500 mg/kg/d i.p. or feed), rats were co-administered ACTH (0.2 mg/kg/day s.c.) or saline for 11 days (prevention studies). In reversal studies, ACTH/saline was administered for 15 days, and from day 9, alpha- or gamma-tocopherol (20 mg/kg/day) was added. ACTH increased SBP compared to saline (p < 0.05). AA or alpha-tocopherol failed to prevent and alpha- or gamma-tocopherol failed to reverse ACTH-induced hypertension. Thus, neither vitamin C (water soluble) nor E (lipid soluble) modified ACTH-induced hypertension in the rat.

Topics: Adrenocorticotropic Hormone; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Hypertension; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Systole; Tocopherols; Vitamins

Contamination of arsenic in drinking water is associated with several human diseases including cancer. It has been reported that oxidative stress plays a vital role in arsenic-induced biochemical and molecular alterations. The aim of the present study was to improve the understanding of arsenic-induced oxidative damage to proteins and to DNA and the role of antioxidants such as ascorbic acid and alpha-tocopherol in alleviating arsenic-induced damages in experimental rats. A significant increase in the levels of protein oxidation, DNA strand breaks, and DNA-protein cross-links was observed in blood, liver, and kidney of rats exposed to arsenic (100 ppm in drinking water) for 30 days. Co-administration of ascorbic acid and alpha-tocopherol to arsenic-exposed rats showed a substantial reduction in the levels of arsenic-induced oxidative products of protein and DNA. The results of this study support that free radical-mediated toxic manifestations of arsenic and also suggest that ascorbic acid and alpha-tocopherol supplementation can improve the arsenic-induced molecular alterations.

Topics: Administration, Oral; alpha-Tocopherol; Animals; Antioxidants; Arsenic Poisoning; Arsenites; Ascorbic Acid; Comet Assay; Cross-Linking Reagents; Disease Models, Animal; DNA Damage; Drug Therapy, Combination; Enzyme Inhibitors; Kidney; Liver; Male; Oxidative Stress; Protein Carbonylation; Rats; Rats, Wistar; Sodium Compounds; Water Supply

Topics: Animals; Antioxidants; Arginine; Ascorbic Acid; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Endothelium; Male; Oxidative Stress; Rats; Renal Insufficiency; Vitamin E

Membrane and morphological abnormalities occur in the striatum of R6/2 transgenics, a widely used mouse model of Huntington's disease. To assess changes in behavior-related neuronal activity, we implanted micro-wire bundles in the striatum of symptomatic R6/2 mice and wild-type controls. Unit activity was recorded in an open-field arena once weekly for the next several weeks. For each recording session, firing rate was monitored before, during, and after a period of light anesthesia to assess the influence of behavioral arousal. Because low ascorbate in striatal extracellular fluid may contribute to Huntington's disease symptoms, all animals received an injection of either 300 mg/kg sodium ascorbate or vehicle for three consecutive days prior to each recording session. In R6/2 mice, regardless of treatment, striatal unit activity was significantly faster than in wild-type controls. The difference in mean (+/-S.E.M.) firing was most apparent during wakefulness (6.4+/-0.8 vs. 3.5+/-0.3 spikes/s) but also persisted during anesthesia (2.0+/-0.3 vs. 0.7+/-0.1 spikes/s). Assessment of treatment duration indicated that R6/2 mean waking discharge rate was significantly slower after three weeks than after one week of ascorbate treatment (3.1+/-0.6 vs. 10.2+/-2.7 spikes/s). Vehicle-treated R6/2s showed no such decline in striatal activity ruling out an age- or injection-related effect. Slow-scan voltammetry in separate animals confirmed that ascorbate-injections returned the level of striatal extracellular ascorbate in R6/2 mice to that of wild-type controls. Our results indicate that although striatal neurons modulate firing in relation to behavioral state, impulse activity is consistently elevated in transgenic relative to wild-type mice. Restoring extracellular ascorbate to the wild-type level reverses this effect suggesting a role for ascorbate in normalizing neuronal function in Huntington's disease striatum.

Topics: Anesthesia; Animals; Antioxidants; Ascorbic Acid; Consciousness; Corpus Striatum; Disease Models, Animal; Electrodes, Implanted; Electrophysiology; Huntington Disease; Male; Mice; Mice, Transgenic; Neurons

Abnormal oxidative stress was observed in hyperphenylalaninemia and other inborn errors of intermediary metabolism, owing to the accumulation of toxic metabolites, free radical production and increased LPO products. In our model of maternal hyperphenylalaninemia, pregnant rats were injected with 300 mg/kg BW l-phenylalanine (PHE) and 50 mg/kg BW p-chlorophenylalanine (PCPA) dissolved in saline. In this research study, we measured LPO-by-products, i.e., malonaldehyde (MDA) and 4-hydroxynonenal (4-HNE) and we demonstrated that maternal hyperphenylalaninemia increased both markers of oxidative stress in the brain and liver mitochondria of the pups. We also demonstrated that administration of melatonin, Vitamin E, and Vitamin C, in this order of potency, prevented the oxidative damage to the mitochondria, especially in the brain. We therefore conclude that maternal hyperphenylalaninemia induces a clear state of oxidative stress that is somehow directly involved in brain and liver impairment, which can be prevented by melatonin, Vitamin E, and Vitamin C.

Topics: Aldehydes; Animals; Animals, Newborn; Ascorbic Acid; Disease Models, Animal; Drug Interactions; Female; Male; Malondialdehyde; Melatonin; Mitochondrial Diseases; Phenethylamines; Phenylalanine; Phenylketonurias; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Time Factors; Vitamin A

Topics: Administration, Oral; Animals; Ascorbic Acid; Cysteine; Disease Models, Animal; Drug Therapy, Combination; Guinea Pigs; Male; Riboflavin; Skin; Skin Diseases; Sodium Dodecyl Sulfate; Vitamin B 6

The objectives of this study were to compare the protective effects of ascorbic acid and iloprost on lung injury caused by ischemia reperfusion (I/R) of the lower extremities of rats. Wistar albino rats (n = 34) were divided into five groups. In the I/R group (n = 6), the aorta was cross-clamped for 3 hr, followed by 1 hr of reperfusion. In the vitamin C group (n = 8), animals were pretreated with 100 mg/kg ascorbic acid via the left jugular vein before aortic cross-clamping. In the iloprost group (n = 8), animals were pretreated with 20 ng/(kg x min) iloprost by constant intravenous infusion via the left jugular venous cannula. In the sham group (n = 6), the abdomen was left open at the same period and a juguler venous line was established. In the control group (n = 6), lungs were removed and blood samples taken immediately after sternotomy. No treatment was given in this group. After both lungs were removed, biochemical parameters were measured and histopathological evaluation was made. Although the arterial blood pO2 and HCO3 levels were statistically significantly high in both the vitamin C and iloprost groups compared to the I/R group, plasma malondialdehyde (MDA) levels were significantly low. Meanwhile, the MDA levels in the lung tissue were significantly low in the vitamin C group compared to the I/R group. The MDA level in the lung tissue in the iloprost group was also low compared to the I/R group, but it was not statistically significant. The lungs of the I/R group displayed intense interstitial leukocytic infiltration in histopathological examination compared to the other groups. Pretreatment of animals with iloprost and vitamin C significantly decreased the pulmonary injury characterized by decreased plasma leukocyte sequestration. The results suggest that both vitamin C and iloprost are useful agents for attenuating the lung injury caused by increased oxidative stress and neutrophil accumulation after a period of I/R of the lower extremities.

Topics: Animals; Aorta, Abdominal; Ascorbic Acid; Constriction; Disease Models, Animal; Free Radical Scavengers; Iloprost; Lipid Peroxidation; Lung; Neutrophils; Platelet Aggregation Inhibitors; Pulmonary Edema; Rats; Rats, Wistar; Reperfusion Injury

Twenty-month-old Swiss mice were allocated into three groups: (A) control; (B) infected group; and (C) infected but treated with 5 mg of the phytocompound MMT. Mice were infected intranasally with 30 microL of 75 HA viral units. MMT markedly blunted the nasal signs of virus infection and the febrile response. Formazan-positive cells, lung and plasma lipoperoxides, and TNF-alpha in lung tissue increased during viral infection, but improvement was seen in the MMT-treated group (P < 0.05). MMT also normalized SOD, catalase activities, and ascorbic acid and determined a significant decrease of lung but not nasal viral titer, although nasal inflammatory infiltrate dropped significantly. MMT has potential clinical applications with and has an excellent safety profile even in old animals.

Topics: Administration, Oral; Aging; Animals; Antioxidants; Ascorbic Acid; Bronchoalveolar Lavage Fluid; Catalase; Chemokine CCL5; Dietary Supplements; Disease Models, Animal; Drug Administration Schedule; Lung; Mice; Orthomyxoviridae Infections; Random Allocation; Superoxide Dismutase; Treatment Outcome; Tumor Necrosis Factor-alpha; Viral Load

The effect of oxidative stress induced by the ascorbate/menadione-redox association was examined in K562 cells, a human erythromyeloid leukaemia cell line. Our results show that ascorbate enhances menadione redox cycling, leading to the formation of intracellular reactive oxygen species (as shown by dihydrorhodamine 123 oxidation). The incubation of cells in the presence of both ascorbate/menadione and aminotriazole, a catalase inhibitor, resulted in a strong decrease of cell survival, reinforcing the role of H(2)O(2) as the main oxidizing agent killing K562 cells. This cell death was not caspase-3-dependent. Indeed, neither procaspase-3 and PARP were processed and only a weak cytochrome c release was observed. Moreover, we observed only 23% of cells with depolarized mitochondria. In ascorbate/menadione-treated cells, DNA fragmentation was observed without any sign of chromatin condensation (DAPI and TUNEL tests). The cell demise by ascorbate/menadione is consistent with a necrosis-like cell death confirmed by both cytometric profile of annexin-V/propidium iodide labeled cells and by light microscopy examination. Finally, we showed that a single i.p. administration of the association of ascorbate and menadione is able to inhibit the growth of K562 cells by about 60% (in both tumour size and volume) in an immune-deficient mice model. Taken together, these results reinforced our previous claims about a potential application of the ascorbate/menadione association in cancer therapy.

Topics: Animals; Ascorbic Acid; Cell Death; Cell Line, Tumor; Disease Models, Animal; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Mice, Nude; Neoplasm Transplantation; Oxidative Stress; Vitamin K 3; Xenograft Model Antitumor Assays

Retinitis pigmentosa (RP) is a label for a group of diseases caused by a large number of mutations that result in rod photoreceptor cell death followed by gradual death of cones. The mechanism of cone cell death is uncertain. Rods are a major source of oxygen utilization in the retina and, after rods die, the level of oxygen in the outer retina is increased. In this study, we used the rd1 mouse model of RP to test the hypothesis that cones die from oxidative damage. A mixture of antioxidants was selected to try to maximize protection against oxidative damage achievable by exogenous supplements; alpha-tocopherol (200 mg/kg), ascorbic acid (250 mg/kg), Mn(III)tetrakis (4-benzoic acid) porphyrin (10 mg/kg), and alpha-lipoic acid (100 mg/kg). Mice were treated with daily injections of the mixture or each component alone between postnatal day (P)18 and P35. Between P18 and P35, there was an increase in two biomarkers of oxidative damage, carbonyl adducts measured by ELISA and immunohistochemical staining for acrolein, in the retinas of rd1 mice. The staining for acrolein in remaining cones at P35 was eliminated in antioxidant-treated rd1 mice, confirming that the treatment markedly reduced oxidative damage in cones; this was accompanied by a 2-fold increase in cone cell density and a 50% increase in medium-wavelength cone opsin mRNA. Antioxidants also caused some preservation of cone function based upon photopic electroretinograms. These data support the hypothesis that gradual cone cell death after rod cell death in RP is due to oxidative damage, and that antioxidant therapy may provide benefit.

Topics: alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; Cell Death; Disease Models, Animal; Electroretinography; Metalloporphyrins; Mice; Mice, Inbred C57BL; Oxidative Stress; Oxygen; Retina; Retinal Cone Photoreceptor Cells; Retinitis Pigmentosa; Thioctic Acid

Oxidative damage has been implicated in the pathogenesis of cerebral ischemia. We previously demonstrated that exogenously supplied dehydroascorbic acid (DHA), an oxidized, blood-brain barrier transportable form of the antioxidant ascorbic acid (AA), improves outcome after experimental stroke.. To investigate the neuroprotective effect of DHA therapy, we measured cerebral AA levels using a novel assay, quantified markers of lipid peroxidation, and evaluated infarct volume after reperfused stroke in a murine model. All experiments were performed using a new citrate/sorbitol-stabilized DHA formulation to improve the stability of the compound.. Intraparenchymal AA levels declined after cerebral ischemia/reperfusion and were repleted in a dose-dependent fashion by postischemic administration of intravenous DHA (P < 0.01). Repletion of these levels was associated with reductions in cerebral malondialdehyde levels (P < 0.05), which were also elevated after reperfused stroke. DHA repletion of interstitial AA levels and reduction in cerebral lipid peroxidation was associated with dose-dependent reductions in infarct volume (P < 0.05).. Together, these results indicate that an intravenous cerebroprotective dose of citrate/sorbitol-stabilized DHA is correlated with increased brain ascorbate levels and a suppression of excessive oxidative metabolism.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain Ischemia; Cerebral Cortex; Cerebral Infarction; Citric Acid; Dehydroascorbic Acid; Disease Models, Animal; Excipients; Infarction, Middle Cerebral Artery; Injections, Intravenous; Lipid Peroxidation; Mice; Mice, Inbred C57BL; Nerve Degeneration; Neuroprotective Agents; Oxidative Stress; Reperfusion Injury; Sorbitol; Treatment Outcome; Up-Regulation

Vibrio cholerae has multiple iron acquisition systems, including TonB-dependent transport of heme and of the catechol siderophore vibriobactin. Strains defective in both of these systems grow well in laboratory media and in the infant mouse intestine, indicating the presence of additional iron acquisition systems. Previously uncharacterized potential iron transport systems, including a homologue of the ferrous transporter Feo and a periplasmic binding protein-dependent ATP binding cassette (ABC) transport system, termed Fbp, were identified in the V. cholerae genome sequence. Clones encoding either the Feo or the Fbp system exhibited characteristics of iron transporters: both repressed the expression of lacZ cloned under the control of a Fur-regulated promoter in Escherichia coli and also conferred growth on a Shigella flexneri mutant that has a severe defect in iron transport. Two other ABC transporters were also evaluated but were negative by these assays. Transport of radioactive iron by the Feo system into the S. flexneri iron transport mutant was stimulated by the reducing agent ascorbate, consistent with Feo functioning as a ferrous transporter. Conversely, ascorbate inhibited transport by the Fbp system, suggesting that it transports ferric iron. The growth of V. cholerae strains carrying mutations in one or more of the potential iron transport genes indicated that both Feo and Fbp contribute to iron acquisition. However, a mutant defective in the vibriobactin, Fbp, and Feo systems was not attenuated in a suckling mouse model, suggesting that at least one other iron transport system can be used in vivo.

Topics: Animals; Artificial Gene Fusion; Ascorbic Acid; ATP-Binding Cassette Transporters; Bacterial Proteins; beta-Galactosidase; Biological Transport; Catechols; Cholera; Disease Models, Animal; Escherichia coli; Escherichia coli Proteins; Ferric Compounds; Ferrous Compounds; Gene Deletion; Genes, Reporter; Genetic Complementation Test; Membrane Transport Proteins; Mice; Oxazoles; Oxidation-Reduction; Promoter Regions, Genetic; Shigella flexneri; Vibrio cholerae; Virulence; Virulence Factors

The aim of the present study was to investigate the impact of the combined administration of Vitamin C and silymarin on lead toxicity. Male albino rats were subdivided into three groups: the first was a control group, the second received lead acetate in diet as 500 mg/kg diet daily, the third received the same lead acetate dose and supplemented with Vitamin C (1 mg/100g body weight) and silymarin (1 mg/100g body weight) by gastric tube three times per week. Blood samples were taken after 2, 4 and 6 weeks of treatment. Significant lead-induced elevations in serum ALT, AST, GGT and ALP activities were observed after different periods of treatment. However, serum LDLc was decreased. The intensities of RNA and apoptotic fragments of DNA were measured as optical density by Gel-pro program. Lead acetate decreased the intensity of DNA at 6 weeks and induced apoptotic DNA fragments reversibly with time. After 2 weeks of lead administration dilation and congestion of terminal hepatic veins and portal vein branches were observed. Lead also induced hepatocyte proliferation without any localized distribution among zones 1-3. Portal inflammatory infiltrate with disruption of the limiting plates (interface hepatitis), steatosis, apoptosis and mild fibrosis were detected especially by sixth week of lead administration. Combined treatment of lead-exposed animals with Vitamin C and silymarin showed marked improvement of the biochemical, molecular and histopathological findings. These experimental results strongly indicate the protective effect of Vitamin C and silymarin against toxic effects of lead on liver tissue.

Topics: Administration, Oral; Alkaline Phosphatase; Animals; Apoptosis; Ascorbic Acid; Cell Proliferation; Cholesterol, LDL; Dietary Supplements; Disease Models, Animal; Drug Therapy, Combination; Hepatocytes; Lead Poisoning; Liver; Male; Organometallic Compounds; Protective Agents; Rats; Silymarin; Transaminases

A "gain-of-function" toxic property of mutant Cu-Zn superoxide dismutase 1 (SOD1) is involved in the pathogenesis of some familial cases of amyotrophic lateral sclerosis (ALS). Expression of a mutant form of the human SOD1 gene in mice causes a degeneration of motor neurons, leading to progressive muscle weakness and hindlimb paralysis. Transgenic mice overexpressing a mutant human SOD1 gene (G93A-SOD1) were used to examine the mitochondrial involvement in familial ALS. We observed a decrease in mitochondrial respiration in brain and spinal cord of the G93A-SOD1 mice. This decrease was significant only at the last step of the respiratory chain (complex IV), and it was not observed in transgenic wild-type SOD1 and nontransgenic mice. Interestingly, this decrease was evident even at a very early age in mice, long before any clinical symptoms arose. The effect seemed to be CNS specific, because no decrease was observed in liver mitochondria. Differences in complex IV respiration between brain mitochondria of G93A-SOD1 and control mice were abolished when reduced cytochrome c was used as an electron donor, pinpointing the defect to cytochrome c. Submitochondrial studies showed that cytochrome c in the brain of G93A-SOD1 mice had a reduced association with the inner mitochondrial membrane (IMM). Brain mitochondrial lipids, including cardiolipin, had increased peroxidation in G93A-SOD1 mice. These results suggest a mechanism by which mutant SOD1 can disrupt the association of cytochrome c with the IMM, thereby priming an apoptotic program.

Topics: Aging; Amyotrophic Lateral Sclerosis; Animals; Apoptosis; Ascorbic Acid; Brain; Cytochromes c; Disease Models, Animal; Electron Transport; Electron Transport Complex IV; Female; Humans; Intracellular Membranes; Lipid Peroxidation; Male; Mice; Mice, Transgenic; Mitochondria; Nitric Oxide Synthase; Spinal Cord; Superoxide Dismutase; Superoxide Dismutase-1; Tetramethylphenylenediamine

Epidemiological studies show that high intake of food-bound vitamin C and E reduces the risk of gastric cancer. Whether dietary supplementation with antioxidant micronutrients interferes with Helicobacter pylori infection and associated diseases is unclear. The aim of this study was to investigate if dietary vitamin C or E supplementation influences the progression of gastritis, gastric mucosal nitrosative and oxidative protein damage, gastric mucosal lipid peroxidation, or gastric mucosal oxidative DNA damage in H. pylori-infected Mongolian gerbils.. Gerbils were divided into four groups: H. pylori-infected animals fed with vitamin C- or vitamin E-supplemented food, and infected and uninfected animals given standard rodent food. Subgroups of animals were killed at different time-points until 52 weeks postinfection. Concentrations of 3-nitrotyrosine and thiobarbituric acid-reactive substances (TBARS) in the gastric mucosa were determined with an immunodot blot and a fluorometric method, respectively. Mucosal concentrations of carbonyl carbons on proteins and 8-hydroxydeoxyguanosine were determined by enzyme-linked immunosorbent assay. Gastritis was scored semiquantitatively.. Vitamin supplements had no effect on the colonization with H. pylori. Vitamin C as well as vitamin E supplements reduced mucosal 3-nitrotyrosine concentrations to normal levels in infected animals. Vitamin E supplements decreased mucosal protein carbonyls and TBARS in short-term gastritis. In addition, vitamin C supplements caused attenuated mucosal oxidative DNA damage and milder mucosal inflammation in short-term gastritis.. Vitamin C or vitamin E supplementation leads to some short-term protective effects on H. pylori-induced gastritis in Mongolian gerbils. These effects seem to subside over time when the infection persists.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Ascorbic Acid; Deoxyguanosine; Dietary Supplements; Disease Models, Animal; Gastric Mucosa; Gastritis; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Male; Stomach Neoplasms; Thiobarbituric Acid Reactive Substances; Tyrosine; Vitamin E; Vitamins

Low molecular weight antioxidants (LMWA), which reflect tissue reducing power, are among the endogenous mechanisms for neutralizing reactive oxygen species (ROS). Ischemic preconditioning (IPC) was associated with decreased oxidative stress. We examined the effect of focal ischemia on LMWA and on prostaglandin E(2) (PGE(2), a product of arachidonic acid oxidation) in the brain, heart, liver, and lungs of rats subjected to 90 min of ischemia and in IPC rats subjected to similar insult.. Transient right middle cerebral artery occlusion (MCAO) was performed for 90 min and at 0, 5, 30, 60, or 240 min of reperfusion, LMWA and PGE(2) were evaluated by cyclic voltametry (CV) and radioimmunoassay, respectively. IPC was induced by 2 min of MCAO, 24 h prior to the major ischemic episode.. LMWA decreased at 5 min of reperfusion in the brain, heart, liver, and lung and rose 4 h later only in the brain. PGE(2) levels increased three to fivefold in all tissues examined. Surprisingly, in IPC rats a dramatic increase of LMWA occurred at 5 min of reperfusion in the brain and in the peripheral organs. Uric acid, but not ascorbic, is the major LMWA increased.. We propose that after ischemia, ROS rapidly consume the antioxidants reserves in the brain and also in peripheral organs, suggesting that the whole body is under oxidative stress. Moreover, part of the neuroprotection afforded by IPC is mediated by the brain's ability to mobilize antioxidants, especially uric acid, that attenuate the massive ROS-mediated oxidative stress.

Topics: Animals; Antioxidants; Arachidonic Acid; Ascorbic Acid; Brain; Brain Ischemia; Dinoprostone; Disease Models, Animal; Free Radicals; Ischemic Preconditioning; Liver; Lung; Male; Myocardium; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Up-Regulation; Uric Acid

We studied superoxide dismutases (SODs) in the encapsulated yeast Cryptococcus neoformans (Cn) variety gattii to analyse the role of mitochondrial MnSOD (SOD2) in fungal biology and virulence. SOD2 was cloned from a Cn cosmid library, sod2 mutant and sod2 + SOD2 reconstituted strains were constructed by homologous recombination, and two sod1sod2 double mutants were constructed by replacing SOD2 in the sod1 mutant with the sod2::HYG allele. The SOD2 protein (SOD2p) encoded 225 amino acids, with 36-66% identity with other fungal SOD2ps. SOD2 deletion rendered Cn highly growth-defective at 37 degrees C in 19-20% oxygen (normal air), and this defect was reversed by limiting oxygen to 1.3% as well in the presence of antioxidant, ascorbic acid. The sod2 mutant accumulated significantly more reactive oxygen species (ROS) at 37 degrees C as well at 30 degrees C in the presence of antimycin A, suggesting that SOD2p is the primary defence of Cn against the superoxide anion (O(2) (.-)) in the mitochondria. The sod2 was also highly susceptible to redox-cycling agents, high salt and nutrient limitations. The sod2 mutant was avirulent in intranasally infected mice and markedly attenuated in its virulence in intravenously infected mice. The virulence defect of sod2 mutant appeared related to its growth defects in high oxygen environment, but not resulting from increased sensitivity to oxidative killing by phagocytes. The sod1sod2 double mutants were avirulent in mice. Additionally, sod1sod2 double mutants showed a marked reduction in the activities of other known Cn virulence factors; and they were more susceptible to PMN killing than was the sod2 single mutant. Previously, we reported that the attenuation of sod1 mutant in mice was resulting from enhanced susceptibility to phagocyte killing, combined with a reduction in the activities of a number of virulence factors. Thus, SOD1p and SOD2p play distinct roles in the biology and virulence of Cn var. gattii via independent modes of action.

Topics: Animals; Antifungal Agents; Antimycin A; Antioxidants; Ascorbic Acid; Cryptococcosis; Cryptococcus neoformans; Disease Models, Animal; DNA, Fungal; Fungal Proteins; Gene Deletion; Genes, Fungal; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Oxygen; Phagocytosis; Reactive Oxygen Species; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Superoxide Dismutase; Superoxide Dismutase-1; Superoxides; Survival Analysis; Virulence

Drugs like haloperidol (Hal) that decrease dopamine (DA) neurotransmission in the striatum induce catalepsy in rodents and Parkinson disease-like symptoms in humans. Nitric oxide synthase (NOS) inhibitors interfere with motor activity, disrupting rodent exploratory behavior and inducing catalepsy. Catalepsy induced by NOS inhibitors probably involves striatal DA-mediated neurotransmission. Antioxidants such as ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) have also been shown to interfere with movement modulation and the DA system.. The objective of the study is to investigate if the antioxidants vitamins C and E would influence the catalepsy produced by Hal and NOS inhibitors.. The effects of the following treatments on catalepsy were examined using the hanging-bar test on male Swiss mice (25-30 g): (1) vitamin C (30-1,000 mg/kg)xHal (1 mg/kg); (2) vitamin C (90-1,000 mg/kg)xN (G)-nitro-L: -arginine (LNOARG, 10 and 40 mg/kg); (3) vitamin C (300 mg/kg)xN (G)-nitro-L: -arginine methylester (LNAME, 20-80 mg/kg); (4) vitamin C (300 mg/kg) x 7-nitroindazole (7NI, 3-50 mg/kg); (5) vitamin C (90 mg/kg i.p.) x LNOARG [40 mg/kg twice a day during 4 days (subchronic treatment)]; (7) vitamin E (3-100 mg/kg) x Hal (1 mg/kg); and (6) vitamin E (3-100 mg/kg) x LNOARG (40 mg/kg).. Vitamin C enhanced the catalepsy produced by NOS inhibitors and Hal. Treatment with vitamin C did not affect tolerance to LNOARG cataleptic effect induced by subchronic treatment. Vitamin E potentiated the catalepsy induced by LNOARG at all doses tested; in contrast, catalepsy induced by Hal was enhanced only by the dose of 100 mg/kg.. Results support an involvement of dopaminergic and nitrergic systems in motor behavior control and provide compelling evidence that combined administration of the antioxidants vitamins C and E with either Hal or NOS inhibitors exacerbates extrapyramidal effects. Further studies are needed to assess possible clinical implications of these findings.

Topics: alpha-Tocopherol; Animals; Ascorbic Acid; Catalepsy; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Synergism; Drug Tolerance; Enzyme Inhibitors; Haloperidol; Indazoles; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroarginine; Time Factors; Vitamins

A multiple analysis of the cerebral oxidative stress was performed on a physiological model of dementia accomplished by three-vessel occlusion in aged rats. The forward rate constant of creatine kinase, k(for), was studied by saturation transfer (31)P magnetic resonance spectroscopy in adult and aged rat brain during chronic hypoperfusion. In addition, free radicals in aging rat brain homogenates before and/or after occlusion were investigated by spin-trapping electron paramagnetic resonance spectroscopy (EPR). Finally, biochemical measurements of oxidative phosphorylation parameters in the above physiological model were performed. The significant reduction of k(for) in rat brain compared to controls 2 and 10 weeks after occlusion indicates a disorder in brain energy metabolism. This result is consistent with the decrease of the coefficient of oxidative phosphorylation (ADP:O), and the oxidative phosphorylation rate measured in vitro on brain mitochondria. The EPR study showed a significant increase of the ascorbyl free radical concentration in this animal model. Application of alpha-phenyl-N-tert-butylnitrone (PBN) and 5,5-dimethyl-1-pyrroline N-oxide (DMPO) spin traps revealed formation of highly reactive hydroxyl radical (.OH) trapped in DMSO as the .CH(3) adduct. It was concluded that the ascorbate as a major antioxidant in brain seems to be useful in monitoring chronic cerebral hypoperfusion.

Topics: Animals; Ascorbic Acid; Brain; Brain Ischemia; Chronic Disease; Creatine Kinase; Cyclic N-Oxides; Dementia; Disease Models, Animal; Energy Metabolism; Free Radicals; Hydroxyl Radical; Male; Mitochondria; Molecular Conformation; Nitrogen Oxides; Oxidative Phosphorylation; Oxidative Stress; Rats; Rats, Wistar; Spin Trapping

The purpose of this study was to determine the effects of combined use of L-carnitine and vitamin C on partially burned skin flap in an experimental rat model.. In the rat dorsal skin, a 10 x 3 cm flap was marked. The most distal 3 x 3 cm part was burned to full thickness. Twenty-four rats were randomized into four groups with 6 animals in each. Group 1 was simply followed up. Group 2 was given 0.5 mg/kg vitamin C per day for 7 days, group 3 100 mg/kg carnitine per day for 7 days, and group 4 both carnitine and vitamin C. On the eighth postoperative day, the animals were sacrificed and examined. The surviving and necrotic areas were determined by macroscopic examination and measured with a planimeter.. The areas of flap necrosis were measured. The median surviving areas and areas of flap necrosis, respectively, of the groups were: group 1, 16.0 cm(2) and 14.0 cm(2); group 2, 18.25 cm(2) and 11.75 cm(2); group 3, 20.0 cm(2) and 10 cm(2) ; and group 4, 23.75 cm(2) and 6.25 cm(2). The surviving areas of the groups were found to be significantly different (p=0.000).. The risk of ischemia-induced necrosis in flap attempts made in damaged tissues may be reduced by the combination of two promising agents, L-carnitine and vitamin C. L-carnitine appears to be the major contributing factor that reduces necrosis, and vitamin C an additive agent.

Topics: Animals; Antioxidants; Ascorbic Acid; Burns; Carnitine; Disease Models, Animal; Rats; Rats, Sprague-Dawley; Skin; Surgical Flaps

In the present study we investigate the effect of homocysteine (Hcy) administration, the main metabolite accumulating in homocystinuria, on butyrylcholinesterase (BuChE) activity in serum of rats. For the acute treatment, 29-day-old Wistar rats received one subcutaneous injection of Hcy (0.6 micromol/g) or saline (control) and were killed 1 h later. For the chronic treatment, Hcy was administered subcutaneously to rats from the 6th to the 28th day of life. Control rats received saline. The rats were killed 12 h after the last injection. In another set of experiments, rats were pretreated for one week with vitamins E and C or saline and 12 h after the last injection received one single injection of Hcy or saline, being killed 1 h later. Serum was used to determine BuChE activity. Our results showed that acute and chronic administration of Hcy significantly decreased BuChE activity. Furthermore, vitamins E and C per se did not alter BuChE activity, but prevented the reduction of this enzyme activity caused by acute administration of Hcy. The data suggest that the inhibitory effect of Hcy on BuChE activity is probably mediated by free radicals, since vitamins E and C administration prevented such effect.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Butyrylcholinesterase; Disease Models, Animal; Down-Regulation; Enzyme Activation; Free Radicals; Homocysteine; Homocystinuria; Hyperhomocysteinemia; Lipid Metabolism; Oxidative Stress; Rats; Rats, Wistar; Vitamin E

Oxidative stress mediates acinar injury in experimental acute pancreatitis (AP) and antioxidants are depleted in human AP. This study tests the hypothesis that exogenous antioxidant supplementation ameliorates experimental AP.. Male Sprague-Dawley rats were randomly allocated to 1 of 4 groups (n = 5/group) and sacrificed at 72 h. AP was induced by 250 mg per 100 g body weight of 20% L-arginine hydrochloride in 0.15 mol/l sodium chloride. Group allocations were: group 1 (control) no intervention; group 2 AP; group 3 early multiple antioxidant (MAOX) intervention comprising 15 microg/kg selenium, 30 microg/kg ascorbate and 300 mg/kg N-acetylcysteine given at 6 and 30 h and group 4 the MAOX combination above given at 24 and 48 h. Endpoints were: serum amylase, antioxidant levels, bronchoalveolar lavage (BAL) protein and lung myeloperoxidase (MPO) activity and histological assessment of pancreatic injury.. L-arginine induced AP characterised by oedema, neutrophil infiltration, acinar cell degranulation and elevated serum amylase. Early MAOX reduced pulmonary MPO and BAL protein and reduced acinar swelling, degranulation and pancreatic parenchymal infiltration by inflammatory cells. These features were absent when intervention was delayed.. In this model, early but not late antioxidant intervention ameliorates pancreatic and pulmonary injury.

Topics: Acetylcysteine; Acute Disease; Amylases; Animals; Antioxidants; Arginine; Ascorbic Acid; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Drug Therapy, Combination; Injections, Intravenous; Lung; Male; Pancreas; Pancreatitis; Peroxidase; Proteins; Rats; Rats, Sprague-Dawley; Selenium; Time Factors

Antioxidative vitamins are known to inhibit metastasis. Therefore we evaluated the impact of vitamins A (retinol), C (ascorbic acid) and E (alpha-tocopherol) on liver metastasis in a model of ductal pancreatic adenocarcinoma in hamster.. One hundred and twenty male Syrian hamsters were randomized into 8 groups (Gr.) (n = 15). Gr. 1-4 were given 0.5 ml normal saline subcutaneously (s.c.) weekly, whereas Gr. 5-8 received 10 mg N-nitrosobis(2-oxopropyl)amine (BOP)/kg body weight s.c. for 3 months for tumor induction. In the 13th week Gr. 2 and 6 were administered retinol, Gr. 3 and 7 received ascorbic acid and Gr. 4 and 8 were given alpha-tocopherol orally. No treatment was performed in Gr. 1 and 5. After 24 weeks animals were sacrificed, pancreas and liver were histologically determined. Activities of glutathione-peroxidase (GSH-Px), superoxide dismutase (SOD) and concentration of thiobarbituric-acid-reactive substances (TBARS) were analyzed in hepatic tissue.. Retinol and alpha-tocopherol decreased the incidence of liver metastases (44.4 vs. 86.7%, p < 0.05). The number and size of liver metastases were significantly reduced by retinol. Activities of GSH-Px and SOD were increased and concentration of TBARS was decreased in NML and LiMe by all vitamins.. Obviously, antioxidative vitamins prevent oxidative stress in hepatocytes. This may be one mechanism decreasing liver metastasis in pancreatic cancer in the present trial.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Carcinoma, Pancreatic Ductal; Cricetinae; Disease Models, Animal; Glutathione Peroxidase; Lipid Peroxidation; Liver Neoplasms; Male; Mesocricetus; Neoplasm Metastasis; Nitrosamines; Pancreatic Neoplasms; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Vitamin A; Vitamin E

The major pathological ramification of Alzheimer's disease (AD) is accumulation of beta-Amyloid (Abeta) peptides in the brain. An emerging therapeutic approach for AD is elimination of excessive Ass peptides and preventing its re-accumulation. Immunization is the most effective strategy in removing preexisting cerebral Abetas and improving the cognitive capacity as shown in transgenic mice model of AD. However, active immunization is associated with adverse effect such as encephalitis with perivascular inflammation and hemorrhage. Details about the mechanistic aspects of propagation of these toxic effects are matter of intense enquiry as this knowledge is essential for the understanding of the AD pathophysiology. The present work aimed to study the oxidative vulnerability in the plasma, liver and brain of the inflammation-induced rats subjected to Ass immunization. Induction of inflammation was performed by subcutaneous injection of 0.5?ml of 2% silver nitrate. Our present result shows that the proinflammatory cytokines such as IL1alpha and TNFalpha are increased significantly in the inflammation-induced, Abeta1-42, Abeta25-35 treated groups and inflammation with Abeta25-35 treated group when compared to control, complete Freund's adjuvant and Abeta35-25 treated groups. These increased proinflammatory cytokines concurrently releases significant amount of free radicals in the astrocytes of respected groups. The present result shows that nitric oxide (NO) level was significantly higher (P<0.001) in plasma, liver and brain of the rat subjected to inflammation, Abeta1-42, Abeta25-35 and inflammation with Abeta25-35 injected groups when compared to control. The increased level of lipid peroxides (LPO) (P<0.001) and decreased antioxidant status (P<0.05) were observed in the plasma, liver and brain of inflammation-induced group when compared to control. Our result shows that significant oxidative vulnerability was observed in the inflammation with Ass treated rats when compared to other groups. Based on our results, we suggest that immunization of AD patients with Ass should be done with caution as the increase in Ass could trigger the brain inflammation in uncontrollable level.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Ascorbic Acid; Astrocytes; Brain; Catalase; Disease Models, Animal; Glutathione Peroxidase; Inflammation; Interleukin-1; Lipid Peroxidation; Liver; Nitric Oxide; Oxidation-Reduction; Peptide Fragments; Rats; Reactive Oxygen Species; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Numerous studies support the notion that an activation of sphingomyelinases and a subsequent increase of the concentration of the bioactive lipid mediator ceramide are critical in the concert of inflammatory stimuli and to the induction of apoptosis during inflammation. Here we show that patients with severe sepsis exhibit an enhanced sphingolytic activity in comparison with controls [262 pmol/(mlxh) vs. 123.6 pmol/(mlxh), P<0.005]. During the clinical course, a further increase was paralleled by the severity of illness and by fatal outcome. Moreover, we show that oxidative stress may partially account for the increased activity through posttranslational modification of the enzyme. In a murine endotoxic shock model, administration of a low molecular weight inhibitor diminished the rise in enzymatic activity and improved the survival rate. In liver specimen, inhibition of activity correlated with a reduced rate of hepato-cellular apoptosis. Our data support the concept that activation of the plasmatic isoform of sphingomyelinase may play a critical role in the development of apoptosis and organ failure in sepsis. An inhibition of the secreted isoform of sphingomyelinase should be explored further as a potential target in the complicated puzzle of sepsis.

Topics: Adult; Aged; Animals; Apoptosis; Ascorbic Acid; Blood Chemical Analysis; Ceramides; Desipramine; Disease Models, Animal; Dose-Response Relationship, Drug; Endotoxins; Female; Gene Expression Regulation, Enzymologic; Humans; Inflammation; Lipids; Liver; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Middle Aged; Models, Statistical; Oxidative Stress; Sepsis; Shock, Septic; Sphingomyelin Phosphodiesterase; Time Factors; Treatment Outcome

Nitrofen induces heart hypoplasia together with congenital diaphragmatic hernia (CDH) in rats. Intracellular oxidative stress might be one of the mechanisms of action of the teratogen, and vitamin A has been shown to reverse in part these effects when administered simultaneously or shortly after it. This study aims at testing the hypothesis that vitamin A and other antioxidant vitamins, such as E and C, could improve myocardial development even when administered late in gestation, a likely useful period for prenatal medication.. Time-mated Sprague-Dawley female rats were exposed to either vehicle (control) or 100 mg of nitrofen (experimental) on day 9.5 of gestation. In 3 additional groups, the animals were exposed to vitamin A (total 15000 IU), vitamin E (total 150 IU), or vitamin C (total 150 IU) on days 16, 17, and 18. The fetuses were recovered on day 21, and randomly selected hearts of those with CDH were processed for histologic studies (hematoxylin-eosin and periodic acid-Schiff stainings), DNA and protein contents, and ki-67 (proliferation) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling (apoptosis) studies. The differences among groups were assessed by analysis of variance with Bonferroni/Dunn post hoc tests and a threshold of significance of P < .05.. Nitrofen induced heart hypoplasia in terms of decreased heart/body weight, cell mass (less DNA and protein), and proportion of proliferating cells with increased apoptosis. Vitamin C alleviated weight hypoplasia and the 3 vitamins were able to restore cell mass and to reestablish near-normal figures of proliferation and apoptosis.. Antioxidant vitamins A, E, and C given late in gestation alleviate heart hypoplasia that accompanies CDH in the rat model. This timing suggests that the beneficial effects are exerted on the maturational phase of development.

Topics: Animals; Apoptosis; Ascorbic Acid; Disease Models, Animal; DNA; Female; Fetal Heart; Heart Defects, Congenital; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; In Situ Nick-End Labeling; Oxidants; Phenyl Ethers; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Teratogens; Vitamin A; Vitamin E; Vitamins

Colon cancer is the third most common cancer and second leading cause of cancer-related death in the United States. A number of recent articles demonstrate the importance of natural products as cancer chemopreventive agents. In this study, we evaluated the chemopreventive efficacy of luteolin, a flavonoid, on tissue lipid peroxidation and antioxidant status, which are used as biomarkers in DMH-induced experimental colon carcinogenesis. Rats were given a weekly subcutaneous injection of DMH at a dose of 20 mg/kg body weight for 15 weeks. Luteolin (0.2 mg/kg body weight/everyday p.o.) was given to the DMH-treated rats at the initiation and post-initiation stages of carcinogenesis. The animals were killed after 30 weeks. After a total experimental period of 32 weeks (including 2 weeks of acclimatization), tumor incidence was 100% in DMH-treated rats. In those DMH-treated rats that had received luteolin during the initiation or post-initiation stages of colon carcinogenesis, the incidence of cancer and the colon tumor size was significantly reduced as compared to that for DMH-treated rats not receiving luteolin. In the presence of DMH, relative to the results for the control rats, there were decreased levels of lipid peroxidation, as denoted by thiobarbituric acid reactive substances (TBARS), conjugated dienes and lipid hydroperoxides, decreased activities of the enzymic antioxidants superoxide dismutase (SOD) and catalase (CAT), and elevated levels of glutathione and the glutathione-dependent enzymes reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and glutathione reductase (GR), and of the non-enzymic antioxidants vitamin C and vitamin E. Our study shows that intragastric administration of luteolin inhibits colon carcinogenesis, not only by modulating lipid peroxidation and antioxidant status, but also by preventing DMH-induced histopathological changes. Our results thus indicate that luteolin could act as a potent chemopreventive agent for colon carcinogenesis.

Topics: 1,2-Dimethylhydrazine; Animals; Ascorbic Acid; Carcinogens; Catalase; Colon; Colonic Neoplasms; Disease Models, Animal; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Humans; Lipid Peroxidation; Lipid Peroxides; Luteolin; Male; Molecular Structure; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Time Factors; Vitamin E

Hallervorden-Spatz syndrome (HSS) is a devastating neurological disease, characterized by iron accumulation in the globus pallidus in the basal ganglia. Most HSS cases are caused by mutations in one of the four human pantothenate kinases (PANK2). This PANK2-caused subgroup of HSS is sometimes referred as PKAN (pantothenate-kinase-associated neurodegeneration). No effective treatment for PKAN or HSS is currently available. fumble, a Drosophila mutant that carries a mutation in Drosophila Pank, has many features similar to those of PKAN patients. In this study, we used fumble as a model to evaluate various compounds or nutritional products for their possible therapeutic efficacy. While no product was found to dramatically improve the symptoms, GKE (containing Ginkgo biloba extract and flavone) and vitamin E showed statistically significant beneficial effects. Our studies indicate that pantothenate is of limited value in alleviating fumble phenotypes and also suggest that some compounds might have deleterious effects.

Topics: Acetylcysteine; Adenosine Triphosphate; Animal Feed; Animals; Ascorbic Acid; Carnitine; Cloning, Molecular; Creatine; Diet; Disease Models, Animal; Drosophila; Drosophila melanogaster; Edetic Acid; Ginkgo biloba; Heterozygote; Humans; Inosine; Iron; Mutation; Neurodegenerative Diseases; Phenotype; Phosphotransferases (Alcohol Group Acceptor); Transgenes; Vitamin E

Chronic hypoxia (CH) alters Ca2+ homeostasis in various cells and may contribute to disturbed Ca2+ homeostasis of Alzheimer's disease. Here, we have employed microfluorimetric measurements of [Ca2+]i to investigate the mechanism underlying augmentation of Ca2+ signalling by chronic hypoxia in type I cortical astrocytes. Application of bradykinin evoked significantly larger rises of [Ca2+]i in hypoxic cells as compared with control cells. This augmentation was prevented fully by either melatonin (150 micro m) or ascorbic acid (200 micro m), indicating the involvement of reactive oxygen species. Given the association between hypoxia and increased production of amyloid beta peptides (AbetaPs) of Alzheimer's disease, we performed immunofluorescence studies to show that hypoxia caused a marked and consistent increased staining for AbetaPs and presenilin-1 (PS-1). Western blot experiments also confirmed that hypoxia increased PS-1 protein levels. Hypoxic increases of AbetaP production was prevented with inhibitors of either gamma- or beta-secretase. These inhibitors also partially prevented the augmentation of Ca2+ signalling in astrocytes. Our results indicate that chronic hypoxia enhances agonist-evoked rises of [Ca2+]i in cortical astrocytes, and that this can be prevented by antioxidants and appears to be associated with increased AbetaP formation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Animals, Newborn; Ascorbic Acid; Astrocytes; Blotting, Western; Bradykinin; Calcium; Cell Hypoxia; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Endopeptidases; Free Radical Scavengers; Immunohistochemistry; Melatonin; Membrane Proteins; Models, Neurological; Oxygen; Presenilin-1; Rats; Rats, Wistar; Reactive Oxygen Species

Hypothermic cardiopulmonary bypass is associated with capillary fluid leakage, resulting in edema and occasionally organ dysfunction. Systemic inflammatory activation is considered responsible. In some studies methylprednisolone has reduced the weight gain during cardiopulmonary bypass. Vitamin C and alpha-trinositol have been demonstrated to reduce the microvascular fluid and protein leakage in thermal injuries. We therefore tested these three agents for the reduction of cold-induced fluid extravasation during cardiopulmonary bypass.. A total of 28 piglets were randomly assigned to four groups of 7 each: control group, high-dose vitamin C group, methylprednisolone group, and alpha-trinositol-group. After 1 hour of normothermic cardiopulmonary bypass, hypothermic cardiopulmonary bypass was initiated in all animals and continued to 90 minutes. The fluid level in the extracorporeal circuit reservoir was kept constant at the 400-mL level and used as a fluid gauge. Fluid needs, plasma volume, changes in colloid osmotic pressure in plasma and interstitial fluid, hematocrit, and total water contents in different tissues were recorded, and the protein masses and the fluid extravasation rate were calculated.. Hemodilution was about 25% after start of normothermic cardiopulmonary bypass. Cooling did not cause any further changes in hemodilution. During steady-state normothermic cardiopulmonary bypass, the fluid need in all groups was about 0.10 mL/(kg.min), with a 9-fold increase during the first 30 minutes of cooling (P <.001). This increased fluid need was due mainly to increased fluid extravasation from the intravascular to the interstitial space at a mean rate of 0.6 mL/(kg.min) (range 0.5-0.7 mL/[kg.min]; P <.01) and was reflected by increased total water content in most tissues in all groups. The albumin and protein masses remained constant in all groups throughout the study.. Pretreatment with methylprednisolone, vitamin C, or alpha-trinositol was unable to prevent the increased fluid extravasation rate during hypothermic cardiopulmonary bypass. These findings, together with the stability of the protein masses throughout the study, support the presence of a noninflammatory mechanism behind the cold-induced fluid leakage seen during cardiopulmonary bypass.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Biomarkers; Capillary Permeability; Cardiopulmonary Bypass; Disease Models, Animal; Erythrocyte Indices; Extracellular Space; Extravasation of Diagnostic and Therapeutic Materials; Female; Hematocrit; Hypothermia, Induced; Inositol Phosphates; Intraoperative Complications; Male; Methylprednisolone; Models, Cardiovascular; Osmolar Concentration; Osmotic Pressure; Plasma Volume; Pulmonary Circulation; Serum Albumin; Swine; Water-Electrolyte Balance

The relationship between hydrogen peroxide (H2O2) concentration in expired breath condensate (EBC) and cytology of the respiratory tract obtained from tracheal wash (TW) or bronchoalveolar lavage (BAL), and epithelial lining fluid (ELF) antioxidant status is unknown. To examine this we analysed the concentration of H2O2 in breath condensate from healthy horses and horses affected by recurrent airway obstruction (RAO), a condition considered to be an animal model of human asthma. The degree of airway inflammation was determined by assessing TW inflammation as mucus, cell density and neutrophil scores, and by BAL cytology. ELF antioxidant status was determined by measurement of ascorbic acid, dehydroascorbate, reduced and oxidised glutathione, uric acid and alpha-tocopherol concentrations. RAO-affected horses with marked airway inflammation had significantly higher concentrations of breath condensate H2O2 than control horses and RAO-affected horses in the absence of inflammation (2.0 +/- 0.5 micromol/l. 0.4 +/- 0.2 micromol/l and 0.9 +/- 0.2 micromol/l H2O2, respectively; p < 0.0001). The concentration of breath condensate H2O2 was related inversely to the concentration of ascorbic acid in ELF (r = -0.80; p < 0.0001) and correlated positively with TW inflammation score (r = 0.76, p < 0.0001) and BAL neutrophil count (r = 0.80, p < 0.0001). We conclude that the concentration of H2O2 in breath condensate influences the ELF ascorbic acid concentration and provides a non-invasive diagnostic indicator of the severity of neutrophilic airway inflammation.

Topics: Airway Obstruction; Animals; Ascorbic Acid; Breath Tests; Bronchoalveolar Lavage Fluid; Bronchoscopy; Cell Count; Dehydroascorbic Acid; Diagnosis, Differential; Disease Models, Animal; Glutathione; Horses; Hydrogen Peroxide; Inflammation; Mucus; Neutrophils; Respiratory Mucosa; Respiratory System; Spectrophotometry

Normal human islet cells are an ideal source for pancreas-targeted cell therapies, but the availability of human donor pancreata for islet isolation is severely limited. To effectively utilize such scarce donor organs for cell therapies, it is crucial to develop an excellent isolation, effective cryopreservation, and efficient gene transfer techniques for the transportation of isolated cells. In the present study, we investigate the effect of University of Wisconsin (UW) solution and ascorbic acid-2 glucoside (AA2G) on the cryopreservation of human islets. We also evaluate the gene transfer efficiency of a lentiviral vector expressing the E. coli LacZ gene, Lt-NLS/LacZ, in human islets. Human islets were isolated with a standard digestion method at the University of Alberta. Isolated islets were transported to Japan for 40 h and then subjected to cryopreservation experiments. The following preservation solutions were tested: UW solution with 100 micro g/mL of AA2G, UW solution, 100% fetal bovine serum (FBS), and CMRL supplemented with 10% FBS. Following three months of cryopreservation, the islets were thawed and analyzed for viability, glucose-sensitive insulin secretion, proinsulin gene expression profile, and in vivo engraftment. The islets were also subjected to monolayer formation with 804G-cell-line-derived extracellular matrix (ECM), followed by Lt-NLS/LacZ transduction. The viability, morphology, glucose-sensitive insulin secretion, proinsulin gene expression, and monolayer formation efficiency of the thawed cryopreserved islets are significantly better maintained by the use of UW solution. When AA2G (100 microg/mL) is combined with UW, such parameters are further improved. The adequate engraftment of UW + AA2G-cryopreserved human islets is achieved in the liver of nude mice. Efficient Lt-NLS/LacZ transduction is identified in monolayered islets cryopreserved with UW solution with AA2G. The present work demonstrates that the combination of UW solution with AA2G (100 microg/mL) would be a useful cryopreservation means for human islets. Human islets monolayer-cultured with 804G-derived ECM are efficiently transduced with a lentiviral vector Lt-NLS/LacZ.

Topics: Adenosine; Allopurinol; Animals; Ascorbic Acid; Cell Survival; Cell Transplantation; Cells, Cultured; Cryopreservation; Disease Models, Animal; DNA; Gene Transfer Techniques; Glutathione; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Mice, Nude; Organ Preservation Solutions; Polymerase Chain Reaction; Raffinose; RNA; Sensitivity and Specificity; Tissue Preservation; Transplantation, Heterologous

To determine whether ascorbic acid might be of benefit for the treatment of spontaneous osteoarthritis (OA) when administered over a long period of time.. We investigated the effects of 8 months' exposure to low, medium, and high doses of ascorbic acid on the in vivo development of histologic knee OA in the male Hartley guinea pig. The low dose represented the minimum amount needed to prevent scurvy. The medium dose was the amount present in standard laboratory guinea pig chow and resulted in plasma levels comparable with those achieved in a person consuming 200 mg/day (5 fruits and vegetables daily). The high dose was the amount shown in a previous study of the guinea pig to slow the progression of surgically induced OA.. We found an association between ascorbic acid supplementation and increased cartilage collagen content but, in contrast to findings in a previous study of surgically induced OA in the guinea pig, ascorbic acid worsened the severity of spontaneous OA. Active transforming growth factor beta (TGF beta) was expressed in marginal osteophytes, whose size and number were significantly increased with increasing intake of ascorbic acid. Synovial fluid levels of cartilage oligomeric matrix protein, a biomarker of cartilage turnover, corroborated the histologic findings.. Ascorbic acid has been shown to activate latent TGF beta. Prolonged intraarticular exposure to TGF beta has been shown to cause OA-like changes. We found expression of active TGF beta in osteophytes, a prominent feature of the joint histology seen in association with ascorbic acid treatment. Thus, the deleterious effects of prolonged ascorbic acid exposure may be mediated in part by TGF beta. This worsening of OA with ascorbic acid supplementation suggests that ascorbic acid intake should not be supplemented above the currently recommended dietary allowance (90 mg/day for men and 75 mg/day for women).

Topics: Animals; Antioxidants; Ascorbic Acid; Bone Density; Cartilage; Collagen; Disease Models, Animal; Extracellular Matrix Proteins; Glycoproteins; Guinea Pigs; Least-Squares Analysis; Male; Matrilin Proteins; Osteoarthritis, Knee; Scurvy; Severity of Illness Index; Synovial Fluid; Transforming Growth Factor beta; Weight Gain

The effect of oxidative stress on coronary microvascular disease is unknown. We investigated whether chronic administration of ascorbic acid (ASC) or glutathione (GSH) prevents microvascular dysfunction and remodeling induced by upstream repeated coronary artery endothelial injury.. Balloon endothelial injury was repeated at the left anterior descending coronary artery (LAD), just distal to an implanted flow meter, every 2 weeks for 6 weeks in pigs. Changes in LAD blood flow induced by acetylcholine (ACh) and 5-hydroxytryptamine were assessed before each endothelial injury and at 8 weeks after the first endothelial injury in pigs without treatment (endothelial injury group, n = 12) and in pigs treated with oral ASC (3 g/day) (ASC group, n = 12) and ASC (3 g/day) plus GSH (1 g/day) (ASC + GSH group, n = 12).. In the endothelial injury group, reduced blood flow in response to ACh was augmented from a decrease of 18 +/- 17% to a decrease of 100% (that is, zero flow, 8 weeks, P < 0.01), accompanied by an increase of ascorbyl free radicals (AFRs) in coronary sinus blood. In contrast, in the ASC + GSH group, blood flow response to ACh was altered to a decrease of 45 +/- 17% (8 weeks, P < 0.01 compared with the endothelial injury group), coronary sinus blood AFRs did not change (8 weeks, 21.4 +/- 12.5 signal intensities, P < 0.01 compared with the endothelial injury group) and the rate of platelet aggregation induced by adenosine diphosphate was small (8 weeks, 56 +/- 17%, P < 0.01 compared with the endothelial injury group).. Chronic administration of antioxidants suppressed microvascular hypercontraction, suggesting that it may be a promising therapeutic strategy for treating coronary microvessel disorders, including microvascular angina.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Animals; Antioxidants; Ascorbic Acid; Biomarkers; Blood Pressure; Coronary Circulation; Coronary Vasospasm; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Free Radical Scavengers; Free Radicals; Glutathione; Heart Rate; Models, Cardiovascular; Oxidative Stress; Pericardium; Platelet Aggregation; Swine; Thromboxane B2; Time Factors

In this study, the effect of ascorbic acid (vitamin C), DL-alpha-tocopherol acetate (vitamin E), and sodium selenate (selenium) on ethanol-induced gastric mucosal injury in rats was investigated morphologically and biochemically. The gastric mucosal injury was produced by administration of 1 mL of absolute ethanol to each rat. Animals received vitamin C (250 mg/kg), vitamin E (250 mg/kg), and selenium (0.5 mg/kg) for 3 d 1 h prior to the administration of absolute ethanol. In gastric mucosa of rats given ethanol according to control groups, neuronal nitric oxide expression decreased. This immunoreactivity was much lower in the group given ethanol+vitamin C+vitamin E+selenium than the control group and the ethanol-induced group. Scanning electron microscopic evaluation of the ethanol-induced group, when compared to control groups, revealed degenerative changes in gastric mucosa, whereas a good arrangement in surface topography of gastric mucosa in the group given ethanol + vitamin C+vitamin E + selenium was observed. In the group administered ethanol, a reduction of the stomach glutathione (GSH) and serum total protein levels and increases in serum sialic acid, triglycerides, and stomach lipid peroxidation (LPO) levels were observed. Vitamin C+vitamin E+Se administration to alcohol-treated rats significantly increased the serum total protein, triglyceride levels, and stomach GSH levels and significantly lowered the levels of serum sialic acid and stomach LPO compared to untreated alcohol-supplemented rats. As a result of these findings, we can say that the combination of vitamin C, vitamin E, and selenium has a protective effect on ethanol-induced gastric mucosal injury of rats.

Topics: alpha-Tocopherol; Animals; Ascorbic Acid; Blood Proteins; Disease Models, Animal; Ethanol; Female; Gastric Mucosa; Glutathione; Immunohistochemistry; Lipid Peroxidation; Microscopy, Electron; Rats; Rats, Sprague-Dawley; Selenic Acid; Selenium Compounds; Tocopherols; Triglycerides

Light-exposed parenteral multivitamins induce in lungs peroxide-like oxidant responses as well as the initiation of fibrosis. We hypothesized that peroxides generated in light-exposed total parenteral nutrition (TPN) affect lung remodeling. The objective was to assess the specific roles of peroxides, multivitamin preparation (MVP), and light exposure on lung remodeling during TPN. Three-day-old guinea pigs fitted with an indwelling catheter were assigned to the following intravenous regimens: TPN or MVP +/- photoprotection, H(2)O(2)+/- glutathione, MVP +/- metabisulfite, or ascorbic acid +/- riboflavin. Fed animals served as controls. After 4 days, lungs were sampled to determine alveolarization (intercepts), beta-actin mRNA (protection assay), and apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling). Data were analyzed by analysis of variance. The infusion of light-exposed multivitamins induced a 20% lower (p < 0.01) alveolarization index than fed controls, and 3-fold higher (p < 0.01) apoptotic events. This was prevented by photoprotecting TPN. The effect of multivitamins on the alveolarization index was reproduced (p < 0.05) by infusion of light-exposed riboflavin in the presence of vitamin C. The alveolarization index correlated (r(2) = 0.35; p < 0.05) with beta-actin mRNA, suggesting alveolar disruption. Antiperoxides conferred no protection against decreased alveolarization. Lung remodeling induced by exposure of TPN to ambient light is not due to a direct effect of infused peroxides but rather to an interaction between vitamin C and peroxides generated by the exposure of riboflavin to light. It is speculated that this interaction may play a role in the development of chronic lung disease of premature infants who receive TPN and have immature antioxidant defenses.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Drug Interactions; Guinea Pigs; Light; Lung Diseases; Riboflavin

Topics: Animals; Ascorbic Acid; Behavior, Animal; Brain; Brain Ischemia; Disease Models, Animal; Drug Combinations; Female; Hemodynamics; Laser-Doppler Flowmetry; Magnesium; Magnesium Compounds; Magnesium Deficiency; Male; Neuroprotective Agents; Rats; Sodium Chloride; Vitamin B 6

To estimate ischemic tissue damage in ovarian cortex and to evaluate the effectiveness of ascorbic acid, an antioxidant, to protect ovarian tissue from apoptosis caused by ischemia.. In vitro laboratory experiments.. Academic research institute.. Fresh and frozen/thawed cortical sections of bovine ovaries were incubated in MEM medium with or without ascorbic acid for a duration of 3, 24, and 48 hours at 37 degrees C.. Oxygen consumption rates, lactate dehydrogenase concentrations, apoptosis rates determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and DNA fragmentation analysis.. The oxygen consumption rates were correlated inversely with the duration of incubation. When the rates of apoptosis in primordial follicles with or without ascorbic acid treatment were compared, there was no statistically significant difference between the two groups. However, the ascorbic acid treatment group showed significantly decreased apoptosis in ovarian cortex (stromal cells) with 24 hours of incubation.. The correlation between ischemic tissue damage and the duration of ischemia was verified. Ovarian cortex could tolerate ischemia at least for 3 hours. Ascorbic acid treatment reduced apoptosis in ovarian cortex up to 24 hours of incubation in vitro. It appeared that stromal cells were more vulnerable to ischemia compared to primordial follicles.

Topics: Animals; Antioxidants; Apoptosis; Ascorbic Acid; Cattle; Disease Models, Animal; Female; Ischemia; Ovary; Oxygen Consumption

Reactive oxygen species play a central role in myocardial ischemic injury and are a target for therapeutic intervention. Vitamin C is an essential antioxidant yet difficult to deliver in pharmacologic concentration to the myocardium. We found that adult rat cardiomyocytes accumulate vitamin C by transporting dehydroascorbic acid (DHA), the oxidized form of vitamin C, but do not transport ascorbic acid. Loading cells with vitamin C by DHA treatment resulted in resistance to hypoxia- and hypoxia/reoxygenation-induced cell death associated with the quenching of reactive oxygen species. When rats were injected with DHA before coronary occlusion, the ascorbic acid content in the heart was six to eight times higher than in untreated controls and myocardial infarction was reduced by 62%. DHA also provided significant protection when administered intravenously 2 h after coronary occlusion. In cardiomyocytes subjected to hypoxia/reoxygenation, DHA treatment resulted in decreased apoptosis associated with inhibition of Bax expression, caspase-3 activation, and cytochrome c translocation into the cytoplasm. DHA treatment also inhibited Jak2, STAT1, and STAT5 phosphorylation, and increased STAT3 phosphorylation, in hypoxic cardiomyocytes and ischemic myocardial tissue. Our findings suggest that DHA may be useful as a cardioprotectant in ischemic heart disease.

Topics: Animals; Apoptosis; Ascorbic Acid; Cell Hypoxia; Dehydroascorbic Acid; Disease Models, Animal; Heart; Hypoxia; Muscle Cells; Myocardial Ischemia; Myocardium; Rats; Rats, Sprague-Dawley; Signal Transduction

Topics: Animals; Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Chromosome Aberrations; Disease Models, Animal; Humans; Mice

Ascorbate is an antioxidant vitamin that is found in high concentrations in the brain which seems to have neuroprotective properties in some experimental models of excitotoxic neurological disorders, including convulsive behavior and reactive species-related damage. In this study we tested whether ascorbate (30, 100 or 300 mg/kg, i.p.) protects against the convulsions, protein carbonylation and inhibition of Na(+),K(+)-ATPase activity induced by pentylenetetrazol (PTZ; 1.8 micromol/striatum), a classical convulsant agent that has been fairly used for the study of epilepsy and screening of new compounds with antiepileptic activity. The intrastriatal injection of PTZ caused convulsive behavior in a dose-dependent manner and an increase in the total protein carbonyl content of the injected striatum. However, duration of PTZ-induced convulsive episodes did not correlate with protein carbonyl content of the injected striatum. Ascorbate, at high doses (300 mg/kg), protected against PTZ-induced convulsions, protein carbonylation and inhibition of Na(+),K(+)-ATPase activity in the rat striatum, further suggesting a anticonvulsant and neuroprotective role for this vitamin. Conversely, intermediate doses of ascorbate (100 mg/kg) potentiated the duration of the convulsive episodes, but had no additive effects on protein carbonylation or Na(+),K(+)-ATPase activity inhibition induced by PTZ. Low doses of ascorbate (30 mg/kg) prevented PTZ-induced increase of total striatal carbonyl protein content, but did not alter PTZ-induced convulsions and Na(+),K(+)-ATPase activity inhibition. Collectively, these data indicate that the anticonvulsant activity of ascorbate is not related to its antioxidant action and support a dual role for this compound as a neuroprotective agent, since while it protects against PTZ-induced cellular oxidative damage, it has a biphasic effect on PTZ-induced convulsions.

Topics: Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; Behavior, Animal; Brain Chemistry; Carbolines; Colorimetry; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Male; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Sodium-Potassium-Exchanging ATPase

In cultured endothelial cells, the antioxidant, L-ascorbic acid (vitamin C), increases nitric oxide synthase (NOS) enzyme activity via chemical stabilization of tetrahydrobiopterin. Our objective was to determine the effect of vitamin C on NOS function and tetrahydrobiopterin metabolism in vivo. Twenty-six to twenty-eight weeks of diet supplementation with vitamin C (1%/kg chow) significantly increased circulating levels of vitamin C in wild-type (C57BL/6J) and apolipoprotein E (apoE)--deficient mice. Measurements of NOS enzymatic activity in aortas of apoE-deficient mice indicated a significant increase in total NOS activity. However, this increase was mainly due to high activity of inducible NOS, whereas eNOS activity was reduced. Significantly higher tetrahydrobiopterin levels were detected in aortas of apoE-deficient mice. Long-term treatment with vitamin C restored endothelial NOS activity in aortas of apoE-deficient mice, but did not affect activity of inducible NOS. In addition, 7,8-dihydrobiopterin levels, an oxidized form of tetrahydrobiopterin, were decreased and vascular endothelial function of aortas was significantly improved in apoE-deficient mice. Interestingly, vitamin C also increased tetrahydrobiopterin and NOS activity in aortas of C57BL/6J mice. In contrast, long-term treatment with vitamin E (2000 U/kg chow) did not affect vascular NOS activity or metabolism of tetrahydrobiopterin. In vivo, beneficial effect of vitamin C on vascular endothelial function appears to be mediated in part by protection of tetrahydrobiopterin and restoration of eNOS enzymatic activity.

Topics: Animals; Aorta; Apolipoproteins E; Arteriosclerosis; Ascorbic Acid; Biopterins; Cyclic AMP; Cyclic GMP; Dietary Supplements; Disease Models, Animal; Endothelium, Vascular; Enzyme Activation; In Vitro Techniques; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Superoxides; Time; Tyrosine; Vasomotor System; Vitamin E

In a model of the high blood viscosity syndrome, developed after myocardial infarction in rats, it was observed that a therapy of a combination of diquertin (20 mg/kg) and ascorbic acid (50 mg/kg) for a -period of 6 days, resulted in an improvement of haemorheological indices. The decrease in blood -viscosity was primarily due to an improved deformability of erythrocytes, and to some extent, due to a decrease in the content of plasma fibrinogen and erythrocyte aggregation.

Topics: Animals; Antioxidants; Ascorbic Acid; Blood Viscosity; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Erythrocyte Aggregation; Fibrinogen; Male; Myocardial Infarction; Phytotherapy; Quercetin; Rats; Rats, Wistar

Normal cellular metabolism produces oxidants that are neutralized within cells by antioxidant enzymes and other antioxidants. An imbalance between oxidant and antioxidant has been postulated to lead the degeneration of dopaminergic neurons in Parkinson's disease. In this study, we examined whether selenium, an antioxidant, can prevent or slowdown neuronal injury in a 6-hydroxydopamine (6-OHDA) model of Parkinsonism. Rats were pre-treated with sodium selenite (0.1, 0.2 and 0.3 mg/kg body weight) for 7 days. On day 8, 2 micro L 6-OHDA (12.5 micro g in 0.2% ascorbic acid in normal saline) was infused in the right striatum. Two weeks after 6-OHDA infusion, rats were tested for neurobehavioral activity, and were killed after 3 weeks of 6-OHDA infusion for the estimation of glutathione peroxidase, glutathione-S-transferase, glutathione reductase, glutathione content, lipid peroxidation, and dopamine and its metabolites. Selenium was found to be successful in upregulating the antioxidant status and lowering the dopamine loss, and functional recovery returned close to the baseline dose-dependently. This study revealed that selenium, which is an essential part of our diet, may be helpful in slowing down the progression of neurodegeneration in parkinsonism.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Antioxidants; Ascorbic Acid; Behavior, Animal; Brain; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Glutathione; Homovanillic Acid; Lipid Peroxidation; Male; Motor Activity; Neuroprotective Agents; Parkinsonian Disorders; Rats; Rats, Wistar; Recovery of Function; Sodium Selenite; Treatment Outcome

One of the hypotheses regarding the pathogenesis of familial ALS (FALS) is a copper-mediated oxidative toxicity derived from the mutant Cu, Zn-superoxide dismutase (SOD1). We have previously demonstrated the efficacy of the combined treatment with a copper chelator (trientine) and an antioxidant (ascorbate) on the disease expression of the FALS-linked mutated SOD1 transgenic mice. Here, we investigated the efficacy of trientine or ascorbate alone on FALS mice when administered before or after the onset of the disease. The mice with a high dose of trientine or ascorbate administered before the onset survived significantly longer than the control. In the combined treatment with a high dose of trientine and ascorbate initiated before the onset, survival lengthened and the motor function of the mice remained more significantly than the control. None of the treatments affected the mean age of the onset, and none of the agents administered after the onset prolonged survival. These findings suggest that better outcomes may be expected by the administration of these agents at the preonset stage of the disease, and the combination of the agents acting on different sites might be useful in preserving the motor performance in FALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Antioxidants; Ascorbic Acid; Chelating Agents; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Male; Mice; Mice, Transgenic; Superoxide Dismutase; Superoxide Dismutase-1; Survival Rate; Treatment Outcome; Trientine

Degradation of extracellular matrix, particularly interstitial collagen, promotes plaque instability and contributes to restenosis after vascular injury. We have explored the effects of vitamins C and E on the collagen content and metalloproteinase-1 (MMP-1) expression after angioplasty in hypercholesterolemic pigs. Iliac angioplasty was performed on 18 minipigs divided into three diet groups: a normal-cholesterol (NC), a high-cholesterol (HC) and a high-cholesterol plus vitamins C+E (HCV). Four weeks later, after sacrifice, the vascular collagen content and MMP-1 protein expression, along with the plasma caseinolytic activity and lipid peroxidation, were measured. MMP-1 was also determined in arterial rings stimulated with native low-density lipoproteins (LDL) isolated from experimental groups. Cholesterol-rich diet augmented plasma lipid peroxidation (P<0.05), reduced the collagen content and increased vascular MMP-1 expression after injury (P<0.05). Enhanced caseinolytic activity (identified as MMP-1) was also observed in HC plasma samples and in supernatants from arterial rings incubated with HC-LDL. Vitamins C and E markedly increased neointimal collagen content (P<0.01), reduced the hypercholesterolemia-induced changes in vascular MMP-1 (P<0.05) and diminished plasma and ex vivo caseinolytic activity. Vitamins C and E may help stabilize atherosclerotic plaque after angioplasty and favor vascular remodeling by increasing collagen content and reducing vascular MMP-1 expression in porcine hypercholesterolemia.

Topics: Analysis of Variance; Angioplasty; Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cholesterol; Cholesterol, Dietary; Diet, Atherogenic; Disease Models, Animal; Hypercholesterolemia; Iliac Artery; Lipid Peroxidation; Matrix Metalloproteinase 1; Probability; Sensitivity and Specificity; Swine, Miniature; Vitamin E

Blood pressure (BP) increases in postmenopausal women. The mechanisms responsible are unknown. The present study was performed to characterize a model of postmenopausal hypertension in the rat and to determine the role that oxidative stress may play in mediating the postmenopausal hypertension. Spontaneously hypertensive rats were ovariectomized (ovx) or left intact (PMR) at 8 months and were aged to 18 months. These animals were compared with young females (YF; 4 or 8 months of age) and old males (18 months) for some measurements. Estradiol levels were decreased in PMR rats to levels not different from YF rats in proestrous or from old males. BP increased progressively with age in PMR rats but not in ovx or male rats, such that the gender difference in hypertension disappeared by 18 months. Glomerular filtration rate was lower in ovx and PMR rats than in YF rats. Renal plasma flow and renal vascular resistance were similar between YF and ovx rats, but lower and higher, respectively, in PMR rats. Serum testosterone increased by 60% in ovx rats and 400% in PMR rats compared with YF rats. Plasma renin activity also increased in PMR rats but not in ovx rats. Chronic treatment (for 8 months beginning at 8 months of age) of PMR rats with vitamins E and C, but not tempol, resulted in a significant reduction in BP and excretion of F2-isoprostanes. In contrast, tempol, but not vitamins E and C, reduced BP in old males. These data suggest that the PMR rats, but not ovx rats, may be a suitable model for the study of postmenopausal hypertension, and that oxidative stress plays a role in the increased BP.

Topics: Age Factors; Animals; Antioxidants; Ascorbic Acid; Blood Pressure; Cyclic N-Oxides; Disease Models, Animal; Estradiol; Female; Hemodynamics; Hypertension; Kidney; Male; Ovariectomy; Oxidative Stress; Postmenopause; Rats; Rats, Inbred SHR; Spin Labels; Vaginal Smears; Vitamin E

Arachidonic acid was investigated for its vascular permeabilizing potential in the rat peritoneal cavity and for its mechanism of action. The antagonistic potential of antioxidants (vitamin E, vitamin C and troxerutin) was also evaluated. Vascular permeability was equated to the rate of extravasation of Evans blue dye from plasma into the peritoneal cavity. Baseline permeability was linear up to 2 h, with a rate constant (k) of 0.0031+/-0.0007 h(-1). Intravenous arachidonate (from 30 microg/kg to 3 mg/kg) induced an immediate, dose-related and significant increase in permeability (ranging from 80% to 150%), which was comparable to the effect induced by similar doses of serotonin. Aspirin (10 mg/kg) reduced the arachidonate-induced permeability by 75%, but interestingly neither the stable thromboxane A(2) receptor agonist U46619 (prostaglandin H(2) endoperoxide epoxymethane) nor prostacyclin was able to increase peritoneal vascular permeability. In contrast, the permeabilizing action of arachidonic acid was very sensitive to antioxidant agents. Thus, vitamin C and the flavonoid compound troxerutin (100 mg/kg) fully abolished arachidonate-induced permeability, whereas vitamin E had only a partial effect (40-100% inhibition). In conclusion, intravenous administration of arachidonic acid strongly enhanced peritoneal vascular permeability in the rat, apparently via free radical generation. This rat peritoneal model can be used to evaluate the in vivo antinflammatory potential of antioxidant drugs.

Topics: Animals; Antioxidants; Arachidonic Acid; Ascorbic Acid; Capillary Permeability; Coloring Agents; Disease Models, Animal; Evans Blue; Extravasation of Diagnostic and Therapeutic Materials; Hydroxyethylrutoside; Injections, Intravenous; Male; Peritoneal Cavity; Rats; Rats, Wistar; Reactive Oxygen Species; Time Factors; Vitamin E

Ameliorative effects of few naturally occurring antioxidants like ascorbic acid (vitamin C), alpha-tocopherol (vitamin E) either alone or in combination with meso-2,3-dimercaptosuccinic acid (DMSA) or monoisoamyl DMSA (MiADMSA), on parameters indicative of oxidative stress in the liver, kidney, brain and blood of lead-exposed rats were studied. Male Wistar rats were exposed to 0.1% lead acetate in drinking water for 3 months and treated thereafter with DMSA or its analogue MiADMSA (50 mg/kg, intraperitoneally), either individually or in combination with vitamin E (5 mg/kg, intramuscularly) or vitamin C (25 mg/kg, orally) once daily for 5 days. The effects of these treatments in influencing the lead-induced alterations in haem synthesis pathway, hepatic, renal and brain oxidative stress and lead concentration from the soft tissues were investigated. Exposure to lead produced a significant inhibition of delta-aminolevulinic acid dehydratase (ALAD) activity from 8.44+/-0.26 in control animals to 1.76+/-0.32 in lead control, reduction in glutathione (GSH) from 3.56+/-0.14 to 2.57+/-0.25 and an increase in zinc protoporphyrin level from 62.0+/-3.9 to 170+/-10.7 in blood, suggesting altered haem synthesis pathway. Both the thiol chelators and the two vitamins were able to increase blood ALAD activity towards normal, however, GSH level responded favorably only to the two thiol chelators. The most prominent effect on blood ALAD activity was, however, observed when MiADMSA was co-administered with vitamin C (7.51+/-0.17). Lead exposure produced a significant depletion of hepatic GSH from 4.59+/-0.78 in control animals to 2.27+/-0.47 in lead controls and catalase activity from 100+/-3.4 to 22.1+/-0.25, while oxidized glutathione (GSSG; 0.34+/-0.05 to 2.05+/-0.25), thiobarbituric acid reactive substance (TBARS; 1.70+/-0.45 to 5.22+/-0.50) and glutathione peroxidase (GPx) levels (3.41+/-0.09 to 6.17+/-0.65) increased significantly, pointing to hepatic oxidative stress. Altered, reduced and oxidized GSH levels showed significant recovery after MiADMSA and DMSA administration while, vitamins E and C were effective in reducing GSSG and TBARS levels and increasing catalase activity. Administration of MiADMSA alone and the combined administration of vitamin C along with DMSA and MiADMSA were most effective in increasing hepatic GSH levels to 4.88+/-0.14, 4.09+/-0.12 and 4.30+/-0.06, respectively. Hepatic catalase also reached near normal level in animals co-administered v

Topics: Animals; Antidotes; Antioxidants; Ascorbic Acid; Chelating Agents; Cysteinyldopa; Disease Models, Animal; Drug Therapy, Combination; Lead Poisoning; Male; Oxidative Stress; Porphobilinogen Synthase; Protoporphyrins; Rats; Rats, Wistar; Succimer; Treatment Outcome; Vitamin E

The loss of soluble brain antioxidants and protective effects of radical scavengers implicate reactive oxygen species in cortical neuronal injury caused by bacterial meningitis. However, the lack of significant oxidative damage in cortex [J. Neuropathol. Exp. Neurol. 61 (2002) 605-613] suggests that cortical neuronal injury may not be due to excessive parenchymal oxidant production. To see whether this tissue region exhibits a prooxidant state in bacterial meningitis, we examined the state of the major cortical antioxidant defenses in infant rats infected with Streptococcus pneumoniae. Adenine nucleotides were co-determined to assess possible changes in energy metabolism. Arguing against heightened parenchymal oxidant production, the high NADPH/NADP(+) ratio ( approximately 3:1) and activities of the major antioxidant defense and pentose phosphate pathway enzymes remained unchanged at the time of fulminant meningitis. In contrast, cortical ATP, ADP and total adenine nucleotides were on average decreased by approximately 25%. However, energy depletion did not lead to a significant decrease in adenylate energy charge (AEC). ATP depletion was likely a consequence of metabolic degradation, since it correlated with both the loss of total adenine nucleotides and accumulation of purine degradation products. Furthermore, the loss of ATP and decrease in AEC correlated significantly with the extent of neuronal injury. These results strongly suggest that energy depletion rather than parenchymal oxidative damage is involved in the observed cortical neuronal injury.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Ascorbic Acid; Cerebral Cortex; Disease Models, Animal; Energy Metabolism; Free Radicals; Meningitis, Bacterial; NAD; NADP; Oxidative Stress; Pentose Phosphate Pathway; Rats; Rats, Wistar; Streptococcal Infections; Streptococcus pneumoniae

In vitro expanded CNS precursors could provide a renewable source of dopamine (DA) neurons for cell therapy in Parkinson's disease. Functional DA neurons have been derived previously from early midbrain precursors. Here we demonstrate the ability of Nurr1, a nuclear orphan receptor essential for midbrain DA neuron development in vivo, to induce dopaminergic differentiation in naïve CNS precursors in vitro. Independent of gestational age or brain region of origin, Nurr1-induced precursors expressed dopaminergic markers and exhibited depolarization-evoked DA release in vitro. However, these cells were less mature and secreted lower levels of DA than those derived from mesencephalic precursors. Transplantation of Nurr1-induced DA neuron precursors resulted in limited survival and in vivo differentiation. No behavioral improvement in apomorphine-induced rotation scores was observed. These results demonstrate that Nurr1 induces dopaminergic features in naïve CNS precursors in vitro. However, additional factors will be required to achieve in vivo function and to unravel the full potential of neural precursors for cell therapy in Parkinson's disease.

Topics: Animals; Antigens, Differentiation; Apomorphine; Ascorbic Acid; Astrocytes; Cell Differentiation; Cells, Cultured; Disease Models, Animal; DNA-Binding Proteins; Dopamine; Gene Expression; Gestational Age; Graft Survival; Male; Mesencephalon; Motor Activity; Neurons; Nuclear Receptor Subfamily 4, Group A, Member 2; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Retroviridae; Stem Cell Transplantation; Stem Cells; Transcription Factors; Transduction, Genetic; Tyrosine 3-Monooxygenase

On the basis of in vitro studies, the antioxidant nutrients vitamins E and C are postulated to interact in vivo.. We developed a guinea pig model to evaluate the combined deficiency of vitamins E and C in vivo.. Weanling guinea pigs were fed a control diet or a vitamin E-deficient diet for 14 d, after which one-half of each group had vitamin C removed from their diet, thus creating 4 diet groups. Some animals were observed for clinical signs. Others were killed for evaluation.. Of 21 guinea pigs that were observed after being fed the diet deficient in both vitamins, 8 died 9 +/- 2 d (x +/- SD) after starting the diet. Eight additional guinea pigs developed a characteristic syndrome at 11 +/- 3 d. First, they became paralyzed in the hind limbs. Within a few hours, the paralysis progressed to include all 4 limbs and caused difficulty in breathing, which would have caused death had the animals not been euthanized. Histopathologic evaluation did not identify a lesion in the muscles or nervous system that could account for the paralysis. Biochemical measurements confirmed the deficiencies and indicated that the double deficiency caused lipid peroxidation in the central nervous system.. A distinct clinical syndrome of combined vitamin E and vitamin C deficiency occurs in guinea pigs. This syndrome indicates that these antioxidant vitamins are related in vivo. We speculate that acute oxidative injury in the central nervous system underlies the clinical syndrome.

Topics: alpha-Tocopherol; Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Brain; Disease Models, Animal; Guinea Pigs; Male; Osmolar Concentration; Paralysis; Sciatic Nerve; Spinal Cord; Vitamin E Deficiency

Cerebral ischaemia-reperfusion injury is associated with the generation of reactive oxygen species during the early phases of reoxygenation. EPC-K1, a phosphate diester of vitamins C and E, has been reported to possess potent hydroxyl radical scavenging activity. This study was performed to investigate the effectiveness of EPC-K1 in attenuating cerebral ischaemia-reperfusion injury in a rat model of transient focal cerebral ischaemia.. We evaluated the efficacy of EPC-K1 by measuring the concentration of cerebral thiobarbituric acid reactive substances (TBARS), an indicator of the extent of lipid peroxidation by free radicals, and infarct size in rats subjected to one hour of cerebral ischaemia and 4, 24, or 72 hours of reperfusion.. EPC-K1 significantly reduced both the cerebral TBARS level and the infarct size in a rat model of transient focal cerebral ischaemia. These results indicate that EPC-K1 administration during the early stages of reperfusion ameliorates ischaemic brain injury by inhibiting lipid peroxidation.. This report is the first to describe the protective mechanism of EPC-K1 by measuring both the TBARS level and infarct size in a rat model of transient focal cerebral ischaemia, and may suggest a potential clinical approach for the treatment of ischaemic cerebrovascular disease.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain Ischemia; Disease Models, Animal; Free Radicals; Lipid Peroxidation; Male; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Thiobarbituric Acid Reactive Substances; Vitamin E

We propose a method for experimental modeling of cardiac arrhythmias. The method consists in intravenous injection of LPO inductors: 5% ascorbic acid (50 mg/kg), 1 min later 1% iron sulfate (10 mg/kg), and after the appearance of giant T waves on ECG infusion of 10% calcium chloride in a nonarrhythmogenic dose 100 mg/kg. Cardiac arrhythmias were induced in 100% animals. A significant relationship between increased permeability of erythrocyte membranes and development of fatal cardiac arrhythmias was detected. We assumed that this methodologically simple membrane-destructive model of cardiac arrhythmia is pathogenetically close to arrhythmogenesis in patients with coronary heart disease.

Topics: Animals; Antioxidants; Arrhythmias, Cardiac; Ascorbic Acid; Calcium Chloride; Cell Membrane Permeability; Disease Models, Animal; Electrocardiography; Erythrocyte Membrane; Female; Humans; Iron Compounds; Lipid Peroxidation; Male; Malondialdehyde; Rats

Chronic exposure to lead results in sustained hypertension in humans and experimental animals. We investigated the possible role of reactive oxygen species (ROS) and their impact on DNA damage in lead-induced hypertension. Further the effect of short-term supplementation of vitamin C is also demonstrated.. Male Wistar rats were treated with either lead acetate (100 ppm) alone or lead acetate plus vitamin C (20 mg/rat/day). The control rats were fed regular rat chow. Blood pressure, antioxidants, total antioxidant status as measured by ferric-reducing antioxidant power, nitric oxide (NO) metabolites, malondialdehyde (MDA) and 8-hydroxy 2-deoxyguanosine were determined after 0, 1, 2 and 3 months.. The lead-exposed group showed a significant rise in blood pressure, lipid peroxidation (MDA) and a substantial oxidative damage to the DNA. A significant fall in NO metabolites, total antioxidant levels and ferric-reducing antioxidant power was also observed in this group. Concomitant administration of vitamin C ameliorated hypertension, normalized NO levels and abrogated lipid peroxidation. Also, it completely prevented oxidative damage to the DNA.. These findings point to enhanced ROS-mediated inactivation and sequestration of NO which can potentially contribute to hypertension, lipid peroxidation, reduced antioxidant status and oxidative DNA damage. The beneficial effects of vitamin C on these parameters support the role of increased ROS activity in the pathogenesis of these abnormalities in this model.

Topics: Animals; Antioxidants; Ascorbic Acid; Deoxyadenosines; Dietary Supplements; Disease Models, Animal; DNA Damage; Hypertension; Lead Poisoning; Lipid Peroxidation; Male; Malondialdehyde; Nitric Oxide; Organometallic Compounds; Oxidation-Reduction; Random Allocation; Rats; Rats, Inbred WKY; Reactive Oxygen Species; Time Factors

This study was designed to investigate the influence of intraischemic liver temperature on oxidative stress during postischemic normothermic reperfusion. In C57BL/6 mice, partial hepatic ischemia was induced for 90 min and intraischemic organ temperature adjusted to 4 degrees C, 15 degrees C, 26 degrees C, 32 degrees C, and 37 degrees C. As detected by electron spin-resonance spectroscopy, plasma/blood concentrations of hydroxyl and ascorbyl radicals were significantly increased in all groups after ischemia/reperfusion independent of the intraischemic temperature. In tissue, however, postischemic lipid peroxidation was attenuated after organ cooling down to 32 degrees C-26 degrees C and not detectable after ischemia at 15 degrees C-4 degrees C. mRNA expression of superoxide dismutase-1 and heme oxygenase-1, measured during reperfusion, was significantly elevated in the group at 37 degrees C as compared to the hypothermic groups at 4 degrees C-32 degrees C. The reduction of radical generation was associated with a prevention of adenosine monophosphate hydrolysis during ischemia in the hypothermic groups. In conclusion, ischemia-reperfusion-induced oxidative stress in the liver tissue is non-linearly-dependent on intraischemic temperature, whereas the plasma/blood concentration of radicals is not affected by organ cooling. Oxidative stress is reduced through mild hypothermia at 32 degrees C-26 degrees C and inhibited completely at 15 degrees C. Reduction of initial intracellular radical generation and prevention of secondary oxidant-induced tissue injury are possible mechanisms of this protection.

Topics: Adenosine Monophosphate; Animals; Ascorbic Acid; Disease Models, Animal; Electron Spin Resonance Spectroscopy; Female; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Hydroxyl Radical; Hypothermia, Induced; Lipid Peroxidation; Liver; Membrane Proteins; Mice; Mice, Inbred C57BL; Microcirculation; Oxidative Stress; Reperfusion; Reperfusion Injury; RNA, Messenger; Superoxide Dismutase; Superoxide Dismutase-1; Temperature

The ingestion of dietary antioxidants, including vitamin C (VC), is suggested to play an important role in the prevention of gastric cancer associated with Helicobacter pylori (HP) infection. Recently, water extracts of Tochu (Du-zhong, Eucommia ulmoidea OLIVER) leaves (WETL) have been reported to have potent antioxidant and antimutagenic effects. The present study investigated the effect(s) of VC and WETL on gastric mucosal injury induced by ammonia and a VC deficient diet. Guinea pigs fed the water containing ammonia and/or a VC-deficient diet were simultaneously treated with WETL or VC. Intramucosal levels of thiobarubiturate reactive substances (TBARS), an index of lipid peroxidation, increased significantly in animals fed ammoniated water and VC-deficient diets. This was accompanied by accelerated cell proliferation and increases in immunohistochemical staining indices for oxidative stress-induced DNA adducts and strand breaks (e.g., BrdU-uptake, 8-OhdG, ssDNA and the TUNEL reaction). The administration of either WETL or VC to the ammoniated water and VC-deficient diets ameliorated the increases in intramucosal TBARS levels and labeling indices of BrdU, 8-OHdG, ssDNA and TUNEL, i.e., the levels were similar to those measured in the normal-fed control animals. These data suggest that insufficient VC ingestion may be an important risk factor for gastric cancer development in patients with HP infections. Furthermore, our results suggest that WETL or some constituent may contribute to the prevention of oxidative gastric injury that precedes carcinogenesis.

Topics: Ammonia; Animals; Anti-Ulcer Agents; Antioxidants; Ascorbic Acid; Ascorbic Acid Deficiency; Cell Division; Disease Models, Animal; DNA Damage; Drugs, Chinese Herbal; Eucommiaceae; Gastric Mucosa; Guinea Pigs; In Situ Nick-End Labeling; Male; Plant Leaves; Plants, Medicinal; Thiobarbituric Acid Reactive Substances

Toluene diisocyanate (TDI)-induced asthma is a common cause of occupational lung disease. In addition, a sore throat is one of the complaints of TDI-exposed workers. The aim of the present study was to determine whether TDI exposure induces laryngeal and/or tracheal lesions in experimental animals.. Guinea pigs underwent naris application of TDI three times, and their respiratory tracts were then examined using light and electron microscopy. Some animals simultaneously received vitamins C and E. which function as antioxidant agents.. When TDI-treated animals showed the clinical sign of labored breathing, many eosinophils had appeared in the lamina propria and mucosa of both the larynx and trachea, which finally infiltrated the tract lumen through the ruptured epithelium. Laryngo-tracheal inflammation was more severe than that observed in the lungs. However, supplementation with antioxidant vitamins in TDI-treated animals ameliorated the respiratory eosinophilia.. Naris application of TDI induced laryngotracheitis. which was significantly suppressed by the antioxidant vitamins, This implies a preventive effect of the vitamins on this occupational disease.

Topics: alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Guinea Pigs; Larynx; Male; Pulmonary Eosinophilia; Toluene 2,4-Diisocyanate; Trachea

To investigate whether combined pretreatment with lipid- and water-soluble antioxidants gave better restoration of energy phosphates after ischaemia-reperfusion of rabbit kidneys than single pretreatment with a lipid-soluble antioxidant.. Thirteen New Zealand white rabbits were used for the study. Changes in energy phosphates were measured in vivo using volume-selective 31P magnetic resonance spectroscopy. The indeno-indole compound H290/51 was chosen as a lipid-soluble antioxidant and ascorbate as a water-soluble antioxidant.. The combined pretreatment led to significantly better restoration of the beta-adenosine triphosphate:inorganic phosphate ratio after 60 min of ischaemia and 120 min of reperfusion compared with the single pretreatment. Analyses of blood pressure and blood gas changes showed that the beneficial effect of combined pretreatment was not caused by a better general condition of the animals in that group but by a direct effect on the kidneys.. Combined pretreatment with lipid- and water-soluble antioxidants leads to better restoration of energy phosphates in rabbit kidneys subjected to ischaemia-reperfusion compared with single pretreatment with a lipid-soluble antioxidant.

Topics: Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Female; Indoles; Ischemia; Kidney Diseases; Kidney Function Tests; Lipid Peroxidation; Magnetic Resonance Spectroscopy; Male; Monitoring, Physiologic; Phosphorus Isotopes; Probability; Rabbits; Random Allocation; Reperfusion Injury; Sensitivity and Specificity; Solubility

We investigated the effect of topical administration of ascorbic acid on the healing process of tympanic membrane perforations in rats.. Thermal myringotomy was induced in both ears of 22 albino rats. The right and left ears were assigned to topical applications of ascorbic acid and saline solution, respectively. The same procedure was performed after 48 hours. Perforations were examined daily by otomicroscopy and healing periods were determined. For histopathologic examination, a single rat in which closure of the tympanic membranes was not completed was sacrificed on days 5, 7, 10, and 12. Data were analyzed with the use of the Student's t-test.. The mean durations of healing in the right and left ears were 7.6 and 8.3 days, respectively. No significant differences were found between the applications of ascorbic acid and saline solution with regard to the duration of closure and histopathologic healing criteria.. Our data suggest that topical application of ascorbic acid have no beneficial effect on the healing of rat tympanic membrane perforations.

Topics: Administration, Cutaneous; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Female; Random Allocation; Rats; Tympanic Membrane Perforation; Wound Healing

The aim of this study was to investigate the effect of heparin on osteoporosis initiation, and the effect of selenium plus vitamins E and C, and the sole combination of vitamins E and C on the progress of osteoporosis induced by heparin through histologic means. Adult female New Zealand white rabbits were divided into three experimental and three control groups. The experimental rabbits were injected with 1000 IU/kg/day heparin (Liquemine) for 4 weeks. These six groups were administered deionized water (CI and EI), 100 mg/kg/day L-ascorbic acid plus 100 mg/kg/day alpha-tocopherol acetate (CII and EII), and 0.05 mg/kg/day sodium selenite, plus these vitamins orally, with a gastric catheter (CIII and EIII), respectively. At the end of the experimental period, the femurs of the animals were collected and investigated under a light photomicroscope. Heparin caused important alterations in bone, such as an improper lamellar structure and a large uncalcified bone matrix. These findings implied the early phase of osteoporosis induced by heparin use. The combination of vitamins E and C given to the experimental rabbits partially prevented this bone tissue destruction. When sodium selenite was given together with vitamins E and C to the osteoporosis model rabbits, the long bone tissue had almost the same structure as in normal rabbits, for example the development of numerous bone trabeculae. Our results suggest that a combination of sodium selenite with vitamins E and C was more effective than combinations of single vitamins to prevent structural alterations in these model bones.

Topics: Animals; Ascorbic Acid; Bone and Bones; Bone Remodeling; Disease Models, Animal; Drug Therapy, Combination; Female; Heparin; Osteoporosis; Probability; Rabbits; Random Allocation; Reference Values; Sensitivity and Specificity; Sodium Selenite; Vitamin E

In light of evidence that diabetes mellitus is associated with oxidative stress and altered antioxidant status, we investigated the effect of Scoparia dulcis plant extracts (SPEt) (aqueous, ethanolic, and chloroform) in streptozotocin diabetic rats. Significant increases in the activities of insulin, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, reduced glutathione, vitamin C, and vitamin E were observed in liver, kidney, and brain on treatment with SPEt. In addition, the treated groups also showed significant decreases in blood glucose, thiobarbituric acid-reactive substances, and hydroperoxide formation in tissues, suggesting its role in protection against lipid peroxidation-induced membrane damage. Thus, the results of the present study indicate that extracts of S. dulcis, especially the aqueous extract, showed a modulatory effect by attenuating the above lipid peroxidation in streptozotocin diabetes.

Topics: Animals; Antioxidants; Ascorbic Acid; Blood Glucose; Catalase; Diabetes Mellitus, Experimental; Disease Models, Animal; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Insulin; Lipid Peroxidation; Liver; Male; Oxidative Stress; Plant Extracts; Random Allocation; Rats; Rats, Wistar; Scoparia; Superoxide Dismutase; Vitamin E

Impaired endothelium-dependent vasodilation has been associated with decreased NO bioavailability in hypercholesterolemia. This study aimed to determine whether antioxidant vitamins C and E could improve hypercholesterolemia-derived endothelial dysfunction in the porcine model, and whether observed in vivo results could be reproduced in vitro by incubation of coronary endothelial cells (EC) in the presence of native low-density lipoproteins (LDL). Adult mini-pigs were fed standard (C), cholesterol rich (HC) or cholesterol rich diet supplemented with vitamins C and E (HCV). Endothelium-dependent blood flow increase in response to acetylcholine was determined. Endothelial nitric oxide synthase (eNOS) expression was measured in arterial samples and in EC incubated with LDL isolated from porcine plasma. Vasomotor response to acetylcholine in HC was significantly lower (P<0.05) than control and HCV. There was a significant (P<0.05) decrease in eNOS immunoreactivity in HC, compared with HCV and control. Native LDL from HC, but not from HCV, induced a significant decrease in eNOS expression. Vitamins C and E treatment improved the endothelium-dependent vasomotor capacity and prevented decreased expression of eNOS in hypercholesterolemic pigs. A similar effect could be demonstrated in vitro, by incubation of EC with native LDL, suggesting that the effect of physiologically-modified LDL on eNOS could have a role in recovering vascular function.

Topics: Analysis of Variance; Animals; Ascorbic Acid; Blotting, Western; Cells, Cultured; Coronary Vessels; Dietary Supplements; Disease Models, Animal; Down-Regulation; Endothelium, Vascular; Hypercholesterolemia; Immunohistochemistry; Male; Nitric Oxide Synthase; Probability; Reference Values; Sensitivity and Specificity; Statistics, Nonparametric; Swine; Vitamin E

Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of the phenylalanine hydroxylation system and is characterized by a block in the conversion of phenylalanine (PHE) to tyrosine. We examined the effects of maternal hyperphenylalaninemia on the morphological and biochemical development of pup rat brain and cerebellum. In our model of PKU we evaluated a number of markers of oxidative stress such as Ehrlich adducts formation, lipid peroxidation, as well as the levels of reduced and oxidized glutathione, and the activities of the enzymes glutathione peroxidase and glutathione reductase. We also studied the expression of heme-oxigenase-1 and mitogen-activated protein kinase 1/2 (MAPK 1/2) as additional markers of oxidative stress. We demonstrate that PKU strongly increased most of the oxidative stress markers studied and induced significant morphological damage. We also showed that daily administration of melatonin (20 mg/kg BW), vitamin E (30 mg/kg BW), and vitamin C (30 mg/kg BW) until delivery prevented the oxidative biomolecular damage in the rat brain and cerebellum. Although no significant differences were observed among the antioxidants studied, it should be noted that the doses of melatonin were less than those for vitamins E and C. We conclude that PKU induces a clear state of oxidative stress that is somehow involved in the brain and body damage occurring in this inborn error. Moreover, melatonin and other antioxidants are capable of preventing completely the damage induced by PKU.

Topics: Animals; Animals, Newborn; Antioxidants; Ascorbic Acid; Brain; Cerebellum; Disease Models, Animal; Female; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Humans; Lipid Peroxidation; Melatonin; Nervous System Malformations; Neurons; Oxidative Stress; Phenylalanine; Phenylketonurias; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Vitamin E

Probiotics and antioxidants could be alternatives to antibiotics in the prevention of bacterial infections in cirrhosis. The aim of the present study was to determine the effect of Lactobacillus johnsonii La1 and antioxidants on intestinal flora, endotoxemia, and bacterial translocation in cirrhotic rats.. Twenty-nine Sprague-Dawley rats with cirrhosis induced by CCl(4) and ascites received Lactobacillus johnsonii La1 10(9)cfu/day in vehicle (antioxidants: vitamin C+glutamate) (n=10), vehicle alone (n=11), or water (n=8) by gavage. Another eight non-cirrhotic rats formed the control group. After 10 days of treatment, a laparotomy was performed to determine microbiological study of ileal and cecal feces, bacterial translocation, endotoxemia, and intestinal malondialdehyde (MDA) levels as index of intestinal oxidative damage.. Intestinal enterobacteria and enterococci, bacterial translocation (0/11 and 0/10 vs. 5/8, P<0.01), and ileal MDA levels (P<0.01) were lower in cirrhotic rats treated with antioxidants alone or in combination with Lactobacillus johnsonii La1 compared to cirrhotic rats receiving water. Only rats treated with antioxidants and Lactobacillus johnsonii La1 showed a decrease in endotoxemia with respect to cirrhotic rats receiving water (P<0.05).. Antioxidants alone or in combination with Lactobacillus johnsonii La1 can be useful in preventing bacterial translocation in cirrhosis.

Topics: Animals; Antioxidants; Ascites; Ascorbic Acid; Bacterial Translocation; Combined Modality Therapy; Disease Models, Animal; Endotoxemia; Glutamic Acid; Intestinal Mucosa; Lactobacillus; Liver Cirrhosis; Male; Malondialdehyde; Oxidative Stress; Peritonitis; Probiotics; Rats; Rats, Sprague-Dawley

It has recently been proposed that nitric oxide synthase, in the presence of suboptimal levels of tetrahydrobiopterin, an essential cofactor of this enzyme, might favor increased production of oxygen radicals. The aim of this study was to clarify whether supplement with tetrahydrobiopterin would exert a cardioprotective effect against ischemia-reperfusion injury.. Isolated perfused rat hearts were subjected to 30 minutes of global ischemia and 30 minutes of reperfusion at 37 degrees C. Hearts were treated with tetrahydrobiopterin or vehicle for 5 minutes just before ischemia and during the first 5 minutes of the reperfusion period. Effects of tetrahydrobiopterin on left ventricular function, myocardial contents of lipid peroxidation and high-energy phosphates, and levels of lactate dehydrogenase and nitrite plus nitrate in perfusate during ischemia and after reperfusion were estimated and further compared with those of superoxide dismutase plus catalase or L-ascorbic acid.. Tetrahydrobiopterin and superoxide dismutase plus catalase both improved contractile and metabolic abnormalities in reperfused hearts. On the other hand, L-ascorbic acid at a dose having an equipotent radical scavenging activity with tetrahydrobiopterin did not significantly affect the postischemic changes. Although tetrahydrobiopterin and superoxide dismutase plus catalase significantly alleviated ischemic contracture during ischemia, diminished perfusate levels of nitrite plus nitrate after reperfusion were restored only with tetrahydrobiopterin.. Results demonstrated that tetrahydrobiopterin lessens ischemia-reperfusion injury in isolated perfused rat hearts, probably independent of its intrinsic radical scavenging action. The cardioprotective effect of tetrahydrobiopterin implies that tetrahydrobiopterin could be a novel and effective therapeutic option in the treatment of ischemia-reperfusion injury.

Topics: Animals; Ascorbic Acid; Biopterins; Catalase; Coronary Circulation; Disease Models, Animal; Free Radical Scavengers; Lipid Peroxidation; Male; Myocardial Reperfusion Injury; Nitric Oxide; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Ventricular Function, Left

Arsenic is an ubiquitous element in the environment causing oxidative burst in the exposed individuals leading to tissue damage. Antioxidants have long been known to reduce the free radical-mediated oxidative stress. Therefore, the present study was designed to determine whether supplementation of alpha-tocopherol (400 mg/kg body weight) and ascorbic acid (200 mg/kg body weight) to arsenic-intoxicated rats (100 ppm in drinking water) for 30 days affords protection against the oxidative stress caused by the metalloid. The arsenic-treated rats showed elevated levels of lipid peroxide, decreased levels of non-enzymatic antioxidants and activities of enzymatic antioxidants. Administration of alpha-tocopherol and ascorbic acid to arsenic-exposed rats showed a decrease in the level of lipid peroxidation (LPO) and enhanced levels of total sulfhydryls, reduced glutathione, ascorbic acid and alpha-tocopherol and so do the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase to near normal. These findings suggest that alpha-tocopherol and ascorbic acid prevent LPO and protect the antioxidant system in arsenic-intoxicated rats.

Topics: Administration, Oral; alpha-Tocopherol; Animals; Antioxidants; Arsenic Poisoning; Arsenites; Ascorbic Acid; Catalase; Disease Models, Animal; Free Radical Scavengers; Glutathione Peroxidase; Lipid Peroxidation; Male; Oxidative Stress; Rats; Rats, Wistar; Sodium Compounds; Superoxide Dismutase; Water Supply

The biological activity of L-dehydroascorbic acid (DHA), which is easily formed from L-ascorbic acid (ASC) during storage and cooking processes, has been considered to be equivalent to that of ASC on the basis of studies made several decades ago, when a specific method to determine ASC was not available. The nutritional activity of orally ingested DHA has now been evaluated by comparing ASC concentrations in 12 tissues of rats administered four different doses of ASC. Determinations were made by using the specific and sensitive method, which had been developed by us. Here it is shown that the efficiency of DHA was almost 10% of that of ASC on a molar basis, based on animal experiments using the inherently scorbutic ODS rat, which is a convenient human model animal to investigate the metabolism of vitamin C. On the basis of these findings, it is proposed that it is necessary to reevaluate the nutritional requirement of vitamin C based on both ASC and DHA contents of foods.

Topics: Administration, Oral; Animals; Ascorbic Acid; Dehydroascorbic Acid; Disease Models, Animal; Male; Nutritional Requirements; Nutritive Value; Rats; Scurvy; Tissue Distribution

The extracellular fluid of the striatum contains a high level of ascorbate, an antioxidant vitamin known to play a key role in behavioral activation. We assessed the extracellular dynamics of ascorbate in R6/2 mice engineered to express the gene for Huntington's disease (HD), an autosomal dominant condition characterized by the loss of striatal neurons. Slow-scan voltammetry was used to measure striatal ascorbate during anesthesia and subsequent behavioral recovery. Although both the HD mice and their littermate controls had comparable ascorbate levels during anesthesia, the gradual return of behavioral activation over the next 120 min led to dramatically different ascorbate responses: a progressive increase in controls and a 25-50% decline in HD mice. In contrast, 3,4-dihydroxyphenylacetic acid, a major dopamine metabolite, showed no group differences. Behaviorally, HD mice were less active overall than controls and showed a relatively restricted range of spontaneous movements. Both the ascorbate and behavioral deficits were evident in 6-week-old HD mice and persisted in all subsequent test sessions through 10 weeks of age. Collectively, although these results are consistent with inadequate antioxidant protection in the HD striatum, they indicate that the ascorbate deficit is confined to periods of behavioral activation.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Ascorbic Acid; Behavior, Animal; Body Weight; Corpus Striatum; Disease Models, Animal; Disease Progression; Electrochemistry; Extracellular Space; Huntington Disease; Male; Mice; Mice, Transgenic; Microelectrodes; Motor Activity; Phenotype; Spatial Behavior

To investigate the efficacy of antioxidant therapy on collagen synthesis in corrosive esophageal burns, 110 Sprague-Dawley rats were divided into five groups of 22 animals each. A standard esophageal caustic burn was produced by 1 ml of 10% sodium hydroxide solution for the rats in groups B to E; group A was instilled only with 0.9% saline after preparation of the distal esophageal segment. Group A animals (controls) were uninjured and untreated. Group B had untreated esophageal burns. Esophageal burns were treated in group C with vitamin E (10 mg/kg IM), in group D with vitamin C (10 mg/kg IP), and in group E with methylprednisolone (30 mg/kg IM) on each of 5 days. Eight rats from each group were killed 4 days after initiation of the study and the abdominal esophagus was studied for tissue malondialdehyde (MDA; micromol/g protein) levels. The other rats were killed 28 days after initiation of the study and determination of hydroxyproline (HP) (microg/g tissue) levels in esophageal tissue was performed for 8 rats in each group. Histopathologic evaluation was also performed in the other 6 rats from each group. MDA levels in esophageal tissue were significantly lower in groups C (9.24 +/- 2.62, P < 0.01) and group E (6.26 +/- 2.22, P < 0.001) than in group B (12.35 +/- 1.80). HP levels were significantly lower in groups A (0.75 +/- 0.21, P < 0.001), C (1.11 +/- 0.15, P < 0.01), and E (0.96 +/- 0.15, P < 0.001) than in group B (1.40 +/- 0.20). Histopathologically, collagen deposition in the submucosa and tunica muscularis was lower in groups C and E than in group B (P < 0.05, and 0.01, respectively). Our results demonstrate that treatment with antioxidant drugs such as vitamin E and methylprednisolone decreased tissue HP levels, and thus inhibited new collagen synthesis and stricture formation in rats with alkali-induced caustic esophageal burns.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Burns, Chemical; Collagen; Disease Models, Animal; Esophagus; Malondialdehyde; Methylprednisolone; Rats; Rats, Sprague-Dawley; Sodium Hydroxide; Statistics, Nonparametric; Vitamin E

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Ascorbic Acid; Cell Differentiation; Cell Division; Connexin 43; Connexins; Disease Models, Animal; Drug Evaluation, Preclinical; Free Radical Scavengers; Humans; Neoplasms; Phosphorylation; Primary Prevention; Rats

Although carvedilol attenuates left ventricular (LV) remodeling in coronary occlusion-reperfusion, it is not known whether it attenuates ischemic LV remodeling because of coronary stenosis (CS) or permanent coronary occlusion (CO).. We administered a vehicle, carvedilol, propranolol (2, 10, and 30 mg/kg per day, each), metoprolol (6, 30, and 90 mg/kg per day), or bunazosin (0.2 and 1 mg/kg per day), orally for 12 weeks to a total of 608 rats with CS or CO. In these groups and the sham (n=40), we assessed LV function by echocardiography, CS severity, myocardial blood flow and coronary flow reserve, serum ascorbyl free radical, and vitamin C. Both CS and CO increased LV end-diastolic and end-systolic diameters and decreased ejection fraction. The 4 agents failed to attenuate LV remodeling caused by CO. In contrast, the 3 beta-blockers attenuated (P<0.01) or tended to attenuate the increase in LV end-diastolic diameters caused by CS. With similar blood pressure and heart rate lowering by 3 beta-blockers, carvedilol additionally attenuated the increase in end-systolic diameters and improved ejection fraction. The CS reduced myocardial blood flow and coronary flow reserve, which was reversed by carvedilol without modifying the CS severity. Among the 4 agents, only carvedilol decreased ascorbyl free radical and increased vitamin C.. The effects of beta blockade on ischemic cardiac dysfunction seem to depend on the different properties of the beta-blockers and the doses used. Among the beta-blockers tested, carvedilol provided potent cardioprotection for compromised ischemic but viable myocardium rather than for infarcted myocardium.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Animals; Ascorbic Acid; Carbazoles; Cardiac Catheterization; Carvedilol; Coronary Disease; Coronary Stenosis; Disease Models, Animal; Dose-Response Relationship, Drug; Echocardiography; Hemodynamics; Male; Metoprolol; Norepinephrine; Propanolamines; Propranolol; Quinazolines; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Stroke Volume; Survival Rate; Thiobarbituric Acid Reactive Substances; Ventricular Function, Left; Ventricular Remodeling

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Collagen; Disease Models, Animal; Disease Progression; Extracellular Matrix; Humans; Mice; Myocardial Infarction; Protein Processing, Post-Translational; Scurvy

Oxidative stress is thought to play an important role in atherogenesis, suggesting that antioxidants could prevent coronary artery disease. However, the efficacy of vitamin C in reducing atherosclerosis is debatable in humans and has not been tested rigorously in animals.. Gulo(-/-)Apoe(-/-) mice were used to test a hypothesis that chronic vitamin C deficiency enhances the initiation and development of atherosclerosis. These mice are dependent on dietary vitamin C because of the lack of L-gulonolactone-gamma-oxidase and are prone to develop atherosclerosis because of lacking apolipoprotein E. Beginning at 6 weeks of age, the Gulo(-/-)Apoe(-/-) mice were fed regular chow or Western-type diets containing high fat and supplemented with either 0.033 g or 3.3 g/L of vitamin C in their drinking water. This regimen produced mice with chronically low vitamin C (average 1.5 microg/mL in plasma) or high vitamin C (average 10 to 30 microg/mL in plasma). Morphometric analysis showed that within each sex, age, and diet group, the sizes of the atherosclerotic plaques were not different between low vitamin C mice and high vitamin C mice. However, advanced plaques in the low vitamin C mice had significantly reduced amounts of Sirius red-staining collagen (36.4+/-2.2% versus 54.8+/-2.3%, P<0.0001), larger necrotic cores within the plaques, and reduced fibroproliferation and neovascularization in the aortic adventitia.. Chronic vitamin C deficiency does not influence the initiation or progression of atherosclerotic plaques but severely compromises collagen deposition and induces a type of plaque morphology that is potentially vulnerable to rupture.

Topics: Animals; Aorta; Apolipoproteins E; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Blood Glucose; Cholesterol; Cholesterol, HDL; Collagen; Crosses, Genetic; Dietary Fats; Dietary Supplements; Disease Models, Animal; Disease Progression; Female; L-Gulonolactone Oxidase; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Sex Factors; Sugar Alcohol Dehydrogenases; Triglycerides

Traumatic brain injury is a common event associated with neurological dysfunction. Oxidative damage, may contribute to some of these pathologic changes. We used a specific and sensitive marker of lipid peroxidation, the isoprostane 8,12-iso-iPF(2alpha) -VI, to investigate whether local and also systemic lipid peroxidation were induced following lateral fluid percussion (FP) brain injury in the rat. Animals were anesthetized and subjected to lateral FP brain injury of moderate severity, or to sham injury as controls. Urine was collected before anesthesia (baseline), 6 and 24 h after injury. Blood was collected at baseline, 1, 6 and 24 h after injury. Animals were killed 24 h after surgery and their brains removed for biochemical analysis. No significant difference was observed at baseline (preinjury) for urine and plasma 8,12-iso-iPF(2alpha) -VI levels between injured and sham-operated animals. By contrast, plasma and urinary levels increased significantly already at 1 and further increased 24 h following brain injury, when compared to sham-operated animals. Finally, compared with sham, injured animals had a significant increase in brain 8,12-iso-iPF(2alpha) -VI levels. These results demonstrate that moderate brain injury induces widespread brain lipid peroxidation, which is accompanied by a similar increase in urine and plasma. Peripheral measurement of 8,12-iso-iPF(2alpha) -VI levels after brain injury may be a reliable marker of brain oxidative damage.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Brain Chemistry; Brain Injuries; Dinoprost; Disease Models, Animal; Lipid Peroxidation; Male; Rats; Rats, Sprague-Dawley; Vitamin E

The present experiment determined the effects of glutathione and ascorbic acid, the two most important hydrophilic antioxidants, on myocardial ischemia-reperfusion injury and evaluated their relative therapeutic values. Isolated rat hearts were subjected to ischemia (30 min) and reperfusion (120 min) and treated with ascorbic acid, glutathione monoethyl ester (GSHme), or their combination at the onset of reperfusion. Administration of 1 mM GSHme alone, but not 1 mM ascorbic acid alone, significantly attenuated postischemic injury (P < 0.05 versus vehicle). Most interestingly, coadministration of ascorbic acid with GSHme markedly enhanced the protective effects of GSHme (P < 0.01 versus vehicle). The protection exerted by the combination of GSHme and ascorbic acid at 1 mM each was significantly greater than that observed with 1 mM GSHme alone (P < 0.05). Moreover, treatment with GSHme alone or GSHme plus ascorbic acid markedly reduced myocardial nitrotyrosine levels, suggesting that these treatments attenuated myocardial peroxynitrite formation. These results demonstrated that 1) GSHme, but not ascorbic acid, exerted protective effects against ischemia-reperfusion injury; and 2) the protective effects of GSHme were further enhanced by coadministration with ascorbic acid, suggesting a synergistic effect between GSHme and ascorbic acid.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Glutathione; Heart; Heart Rate; Incidence; Lipid Peroxidation; Myocardial Reperfusion Injury; Myocardium; Protective Agents; Rats; Reperfusion Injury; Tachycardia; Tyrosine; Ventricular Fibrillation

It is well known that eating fruits and vegetables lowers the risk of chronic diseases such as heart disease and cancer. The question of what is/are the active ingredient(s) is still unresolved. The initial hypothesis was that the antioxidant vitamins were responsible. However, recently the polyphenols have been investigated since they have been found to have beneficial properties such as being strong antioxidants. We measured the polyphenol content of citrus juices by an oxidation-reduction colorimetric method (Folin) using catechin as the standard. The order was tangerine juice > grapefruit juice > orange juice. The antioxidant contribution of ascorbic acid was measured by the difference in Folin reactive content following removal by ascorbate oxidase. Ascorbate contributed 56 to 77% of the antioxidant content of orange juice, 46% of the single tangerine juice measured, and 66 to 77% of grapefruit juices. Polyphenol quality in the juices was analyzed by using the inhibition of lower density lipoprotein oxidation promoted by cupric ion, an in vitro model of heart disease. Quality decreased in the following order: orange juice > grapefruit juice > tangerinejuice. In orange juice polyphenols accounted for 84-85% of antioxidant quality. The pure polyphenol hesperidin, which is common in juices, ascorbic acid, and the citrus juices, were not able to bind with LDL+VLDL and protect it from oxidation. In a hamster model of atherosclerosis, the juices were able to significantly inhibit atherosclerosis and lowered cholesterol and triglycerides. Ascorbic acid alone in the dose provided by the juices was found to have the same effect on atherosclerosis. However, the polyphenols in the citrus

Topics: Adult; Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Beverages; Citrus; Cricetinae; Diet, Atherogenic; Disease Models, Animal; Drug Evaluation; Drug Evaluation, Preclinical; Female; Flavonoids; Heart Diseases; Hesperidin; Humans; Hypercholesterolemia; Hypertriglyceridemia; Lipids; Male; Mesocricetus; Middle Aged; Oxidation-Reduction; Phenols; Plant Extracts; Polymers; Species Specificity

Reactive oxygen species (ROS) induce HSCs activation, proliferation and collagen gene expression in vitro. Nitric oxide (NO) represents a reactive molecule that reacts with ROS, yielding peroxynitrite. We thus verified the effect of NO on ROS-induced HSCs proliferation in vitro and correlated iNOS expression and ROS formation to HSCs activation in the early phase of liver injury leading to hepatic fibrosis in vivo.. HSCs were incubated with iron ascorbate (FeAsc) in vitro, which induced ROS production, ERK1/2 phosphorylation and increased cell proliferation. This effect was significantly reduced by the presence of the NO donor S-nitroso-N-acetylpenicillamine. Liver injury was induced in vivo in rats by dimethylnitrosamine administration. HSCs activation started 6 h after DMN administration and peaked at 1 week. ROS generation and neutrophil infiltration were evident for at least 48 h after DMN treatment, showing an identical distribution pattern. Only a few inflammatory cells expressed iNOS 6 h after DMN administration.. we have shown that NO acts as a ROS scavenger in vitro, thus inhibiting HSCs proliferation. ROS production by infiltrating neutrophils occurs in the early phase of liver fibrosis and can represent a stimulus to HSCs activation in vivo. The reduced iNOS expression may account for the low NO levels and the inability to prevent the ROS-induced HSC activation in vivo.

Topics: Animals; Ascorbic Acid; Cell Division; Cells, Cultured; Dimethylnitrosamine; Disease Models, Animal; Drug Interactions; Free Radicals; Immunohistochemistry; Liver; Liver Cirrhosis; Male; Neutrophils; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Penicillamine; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; S-Nitroso-N-Acetylpenicillamine

The involvement of mitochondrial dysfunction promoting neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), has been suggested. Histopathological and biochemical mitochondrial abnormalities have been reported in both sporadic and familial patients and suggest the contention that mitochondria may play a key role promoting ALS. Animal models of ALS provide a unique opportunity to study this incurable and fatal human disease. In the present study we tested the hypothesis that alterations in mitochondrial physiology occur in the brain of wobbler mice. No significant difference was found in the respiratory control index or adenosine diphosphate/oxygen ratio values between isolated mitochondria of wobbler and control mice. When pyruvate and malate were used as substrates, oxygen consumption was decreased significantly by approximately 33% in mitochondria isolated from wobbler mouse brain compared to controls. Oxygen consumption in the presence of ascorbate and N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) was decreased significantly by approximately 21% in wobbler brain mitochondria compared to controls, which suggests impairment in the function of complex IV. These findings are the first demonstration of mitochondrial respiratory chain dysfunction in the brain of the wobbler mouse.

Topics: Amyotrophic Lateral Sclerosis; Animals; Ascorbic Acid; Brain; Cell Respiration; Disease Models, Animal; Electron Transport; Malates; Mice; Mice, Neurologic Mutants; Mitochondria; Oxygen Consumption; Pyruvic Acid

This study examined the effects of antioxidant vitamins A, C, and E on nuclear transcription factor-kappa B (NF-kappaB) nuclear translocation, on secretion of inflammatory cytokines by cardiac myocytes, and on cardiac function after major burn trauma.. Adult rats were divided into four experimental groups: group I, shams; group II, shams given oral antioxidant vitamins (vitamin C, 38 mg/kg; vitamin E, 27 U/kg; vitamin A, 41 U/kg 24 hours before and immediately after burn); group III, burns (third-degree scald burn over 40% total body surface area) given lactated Ringer's solution (4 mL/kg/% burn); and group IV, burns given lactated Ringer's solution plus vitamins as described above. Hearts were collected 4, 8, 12, and 24 hours after burn to assay for NF-kappaB nuclear translocation, and hearts collected 24 hours after burn were examined for cardiac contractile function or tumor necrosis factor-alpha secretion by cardiomyocytes.. Compared with shams, left ventricular pressure was lower in burns given lactated Ringer's solution (group III) (88 +/- 3 vs. 64 +/- 5 mm Hg, p < 0.01) as was +dP/dt max (2,190 +/- 30 vs. 1,321 +/- 122 mm Hg/s) and -dP/dt max (1,775 +/- 71 vs. 999 +/- 96 mm Hg, p < 0.01). Burn injury in the absence of vitamin therapy (group III) produced cardiac NF-kappaB nuclear migration 4 hours after burn and cardiomyocyte secretion of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 by 24 hours after burn. Antioxidant therapy in burns (group IV) improved cardiac function, producing left ventricular pressure and +/-dP/dt (82 +/- 2 mm Hg, 1,880 +/- 44 mm Hg, and 1,570 +/- 46 mm Hg/s) comparable to those measured in shams. Antioxidant vitamins in burns inhibited NF-kappaB nuclear migration at all times after burn and reduced burn-mediated cytokine secretion by cardiomyocytes.. These data suggest that antioxidant vitamin therapy in burn trauma provides cardioprotection, at least in part, by inhibiting translocation of the transcription factor NF-kappaB and interrupting cardiac inflammatory cytokine secretion.

Topics: Animals; Antioxidants; Ascorbic Acid; Body Surface Area; Burns; Disease Models, Animal; Drug Evaluation, Preclinical; Hemodynamics; Inflammation; Injury Severity Score; Interleukin-1; Interleukin-6; Myocardial Contraction; Myocardium; NF-kappa B; Oxidative Stress; Protein Transport; Rats; Rats, Sprague-Dawley; Time Factors; Tumor Necrosis Factor-alpha; Vitamin A; Vitamin E

Inhaled urban particulate matter (PM) often contains metals that appear to contribute to its toxicity. These particles first make contact with a thin layer of epithelial lining fluid in the respiratory tract. Antioxidants present in this fluid and in cells might be important susceptibility factors in PM toxicity. We investigated the role of ascorbic acid (C) and glutathione (GSH) as determinants of susceptibility to inhaled residual oil fly ash (ROFA) in guinea pigs (male, Hartley). Guinea pigs were divided into four groups, +C+GSH, +C-GSH, -C+GSH, and -C-GSH, and exposed to clean air or ROFA (< 2.5 micron diameter, 19--25 mg/m(3) nose-only for 2.0 h). C and/or GSH were lowered by either feeding C-depleted diet (1 microg C/kg diet, 2 weeks) and/or by ip injection of a mixture of buthionine-S,R-sulfoximine (2.7 mmol/kg body weight) and diethylmaleate (1.2 mmol/kg, 2 h prior). Nasal lavage (NL) and bronchoalveolar lavage (BAL) fluid and cells were examined at 0 h and 24 h postexposure to ROFA. The C-deficient diet lowered C concentrations in BAL fluid and cells and in NL fluid by 90%, and the GSH-depletion regimen lowered both GSH and C in the BAL fluid and cells by 50%. ROFA deposition was calculated at time 0 from lung Ni levels to be 46 microg/g wet lung. In unexposed animals, the combined deficiency of C and GSH modified the cellular composition of cells recovered in lavage fluid, i.e., the increased number of eosinophils and macrophages in BAL fluid. ROFA inhalation increased lung injury in the -C-GSH group only (evidenced by increased BAL protein, LDH and neutrophils, and decreased BAL macrophages). ROFA exposure decreased C in BAL and NL at 0 h, and increased BAL C and GSH (2- to 4-fold above normal) at 24 h in nondepleted guinea pigs, but had no effect on C and GSH in depleted guinea pigs. Combined deficiency of C and GSH resulted in the highest macrophage and eosinophil counts of any group. GSH depletion was associated with increased BAL protein and LDH, increased numbers of BAL macrophages and eosinophils, and decreased rectal body temperatures. We conclude that combined deficiency of C and GSH increased susceptibility to inhaled ROFA; caused unusual BAL cellular changes; resulted in lower antioxidant concentrations in BAL than were observed with single deficiencies. Antioxidant deficiency may explain increased susceptibility to PM in elderly or diseased populations and may have important implications for extrapolating animal toxicity data to huma

Topics: Administration, Inhalation; Air Pollutants; Animals; Antioxidants; Ascorbic Acid; Ascorbic Acid Deficiency; Body Temperature; Bronchoalveolar Lavage Fluid; Carbon; Cell Count; Coal Ash; Disease Models, Animal; Eosinophils; Glutathione; Guinea Pigs; L-Lactate Dehydrogenase; Lung; Lung Diseases; Macrophages, Alveolar; Male; Nasal Lavage Fluid; Neutrophils; Particle Size; Particulate Matter; Survival Rate; Time Factors; Uric Acid

Reperfusion injury can be seen after acute arterial occlusion, acute myocardial infarctus and during open heart surgery and vascular surgery. Protective effects of ascorbic acid and carnitine on reperfusion damage were tested and compared using histopathologic examination on ischemia model in the rabbit hind limb.. Four groups (each containing ten animals) were used. In group I (G1), only anesthesia was administered and a biopsy was taken from the soleus muscle after 6 h. In group II (G2), group III (G3), and group IV (G4), after induction of anesthesia, arterial blood circulation of right posterior extremity was blocked by a tourniquet proximally. After four hours of ischemia, just before releasing of tourniquet, physiologic saline solution, sodium ascorbate (Redoxan) and L-carnitine (Carnitine) were administered intravenously to G2, G3 and G4, respectively. Following 2 h of reperfusion, biopsies were taken from soleus muscles. All of the biopsy slides were observed under the light microscope from the aspect of six different histopathologic criteria (loss of striation, nuclear centralisation, formation of ring and/or splitting, changing on diameters of muscle fibers, necrosis and minimal fibrosis) of ischemic muscle.. Ischemic change criteria were seen less frequency in both vitamin C and carnitine groups compared to the control and placebo groups. However, this protective effect was statistically significant only for the aspect of segmental necrosis, centralization of nuclei and diameter change parameters in G3 and in G4. When G3 and G4 were compared, the differences on protective effects were significant only from the aspect of fibrosis (P<0.001) and changing on diameter of the fibers (P<0.001).. Both sodium ascorbate and carnitine are effective on reducing the reperfusion injury in skeletal muscle. But when we compared these two agents to each other, we found that carnitine seems a little more protective on our experimental model.

Topics: Animals; Antioxidants; Ascorbic Acid; Carnitine; Disease Models, Animal; Female; Muscle Fibers, Skeletal; Myocardial Reperfusion Injury; Rabbits

Lead exposure related oxidative stress has been incriminated, at least in part, to its toxic effects in different organs. The present investigation was carried out to study the ameliorative effects of antioxidant (ascorbic acid, alpha tocopherol or L-methionine) alone and antioxidant (alpha tocopherol) plus a conventional chelator (CaNa2 EDTA) on some of the parameters indicative of oxidative stress in the liver, kidney and brain in lead-exposed rats. Rats were given 0 (n=6, healthy controls) or 1 mg of Pb(2+)/kg b.w (n=30) as lead acetate solution in sterile normal saline ip for a period of 4 weeks. The ip injections were then withdrawn and lead exposed rats were randomly divided into five equal groups. Six lead-exposed rats were given no treatment during the 5th week (Pb group) to serve as positive controls. The rest four groups received either ascorbic acid, alpha tocopherol or L-methionine in the 5th week at the daily dose of 100 mg/kg b.w orally or alpha tocopherol as above plus CaNa2 EDTA at the rate of 110 mg/kg b.w twice a day ip for a period of 4 days. All the animals were sacrificed 1 day after the end of the experiment, and the liver, kidney and brain were quickly excised for the estimation of lead burden and alteration in the oxidative indices. Lead exposure for a period of 4 weeks followed by a period of 1 week to recover, resulted in significantly (P<0.05) higher accumulation of lead, associated with significant (P<0.05) increases in lipid peroxide level in the liver and brain, and non-protein bound thiol contents in the brain. Changes in the superoxide dismutase and catalase activities in lead-exposed rats did not reach statistical (P<0.05) significance. Treatment with antioxidants alone resulted in reversal of oxidative stress without significant decline in tissue lead burden. Tissue specific changes, following lead exposure and responses to the treatment with different antioxidants were recorded in the parameters of oxidative damage viz. lipid peroxide level, antioxidant enzymes and thiol contents.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain; Chelating Agents; Disease Models, Animal; Edetic Acid; Kidney; Lead; Lipid Peroxides; Liver; Methionine; Organ Size; Oxidative Stress; Rats; Vitamin E

We sought to investigate the effects of EPC-K1, a free radical scavenger, on reducing heparin-produced cerebral hemorrhage in a rabbit model of middle cerebral artery (MCA) photothrombosis and to investigate whether the combination of EPC-K1 and heparin enhances neuroprotection from cerebral ischemic damage.. In the heparin-alone group (n=8), heparin was administered intravenously for 24 hours, starting from 3 hours after MCA occlusion. In the EPC-K1-alone group (n=8), EPC-K1 was administered as a bolus injection (10 mg/kg) twice at 3 and 6 hours after MCA occlusion. In the combination group (n=8), EPC-K1 and heparin both were administered as in the single-drug procedures. In the vehicle group (n=10), saline were infused for 24 hours.. Heparin prolonged activated partial thromboplastin time by approximately 3 times that of control animals. In the heparin-treated animals, the hemorrhage size was significantly increased (P<0.0001) and neurological symptoms were significantly worse (P<0.01) than in control animals at 48 hours. The combination of EPC-K1 and heparin dramatically reduced heparin-produced cerebral hemorrhage (P<0.0001), with a significant reduction in infarct volume (reduction by 63.2% and 57.2% of heparin-alone and control animals, respectively, P<0.0001) and a significant improvement in neurological symptoms (P<0.01 versus heparin-alone and control animals, respectively).. These data indicate that free radical formation may play a key role in intracerebral hemorrhage exacerbated by heparin treatment and that the combination of a free radical scavenger and heparin augmented neuroprotection from acute brain ischemia. The results of the present study may suggest a potential clinical approach for the treatment of acute stroke.

Topics: Animals; Ascorbic Acid; Blood Flow Velocity; Body Temperature; Cerebral Hemorrhage; Disease Models, Animal; Drug Therapy, Combination; Free Radical Scavengers; Heparin; Infarction, Middle Cerebral Artery; Light Coagulation; Middle Cerebral Artery; Partial Thromboplastin Time; Rabbits; Reperfusion; Treatment Outcome; Vitamin E

Oxygen free radicals (OFR) and neutrophils are potent sources of reperfusion injury. We compared the effect of EPC-K1, a new OFR scavenger, and neutrophil depletion on the reperfusion injury in skeletal muscle, using an ischemic revascularized hindlimb model in rats. Warm ischemia, produced by vascular pedicle clamping, was sustained for 4 h. After 24 h of reperfusion, muscle function and damage were evaluated in 4 groups: a sham operation group, a control study group, a group treated by EPC-K1 (EPC group), and a group that received nitrogen mustard to induce neutropenia (NM group). Both the EPC and NM groups had limited muscle damage compared to the control group. The EPC group preserved muscle function significantly better than the control group and the mean isometric tetanic tension in the EPC group appeared to be higher than that in the NM group. Furthermore, levels of lipid peroxides in muscle and serum, and muscle edema in the EPC group, were significantly lower than in the NM group. Histological examinations supported these results. These findings suggest that limiting OFR generation by EPC-K1 in the early phase of reoxygenation is more potent than depletion of neutrophils in reducing reperfusion injury.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Drug Evaluation, Preclinical; Free Radical Scavengers; Isometric Contraction; Leukocyte Count; Lipid Peroxidation; Male; Muscle, Skeletal; Neutropenia; Neutrophils; Random Allocation; Rats; Rats, Inbred Lew; Reperfusion Injury; Vitamin E

Oxidative stress has a key role in the pathogenesis of diabetic complications. We have previously reported that taurine (T), which is known to counteract oxidative stress in tissues (lens, kidney, retina) of diabetic rats, attenuates nerve blood flow and conduction deficits in early experimental diabetic neuropathy (EDN). The purpose of this study was to evaluate whether dietary T supplementation counteracts oxidative stress and the nerve growth factor (NGF) deficit in the diabetic peripheral nerve. The experiments were performed in control rats and streptozotocin-diabetic rats fed standard or 1% T-supplemented diets for 6 weeks. All measurements were performed in the sciatic nerve. Malondialdehyde (MDA) plus 4-hydroxyalkenals (4-HA) were quantified with N-methyl-2-phenylindole. GSH, GSSG, dehydroascorbate (DHAA), and ascorbate (AA) were assayed spectrofluorometrically, T by reverse-phase HPLC, and NGF by ELISA. MDA plus 4-HA concentration (mean +/- SEM) was increased in diabetic rats (0.127 +/- 0.006 vs 0.053 +/- 0.003 micromol/g in controls, P < 0.01), and this increase was partially prevented by T (0.096 +/- 0.004, P < 0.01 vs untreated diabetic group). GSH levels were similarly decreased in diabetic rats treated with or without taurine vs controls. GSSG levels were similar in control and diabetic rats but were lower in diabetic rats treated with T (P < 0.05 vs controls). AA levels were decreased in diabetic rats (0.133 +/- 0.015 vs 0.219 +/- 0.023 micromol/g in controls, P < 0.05), and this deficit was prevented by T. DHAA/AA ratio was increased in diabetic rats vs controls (P < 0.05), and this increase was prevented by T. T levels were decreased in diabetic rats (2.7 +/- 0.16 vs 3.8 +/- 0.1 micromol/g in controls, P < 0.05) and were repleted by T supplementation (4.2 +/- 0.3). NGF levels were decreased in diabetic rats (2.35 +/- 0.20 vs 3.57 +/- 0.20 ng/g in controls, P < 0.01), and this decrease was attenuated by T treatment (3.16 +/- 0.28, P < 0.05 vs diabetic group). In conclusion, T counteracts oxidative stress and the NGF deficit in early EDN. Antioxidant effects of T in peripheral nerve are, at least in part, mediated through the ascorbate system of antioxidative defense. The findings are consistent with the important role for oxidative stress in impaired neurotrophic support in EDN.

Topics: Aldehydes; Animals; Ascorbic Acid; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dietary Supplements; Disease Models, Animal; Glutathione; Lipid Peroxidation; Male; Malondialdehyde; Nerve Growth Factor; Oxidative Stress; Rats; Rats, Wistar; Sciatic Nerve; Streptozocin; Taurine

To investigate the effects of ascorbic acid deficiency on the pathogenesis of hypertension and/or its complications, we established a rat strain with both genetic hypertension and a defect of ascorbic acid biosynthesis. The od gene (L-gulono-gamma-lactone oxidase gene) of the ODS (Osteogenic Disorder Shionogi) rat, which is a rat mutant unable to synthesize ascorbic acid, was introduced into spontaneously hypertensive rats (SHR), and a novel congenic strain, SHR-od, was established. SHR-od showed scurvy when fed an ascorbic acid-free diet. Systolic blood pressure of male SHR-od began to increase at 9 weeks of age and reached 190-200 mmHg at 20 weeks of age. In 25-week-old SHR-od, ascorbic acid deficiency when fed an ascorbic acid-free diet for 6 weeks caused a remarkable reduction of blood pressure to lower than 110 mmHg. The wall to lumen ratio of the testicular artery in ascorbic acid-deficient SHR-od was lower than that of the control rats. When rats were fed a diet supplemented with ascorbic acid (300 mg/kg), ascorbic acid concentration in SHR-od was lower in the serum and liver than that in ODS rats. These results indicate that ascorbic acid could be closely related to the development of hypertension in SHR-od. We believe that SHR-od will be a useful model for experimental studies on hypertension and its complications, since all of them suffer from hypertension spontaneously and the level of ascorbic acid deficiency in these rats could be controlled at will both in concentration and duration.

Topics: Aging; Alkaline Phosphatase; Animals; Animals, Congenic; Arteries; Ascorbic Acid; Ascorbic Acid Deficiency; Blood Pressure; Disease Models, Animal; Epinephrine; Heterozygote; Hypertension; L-Gulonolactone Oxidase; Liver; Male; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Mutant Strains; Sugar Alcohol Dehydrogenases; Testis

Iron supplementation may increase disease activity in ulcerative colitis, possibly through the production of reactive oxygen species from the Fenton reaction.. To assess the effects of two doses of oral iron on intestinal inflammation and oxidative stress in experimental colitis.. Colitis was induced in rats by giving 5% dextran sulphate sodium in drinking water for 7 days. First, using a 2 x 2 factorial design, rats with or without dextran sulphate sodium received the regular diet or a diet containing iron 3%/kg diet. Second, rats with dextran sulphate sodium-induced colitis were supplemented with iron 0.3%/kg diet and compared with rats on dextran sulphate sodium and regular diet. The body weight change, histological scores, colon length, rectal bleeding, plasma and colonic lipid peroxides, colonic glutathione peroxidase and plasma vitamin E and C were measured. Faecal analysis for haem and total, free and ethylenediaminetetra-acetic acid-chelatable iron was also performed.. Iron 3% and iron 0.3% increased the activity of dextran sulphate sodium-induced colitis, as demonstrated by higher histological scores, heavier rectal bleeding and further shortening of the colon. This was associated with increased lipid peroxidation and decreased antioxidant vitamins. Faecal iron available to the Fenton reaction was increased in a dose-dependent manner.. Iron supplementation taken orally enhanced the activity of dextran sulphate sodium-induced colitis and is associated with an increase in oxidative stress.

Topics: Administration, Oral; Animals; Antioxidants; Ascorbic Acid; Colitis; Dextran Sulfate; Dietary Supplements; Disease Models, Animal; Drug Interactions; Glutathione Peroxidase; In Vitro Techniques; Inflammation; Intestines; Iron; Lipid Peroxidation; Male; Mucous Membrane; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Vitamin E

The olfactory bulbectomized (OB) rat has been developed as an animal model of depression and exhibits several behavioural and neurochemical characteristics that are qualitatively similar to those found in clinically depressed patients. In addition to the behavioural and neurochemical abnormalities seen in OB rats, it has been reported that these animals have alterations in a number ex vivo measures of immune function many of which are reversed following chronic antidepressant treatment. In the present study we sought to examine the effects of olfactory bulbectomy on responsiveness to an in vivo immune challenge with bacterial lipopolysaccharide (LPS; 100 microg/kg, i.p.). In addition, the effect of chronic treatment with the tricyclic antidepressant desipramine (7.5 mg/kg, i.p.) on bulbectomy related behavioural changes, hypothalamic-pituitary-adrenal axis activity and immune responsiveness was evaluated. To our knowledge this is the first time that in vivo immunological responsiveness has been examined in the OB rat model of depression. OB rats exhibited a characteristic hyperactive response in a novel 'open field' environment, which was attenuated following chronic desipramine treatment. LPS provoked a large increase in circulating interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha in vehicle treated sham operated animals. Vehicle treated OB rats displayed a significant impairment in LPS-induced IL-1beta (54%) and TNF-alpha (70%) secretion compared to their sham operated controls, an effect that was potentiated following chronic desipramine treatment. Furthermore, sham animals that were chronically treated with desipramine displayed decreases in LPS-provoked IL-1beta (51%) and TNF-alpha (49%) secretion compared to vehicle treated counterparts. In addition, LPS-induced alterations in corticosterone and adrenal ascorbic acid concentrations were also attenuated by bulbectomy, an effect that was further enhanced following chronic desipramine treatment. In conclusion, these data provide evidence that olfactory bulbectomy in the rat impairs the ability of macrophages to produce the proinflammatory cytokines IL-1beta and TNF-alpha following an in vivo challenge with bacterial LPS. Whilst chronic treatment with desipramine normalized the behavioural hyperactivity observed in OB rats, such treatment further impaired LPS-induced IL-1beta and TNF-alpha secretion in bulbectomized rats.

Topics: Adrenal Cortex; Animals; Antidepressive Agents, Tricyclic; Ascorbic Acid; Behavior, Animal; Corticosterone; Depression; Desipramine; Disease Models, Animal; Hypothalamo-Hypophyseal System; Interleukin-1; Lipopolysaccharides; Male; Neuroimmunomodulation; Olfactory Bulb; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Antioxidants in the blood plasma of rats were measured as part of a comprehensive, multilaboratory validation study searching for noninvasive biomarkers of oxidative stress. For this initial study an animal model of CCl(4) poisoning was studied. The time (2, 7, and 16 h) and dose (120 and 1200 mg/kg, intraperitoneally)-dependent effects of CCl(4) on plasma levels of alpha-tocopherol, coenzyme Q (CoQ), ascorbic acid, glutathione (GSH and GSSG), uric acid, and total antioxidant capacity were investigated to determine whether the oxidative effects of CCl(4) would result in losses of antioxidants from plasma. Concentrations of alpha-tocopherol and CoQ were decreased in CCl(4)-treated rats. Because of concomitant decreases in cholesterol and triglycerides, it was impossible to dissociate oxidation of alpha-tocopherol and the loss of CoQ from generalized lipid changes, due to liver damage. Ascorbic acid levels were higher with treatment at the earliest time point; the ratio of GSH to GSSG generally declined, and uric acid remained unchanged. Total antioxidant capacity showed no significant change except for 16 h after the high dose, when it was increased. These results suggest that plasma changes caused by liver malfunction and rupture of liver cells together with a decrease in plasma lipids do not permit an unambiguous interpretation of the results and impede detection of any potential changes in the antioxidant status of the plasma.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Carbon Tetrachloride Poisoning; Disease Models, Animal; Electron Spin Resonance Spectroscopy; Free Radicals; Glutathione; Liver; Oxidative Stress; Rats; Rats, Inbred F344; Ubiquinone; Uric Acid; Vitamin E

Helicobacter pylori infection in humans is associated with chronic type B gastritis, peptic ulcer disease, and gastric carcinoma. A high intake of carotenoids and vitamin C has been proposed to prevent development of gastric malignancies. The aim of this study was to explore if the microalga Haematococcus pluvialis rich in the carotenoid astaxanthin and vitamin C can inhibit experimental H. pylori infection in a BALB/cA mouse model. Six-week-old BALB/cA mice were infected with the mouse-passaged H. pylori strain 119/95. At 2 weeks postinoculation mice were treated orally once daily for 10 days (i) with different doses of algal meal rich in astaxanthin (0.4, 2, and 4 g/kg of body weight, with the astaxanthin content at 10, 50, and 100 mg/kg, respectively), (ii) with a control meal (algal meal without astaxanthin, 4 g/kg), or (iii) with vitamin C (400 mg/kg). Five mice from each group were sacrificed 1 day after the cessation of treatment, and the other five animals were sacrificed 10 days after the cessation of treatment. Culture of H. pylori and determination of the inflammation score of the gastric mucosae were used to determine the outcome of the treatment. Mice treated with astaxanthin-rich algal meal or vitamin C showed significantly lower colonization levels and lower inflammation scores than those of untreated or control-meal-treated animals at 1 day and 10 days after the cessation of treatment. Lipid peroxidation was significantly decreased in mice treated with the astaxanthin-rich algal meal and vitamin C compared with that of animals not treated or treated with the control meal. Both astaxanthin-rich algal meal and vitamin C showed an inhibitory effect on H. pylori growth in vitro. In conclusion, antioxidants may be a new strategy for treating H. pylori infection in humans.

Topics: Agar; Animals; Ascorbic Acid; beta Carotene; Carotenoids; Disease Models, Animal; Helicobacter Infections; Helicobacter pylori; Lipid Peroxidation; Mice; Mice, Inbred BALB C; Xanthophylls

It has been suggested that increased oxidative stress might be involved in the pathophysiology of diabetic complications. In this study, we investigated the effect of diabetes on the susceptibility of synaptosomes to oxidative stress (induced by the oxidizing pair ascorbate/Fe(2+)) and on the uptake of the amino acid neurotransmitters gamma-aminobutyric acid (GABA) and glutamate. We found a lower susceptibility of synaptosomes isolated from Goto-Kakizaki (GK) rats, a model of non-insulin-dependent diabetes mellitus, to lipid peroxidation as compared with synaptosomes isolated from Wistar control rats (6.40+/-1.05 and 12.14+/-1.46 nmol thiobarbituric acid reactive substance/mg protein, respectively). The lower susceptibility of GK rat synaptosomes to membrane lipid peroxidation correlates with an increase in synaptosomal vitamin E levels (835+/-58.04 and 624.26+/-50.26 pmol/mg protein in diabetic and normal rats, respectively). In the absence of ascorbate/Fe(2+), no significant differences were observed between the levels of lipid peroxidation of synaptosomes isolated from diabetic and normal rats. Studies of neurotransmitter uptake show that the [(3)H]glutamate uptake was decreased by about 30% in diabetic GK rats as compared with control Wistar rats, whereas the [(3)H]GABA uptake was not significantly different from controls. Under oxidizing conditions, the glutamate uptake in diabetic rats was unaffected, and a decreased GABA uptake (41.39+/-4.41 and 60.96+/-6.4% of control in GK and Wistar rats, respectively) was observed. We conclude that the increased resistance to oxidative stress in GK rat synaptosomes may be due to the increased vitamin E content and that diabetic state and oxidative stress conditions differentially affected the uptake of the neurotransmitters GABA and glutamate.

Topics: Animals; Ascorbic Acid; Blood Glucose; Body Weight; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; gamma-Aminobutyric Acid; Glucose; Glutamic Acid; Glycated Hemoglobin; Lipid Peroxidation; Male; Oxidative Stress; Rats; Rats, Inbred Strains; Synaptosomes; Tritium

Oxidative stress may contribute to many pathophysiologic changes that occur after traumatic brain injury. In the current study, contemporary methods of detecting oxidative stress were used in a rodent model of traumatic brain injury. The level of the stable product derived from peroxidation of arachidonyl residues in phospholipids, 8-epi-prostaglandin F(2alpha), was increased at 6 and 24 h after traumatic brain injury. Furthermore, relative amounts of fluorescent end products of lipid peroxidation in brain extracts were increased at 6 and 24 h after trauma compared with sham-operated controls. The total antioxidant reserves of brain homogenates and water-soluble antioxidant reserves as well as tissue concentrations of ascorbate, GSH, and protein sulfhydryls were reduced after traumatic brain injury. A selective inhibitor of cyclooxygenase-2, SC 58125, prevented depletion of ascorbate and thiols, the two major water-soluble antioxidants in traumatized brain. Electron paramagnetic resonance (EPR) spectroscopy of rat cortex homogenates failed to detect any radical adducts with a spin trap, 5,5-dimethyl-1-pyrroline N:-oxide, but did detect ascorbate radical signals. The ascorbate radical EPR signals increased in brain homogenates derived from traumatized brain samples compared with sham-operated controls. These results along with detailed model experiments in vitro indicate that ascorbate is a major antioxidant in brain and that the EPR assay of ascorbate radicals may be used to monitor production of free radicals in brain tissue after traumatic brain injury.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Brain Chemistry; Brain Injuries; Cerebral Cortex; Chromatography, High Pressure Liquid; Cyclooxygenase 2; Dinoprost; Disease Models, Animal; Electron Spin Resonance Spectroscopy; F2-Isoprostanes; Free Radicals; Hippocampus; Isoenzymes; Male; Oxidation-Reduction; Oxidative Stress; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Wounds, Nonpenetrating

Oxidative stress has been postulated to play important roles in the pathogenesis of various diseases such as atherosclerosis in hyperlipidemic subjects. Although the possible role of oxidation of low-density lipoprotein (LDL) in the etiology of atherosclerosis has been studied extensively, the turnover of endogenous antioxidants, which is an important protection system against oxidative stress, remains to be elucidated. The aim of our study was to determine the change of the turnover of endogenous antioxidants such as glutathione and ascorbic acid in case of hyperlipidemia, using Japanese white rabbits (JW) and Watanabe heritable hyperlipidemic rabbits (WHHL). The levels of total glutathione and low molecular weight thiols in the liver, kidney, and other organs in both strains of rabbits were similar. However, a kinetic analysis using L-buthionine-(S,R)-sulfoximine revealed that the rate of glutathione turnover in the liver and kidney of WHHL was about 50%) lower than that of JW. Furthermore, intravenously administered ascorbic acid disappeared more slowly in WHHL than in JW. These results indicate that the turnovers of both glutathione and ascorbic acid in WHHL are depressed in comparison with that in JW. These changes would be closely related to the increased oxidizability of lipids in the circulation of hyperlipidemic subjects.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Disease Models, Animal; Glutathione; Hyperlipidemia, Familial Combined; Kidney; Lipoproteins, LDL; Liver; Male; Oxidative Stress; Rabbits

Many changes in endothelial function have been described in hypertension. Endothelium-dependant dilatation due to the stimulation of specific receptors or related to changes in flow, are reduced both in experimental models and in clinical observations of hypertensive patients. Many mechanisms of this endothelial dysfunction have been proposed. Reduction of the activity of the enzyme synthesising nitric oxide has been found in some animal modes of hypertension (salt-related) and in hypertensive subjects whereas in other experimental models, this enzyme's activity is increased. Other mechanisms, therefore, play a role, such as increased synthesis of constricting prostanoids and increased synthesis of oxygen radicals. The inhibition of cyclooxygenase or intra-arterial administration of Vitamin C in hypertensive patients may restore endothelium-dependant vasodilatation. In view of the many endothelium-dependant mechanisms described in the pathogenesis of hypertension, the authors underline the fact that in most studies each mechanism has been studied individually. However, understanding the interactions of the different endothelial dependant mechanisms is the key to reconciling the many physiopathological disturbances observed in hypertension, differentiating direct from indirect changes induced by the complex network of interactions one with another. This will also result in a more accurate appreciation of the similarities and differences of effects of antihypertensive drug therapy targeted on endothelial function.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Endothelium; Free Radicals; Humans; Hypertension; Nitric Oxide Synthase; Vasodilation

We previously reported that the common toxic gain-of-function in various mutant copper-zinc superoxide dismutases (SOD1) seen in patients with familial amyotrophic lateral sclerosis (ALS) was an abnormal copper release from the enzyme protein. In this study, trientine and ascorbate, known to have a beneficial effect in an animal model of Wilson disease, were administered to transgenic mice overexpressing a mutated human SOD1 (G93A). The onset of neurological signs in the treated group was significantly delayed compared with that in the control group, and the time to reach total paralysis in the treated group was delayed as well. Since the agents used in this study cause low toxicity in animals and humans, this treatment may be a good candidate for clinical application.

Topics: Amyotrophic Lateral Sclerosis; Animals; Ascorbic Acid; Chelating Agents; Copper; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Humans; Mice; Mice, Transgenic; Superoxide Dismutase; Survival Analysis; Trientine

EPC-K1, a phosphate diester of alpha-tocopherol and ascorbic acid, is a new hydroxyl radical scavenger. We examined the effects of EPC-K1 according to differences in the timing of its administration. Warm ischemia, produced by vascular pedicle clamping, was sustained for 4 hours. After 24 hours of reperfusion, muscle injury was evaluated in 4 groups: the first group received a sham operation, the second group was treated with an intravenous injection of EPC-K1 prior to ischemia, the third group was treated with EPC-K1 prior to reperfusion, and the fourth group was controls. Compared with the control group, both the preischemic and pre-reperfusion EPC-K1-treated groups showed a statistically significant amelioration in the reduction of isometric muscle contraction. There were also significant reductions in the muscle and serum levels of thiobarbituric acid reactive substances (TBA-RS) and muscle damage, indicated by the biochemical and histological study. A comparison of the timing of EPC-K1 administration revealed that only the muscle TBA-RS level in the pre-reperfusion EPC-K1-treated group was significantly higher than that in the preischemic EPC-K1-treated group. These observations indicate that EPC-K1 not only by preischemic but also by pre-reperfusion administration acted effectively on reperfusion injury in muscle, thereby improving muscle function.

Topics: Animals; Antioxidants; Ascorbic Acid; Biopsy; Disease Models, Animal; Drug Administration Schedule; Drug Evaluation, Preclinical; Free Radical Scavengers; Injections, Intravenous; Ischemia; Isometric Contraction; Male; Muscle, Skeletal; Random Allocation; Rats; Rats, Inbred Lew; Reperfusion Injury; Thiobarbituric Acid Reactive Substances; Time Factors; Vitamin E

edema formation after thermal injury is rapid and fulminant within the first hour after injury and increased microvascular permeability has been claimed to be the main responsible mechanism. An acute decrease in interstitial fluid hydrostatic pressure (P(if)) down to -150 mm Hg has recently been reported in dermal burns. This strong negative tissue pressure creates a 'suction' on the fluid in the capillaries. Furthermore, high dose vitamin C (VC) has been shown to reduce postburn edema and fluid requirements following major burn injuries. This led to the present study, aimed at investigating whether VC administered after thermal injury in rats, could attenuate the strongly negative P(if). Edema volume was measured by total tissue water content (TTW) and extravasation of albumin (Ealb).. a prospective, open experimental study.. pentobarbital-anesthetized rats received either a full-thickness burn injury covering 10% of total body surface area, or a sham burn. The rats were given VC or equal volumes normal saline (NS) either before the burn, 5 or 30 min after the injury. VC (25 mg/ml in NS, osmolality 272 mOsm/l) was administered as a bolus (66 mg/kg) followed by infusion (33 mg/kg/h). The animals were divided into 7 groups (6 animals in each) according to the timing of VC/NS administration: (1) VC-preburn, (2) VC-5 min postburn, (3) VC-30 min postburn, (4) NS-preburn, (5) NS-5 min postburn, (6) NS-30 min postburn and (7) VC-pre sham burn group. All groups were duplicated for series I and II.. in series I; P(if) was measured using a sharpened glass micropipette connected to a servo-controlled counter pressure system. Measurements were averaged in the following time periods: preburn, 5-20, 21-40, 41-60 and 61-90 min postburn. In series II; Ealb and TTW were measured in burned and non-burned skin by radio-labelled albumin and wet-dry weights, respectively.. in the sham control group (VC-pre-sham burn), P(if) ranged between -1 and -2 mm Hg and did not change throughout the experimental period. In the NS group (placebo), P(if) fell to -46.8 +/- 10.1 (1 S.D.) mm Hg at 5-20 min after the injury and were -23.1 +/- 13.4 and -11.6 +/- 4.1 mm Hg at 21-40 and 41-60 min postburn. P(if) returned to preburn values at 61-90 min post injury. In the VC groups, there was a marked attenuation of the negative P(if) to average -10.1 +/- 11.8 mm Hg at 5-20 min, -2 +/- 1.7 and -0.6 +/- 1.2 mm Hg at 21-40 and 41-60 min after injury, respectively (all p < 0.01 compared to NS). TTW in burned skin of the NS-5 min groups was 3.12 +/- 0.28, VC5-min group was 2.57+/-0.69 and VC sham was 1.77+/-0.19 ml/g DW, respectively (p < 0.01 compared to sham control for all values). In all the VC-groups TTW values were higher than sham control and lower than in the corresponding NS-groups (p > 0.05 both ways). No statistical significant differences were found between Ealb-values in the VC- and NS-groups.. high-dose vitamin C attenuates the development of strongly negative P(if) in burned dermis and reduces the edema as measured by TTW. No significant change in Ealb was found. Vitamin C was thus found to have potential beneficial effects on the acute postburn edema generation.

Topics: Analysis of Variance; Animals; Ascorbic Acid; Burns; Cell Membrane Permeability; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Extracellular Space; Hydrostatic Pressure; Rats; Rats, Wistar; Reference Values; Time Factors; Wound Healing

Previously it has been reported that forced swim test (FST) exposure activates the HPA-axis and produces alterations in both cellular and noncellular immunity in rats. Furthermore, there is evidence to suggest that pretreatment with antidepressants has a protective effect against FST-induced immune changes. The purpose of the present study was to examine the effect of subacute treatment with the tricyclic antidepressant desipramine (DMI, 5 and 10 mg/kg; I.P.) on immobility in the FST, and on FST-induced changes in endocrine and immune parameters in the rat. DMI treatment at a dose of 10 mg/kg produced a significant reduction in immobility time in the FST, while the 5 mg/kg dose was ineffective. FST exposure produced a significant increase in serum corticosterone and a decrease in adrenal ascorbic acid concentrations, neither of which were significantly attenuated by DMI pretreatment. There was a slight but nonsignificant suppression of PHA-induced lymphocyte proliferation 15 min post-FST exposure. However, DMI treatment produced a significant increase in lymphocyte proliferation at this time point. FST exposure caused a reduction in the percentage of lymphocytes and an increase in the percentage of neutrophils in the peripheral blood; DMI treatment failed to significantly alter these stress-induced changes. There was a profound reduction in relative spleen weight observed in DMI-treated animals 120 min post-FST exposure and this was accompanied by an increase in circulating RBC concentrations. In conclusion, although the FST-induced behavioral changes were normalized by DMI treatment the peripheral aberrations induced by FST exposure (with the exception of lymphocyte proliferation) were not. In addition, DMI pretreatment induced stress-like changes in corticosterone, adrenal ascorbic acid and leucocyte subpopulations in the control animals.

Topics: Adrenal Glands; Animals; Antidepressive Agents, Tricyclic; Ascorbic Acid; Corticosterone; Depression; Desipramine; Disease Models, Animal; Drug Evaluation, Preclinical; Endocrine System; Immune System; Leukocytes; Male; Organ Size; Rats; Rats, Sprague-Dawley; Swimming

Streptozotocin (STZ) is widely used as a strong inducer of insulin-dependent diabetes in experimental animals. Although nitric oxide (NO) generation from STZ has been proposed to be responsible for the toxicity of pancreatic B-cells, the mechanism is yet unknown. We found that STZ generates NO in the presence of Cu(II) plus ascorbate. In addition, nicotinamide, which is an antidiabetic agent against STZ, has been found to inhibit NO generation from STZ during the reaction with Cu(II) plus ascorbate. Since rat pancreatic islets contain both ascorbate and Cu at the concentrations of 3.5 mM and 1. 0 nmol/mg protein, respectively, our present results indicate that (1>) NO generation is responsible for the development of STZ-induced diabetes and (2) mechanism for the protection of diabetes by nicotinamide is due to the inhibition of NO generation from STZ through complex formation between nicotinamide and Cu (I), which is reduced by ascorbate.

Topics: Animals; Ascorbic Acid; Chelating Agents; Copper; Diabetes Mellitus, Experimental; Disease Models, Animal; Edetic Acid; Electron Spin Resonance Spectroscopy; Free Radical Scavengers; Hemin; Hypoglycemic Agents; Islets of Langerhans; Niacinamide; Nitric Oxide; Phenanthrolines; Rats; Spectrophotometry; Streptozocin

Antioxidant vitamins are hypothesized to help prevent atherosclerosis by blocking lipoprotein oxidation. We investigated the effects of dietary vitamins C and E on atherosclerosis in rabbits.. Forty New Zealand male rabbits were divided into 4 groups: 0.3% cholesterol diet with (LV) and without vitamin (LC), and 0.5% cholesterol diet with (HV) and without vitamins (HC). The treated groups consumed 137 +/- 8 mg/day vitamin C and 80 +/- 4 mg/day vitamin E for 10 weeks. Vitamin treatment did not significantly affect serum lipids. Alpha-tocopherol values were significantly higher in both serum (mg/dl) and omental fat (microg/g) among the treated rabbits (3.9 +/- 0.5 and 31.6 +/- 2.1 for LV, 1.7 +/- 0.2 and 12.1 +/- 1.9 for LC, 5.6 +/- 0.8 and 51.3 +/- 9.3 for HV and 1.9 +/- 0.3 and 8.2 +/- 0.4 for HC; p < 0.001). Vitamin treatment did not affect the percent of surface lesions in the aorta and pulmonary artery (23.8 +/- 5.2 and 20.1 +/- 3.3% for LV, 19.8 +/- 5.6 and 23.2 +/- 3.5% for LC, 28.1 +/- 6.5 and 51.1 +/- 4.2% for HV and 32.4 +/- 5.5 and 43.7 +/- 3.9% for HC, respectively; p = 0.981 and p = 0.562.. Although significantly higher values of alpha-tocopherol were found in both serum and omental fat, antioxidant vitamins C and E did not demonstrate a significant protective effect on atherosclerosis in lipid-fed rabbits during the 10-week study period.

Topics: Animals; Antioxidants; Aorta, Thoracic; Arteriosclerosis; Ascorbic Acid; Cholesterol; Cholesterol, Dietary; Disease Models, Animal; Drug Combinations; Lipoproteins; Male; Oxidation-Reduction; Pulmonary Artery; Rabbits; Random Allocation; Triglycerides; Vitamin E

1. The ability of EPC-K1 to improve myocardial infarction was evaluated in a rat model with coronary artery occlusion and reperfusion. 2. The myocardial infarct size was 30.5 +/- 1.7% by intravenous (i.v.) administration and 28.8 +/- 2.7% by intraduodenal (i.d.) administration of the saline EPC-K1 at doses between 1 and 10 mg/kg, i.v. and at doses between 50 and 200 mg/kg, i.d., reduced myocardial infarct size dose dependently. Significant reduction in myocardial infarct size was found at a dose of 10 mg/kg, i.v., and 200 mg/kg, i.d.

Topics: Animals; Antioxidants; Arterial Occlusive Diseases; Ascorbic Acid; Combined Modality Therapy; Coronary Disease; Disease Models, Animal; Free Radical Scavengers; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Rats; Rats, Wistar; Vitamin E

Previous studies demonstrating reduced plasma concentrations of ascorbic acid (AA) in diabetes and interactions between this vitamin and biochemical mechanisms such as synthesis of structural proteins, oxidative stress, polyol pathway and nonenzymatic glycation of proteins suggest that disturbed AA metabolism may be important in the pathogenesis of diabetic microangiopathy. However, limited information is available on the concentration of AA in tissues which develop diabetic complications. This study demonstrates reduced renal but not sciatic nerve or plasma AA concentration in two animal models of insulin-dependent diabetes mellitus, namely the STZ-diabetic rat and the spontaneously diabetic BB rat. Decreased lens AA concentration was also observed in STZ-diabetic rats. Improvement of glycaemic control by insulin treatment (albeit insufficient to achieve normoglycaemia) partially corrected lens and renal AA concentration in STZ-diabetic rats. AA treatment increased kidney and lens AA concentrations of STZ-diabetic and non-diabetic rats and corrected the abnormalities observed for untreated diabetic rats. Sciatic nerve AA concentration was not increased by AA treatment in any group. Tissue ratios of dehydroascorbic acid (DHAA)/AA, one index of oxidative stress, were not different between the diabetic and non-diabetic groups and were unaltered by AA supplementation. AA treatment of STZ-diabetic rats had no effect on elevated tissue concentrations of glucose, sorbitol and fructose or reduced myo-inositol concentration. The effect of reduced tissue AA levels in diabetes on either collagen synthesis or ability to combat increased free radical production is not known. However, correction of abnormal kidney and lens AA concentrations in experimental diabetes by AA supplementation suggests that if AA does have a role in the development or progression of the renal and ocular complications of diabetes, this treatment could be beneficial.

Topics: Animals; Ascorbic Acid; Dehydroascorbic Acid; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Female; Hypoglycemic Agents; Insulin; Kidney; Lens, Crystalline; Male; Oxidative Stress; Polymers; Rats; Rats, Inbred BB; Rats, Wistar; Reference Values; Sciatic Nerve; Streptozocin; Tissue Distribution

The learned helplessness model of depression in rats was tested. It was hypothesized that 5'-ectonucleotidase (NT), ascorbate, and antibody to sheeps' red blood cells (SRBC) are significantly reduced in rats who experienced uncontrollable shock, compared with rats who did not receive shock or could control it. During a learned-helplessness manipulation, antibody response to SRBC and NT values were unaffected. However, tissue ascorbate stores fell significantly, by 20-30%. The lack of effects on antibody responses and NT are discussed n terms of the acute nature of the stressor used in this model, as opposed to the more chronic stressors that have occurred in the human model.

Topics: 5'-Nucleotidase; Analysis of Variance; Animals; Antibody Formation; Antioxidants; Ascorbic Acid; Depression; Disease Models, Animal; Electroshock; Escape Reaction; Helplessness, Learned; Rats; Rats, Sprague-Dawley; Stress, Psychological; Time Factors

HPLC/electrochemical detection was used to identify five major low MW water soluble electrochemically active molecules from the aqueous humor of three species of mammals: New Zealand White rabbits and humans (diurnal) and Sprague-Dawley rats (nocturnal). These molecules are L-cysteine (CYS), L-ascorbic acid (AA), glutathione (GSH), uric acid (UA) and L-tyrosine (TYR); all of these molecules have known antioxidant properties. Nocturnal rat aqueous humor is concentrated in two thiols: GSH (125 microM; n = 24 pooled eyes) and CYS (63 microM), in contradistinction to diurnal species which have high concentrations of AA. No deterioration of any of these antioxidants occurs in a synthetic aqueous humor mixture irradiated with a physiologically relevant spectral UV B dose of 30 mJ/cm2/h (5.5 UV equivalent sunlight hours). The same result occurred with addition of the endogenous aqueous humor UV B photosensitizer L-tryptophan. In a second set of experiments, human synthetic aqueous humor was subjected to hydrogen peroxide induced oxidant stress. The decay of antioxidants was CYS > GSH > AA > UA > TYR. The second highest concentrated antioxidant in human aqueous humor is TYR. Yet TYR failed to protect AA against H2O2-induced free radical damage in a synthetic aqueous humor model system (P = 0.10; ANOVA). The existence of multiple electrochemically active constituents and their thermodynamic interactions must be recognized when choosing animal models to evaluate human aqueous humor antioxidant defense.

Topics: Aged; Analysis of Variance; Animals; Antioxidants; Aqueous Humor; Ascorbic Acid; Cataract; Chromatography, High Pressure Liquid; Cysteine; Disease Models, Animal; Female; Glutathione; Humans; Hydrogen Peroxide; Mammals; Oxidants; Rabbits; Rats; Rats, Sprague-Dawley; Tryptophan; Tyrosine; Ultraviolet Rays; Uric Acid

A number of antioxidants are present in human tissues, which comprise the secondary defence system against the oxygen-free radicals and oxidative stress. Therefore, this study was undertaken in an animal model to investigate the effects of antioxidants such as vitamin E, vitamin C, methyl prednisolone, and mannitol, on the treatment of intestinal reperfusion injury when given during ischemia.. The study was performed on six groups of animals, each composed of six rabbits: Group I, mesenteric ischemia group; group R, ischemia-reperfusion group; group E, ischemia-reperfusion plus Vitamin E treatment; group C, ischemia-reperfusion plus vitamin C treatment; group CS, ischemia-reperfusion plus corticosteroid treatment; and Group M, ischemia-reperfusion plus mannitol treatment. Malondialdehyde (MDA) and glutathione (GSH) levels of the intestinal mucosa were assayed to reflect the free radical formation.. Mucosal injury scores in the M and C groups were significantly lower than the R group (P< .01 and P< .01, respectively), and in the E and CS groups, mucosal injury scores were not significantly different from R group. MDA levels in the M and C groups were significantly lower than the R group (P < .01 and P < .01, respectively). GSH levels in the E, C, and M groups, were significantly higher than R group (P < .01, P < .05, and P < .01, respectively).. The results of this study showed that antioxidant drugs, such as vitamin C and mannitol, may play a role in attenuating reperfusion injury of the gut demonstrated by depression of tissue MDA levels and by elevation of tissue GSH levels.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Glucocorticoids; Glutathione; Intestinal Mucosa; Intestines; Ischemia; Malondialdehyde; Mannitol; Methylprednisolone; Rabbits; Reperfusion Injury; Vitamin E

Comparative investigations were performed to study the effect of endogenous and exogenous N-nitrosodiethylamine on the dynamics of content variations of oxidized cytochrome P-450 and its isoforms in the monooxygenase system of rat liver. The variations of cytochrome P-450 contents in both cases were demonstrated to be of the same character correlating with hepatocarcinogenesis stages. Higher quantities of oxidized cytochrome P-450 and its isoforms with MM 52, 53, and 56 kDa in the rat liver when acted upon by NDEA precursors are seen as the precondition of enhancing the monooxygenase reaction of NDEA bioactivation and, as a result, of the carcinogenic effects. Ascorbic acid is assumed to block the synthesis of NDEA from its precursors giving use to a compound whose metabolism does not influence the activity of the monooxygenase system of liver cells.

Topics: Animals; Antioxidants; Ascorbic Acid; Carcinogens; Cytochrome P-450 Enzyme System; Diethylnitrosamine; Disease Models, Animal; Drug Evaluation, Preclinical; Liver Neoplasms, Experimental; Male; Oxidation-Reduction; Protein Isoforms; Rats

L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl- 2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl hydrogen phosphate] potassium salt (EPC-K1), a phosphate diester of alpha-tocopherol and ascorbic acid, is a potent antioxidant. We examined the effects of EPC-K1 on ischemia-reperfusion injury in the skeletal muscle of rats, using an ischemic revascularized hind limb model. Warm ischemia (25 degrees C), produced by vascular pedicle clamping, was sustained for 4 hours. After 24 hours of reperfusion, skeletal muscle injury was evaluated in 2 groups: one group treated by intravenous injection of EPC-K1 (10 mg/kg) prior to ischemia, and a group of controls. The EPC-K1-treated group showed a statistically significant amelioration in the reduction of the isometric muscle contraction, inhibition of the elevation of the muscle wet- to dry-weight ratio, limitation of the muscle level of thiobarbituric acid reactive substances and the serum levels of creatine phosphokinase, lactate dehydrogenase and mitochondrial glutamic oxaloacetic transaminase, and reduction of the extent of muscle injury according to the histological findings. These observations indicate that EPC-K1 acted effectively on ischemia-reperfusion injury in the rat skeletal muscle and thereby improved muscle function.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Drug Evaluation, Preclinical; Free Radical Scavengers; Isometric Contraction; Male; Muscle, Skeletal; Rats; Rats, Inbred Lew; Reperfusion Injury; Vitamin E

In this experimental study is illustrated an original model of cerebral asymmetric ischemia and reperfusion in the rat, induced by unilaterally elevating ICP and clamping the corresponding common carotid artery, that allows a direct comparison of the two brain hemispheres, one normal and the other ischemic, of the same animal.. The experimental procedure consisted in grafting two screws through the skull on the right side of the sagittal suture, one of them being connected to a Queckenstedt manometer for monitoring ICP variations. A nitroprusside solution (1 mg/ml administered through the femoral vein at a flow rate of 0.103 ml/min) was infused to achieve a significant drop of MABP. At this time point, animals were subjected to 5 min of ischemia and 10 min of reperfusion induced by clamping and declamping the right common carotid artery. During the whole period of ischemia and reperfusion ICP and MABP were constantly monitored. In order to provide an outlook on the metabolic alterations of brain tissue occurring during ischemia and reperfusion phenomena, several biochemical parameters of cellular energy metabolism and of oxygen radical-induced membrane damage were determined by a sensitive and reproducible HPLC method on perchloric acid tissue extracts.. The validity of the present model was supported by the finding of significant intrahemispheric differences in the concentration of several compounds considered as biochemical markers of tissue injury, such as adenosine 5'-triphosphate catabolites and malondialdehyde, this last indicating the damaging action of oxygen free radicals on cell membrane phospholipids.

Topics: Animals; Ascorbic Acid; Blood Pressure; Brain Ischemia; Carotid Stenosis; Chromatography, High Pressure Liquid; Disease Models, Animal; Intracranial Pressure; Lipid Peroxidation; Male; Malondialdehyde; Neurons; Rats; Rats, Wistar; Reperfusion Injury; Reproducibility of Results; Sensitivity and Specificity

The inhibition of lipoprotein catabolism after triton WR-1339 intravenous administration is associated with an impressive modification in the balance between plasma peroxidable substrates and antioxidants. Treated rat plasma and membrane lipids become peroxiaable when they are incubated with phenylhydrazine in standardized conditions and the production of thiobarbituric acid-reactive substances (lipoperoxidation markers) significantly increases. An accumulation of native lipoproteins which present a decreased alpha-tocopherol on triglycerid ratio and a modification in the plasmatic balance between alpha-tocopherol and ascorbate could explain these observations.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Erythrocytes; Fatty Acids; Humans; Hyperlipidemias; In Vitro Techniques; Lipid Peroxidation; Lipids; Male; Polyethylene Glycols; Rats; Rats, Wistar; Surface-Active Agents; Vitamin E

An animal unable to synthesize ascorbic acid uniquely mimicks human and non-human primates. Therefore, in this study we used the rainbow trout, a teleost fish, as the model animal to study the importance of dietary ascorbic acid on the fertilizing ability of sperm. A high concentration of ascorbic acid in semen plays a key role in maintaining the genetic integrity of sperm cells, by preventing oxidative damage to sperm DNA. This study will show that the concentration of ascorbic acid in seminal plasma reflects the dietary intake of vitamin C. The concentration of ascorbic acid in seminal plasma of fish declined significantly in groups fed either an ascorbate-free diet (from 4.74 +/- 0.9 to 0.16 +/- 0.08 microgram ml-1) or an ascorbate-rich diet (from 37.9 +/- 4.7 to 17.7 +/- 3.2 microgram ml-1) during the spermiation season. The relationship between ascorbate status and fertility was studied in six groups of fish fed graded levels of ascorbic acid, which spermiated over a 150-day-period. Sperm from individual males was used to fertilize several batches of eggs. When the seminal plasma ascorbate concentration decreased to 7.3 microgram ml-1 a significant decrease of fertilization rate and the hatching rate of embryos resulted. This is the first evidence that dietary ascorbate level directly affected sperm quality and influenced male fertility in a scurvy-prone vertebrate.

Topics: Animals; Ascorbic Acid; Diet; Disease Models, Animal; Embryo, Nonmammalian; Female; Fertilization; Humans; Infertility, Male; Male; Oncorhynchus mykiss; Primates; Semen; Spermatozoa

This study used the scorbutic Osteogenic Disorder Shionogi rat model and a specific diet to reliably induce a state of sub-scurvy scorbutus. Under these conditions overall somatic growth was assessed, as well as that of the caudal vertebrae, as an example of scorbutic bone growth. Tail loops were then used to mechanically stress mature caudal vertebrae under scorbutic conditions, and the vertebrae's adaptation to these applied forces was assessed, using measurements of bend deformation and histologic analysis of osteogenesis. Scorbutic animals exhibited significant somatic growth retardation (p < 0.05), and abnormal reductions in osteogenesis and periosteal responsiveness to growth. Scorbutic vertebrae also showed greater bend angles of deformation (p < 0.05), and a marked reduction in cortical osseous remodelling and periosteal differentiation. It appeared that the sub-scurvy scorbutic bones were smaller, weaker and less able to adapt to physical stresses: this pattern was reflected at the histologic level.

Topics: Animals; Ascorbic Acid; Body Composition; Bone Remodeling; Disease Models, Animal; Epiphyses; Female; Growth; Male; Osteogenesis; Periosteum; Rats; Rats, Inbred Strains; Scurvy; Spine; Stress, Mechanical

Anti-oxidant therapy has been effective for treatment of experimental shock. In this study, the efficacy of Trolox (Aldrich Chemical Co., Milwaukee, WI), a water-soluble vitamin E analogue, and ascorbic acid (vitamin C) was evaluated in a rat model of hemorrhagic shock and resuscitation. In two prospective trials, rats were phlebotomized (27 mL/kg) and left in shock for 45 minutes. Resuscitation was then instituted by continuous IV infusion with lactated Ringer's (LR) (54 mL/kg) over 60 min. In Trial 1, rats were randomized to receive either placebo (LR) or Trolox (50 mg/kg) in LR. In Trial 2, rats were randomized to LR alone or ascorbic acid (50 mg/kg) in LR. Survival for ascorbic acid-treated rats (35 per cent) was not different than for control rats (35 per cent). However, the addition of Trolox to infusion significantly improved 72 hour survival, 75 per cent versus 40 per cent respectively, for Trolox-treated and control animals. These data demonstrate that Trolox is of survival benefit when added to resuscitation in this model. This benefit does not appear to be related to blood pressure or white cell adhesion. Trolox is more effective than ascorbic acid in this model.

Topics: Animals; Antioxidants; Ascorbic Acid; Blood Pressure; Chromans; Disease Models, Animal; Fluid Therapy; Leukocyte Adherence Inhibition Test; Leukocytes; Prospective Studies; Rats; Rats, Sprague-Dawley; Resuscitation; Shock, Hemorrhagic; Vitamin E

Considerable interest has been recently generated concerning the use of natural compounds, anti-oxidants in particular, in photoprotection. Two of the best known anti-oxidants are vitamins C and E, both of which have been shown to be somewhat effective in different models of photodamage. Very little has been reported, however, on the effectiveness of a combination of the two (known to be biologically the more relevant situation); nor have there been detailed studies on the ability of these antioxidants to augment commercial sunscreen protection against UV damage. We report that (in swine skin) vitamin C is capable of additive protection against acute UVB damage (sunburn cell formation) when combined with a UVB sunscreen. A combination of both vitamins E and C provided very good protection from a UVB insult, the bulk of the protection attributable to vitamin E. However, vitamin C is significantly better than vitamin E at protecting against a UVA-mediated phototoxic insult in this animal model, while the combination is only slightly more effective than vitamin C alone. When vitamin C or a combination of vitamin C and E is formulated with a commercial UVA sunscreen (oxybenzone), an apparently greater than additive protection is noted against the phototoxic damage. These results confirm the utility of anti-oxidants as photoprotectants but suggest the importance of combining the compounds with known sunscreens to maximize photoprotection.

Topics: Administration, Cutaneous; Animals; Antioxidants; Ascorbic Acid; Benzophenones; Cellulose; Dermatologic Agents; Disease Models, Animal; Drug Combinations; Drug Synergism; Male; Pharmaceutical Vehicles; Propylene Glycol; Propylene Glycols; Radiation Protection; Skin; Skin Aging; Sunburn; Sunscreening Agents; Swine; Ultraviolet Rays; Vitamin E

After partial ligation of the common bile duct (CBD) of guinea pigs, 14 of 16 animals developed pigment gallstones within one week (S group). Intraperitoneal injection of Vit. E and C, each 10 mg/kg daily from 3 days before CBD ligation to one week after the operation (S+V group), decreased the gallstone incidence to 5/14 (exact probability < 0.01). The gallstone incidence in the control group, that only received laparotomy without ligation of the CBD, was 0/15. Biochemical analysis of the gallbladder bile showed that stricture of the CBD was associated with a significant increase in levels of unconjugated bilirubin (UCB) and Ca2+ (p < 0.05 and < 0.01). Simultaneously the scavenging rate (SR) of superoxide radical in bile significantly decreased (p < 0.05). Comparing S+V group with S group, the effect of Vit. E and C on the concentrations of UCB and Ca2+ in bile was not significant (both p > 0.05), but Vit. E and C normalized the SR, and the difference between S group and S+V group was significant (p < 0.05). These results suggested that Vit. E and C, known as antioxidants, enhanced the ability to scavenge oxygen radical in S+V group; and that in addition to the increases of UCB and Ca2+ concentrations, the participation of oxygen radicals might be of importance for pigment gallstone formation induced by bile duct obstruction.

Topics: Animals; Ascorbic Acid; Bile; Bile Pigments; Cholelithiasis; Common Bile Duct; Disease Models, Animal; Drug Evaluation, Preclinical; Free Radical Scavengers; Guinea Pigs; Incidence; Injections, Intraperitoneal; Ligation; Male; Oxidants; Vitamin E

Rats with hereditary defects in ascorbic acid (AsA) synthesis (ODS rats) subjected to AsA-deficiency for 3 weeks showed reductions of plasma alkaline phosphatase and dry and ash weights of the tibia, but no body weight alteration. In accordance with the chemical changes, bone loss and decrease of bone formation by AsA deficiency but not by malnutrition were observed in contact microradiographs of the tibia and by a tetracycline double labeling technique, respectively. The mechanical properties of femora measured by a three point-bending procedure were also altered by AsA deficiency for 3 weeks and showed decreases of 59% in toughness, 32% in strength, 32% in ductility and 22% in stiffness. The biomechanical changes by AsA deficiency were greater than the chemical changes in bone, indicating the usefulness of measuring mechanical properties as a sensitive method for the evaluation of the bone status. The second moment of the area of the femur was not changed by AsA deficiency. These results suggest that AsA deficiency in ODS rats causes marked bone loss and reduction in bone formation, which is accompanied by a greater reduction in biomechanics of the femur without causing macroarchitectural changes.

Topics: Animals; Ascorbic Acid; Body Weight; Bone and Bones; Bone Diseases; Disease Models, Animal; Femur; L-Gulonolactone Oxidase; Male; Rats; Rats, Inbred Strains; Sugar Alcohol Dehydrogenases; Tibia; Time Factors

A large number of experimental studies suggests that oxygen free radicals play a major role in the pathogenesis of the myocardial lesions observed during the sequence ischemia-reperfusion. The purpose of this study was to determine whether oxygen free radicals can induce thrombosis. In so doing we have developed a new experimental thrombosis model. Reproducible focal thrombosis has been achieved by irradiating mesenteric arterioles of rat for variable time with green filtered light issuing from a mercury lamp after systemic injection of different rose bengal doses. The number of emboli that remove in the blood (N), the duration of total occlusion (T) and the number of emboli per minute were then measured. As control, no rose bengal administration was done and the vessels were exposed to the filtered light. In comparison with this control, results clearly showed that free radicals always induced thrombosis and the induced thrombus was mainly composed of platelets. In this new thrombosis model induced by free radicals antithrombotic drugs (aspirin, 200 mg/Kg, heparin, 2 mg/Kg) and antioxidants (vitamin C, 10 and 20 mg/Kg, allopurinol, 200 and 300 mg/Kg, vitamin E, 500 and 1000 mg/Kg) have been tested. Results have shown that only heparin and vitamin E had an antithrombotic effect on thrombus formation induced by free radicals. This model should be useful in studying the effects of different drugs and could lead to new treatment modalities for ischemic accident and other cardiovascular diseases.

Topics: Allopurinol; Animals; Antioxidants; Arterioles; Ascorbic Acid; Aspirin; Blood Coagulation; Blood Platelets; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Fibrinolytic Agents; Free Radicals; Heparin; Male; Mesenteric Vascular Occlusion; Microscopy; Oxygen; Photochemistry; Rats; Rats, Wistar; Rose Bengal; Singlet Oxygen; Videotape Recording; Vitamin E

Expression of beta 1 integrins was studied in vitro as articular chondrocytes reestablished a matrix in culture and in situ in a nonhuman primate model of osteoarthritis in order to investigate a potential role for integrins in mediating cell-extracellular matrix interactions in cartilage. Chondrocytes were found to express alpha 1 beta 1, alpha 3 beta 1, and alpha 5 beta 1 integrins both in vitro and in situ. Cell surface expression of beta 1 integrins increased as chondrocytes were maintained in cultured from 3 to 7 days. Increased beta 1 integrin expression was also observed in osteoarthritic cartilage compared with normal cartilage. The greatest relative increase in both systems was noted for the alpha 1 beta 1 integrin. The increase in chondrocyte beta 1 integrin expression in vitro was noted in both monolayer and alginate cultures and occurred prior to detectable changes in the differentiated phenotype of the chondrocyte. Disruption of the cytoskeleton with the drug dihydrocytochalasin B inhibited the cell culture induced increase in integrin expression, while treatment of cultured cells with TGF-beta resulted in increased expression of the alpha 5 beta 1 integrin. The modulation of beta 1 integrin expression noted in vitro and in situ indicates that chondrocytes are capable of regulated expression of beta 1 integrins and suggests that beta 1 integrins may play an important role in mediating chondrocyte-extracellular matrix interactions in cartilage.

Topics: Animals; Ascorbic Acid; Base Sequence; Cartilage, Articular; Cattle; Cell Adhesion; Cell Membrane; Cells, Cultured; Cytochalasin B; Cytoskeleton; Disease Models, Animal; DNA Primers; Extracellular Matrix; Humans; Integrin beta1; Integrins; Lymphotoxin-alpha; Macaca fascicularis; Molecular Sequence Data; Osteoarthritis; RNA, Messenger

There is controversy concerning the ability of antioxidant vitamins to reduce myocardial infarct size. We sought to determine whether a brief prophylactic treatment of vitamin C or vitamin C plus Trolox (a water-soluble form of vitamin E) could reduce myocardial infarct size in an experimental model. We used an anesthetized open-chest rabbit model in which a branch of the circumflex coronary artery was ligated for 30 minutes followed by 4 hours of reperfusion. Experiments were performed in a randomized and blinded fashion. An IV injection of normal saline pH balanced to 7.4 (control group n = 15), vitamin C (150 mg/kg, n = 14), or vitamin C plus Trolox (150 mg/kg plus 100 mg/kg, respectively, n = 15) was administered prior to coronary occlusion. Collateral blood flow during coronary occlusion was measured by radioactive microspheres, myocardial risk zone (AR) was assessed by blue dye injection, and myocardial infarct size (AN) was assessed by triphenyltetrazolium chloride staining. All rabbits received comparable ischemic insult: Collateral blood flow and AR were similar among all three groups. Infarct size, measured as a percent of AR, did not differ significantly among the controls (21%), vitamin C (29%), or the vitamin C plus Trolox (18%) groups. Therefore, in this ischemia/reperfusion model, antioxidant vitamins did not alter myocardial infarct size.

Topics: Animals; Antioxidants; Ascorbic Acid; Blood Pressure; Chromans; Disease Models, Animal; Drug Therapy, Combination; Free Radical Scavengers; Heart Rate; Hydrogen-Ion Concentration; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Rabbits; Random Allocation; Staining and Labeling; Tetrazolium Salts; Vitamin E

It is speculated that hypochlorous acid (HOCl), produced by neutrophils, can disrupt the tracheal epithelial barrier without damage to epithelial cells. This was investigated with solute permeability (P) and electrical conductance (G) measurements on tracheae from 4-wk-old rabbits. A new system for epithelial bioelectric measurements on intact tracheae was developed and validated. Control values of G, short-circuit current, and spontaneous potential difference were 4.9 +/- 0.5 (SE) mS/cm2, 42.6 +/- 4.7 microA/cm2, and 8.9 +/- 1.0 mV (lumen negative), respectively (n = 5). Control P values for sucrose, inulin, and Dextran-20 were 5.14 +/- 0.48, 0.63 +/- 0.10, and 0.057 +/- 0.007 x 10(-7) cm/s, respectively (n = 6). Tracheae treated with HOCl had no effect; 6 mM HOCl, a concentration that could exist in infected airways, significantly increased both P and G (about two- to fourfold) without damage to epithelial cells; and 12 and 30 mM HOCl caused more than 10-fold increases for both P and G with cell disruption. Vitamin C blocked epithelial damage caused by 30 mM HOCl. Tracheae from 1-wk-old rabbits were significantly more sensitive to HOCl than those from 4-wk-old or adult rabbits. This study validated a new bioelectric measurement system and showed that HOCl has both dose- and age-dependent effects on the tracheal epithelium.

Topics: Aging; Animals; Ascorbic Acid; Cell Membrane Permeability; Disease Models, Animal; Epithelium; Hypochlorous Acid; Ion Transport; Male; Membrane Potentials; Patch-Clamp Techniques; Rabbits; Respiratory Tract Diseases; Trachea

We measured ascorbic acid (reduced and oxidized) in brain, CSF and blood, before, during and after cerebral ischemia in newborn piglets. Bilateral carotid ligation induced a 54% decrease in cerebral blood flow (p < 0.01) and a 43% decrease in the cerebral metabolic rate of oxygen (p < 0.01). After ischemia and reperfusion, we obtained a 60% decrease (p < 0.01) in total brain ascorbic acid content. CSF ascorbic acid increased during reperfusion: +60% at 30 min (p < 0.001) and +160% at 120 min (p < 0.05). Blood ascorbic acid content did not change. These changes and the absence of massive oxidation of ascorbic acid in brain tissue suggest release of ascorbic acid by the brain during ischemia.

Topics: Animals; Animals, Newborn; Ascorbic Acid; Brain; Brain Ischemia; Cerebrovascular Circulation; Disease Models, Animal; Swine

We wished to determine whether histidine scavenges hydroxyl radical, H2O2, and superoxide anion in vitro and to investigate the protective effect of histidine on isolated perfused rat hearts after global ischemia (40 min) and reperfusion (30 min) (I/R). Left ventricular (LV) function was recorded and coronary effluent was collected for measurement of lactate dehydrogenase (LDH) before ischemia and at 5, 10, 15, and 30 min of reperfusion. At the end of the experiment, a portion of the LV wall was fixed with 2% glutaraldehyde for morphological analysis; the remaining heart was immediately frozen in liquid nitrogen for determination of adenine nucleotides. Histidine effectively quenched hydroxyl radicals and H2O2, but not superoxide anions, in in vitro and in vivo conditions. Hearts treated with histidine exhibited significantly greater functional recovery during reperfusion as compared with nontreated hearts (p < 0.05). Cell morphology was well preserved, and enzyme release was significantly attenuated by histidine treatment (p < 0.05). Histidine raised the ATP level to 73% and the creatine phosphate level to 68% of normal control during reperfusion. Total adenine nucleotide pool and energy charge rate in histidine-treated hearts significantly increased as compared with those in nontreated hearts (p < 0.05), but no effect on ATP and creatine phosphate was noted during ischemia, Histidine prevents postischemic reperfusion injury in isolated heart by inhibiting reactive O2 species and preserving high-energy phosphates (HEP).

Topics: Adenosine Triphosphate; Animals; Ascorbic Acid; Chromatography, High Pressure Liquid; Disease Models, Animal; Free Radical Scavengers; Gentisates; Glutaral; Heart Ventricles; Histidine; Hydrogen Peroxide; Hydroxybenzoates; Hydroxyl Radical; L-Lactate Dehydrogenase; Male; Myocardial Reperfusion Injury; Phosphates; Phosphocreatine; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxides; Tissue Embedding; Ventricular Function, Left

We developed a new gastric ulcer model in which the ulcers are induced by the local injection of a ferrous iron and ascorbic acid (Fe/ASA) solution into the gastric wall. These ulcers resemble human gastric ulcers that penetrate the muscularis mucosa. The involvement of oxygen radical-mediated lipid peroxidation as the cause of these ulcers was investigated. With ferrous iron or ascorbic acid alone, gastric ulcers did not form, whereas penetrating ulcers were produced by the simultaneous injection of the Fe/ASA solution in a dose-dependent manner. Lipid peroxides significantly accumulated in the gastric mucosa from 1 to 24 h after the injection of the Fe/ASA solution. This increase in lipid peroxides preceded grossly evident gastric ulcer. Treatment with superoxide dismutase (SOD, recombinant human CuZnSOD) significantly reduced the size of the ulcers and inhibited the accumulation in lipid peroxides in the gastric mucosa, while treatment with apo-SOD or heat-inactivated SOD did not. These results suggest that lipid peroxidation mediated by oxygen radicals plays a crucial role in the pathogenesis of the gastric ulceration induced by the Fe/ASA solution.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Ferrous Compounds; Gastric Mucosa; Injections; Lipid Peroxides; Male; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

This study demonstrates that gentamicin ototoxicity depends on dietary factors and correlates with tissue glutathione levels. After 15 days of gentamicin injections (100 mg/kg/day s.c.) guinea pigs on a regular protein diet (18.5% protein) had an average hearing loss of 9 dB at 3 kHz, 31 dB at 8 kHz and 42 dB at 18 kHz. Guinea pigs on a 7% protein diet showed an increased hearing loss of 52 dB at 3 kHz, 63 dB at 8 kHz and 74 dB at 18 kHz. Supplementing the low protein diet with either essential or sulfur-containing amino acids did not protect against gentamicin ototoxicity. Glutathione levels in the cochlear sensory epithelium were decreased in animals on a low protein diet and could be restored to normal by oral administration of glutathione monoethyl ester (1.2 g/kg/day) in combination with vitamin C (100 mg/kg/day). Glutathione supplementation significantly reduced the magnitude of hearing loss in the low protein diet group at all frequencies (43 dB reduction at 3 kHz, 27 dB reduction at 8 kHz and 21 dB reduction at 18 kHz). In animals on a full protein diet, dietary glutathione neither increased cochlear glutathione levels nor attenuated hearing loss. Serum gentamicin levels did not differ between animals on the various diets with or without glutathione supplement. These results suggest that gentamicin toxicity and detoxifying mechanisms are affected by the metabolic state of the animal and the glutathione content of the tissue. Thus, compounds that could potentially protect against gentamicin ototoxicity may be more correctly assessed in animal models of deficient nutritional states in which endogenous detoxifying mechanisms are compromised. This animal model might also be more realistically related to the clinical situation of a critically ill patient receiving gentamicin treatment.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Ascorbic Acid; Cochlea; Diet; Dietary Proteins; Disease Models, Animal; Drug Therapy, Combination; Epithelium; Evoked Potentials, Auditory, Brain Stem; Food, Fortified; Gentamicins; Glutathione; Guinea Pigs; Hearing Loss, Sensorineural; Injections, Subcutaneous; Male; Nutritional Status; Temporal Lobe; Vestibule, Labyrinth; Weight Gain

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Disease Models, Animal; Endothelium, Vascular; Homocysteine; Homocystinuria; Humans; Male; Microscopy, Electron, Scanning; Perfusion; Rats; Rats, Sprague-Dawley

Topics: Animals; Ascorbic Acid; Cadmium; Disease Models, Animal; Drug Interactions; Fishes; Gills; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Kidney; Liver; Muscles; Oxygen Consumption; Respiratory Distress Syndrome, Newborn; Selenium; Tissue Distribution; Water Pollutants; Zinc

A series of 16 experiments, using a total of 2,000 BD6 rats, was designed in order to assess the ability of 8 individual agents or their combinations to modulate the liver and oesophageal carcinogenesis induced by multiple doses of diethylnitrosamine (DEN). Of the antioxidants tested, sodium selenite, ascorbic acid, and butylated hydroxytoluene generally exhibited protective effects on both types of tumors. In contrast, retinoic acid behaved as a promoter of DEN hepatocarcinogenesis, but this effect could be eliminated by its combination with either selenite or butylated hydroxytoluene. Caffeine and theophylline, when individually assayed, were devoid of significant protective effects, and the latter methylxanthine stimulated oesophageal tumorigenesis when administered after exposure to the carcinogen. Caffeine tended to decrease the multiplicity of liver tumors and potentiated the inhibitory effect of selenite in the liver. Irrespective of combination with caffeine, treatment with phenobarbital before each DEN injection tended to reduce the multiplicity of both liver and oesophageal tumors. On the other hand, the metabolic inhibitor diethyldithiocarbamate, given after each DEN injection, dramatically enhanced the incidence and multiplicity of oesophageal tumors. Thus, on the whole, modulation of DEN carcinogenesis varied depending on test agents, their combinations, dosages, treatment schedules, and target organ.

Topics: Animals; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Caffeine; Diethylnitrosamine; Disease Models, Animal; Esophageal Neoplasms; Female; Liver Neoplasms, Experimental; Neoplasms, Experimental; Phenobarbital; Rats; Rats, Inbred Strains; Survival; Theophylline; Tretinoin

Topics: Animals; Aqueous Humor; Ascorbic Acid; beta Carotene; Carotenoids; Cataract; Crystallins; Diabetes Mellitus, Experimental; Disease Models, Animal; Drug Combinations; Female; Image Processing, Computer-Assisted; Rats; Rats, Wistar; Vitamin E; Vitamins; Vitreous Body

Topics: Animal Husbandry; Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Diet; Disease Models, Animal; Guinea Pigs; Paper; Wood

A detailed investigation on the anti-inflammatory activity of the butanol fraction of a methanol extract (BMEL) of the defatted leaves of Paederia foetida was undertaken to find the pharmacological basis for the ethnomedical use of the plant. This fraction produced a significant inhibition of granulation tissue formation in cotton-pellet implanted rats. It decreased liver aspartate transaminase activity without affecting serum aspartate transaminase activity. It did not, however, affect adrenal weight and ascorbic acid content significantly, thus ruling out a stimulation of the adrenal-pituitary axis. BMEL antagonised hyposaline-induced haemolysis of human red blood cells and an elevation of rat serum acid phosphatase activity, indicating the presence of a membrane stabilising activity. It also inhibited the elevation of serum orosomucoid levels in rats, suggesting the possibility of the presence of disease-modifying antirheumatic activity. The results indicate that there is some rationale behind the ethnomedical use of the plant for treating inflammatory disorders.

Topics: 1-Butanol; Acid Phosphatase; Adrenal Glands; Animals; Anti-Inflammatory Agents; Ascorbic Acid; Aspartate Aminotransferases; Blood Proteins; Butanols; Chemical Fractionation; Disease Models, Animal; Erythrocyte Membrane; Female; Granuloma; Hemolysis; Humans; Liver; Male; Medicine, Traditional; Methanol; Organ Size; Orosomucoid; Plant Extracts; Rats; Spleen

Our aim was to investigate whether ascorbic acid can reduce reactive oxygen metabolite-mediated acute lung injury. The effects of intravenous administration of Escherichia coli endotoxin were studied, with and without ascorbic acid infusion, on haemodynamics, lung lymph flow, cardio-respiratory and neutrophil function in chronically instrumented sheep. Paired experiments were performed on eight sheep in which they received either endotoxin alone (0.5 micrograms kg-1 b.w.) (ET group) or in combination with an ascorbic acid infusion (1 g kg-1 b.w. bolus injection followed by 0.2 g kg-1 h-1 continuous infusion) ET + ASC group) in random order. Four of the animals also received ascorbic acid alone (ASC group). As a result, for the ET + ASC group a general and mostly significant improvement (P < 0.05) in the early hypertensive phase (0-60 min, P values) and in the late permeability phase (2-4 h, *P values) of cardiorespiratory function (mean artery pressure: P/*P = 0.283/0.049; mean pulmonary artery pressure: P/*P = 0.0001/0.0001; mean pulmonary artery wedge pressure: P/*P = 0.012/0.001; right ventricular stroke work index: P/*P = 0.02/0.0001; cardiac index: P/*P = 0.797/0.755; arterial oxygen saturation: P/*P = 0.0059/0.01; arterial-venous difference of oxygen tension: P/*P = 0.011/0.0005), oxygen consumption: P/*P = 0.013/0.035, lung lymph flow: P/*P = 0.562/0.012, lymph/plasma protein ratio: P/*P = 0.304/0.008 and protein clearance: P/*P = 0.56/0.05 was observed in comparison with the ET group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Endotoxins; Female; Hemodynamics; Leukocyte Count; Lymphatic System; Neutrophils; Reactive Oxygen Species; Respiratory Distress Syndrome; Sheep

A study was initiated to determine the impact of vitamins A, C, E, and selenium compound (Se) on the prevention of liver cancer. Sixty animals were fed a diet with or without these vitamins followed by aflatoxin B treatment for a period of 24 months. Most of the animals fed a diet devoid of vitamins developed liver cancer, while none or only a few of the animals given vitamins suffered during this period. We suggest that vitamins can inhibit liver cancer by inducing hepatic microsomal enzymes that metabolise aflatoxins to noncarcinogenic products.

Topics: Aflatoxin B1; Aminopyrine N-Demethylase; Animals; Ascorbic Acid; Cytochrome P-450 Enzyme System; Dimethyl Sulfoxide; Disease Models, Animal; Drug Evaluation, Preclinical; Liver Neoplasms, Experimental; Male; Rats; Rats, Wistar; Selenium; Vitamin A; Vitamin E

The concentration of endogenous antioxidants has been studied in rats with a carrageenan-induced granuloma. This animal model of inflammation allowed us to study the antioxidant defenses and the oxidative stress in plasma and in the site of inflammation (exudate) and their modulation by the levels of iron in the organism after iron-dextran or desferrioxamine administration. In inflamed rats without supplementary treatment, an interrelation between urate, ascorbate and vitamin E levels has been observed and it appears to be an important mechanism to prevent the depletion of the antioxidants. Further, the sulphydryl groups, caeruloplasmin and retinol also contribute to the defense in this experimental model. Iron overload increases the production of malondialdehyde and decreases some antioxidants such as ascorbic acid and SH groups but, on the other hand, it raises the levels of urate and caeruloplasmin. However, the protective effect of desferrioxamine has not been observed, and in our conditions this may be due to the induced mobilization of iron. Our results show that antioxidants have an important role in the prevention of lipid peroxidation by free radicals produced during inflammatory processes. This protective effect depends on the stage of inflammation.

Topics: Animals; Antioxidants; Ascorbic Acid; Carrageenan; Deferoxamine; Disease Models, Animal; Granuloma; Male; Rats; Rats, Sprague-Dawley; Uric Acid; Vitamin A

Neurolathyrism is a neurological condition seen among people who eat the seeds of Lathyrus sativus (LS) as a principal source of food energy for 2 months or more. It is characterized by severe muscular rigidity and paralysis of the lower limbs. beta-N-Oxalyl-L-alpha,beta-diaminopropionic acid is the principal toxin found in the seed. No experimental animal model for neurolathyrism could be produced by feeding either the seeds or the toxin, although the condition has been known for centuries. We discovered that experimental neurolathyrism could be produced in guinea pigs and primates that needed an external supply of ascorbic acid by making them subclinically deficient in ascorbic acid and feeding them the seeds of LS or extracts thereof. Autoclaving the seeds of LS with lime removes the toxin.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Disease Models, Animal; Fabaceae; Food Contamination; Guinea Pigs; Haplorhini; Lathyrism; Male; Muscular Diseases; Plants, Medicinal

Renal scars have been considered to occur in later stages of chronic pyelonephritis. In our experimental pyelonephritis model, bacteria which possessed mannose-sensitive (MS) pili on the surface promoted renal scarring following inoculation to the renal parenchyma. Polyethylene glycol-modified superoxide dismutase (PEG-SOD) and 2-O-octadecylascorbic acid (CV3611) significantly suppressed scarring when administered orally or parenterally during the early stage of kidney infection with MS-piliated bacteria. These findings suggest that the superoxide and other active oxygens play an important role in renal scarring following infection and that PEG-SOD and CV3611 may be agents capable of preventing renal scarring following bacterial pyelonephritis.

Topics: Administration, Oral; Animals; Antioxidants; Ascorbic Acid; Cicatrix; Disease Models, Animal; Drug Resistance; Escherichia coli; Escherichia coli Infections; Female; Fimbriae, Bacterial; Kidney; Mannose; Polyethylene Glycols; Pyelonephritis; Rats; Serratia Infections; Serratia marcescens; Superoxide Dismutase

The effect of ozone (3 ppm, 15-120 min) on bronchial reactivity in the guinea-pig was studied. Ozone induced marked (6-250-fold) bronchial hyperreactivity (BHR) to a range of inhaled, but not intravenous bronchoconstrictors. The degree of BHR was related to the duration of prior ozone exposure. The glutathione redox status was shifted to a more oxidized state in lung after 120 min ozone treatment, although no changes were found in the energy status of lung tissue, as judged by the concentrations of adenosine phosphates. Ascorbic acid pretreatment prevented BHR induced by 30 min ozone exposure. Neutral endopeptidase inhibitors elicited BHR to both substance P and histamine, but did not further enhance bronchoconstriction to substance P after ozone exposure for 120 min. Neither mepyramine, fentanyl, indomethacin nor a 5-lipoxygenase inhibitor (BW B70C), given prior to ozone exposure prevented the induction of BHR to histamine. Atropine or bilateral vagotomy reduced BHR after a 120-min, but not 30-min exposure to ozone. We conclude that in the guinea-pig, ozone induces non-specific, route-dependent BHR by oxidative injury, reducing airway NEP activity and enhancing the cholinergic and peptidergic component to bronchoconstriction. Neither cyclooxygenase nor 5-lipoxygenase products appear to play a role in ozone-induced BHR in this animal model.

Topics: Adenine Nucleotides; Animals; Ascorbic Acid; Atropine; Bronchial Hyperreactivity; Bronchoconstriction; Disease Models, Animal; Fentanyl; Glutathione; Guinea Pigs; Histamine; Indomethacin; Lipoxygenase Inhibitors; Male; Neprilysin; Oligopeptides; Oxidation-Reduction; Ozone; Pyrilamine; Substance P; Vagus Nerve

Isolated perfused livers from rats fasted overnight were subjected to 30 min. of hypoxia followed by reoxygenation for 60 min., resulting in marked cytotoxicity as evidenced by an enhanced release of cytosolic enzymes (lactate dehydrogenase: 14-fold over controls, glutamate-pyruvate-transaminase: 12-fold over controls) and glutathione (twofold over controls) into the perfusate, by calcium accumulation (by a factor of 1.4) in the tissue and by an 80% inhibition of bile secretion. Virtually no mitochondrial injury became apparent and no evidence for lipid peroxidation could be found. In the presence of ascorbate, an augmentation of hepatic injury was observed. This might be due to the pro-oxidant activity of ascorbate in the presence of ionized iron, which is easily released from high molecular weight stores under reductive (e.g. hypoxic) conditions. The water soluble vitamin E analogue trolox C as well as propyl gallate clearly protected the liver against hypoxia/reoxygenation injury, yielding further evidence for a causative role of oxidative stress in this model. Due to their water solubility and their high efficacy as free radical scavengers, these antioxidants might be of therapeutic value.

Topics: Animals; Antioxidants; Ascorbic Acid; Bile; Cell Hypoxia; Chromans; Disease Models, Animal; Glutamate Dehydrogenase; Glutathione; L-Lactate Dehydrogenase; Liver; Male; Oxygen Consumption; Propyl Gallate; Rats; Rats, Wistar

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Ascorbic Acid Deficiency; Disease Models, Animal; Humans; Lipid Peroxidation; Lipoproteins, LDL; Rats; Vitamin E; Vitamin E Deficiency

Oxygen-induced retinopathy (OIR) was produced by subjecting newborn albino rats to a 60% oxygen atmosphere for 14 days before they were killed and retinal analysis was done. The extent of OIR was measured by estimating the severity of retinal vasoobliteration in ink-perfused flat-mounted retinas. This was done with the aid of a digitizing camera and an image-analysis system designed to create binary images of the retinal blood vessels. Retinal levels of several antioxidant molecules also were measured. Alpha-tocopherol and ascorbic acid were reduced in oxygen-exposed rats by 34% and 20%, respectively, compared with room air-raised control animals. Retinal glutathione reductase, S-transferase, and peroxidase showed no differences between oxygen-treated and -untreated rats. Attempts to increase the newborn rats' retinal ascorbic acid by administering daily subcutaneous injections (5 g/kg body weight) to the mother rats were unsuccessful. However, the level of retinal alpha-tocopherol of newborn rats could be altered by dietary manipulation of the mothers. The mothers were fed diets containing either 1 g alpha-tocopherol acetate/kg food or none, starting 21-25 days before the birth of their litters and lasting throughout the exposure period. This treatment resulted in three- to fourfold differences in the retinal alpha-tocopherol levels of the pups. The combination of dietary and oxygen treatments also resulted in significant differences in retinal glutathione peroxidase activity, with the vitamin E-deprived, oxygen-exposed group having highest levels. Newborn rats both supplemented with and deprived of alpha-tocopherol had less vasoobliteration than did those nursed by mothers fed rat chow.

Topics: Animals; Animals, Newborn; Ascorbic Acid; Disease Models, Animal; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Humans; Infant, Newborn; Oxygen; Rats; Rats, Inbred Strains; Retinal Vessels; Retinopathy of Prematurity; Vitamin E

The etiology of the juvenile type of the human ceroid-lipofuscinosis (JCL) is unknown, in spite of the fact that the first report of this disease was given more than 160 years ago. The necessity of good animal models for scientific progress in chronic metabolic diseases in humans is obvious. The inbred strain of English setter with ceroid-lipofuscinosis (CCL) seems to be a perfect model for human JCL. Dogs with CCL and organs for research purposes are available from Dr. Koppang's experimental kennel in Norway.

Topics: Animals; Ascorbic Acid; Bone Marrow Transplantation; Brain; Butylated Hydroxytoluene; Disease Models, Animal; Dogs; Electroencephalography; Female; Humans; Infant; Liver Transplantation; Male; Methionine; Neuronal Ceroid-Lipofuscinoses; Pigment Epithelium of Eye; Vitamin E

Sodium nitrite induced poisoning resulted into oxidation-reduction disorders with concomitant changes in the ratio of the oxidated and reduced forms towards accumulation of the oxidated equivalents. Antioxidants unithiol, tocopherol acetate, ascorbic acid, methylene blue, violuric acid influenced the oxidation-reduction balance in different ways. The protective action of violuric acid was comparable with that of methylene blue and exceeded the unithiol protective properties. Violuric acid, as compared with unithiol, ascorbic acid and tocopherol, was more effective in decreasing methemoglobin and nitrates contents in blood in methemoglobinemia cases. The violuric acid and methylene blue protective mechanisms are in all probability influenced by the antioxidant properties of these substances and their reductase activity.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Male; Methemoglobinemia; Rats; Unithiol; Vitamin E

It has been proposed that free radical reactions are involved in ischemic brain damage. Since irreversible pathological changes occurs very early phase of the focal ischemia and the ischemic brain edema reaches its peak at about 2 days of ischemia, the free radical reactions must take place before these changes. Superoxide dismutase is a famous enzyme that dismutase superoxide anion, which is believed to be one of the initiator of the free radical reactions. If superoxide anion plays a pivotal role in the genesis of pathological ischemic brain damage and edema, the activity of the enzyme may decrease in the early phase of ischemia. Ascorbic acid is also known to be a scavenger of superoxide anion, and brain tissue contains it in a high concentration. We investigated the changes in superoxide dismutase activity and concentration of reduced ascorbate in focal ischemia. Focal ischemia was produced in rats by permanent occlusion of the left middle cerebral artery. The animals were decapitated 30 minutes, 4, 24, and 48 hours after the operation. Middle cerebral artery territory of each cerebral hemisphere was homogenized and centrifuged with phosphate buffer. The supernatant was divided into two aliquots; one was dialyzed to remove ascorbate and the other was not. The SOD activity was measured by electron-spin-resonance (ESR) spin trapping method, and the ascorbic acid concentration was measured by high performance liquid chromatography with electrochemical detection (HPLC-ECD). Protein concentration was measured by Lowry's method. The enzyme activity was expressed as unit/mg protein, and the ascorbic acid concentration was expressed as microgram/g tissue. The SOD activity decreased markedly by dialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Ascorbic Acid; Dialysis; Disease Models, Animal; Free Radicals; Ischemic Attack, Transient; Male; Rats; Rats, Inbred Strains; Superoxide Dismutase; Time Factors

The incidence of ulceration and perforation in the cornea of alkali-injured eyes is significantly reduced by treatment with trisodium citrate or sodium ascorbate. Topical citrate reduces the inflammatory response in the cornea by inhibiting polymorphonuclear leukocytes. Topical ascorbate elevates the depressed level of this vitamin in the alkali-injured cornea, reversing a scorbutic condition. The purpose of the current study was to determine whether combined treatment with topical citrate and ascorbate has an additional therapeutic value when compared with citrate alone. Adsorbotear without EDTA was used as the vehicle for both medications. Rabbit eyes were injured with 1N NaOH for 35 s using a 12-mm well and were rinsed. Group I (47 eyes) received two drops of 10% citrate every hour on the hour and Adsorbotear on the half-hour for 14 h/day. Group II (48 eyes) received two drops of 10% citrate every hour on the hour and 10% ascorbate every hour on the half-hour for 14 h/day. The citrate/ascorbate group had significantly fewer ulcerations during the experiment than did the group receiving citrate alone (2 of 48 versus 10 of 47, 0.01 less than p less than 0.02). Both anterior ulcers in the citrate/ascorbate group and five ulcers in the citrate group healed to no ulcer by the end of the experiment (0 of 48 versus 5 of 47, 0.02 less than p less than 0.05). The average depth of ulceration was significantly less for the citrate/ascorbate group (p less than 0.001). No descemetoceles or perforations were observed in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alkalies; Animals; Antacids; Ascorbic Acid; Burns, Chemical; Citrates; Citric Acid; Corneal Ulcer; Disease Models, Animal; Drug Combinations; Eye Burns; Rabbits

The concept that lipoprotein(a) [Lp(a)] is a surrogate for ascorbate is suggested by the fact that this lipoprotein is found generally in the blood of primates and the guinea pig, which have lost the ability to synthesize ascorbate, but only rarely in the blood of other animals. Properties of Lp(a) that are shared with ascorbate, in accordance with this hypothesis, are the acceleration of wound healing and other cell-repair mechanisms, the strengthening of the extracellular matrix (e.g., in blood vessels), and the prevention of lipid peroxidation. High plasma Lp(a) is associated with coronary heart disease and other forms of atherosclerosis in humans, and the incidence of cardiovascular disease is decreased by elevated ascorbate. Similar observations have been made in cancer and diabetes. We have formulated the hypothesis that Lp(a) is a surrogate for ascorbate in humans and other species and have marshaled the evidence bearing on this hypothesis.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Biological Evolution; Cardiovascular Diseases; Diabetes Mellitus; Disease Models, Animal; Humans; Lipoprotein(a); Lipoproteins; Neoplasms; Wound Healing

Ascorbic acid is required in the synthesis of collagen and is also an important anti-oxidant. In a previous study, plasma ascorbic acid concentration was found to be decreased in diabetic patients but there was no relationship with blood glucose level. In the current study of diabetic patients, both plasma ascorbic acid and its urinary excretion correlated inversely with glycosylated hemoglobin level. Plasma ascorbic acid was also lower in diabetic rats but urinary ascorbic acid was elevated. The divergent trend in urinary ascorbic acid excretion observed in diabetic patients and diabetic rats may be due to difference in the ability of these two species to synthesize ascorbic acid. Difference in renal reabsorption of ascorbic acid may also be a relevant factor. The lower plasma and urinary ascorbic acid levels in diabetic patients with more severe hyperglycaemia indicates that this group of patients is particularly at risk of developing deficiency of this vitamin. As ascorbic acid has many important functions in the body, it may be necessary to supplement this vitamin in patients with chronically poorly controlled diabetes.

Topics: Adult; Animals; Ascorbic Acid; Diabetes Mellitus; Diabetes Mellitus, Experimental; Disease Models, Animal; Female; Humans; Middle Aged; Rats; Rats, Inbred Strains

Cartilage degeneration was induced in the hind knees of guinea-pigs by surgery. Partial medial meniscectomy induced rapidly progressing lesions whereas the lesions induced by section of the lateral collateral ligament with or without section of the medial collateral ligament developed later and progressed more slowly. In all cases the lesions were first seen focally on the medial tibial plateau where they extended both laterally and deeper into the cartilage. Later, lesions appeared on the medial femoral condyle and meniscus, and eventually also on cartilage in the lateral joint compartment. During the later stages, these models had many features of human osteoarthritis. The appearance and progression of spontaneous lesions in the hyaline cartilage of the hind knees of young guinea-pigs first reported by Bendele and Hulman (1988) has been confirmed. Extra ascorbic acid added to the drinking water had a slight chondroprotective effect on the development of spontaneous lesions but gave no significant protection against the development of lesions induced by lateral collateral ligament section.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Drinking; Guinea Pigs; Knee Joint; Ligaments, Articular; Male; Menisci, Tibial; Osteoarthritis

This work attempts to determine the influence of vitamin C on locally induced inflammation and arthritis in rat paws, as measured by rat paw swelling, polymorphonuclear leukocyte infiltration, pain, and surface skin temperature. Daily subcutaneous administration of 150 mg/kg of vitamin C over 20 days reduced arthritic swelling, increased pain tolerance, and decreased polymorphonuclear leukocyte infiltration, with no significant change in surface temperature. Vitamin C may provide podiatrists with a supplemental or alternative treatment for patients with rheumatoid arthritis.

Topics: Animals; Arthritis, Rheumatoid; Ascorbic Acid; Body Temperature; Disease Models, Animal; Edema; Male; Pain; Rats; Rats, Inbred Strains

Normal and streptozotocin diabetic female Wistar rats were given vitamin C (VC) at 0.3% or 1.0% (w/w) in the diet: 1% dietary VC resulted, in 12-24 hr, in significant increases in serum ascorbate levels and lens ascorbate concentrations in normal rats. The increase was biphasic, with VC concentrations falling to a lower level which was still significantly elevated compared to controls in the period of 1.7-4 days for serum and 1.7-5 days for lenticular VC. At the end of 10 weeks the rats were examined for weight gain or loss, general body condition and cataracts. At the time of killing, blood was collected for measurement of serum glucose. Alpha-crystallin levels were determined in vitreous and aqueous humours using a radioimmunoassay. One lens from each rat was fixed for either scanning electron microscopy or light microscopy; the other lens was homogenized in 8 M guanidinium chloride for adenosine triphosphate analysis. In normal rats, a small amount of gamma-crystallin was found in the vitreous humour, and an even smaller amount in the aqueous humour. Diabetes caused a five-fold increase in the vitreous humour and a 2.5-fold increase in gamma-crystallin in the aqueous humour. Diabetes also led to a significant worsening in general body condition, loss of body weight, formation of cataracts, and decrease in lens adenosine triphosphate levels. Addition of VC to the diet of diabetic animals resulted in reduction in cataracts and a decrease of gamma-crystallin leakage into the aqueous and vitreous humours. VC had no effect on lens adenosine triphosphate levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aqueous Humor; Ascorbic Acid; Cataract; Crystallins; Diabetes Mellitus, Experimental; Diet; Disease Models, Animal; Female; Lens, Crystalline; Rats; Rats, Inbred Strains; Vitreous Body

The authors studied the effect of toxic doses of thyroxin on the content of vitamins C and B1 in different tissues of rats. On the 15-th day after administration of thyroxin one could observe a reduction of thiamin in the tissues of the animals. These changes were most pronounced in the liver. The content of vitamin in the tissues also showed a reduction. These changes in the content of the ascorbic acid occurred after prolonged administration of thyroxin.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Liver; Rats; Thiamine; Thyrotoxicosis; Thyroxine; Tissue Distribution

Both Trolox (a water-soluble analogue of alpha-tocopherol) and ascorbic acid were more effective than superoxide dismutase or catalase in protecting myocyte cell cultures from free radical attack (induced by hypoxanthine and xanthine oxidase). In a canine model of two hours of left anterior descending coronary artery occlusion followed by four hours of reperfusion, Trolox and ascorbic acid reduced the area of infarction within the area at risk. The Trolox group received 500 mL of deoxygenated saline solution containing 2.0 g of Trolox, 3.0 g of ascorbic acid, and 18 mg of EDTA (ethylenediaminetetraacetic acid) infused into the ascending aorta 30 seconds before and four minutes after reperfusion. Saline controls received 500 mL of deoxygenated saline solution containing 18 mg of EDTA. The angioplasty group had unmodified reperfusion by simple release of the occlusion. The area at risk and the area infarcted were estimated with Evans blue and triphenyl tetrazolium hydrochloride stains, respectively. The ratio of the area infarcted to the area at risk was significantly lower with Trolox (angioplasty, 30.4% +/- 5.1%; saline, 20.8% +/- 2.9%; and Trolox, 8.7% +/- 4.0%; p less than 0.01). In summary, the antioxidants Trolox and ascorbic acid effectively reduced myocardial necrosis after ischemia.

Topics: Animals; Antioxidants; Ascorbic Acid; Benzopyrans; Cells, Cultured; Chromans; Disease Models, Animal; Dogs; Free Radicals; Heart; Hemodynamics; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Necrosis

Topics: Administration, Topical; Aloe; Animals; Arthritis; Arthritis, Experimental; Ascorbic Acid; Disease Models, Animal; Drug Combinations; Male; Plant Extracts; Plants, Medicinal; Rats; Rats, Inbred Strains; RNA

The development of permanent paraplegia in spinal injured cats is accompanied by a large progressive decline in total ascorbic acid (AA) and a transient increase in oxidized (AAox) ascorbate. Since AA is involved in a variety of processes required for normal central nervous system (CNS) performance we suggested that such large ascorbate loss may contribute to derangements in spinal cord function following injury. We now demonstrate that methylprednisolone (15 mg/kg) and naloxone (10 mg/kg), two treatments that preserve neurologic function in this model, rapidly block deteriorating ascorbate status. Naloxone at 1 mg/kg, a treatment providing no therapeutic benefit, has no protective effect on ascorbate. The results strongly support the hypothesis that loss of ascorbate homeostasis reflects irreversible loss of neurologic function following spinal cord injury.

Topics: Animals; Ascorbic Acid; Cats; Disease Models, Animal; Homeostasis; Locomotion; Methylprednisolone; Naloxone; Paraplegia; Spinal Cord Injuries; Time Factors

Marked sensitivity of tumor tolerance to blood glucose level is demonstrated in a mouse model of human breast cancer. A theory is cited that explains the high association of hyperglycemia with malignancy, especially breast cancer, via glycemic modulation of cellular immunity. Three groups of BALB/C mice were injected with an aggressive mammary tumor and placed on three dietary regimens designed to produce three different glycemic levels. Mortalities 70 days after injection were 16 of 24 hyperglycemic mice, 8 of 24 normoglycemic, and 1 of 20 hypoglycemic (chi-square p less than .005). Taken together with other experiments and human data discussed briefly, this result suggests that glycemic modulation of tumor tolerance should be evaluated in human trials.

Topics: Animals; Ascorbic Acid; Blood Glucose; Disease Models, Animal; Female; Leukocytes; Mammary Neoplasms, Experimental; Melanoma; Mice; Mice, Inbred BALB C; Phagocytosis

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Guinea Pigs; Osteoarthritis; Proteoglycans; Vitamin E

Throughout adult life, there is progressive alteration in body composition and tissue function. There is loss of lean body mass, notably by muscle, with a gain in body fat. We do not know whether nutritional factors affect these gross changes. In the case of loss of bone density (osteoporosis), however, there is evidence that the process is retarded by raising the intake of calcium and by exercise. Aging also adversely affects tissue function at the level of the whole organ and tissue as well as at the cellular and subcellular level. Animal models show similar age-related changes, and demonstrate further that alterations in nutrient intake or exercise can alter the rate of loss of tissue and cellular function. In addition to the effects of adult aging on tissue function, certain chronic diseases and disabilities are related to aging. These conditions include atherosclerosis, hypertension, coronary thrombosis, cancer, etc. Both human epidemiological studies and animal experiments on aging suggest strongly that nutrition plays a role in the onset and development of these conditions. There is a need for more accurate assessments of the nutrient needs of people over 65 years of age. A few selected nutrients are discussed. Studies of energy intake during adult life show a progressive reduction with increasing age, due mainly to reduced physical activity. Vitamin C levels in the white blood cells of elderly women can be half those of young adults; these respond to supplementary vitamin C without evidence of clinical benefit. Nitrogen balance studies suggest that the allowance of protein for older adults is not less than for young. Finally, surveys of elderly in whole populations and in selected groups show that, by the nutritional standards of young adults, there may exist a significant amount of malnutrition in people as they grow old, though we do not know whether this affects rate of loss of tissue function with age.

Topics: Aged; Ascorbic Acid; Body Composition; Chronic Disease; Dietary Proteins; Disease Models, Animal; Energy Metabolism; Female; Humans; Male; Nutritional Physiological Phenomena; Osteoporosis; Sex Factors

The biological mode of action of tumor promoters, exemplified by the phorbol esters, is a subject of intensive study in a number of laboratories. A few investigators have recently begun to examine the role of dietary nutrients in tumor promotion, but the available data are sparse and interpretation difficult. A few examples are provided to indicate that some nutrients may be important in the promotion of cancer. However, the fine dividing line between effects on initiation or on promotion, so clearly shown in the mouse two-stage skin cancer model, is not so clear as yet in models used for studies in nutritional carcinogenesis. The animal models for these studies have been primarily rats, mice and hamsters. These have shown that nutrients which appear to have promotion activity are zinc deficiency and 13-cis-retinoic acid for the esophagus; vitamin A deficiency and lipotrope deficiency for the forestomach, unsaturated fat and vitamin A deficiency for liver and colon, lipotrope deficiency for the liver; selenium for the liver. It is probably more correct at this early stage of investigation to consider the effects of nutrients acting either during the time of exposure to the carcinogen, or, after such exposure and when no detectable carcinogen is found in the animals tissues, rather than as promoters in the strict sense.

Topics: Animals; Ascorbic Acid; Carcinogens; Cocarcinogenesis; Colonic Neoplasms; Cricetinae; Diet; Disease Models, Animal; Esophageal Neoplasms; Gastrointestinal Neoplasms; Liver Neoplasms; Mice; Neoplasms, Experimental; Pancreatic Neoplasms; Rats; Stomach Neoplasms; Zinc

Topics: Adrenal Glands; Aging; Alcoholism; Animals; Ascorbic Acid; Body Weight; Disease Models, Animal; Ethanol; Humans; Kidney; Liver; Male; Organ Size; Rats; Rats, Inbred Strains; Spleen; Tissue Distribution

Guinea pigs fed an ascorbic acid-deficient diet develop scurvy because of the absence of the enzyme L-gulonolactone oxidase. In theory if this enzyme is provided and its substrate L-gulonolactone is present at adequate concentrations ascorbic acid will be synthesized and the development of scurvy prevented. Using this model we tested whether a viable segment of intestine could be used to contain the administered enzyme and act as an artificial organ for the production of ascorbic acid. A surgical procedure was developed to prepare an externalized pouch of intestine with its circulation left intact. When enzyme is inserted in this intestinal bag it is not toxic and not antigenic in some animals, whereas, enzyme injected intraperitoneally is clearly antigenic. Synthesis of ascorbic acid by this artificial organ could not, however, be detected by elevation of plasma concentrations of the vitamin.

Topics: Animals; Artificial Organs; Ascorbic Acid; Ascorbic Acid Deficiency; Bioprosthesis; Disease Models, Animal; Evaluation Studies as Topic; Guinea Pigs; Intestine, Small; L-Gulonolactone Oxidase; Male; Scurvy; Sugar Alcohol Dehydrogenases

The effect of variation in dietary ascorbic acid on surgically induced osteoarthritis was examined in the stifle joints of guniea pigs. Two different surgical procedures were used to induce osteoarthritis in the right stifle joint of these animals. Guinea pigs were maintained either on a high (150 mg/day) or low (2.4 mg/day) dietary intake of vitamin C. Regardless of the surgical procedure used to induce osteoarthritis, the animals maintained on the high level of vitamin C consistently showed severe joint damage than animals on the low level of the vitamin.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Female; Guinea Pigs; Hindlimb; Male; Menisci, Tibial; Methods; Osteoarthritis

The curly-tail mouse is an animal model for human neural tube defects (NTD). Around 60% have either overt lesions of the neural tube or a curly tail. They were used to examine the gene/environment interaction which is implicated in the aetiology of human NTD. Both a fetal and a maternal genotype contribution to the cause, together with a triggering effect of an environmental component, could be demonstrated in the mice. The environmental limb of the cause appears to be relatively specific. Under certain conditions, administration of an environmental agent to the pregnant curly-tail mouse markedly reduced the incidence of NTD in her offspring. Primary prevention of NTD was thus shown to be possible. The apparent primary prevention of NTD in humans is also described. A multicentre collaborative project which supplemented women "at risk" for NTD with a standard multivitamin tablet with folic acid before they conceived again and in the early stages of pregnancy was associated with a recurrence of only 0.5% compared with 4.3% in unsupplemented controls at a comparable risk. The difference is statistically significant (p = less than 0.01).

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Female; Folic Acid; Genotype; Gestational Age; Humans; Mice; Mice, Neurologic Mutants; Neural Tube Defects; Pregnancy; Sex Factors; Spina Bifida Occulta; Vitamin A

To test the hypothesis that superoxide radicals are involved in tissue destruction after alkali burns, superoxide dismutase, ascorbic acid, and glutathione were used as superoxide radical scavenging agents. Daily subconjunctival injections were given in rabbit eyes after alkali burns. Both superoxide dismutase and ascorbic acid were effective in preventing corneal perforations. Glutathione did not show any beneficial effect. These experiments suggest that superoxide radical scavenging agents may be useful in the treatment of ocular alkali burns.

Topics: Alkalies; Animals; Ascorbic Acid; Burns, Chemical; Disease Models, Animal; Eye Burns; Glutathione; Rabbits; Superoxide Dismutase

Siderosis of rabbit articular chondrocytes was produced in vitro as a model for the cartilage damage of hemophilic arthropathy. Both FeSO4 0.1-2.5 mM and rabbit hemoglobin (as hemolyzed serum, 14 mg/ml) caused iron storage in cell and organ culture. FeSO4 was far more effective. The fine structure of the siderosomes resulting from both iron sources was comparable to that observed in hemophilic and other forms of hemosiderosis. Particles resembling ferric oxyhydroxide were included in the FeSO4 but not the hemoglobin derived siderin. Iron storage following FeSO4 was enhanced 5-fold by culturing with rabbit rather than fetal calf serum. Despite repeated washing of the cultures and detachment with trypsin, an extracellular pool of Fe3+ persisted in the cell pellets. Cytotoxicity of Fe was manifested by formation of myelin bodies and a dose-dependent reduction of cell number. There was an inverse relationship between cytotoxicity and iron storage following administration of FeSO4 to five other cell types. Ascorbate 40 micrograms/ml stimulated DNA synthesis but had no protective effect against the cytotoxicity of FeSO4. Little erythrophagocytosis was showen by the chondrocytes. Desferrioxamine (0.01--2.5 mM) was markedly toxic for dividing but not for stationary chondrocytes. Administered after iron storage had been induced with FeSO4, 1.0--2.5 mM desferrioxamine removed stainable siderin granules over the course of 4 days.

Topics: Animals; Ascorbic Acid; Cartilage, Articular; Cattle; Cells, Cultured; Deferoxamine; Disease Models, Animal; Erythrocytes; Ferrous Compounds; Iron; Organ Culture Techniques; Phagocytes; Rabbits; Siderosis

Severe ocular alkali burns in rabbits result in a decrease in aqueous humor ascorbate levels to one-third normal levels. If this deficiency is reversed by immediate treatment with parenteral or topical ascorbate, there is a significantly decreased incidence of subsequent corneal ulceration and perforation. The morphologic changes in these ulcerating corneas are typical of those noted in scorbutus (scurvy). It is concluded that alkali injury to the ciliary epithelial transport processes or ciliary body vasculature results in localized deficiency of ascorbic acid in the aqueous humor and cornea. The development of corneal ulceration is thought to be based on this deficiency which results in the failure of fibroblasts to produce sufficient collagen for repair. A randomized clinical trial of ascorbic acid in the treatment of human alkali burned eyes is now underway.

Topics: Alkalies; Animals; Aqueous Humor; Ascorbic Acid; Burns, Chemical; Cornea; Corneal Injuries; Corneal Ulcer; Disease Models, Animal; Eye Burns; Rabbits; Scurvy

There is an important need to develop animal models to simulate the response of humans to environmental pollutants. The rodent model has been commonly employed to predict the effects of ambient ozone on human RBCs. The use of rodent models for such a purpose is questioned. This challenge is based on the a) ability of mice to significantly enhance ascorbic acid synthesis following ozone stress, b) the ability of ascorbic acid to prevent oxidant [i.e. acetylphenylhydrazine (APH)] stress to human G-6-PD deficient RBCs and c) the lack of ability of humans to synthesize ascorbic acid.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Erythrocytes; Glucosephosphate Dehydrogenase Deficiency; Humans; Ozone; Rats

Following initial weight gain, reduction in appetite and pronounced weight loss occurred in scorbutic unsupplemented guinea-pigs. Hepatic ascorbic acid levels were significantly reduced and cholesterol concentration increased in the liver. Fenfluramine administration caused immediate loss of weight and appetite in the scorbutic guinea-pigs, these changes being more pronounced in the males. Hepatic ascorbic acid, cholesterol and triglycerides were reduced to lower levels in the fenfluramine-treated scorbutic animals than in the scorbutic guinea-pigs receiving diet alone. In contrast, weight and appetite increased in vitamin-C-supplemented animals while they were receiving fenfluramine. Their hepatic cholesterol and triglyceride levels became significantly reduced. It has been shown that supplementary vitamin C can inhibit the anti-obesity and anorectic actions of fenfluramine and counteract its effect in raising tissue cholesterol.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Body Weight; Cholesterol; Disease Models, Animal; Female; Fenfluramine; Growth; Guinea Pigs; Lipid Metabolism; Liver; Male; Obesity; Sex Factors; Triglycerides

Five-week old, male, Japanese quail (Coturnix coturnix japonica) were given ad libitum access to glucose- soybean meal-10% fat diets containing 0, 0.25, 0.5, or 1% cholesterol, with or without the addition of a vitamin supplement (vitamin C--1 g/kg of diet, vitamin E--30 I.U./kg of diet and choline chloride--5.5 g/kg of diet). After 12 weeks, 9 quail from the 24 quail fed each diet were killed and the total cholesterol concentration of serum, liver, kidney, and aorta was determined. Cholesterol concentrations of these organs increased with increasing levels of dietary cholesterol. The vitamin supplementation enhanced the increase in the cholesterol concentration of serum and kidney, lessened the elevation of the liver cholesterol concentration and had no effect on the aorta cholesterol concentration. The remaining quail were fed the same diets, for a subsequent 12 week period, except that cholesterol was deleted. At the termination of the experiment, the total cholesterol concentration of serum, liver, and kidney returned to control level for all treatments in which organ cholesterol concentrations had been increased previously. Aortic cholesterol concentration decreased during the second 12 week period (0.5 and 1% cholesterol diets fed for the first 12 weeks), however, the aortic cholesterol concentration remained higher than those of the control at 24 weeks. No significant effect of vitamin supplementation on organ cholesterol concentration was noted at 24 weeks although serum cholesterol concentration was significantly lower for the vitamin- fed groups at all levels of dietary cholesterol. Aortic ahteromata were observed at both 12 and 24 weeks in all groups fed 0.5 and 1% cholesterol.

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Ascorbic Acid; Cholesterol; Cholesterol, Dietary; Choline; Coturnix; Disease Models, Animal; Kidney; Liver; Male; Vitamin E

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Fatty Alcohols; Freund's Adjuvant; Gluconates; Inactivation, Metabolic; Inflammation; Liver; Male; Mycobacterium tuberculosis; Rats; Sugar Alcohol Dehydrogenases

The hypotensive effect of ascorbate on intraocular pressure has been reported following topical application, oral administration, or anterior chamber infusion in animals. The present report describes the correlation of aqueous humor ascorbate concentration with intraocular pressure as well as outflow facility in vivo. Low aqueous ascorbate level was seen in buphthalmic eyes with high intraocular pressure and low outflow facility. The opposite correlation was observed in normal eyes. Ascorbate concentration in the anterior chamber of the rabbit eye is apparently related to the alteration of outflow facility and the movement of fluid in the anterior chamber.

Topics: Animals; Aqueous Humor; Ascorbic Acid; Disease Models, Animal; Hydrophthalmos; Intraocular Pressure; Rabbits

Because the dietary requirement for ascorbic acid is similar in humans and guinea pigs, galactose-induced cataract research with the guinea pig as an experimental model instead of the rat might be appropriate and may represent a closer analogy to galactosemic cataract formation in humans. In this study, dietary ascorbic acid was found in all guinea pigs to have a retarding or delaying effect on the development of galactose-induced cataracts.

Topics: Animals; Ascorbic Acid; Cataract; Diet; Disease Models, Animal; Galactosemias; Guinea Pigs

There is little information available concerning the possible effects of ascorbic acid on glucose-6-phosphate dehydrogenase (G-6-PD) -deficient erythrocytes. We therefore studied the survival of G-6-PD-deficient cells, incubated with ascorbic acid, in rats with partial reticuloendothelial and complement blockade. Animals were pretreated with ethyl palmitate and cobra venom factor. They were then transfused with 51Cr-labeled erythrocytes which had been incubated in the presence or absence of ascorbic acid. G-6-PD-deficient cells, incubated with ascorbic acid, had impaired survival when compared to that of controls. G-6-PD-deficient cells, in the absence of ascorbic acid, had survival times equal to those of normal control erythrocytes. At the concentrations used, ascorbic acid did not appear to alter the survival of normal cells. Ascorbic acid causes premature loss of G-6-PD-deficient human erythrocytes in this rat model. On the basis of previous clinical and experimental observations, as well as this study, caution should be used when administering ascorbic acid in large doses to individuals who might be G-6-PD deficient.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Erythrocyte Aging; Erythrocytes; Glucosephosphate Dehydrogenase Deficiency; Humans; Male; Rats

Topics: Acne Vulgaris; Adult; Animals; Ascorbic Acid; Cats; Disease Models, Animal; Dogs; Esophagitis; Esophagogastric Junction; Female; Humans; Mucous Membrane; Pressure

Some aqueous humor constituents, including ascorbate, protein, and sodium, potassium, and calcium ions, were analyzed in three groups of adult buphthalmic (bu/bu) rabbits from strain AXBU/J and in control rabbits of the closely related strain AX/J. Aqueous humor ascorbate concentration of the normal strain was 22.5/"2.3mg/100ml. The buphthalmic rabbits that had no meaningful clinical signs of glaucoma at the time of sample collection had lower values (11.7/"1.7mg/100ml). Much lower values were observed in the bu/bu mutant rabbits that showed mild to severe glaucoma: 8.9/"3.8mg/100 ml and 1.9"/0.4mg/100ml, respectively. It was concluded that reduction of aqueous ascorbate is a biochemical change associated with the pathological development of buphthalmia in rabbits of the AXBU/J strain. However, the exact mechanism is still unclear.

Topics: Animals; Aqueous Humor; Ascorbic Acid; Calcium; Disease Models, Animal; Eye Proteins; Genotype; Glaucoma; Hydrophthalmos; Intraocular Pressure; Potassium; Rabbits; Sodium

There is increasing evidence that the liver microsomal drug metabolizing system is affected by various vitamins such as ascorbic acid, riboflavin, and alpha-tocopherol. In regard to ascorbic acid deficiency there is a decrease in the quantity of hepatic microsomal electron transport components such as cytochrome P-450 and NADPH-cytochrome P-450 reductase, as well as decreases in a variety of drug enzyme reactions such as N-demethylation, O-demethylation, and steroid hydroxylation. In addition, young animals given high supplements of vitamin C have increased quantities of electron transport components and overall drug metabolism activities. Kinetic studies indicate no change in the apparent Km of N-demethylase, O-demethylase or hydroxylase for drug substrates in animals depleted or given high amounts of the vitamin. However, there are qualitative changes in both type I and II substrate-cytochrome P-450 binding. Ascorbic acid is not involved in microsomal lipid peroxidation or in any qualitative or quantitative change in phosphatidylcholine. Replenishing vitamin C-deficient animals with ascorbic acid required 3 to 7 days for the electron transport components and drug metabolism activities to return to normal levels. Induction with phenobarbital and 3-methylcholanthrene is not impaired in the deficient animal since drug metabolism activities are induced to the same extent as normal controls; however, the administration of delta-aminolevulinic acid, a precursor of heme synthesis, to deficient animals caused an increase in the quantity of cytochrome P-450. The effects of riboflavin deficiency on electron transport components and drug metabolism activities have been noted only in adult animals after prolonged periods of deficiency. Decreases in drug metabolism activities occur with both type I (aminopyrine and ethylmorphine) and type II (aniline) substrates. As was found with ascorbic acid deficiency, drug enzyme induction occurred to the same extent with phenobarbital in deficient and normal animals. In addition, it required from 10 to 15 days for the drug metabolism activities to return to normal levels when deficient animals were replenished with riboflavin. The effect of vitamin E on drug metabolism is specific in N-demethylase activities decrease while O-demethylase activities are not affected in the deficient state. This vitamin differs from ascorbic acid and riboflavin in that several laboratories have reported no quantitative decrease in cytochrome P-45

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Avitaminosis; Cytochrome P-450 Enzyme System; Cytochrome Reductases; Disease Models, Animal; Enzyme Induction; Guinea Pigs; Kinetics; Liver; Microsomes, Liver; Mixed Function Oxygenases; Oxidoreductases; Oxidoreductases, N-Demethylating; Phenobarbital; Riboflavin Deficiency; Vitamin E Deficiency

Depressed aqueous humor glucose and ascorbic acid levels returned to control values within 14 days following a 20 sec, 6 mm. diameter, 1N sodium hydroxide burn of the rabbit cornea. These corneas did not ulcerate or perforate. After a 20 sec., 12 mm. diameter, 1N sodium hydroxide burn, aqueous humor glucose levels returned to normal values, but ascorbic acid levels remained significantly depressed for up to 30 days. These corneas became markedly ulcerated in about 60 per cent of animals and frequently perforated. Following 12 mm. alkali burns, rabbits treated daily with 1.5 Gm. of subcutaneous ascorbic acid rarely developed corneal ulcerations and the corneas did not perforate. It is suggested that exogenous maintenance of adequate aqueous humor levels of ascorbic acid overcomes the relatively scorbutic state of the anterior segment induced by a 12 mm. alkali burn, thereby impairing the development of corneal ulceration and perforation. Elevated aqueous humor levels of ascorbic acid had no influence on corneal epithelial cell migration patterns following alkali burns.

Topics: Alkalies; Animals; Aqueous Humor; Ascorbic Acid; Burns, Chemical; Corneal Ulcer; Disease Models, Animal; Eye Burns; Female; Glucose; Male; Rabbits

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Black People; Child; Disease Models, Animal; Guinea Pigs; Hemosiderosis; Humans; Iron; Leukocytes; Liver; Oxalates; South Africa; Thalassemia

Topics: Animals; Arteriosclerosis; Ascorbic Acid; Disease Models, Animal; Guinea Pigs; Humans; Lipid Metabolism; Scurvy; Time Factors

Topics: Administration, Oral; Animals; Ascorbic Acid; Benzoates; Blood Transfusion; Body Weight; Calcium; Carboxylic Acids; Catechols; Chelating Agents; Copper; Deferoxamine; Disease Models, Animal; Feces; Hemochromatosis; Hydroxylation; Injections, Intraperitoneal; Iron; Iron Chelating Agents; Iron Radioisotopes; Lethal Dose 50; Magnesium; Mice; Mice, Inbred Strains; Rats; Zinc

Topics: Adult; Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Cholelithiasis; Cholesterol; Disease Models, Animal; Edema; Female; Gallbladder; Guinea Pigs; Humans; Liver

Topics: Animals; Anti-Inflammatory Agents; Arthritis; Ascorbic Acid; Aspirin; Carrageenan; Disease Models, Animal; Edema; Erythema; Female; Freund's Adjuvant; Glucuronidase; Guinea Pigs; In Vitro Techniques; Liver; Lysosomes; Male; Phenylbutazone; Rats; Rats, Inbred Strains; Ultraviolet Rays

Topics: Alkaline Phosphatase; Animals; Ascorbic Acid; Body Weight; Bone and Bones; Bone Development; Calcinosis; Calcium; Calcium, Dietary; Dietary Proteins; Disease Models, Animal; Fluoride Poisoning; Fluorides; Haplorhini; Macaca; Phosphorus; Radiography; Statistics as Topic

Topics: Animals; Ascorbic Acid; Body Weight; Bone and Bones; Calcium; Calcium Isotopes; Calcium, Dietary; Dietary Proteins; Disease Models, Animal; Fluoride Poisoning; Haplorhini; Phosphorus

Topics: Animals; Aorta; Ascorbic Acid; Ascorbic Acid Deficiency; Bile; Bile Acids and Salts; Body Weight; Carbon Dioxide; Carbon Isotopes; Cholesterol; Chronic Disease; Disease Models, Animal; Feces; Guinea Pigs; Hydrogen-Ion Concentration; Hydroxylation; Liver; Male; Oxidation-Reduction; Sterols; Thoracic Arteries; Time Factors

Topics: Animals; Ascorbic Acid; Coumarins; Disease Models, Animal; Ligation; Lymphatic Diseases; Male; Massage; Pantothenic Acid; Plethysmography; Pyridoxine; Rats; Thiamine

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Cholesterol; Cholesterol, Dietary; Diet, Atherogenic; Disease Models, Animal; Hypercholesterolemia; Rabbits

Topics: Ammonia; Animals; Anti-Bacterial Agents; Ascorbic Acid; Bacitracin; Chloramphenicol; Chlortetracycline; Demeclocycline; Depression, Chemical; Disease Models, Animal; Enzyme Repression; Erythromycin; Female; Hydroxamic Acids; In Vitro Techniques; Intestines; Kanamycin; Male; Neomycin; Niacinamide; Oxytetracycline; Penicillin G; Rats; Streptomycin; Sulfamethoxypyridazine; Sulfisoxazole; Sulfonamides; Tetracycline; Urease

Topics: Animals; Ascorbic Acid; Collagen; Disease Models, Animal; Hydroxyproline; Iron; Ketoglutaric Acids; Mixed Function Oxygenases; Proline; Pulmonary Fibrosis; Rats; Silicosis

Topics: Alkaptonuria; Ascorbic Acid; Binding Sites; Carbon Isotopes; Connective Tissue; Disease Models, Animal; Ochronosis; Penicillamine; Phenylacetates; Sternum; Tendons; Tyrosine

Topics: Adrenal Glands; Animals; Arteriosclerosis; Ascorbic Acid; Body Weight; Cholesterol; Disease Models, Animal; Histocytochemistry; Hypercholesterolemia; Lipids; Male; Methods; Organ Size; Rabbits; Time Factors