vitamin-b-12 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

Porphyra sensu lato belongs to Bangiales, the most genetically diverse order of red algae. Porphyra or Pyropia is widely cultivated in East Asian countries, such as China, Japan, and Korea. Dried Porphyra contains numerous nutritional and biofunctional compounds, including proteins, minerals, dietary fiber, polyunsaturated fatty acids, carotenoids, saccharides, and mycosporine-like amino acids. In addition, the compound is most abundant in Porphyra, such as polysaccharides and phycobiliproteins, and demonstrates various immunomodulating, anticancer, antihyperlipidemic, and antioxidative activities. This review summarizes our current knowledge concerning the pharmacologically active substances found in Porphyra species. The biological activities and potential applications of certain carbohydrates, proteins, peptides, and other small molecules purified from Porphyra are also described, and possible areas for future studies are discussed.

Topics: Animals; Anti-Allergic Agents; Antineoplastic Agents; Antioxidants; Carotenoids; China; Dietary Fiber; Dietary Proteins; Disease Models, Animal; Fatty Acids, Unsaturated; Humans; Hypolipidemic Agents; Immunomodulation; Japan; Nutritive Value; Phycobiliproteins; Plant Preparations; Polysaccharides; Porphyra; Republic of Korea; Trace Elements; Vitamin B 12

Reduced expression of tumor suppressor genes (TSG) increases the susceptibility to breast cancer. However, only a small percentage of breast tumors is related to family history and mutational inactivation of TSG. Epigenetics refers to non-mutational events that alter gene expression. Endocrine disruptors found in foods and drinking water may disrupt epigenetically hormonal regulation and increase breast cancer risk. This review centers on the working hypothesis that agonists of the aromatic hydrocarbon receptor (AHR), bisphenol A (BPA), and arsenic compounds, induce in TSG epigenetic signatures that mirror those often seen in sporadic breast tumors. Conversely, it is hypothesized that bioactive food components that target epigenetic mechanisms protect against sporadic breast cancer induced by these disruptors.. This review highlights (i) overlaps between epigenetic signatures placed in TSG by AHR-ligands, BPA, and arsenic with epigenetic alterations associated with sporadic breast tumorigenesis; and (ii) potential opportunities for the prevention of sporadic breast cancer with food components that target the epigenetic machinery.. Characterizing the overlap between epigenetic signatures elicited in TSG by endocrine disruptors with those observed in sporadic breast tumors may afford new strategies for breast cancer prevention with specific bioactive food components or diet.

Topics: Animals; Arsenic; Benzhydryl Compounds; Breast Neoplasms; Diet; Disease Models, Animal; Endocrine Disruptors; Epigenesis, Genetic; Female; Folic Acid; Food Analysis; Food Contamination; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Genistein; Humans; Isothiocyanates; Phenols; Phytochemicals; Receptors, Aryl Hydrocarbon; Vitamin B 12

Topics: Acetylcysteine; Animals; Antipsychotic Agents; Aripiprazole; Autistic Disorder; Complementary Therapies; Disease Models, Animal; Evidence-Based Medicine; Free Radical Scavengers; Gastrointestinal Tract; Humans; Inflammation; Mice; Oxidative Stress; Randomized Controlled Trials as Topic; Risperidone; United States; United States Food and Drug Administration; Vitamin B 12

Vitamin B(12) (cobalamin, Cbl) is required for cellular metabolism. It is an essential coenzyme in mammals for two reactions: the conversion of homocysteine to methionine by the enzyme methionine synthase and the conversion of methylmalonyl-CoA to succinyl-CoA by the enzyme methylmalonyl-CoA mutase. Symptoms of Cbl deficiency are hematological, neurological and cognitive, including megaloblastic anaemia, tingling and numbness of the extremities, gait abnormalities, visual disturbances, memory loss and dementia. During pregnancy Cbl is essential, presumably because of its role in DNA synthesis and methionine synthesis; however, there are conflicting studies regarding an association between early pregnancy loss and Cbl deficiency. We here review the literature about the requirement for Cbl during pregnancy, and summarized what is known of the expression pattern and function of genes required for Cbl metabolism in embryonic mouse models.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Acyl Coenzyme A; Animals; Disease Models, Animal; Embryonic Development; Female; Homocysteine; Humans; Methionine; Methylmalonyl-CoA Mutase; Mice; Pregnancy; Vitamin B 12; Vitamin B 12 Deficiency

To assess the effects, associations, mechanisms of action, and safety of B vitamins and, separately, berries and their constituents on age-related neurocognitive disorders-primarily Alzheimer's (AD) and Parkinson's disease (PD).. MEDLINE and CAB Abstracts. Additional studies were identified from reference lists and technical experts.. Vitamins B1, B2, B6, B12, and folate, and a dozen types of berries and their constituents were evaluated. Human, animal, and in vitro studies were evaluated. Outcomes of interest from human studies were neurocognitive function or diagnosis with AD, cognitive decline, PD, or related conditions. Intervention studies, associations between dietary intake and outcomes, and associations between B vitamin levels and outcomes were evaluated. Specific mechanisms of action were evaluated in animal and in vitro studies. Studies were extracted for study design, demographics, intervention or predictor, and neurocognitive outcomes. Studies were graded for quality and applicability.. In animal studies, deficiencies in vitamins B1 or folate generally cause neurological dysfunction; supplementation with B6, B12, or folate may improve neurocognitive function. In animal experiments folate and B12 protect against genetic deficiencies used to model AD; thiamine and folate also affect neurovascular function and health. Human studies were generally of poor quality. Weak evidence suggests possible benefits of B1 supplementation and injected B12 in AD. The effects of B6 and folate are unclear. Overall, dietary intake studies do not support an association between B vitamin intake and AD. Studies evaluating B vitamin status were mostly inadequate due to poor study design. Overall, studies do not support an association between B vitamin status and age-related neurocognitive disorders. Only one study evaluated human berry consumption, finding no association with PD. Animal studies of berries have almost all been conducted by the same research group. Several berry constituents have been shown to affect brain and nerve tissue function. Blueberry and strawberry extract were protective of markers of disease, although effects on neurocognitive tests were less consistent. Berry extracts may protect against the deleterious effects of compounds associated with AD. Reporting of adverse events was uncommon. When reported, actual adverse events from B vitamins were rare and minor.. The current research on B vitamins is largely inadequate to confidently assess their mechanisms of action on age-related neurocognitive disorders, their associations with disease, or their effectiveness as supplements. B vitamin supplementation may be of value for neurocognitive function, but the evidence is inconclusive.

Topics: Aging; Alzheimer Disease; Animals; Blueberry Plants; Cognition; Disease Models, Animal; Folic Acid; Fragaria; Fruit; Humans; Neurodegenerative Diseases; Parkinson Disease; Plant Extracts; Riboflavin; Thiamine; Vitamin B 12; Vitamin B 6; Vitamin B Complex

Subacute combined degeneration (SCD) is a neuropathy due to cobalamin (Cbl) (vitamin B(12)) deficiency acquired in adult age. Hitherto, the theories advanced to explain the pathogenesis of SCD have postulated a causal relationship between SCD lesions and the impairment of either or both of two Cbl-dependent reactions. We have identified a new experimental model, the totally gastrectomized rat, to reproduce the key morphological features of the disease [spongy vacuolation, intramyelinic and interstitial edema of the white matter of the central nervous system (CNS), and astrogliosis], and found new mechanisms responsible for the pathogenesis of SCD: the neuropathological lesions in TGX rats are not only due to mere vitamin withdrawal but also to the overproduction of the myelinolytic tumor necrosis factor (TNF)-alpha and the reduced synthesis of the two neurotrophic agents, epidermal growth factor (EGF) and interleukin-6. This deregulation of the balance between TNF-alpha and EGF synthesis induced by Cbl deficiency has been verified in the sera of patients with pernicious anemia (but not in those with iron-deficient anemia), and in the cerebrospinal fluid (CSF) of SCD patients. These new functions are not linked to the coenzyme functions of the vitamin, but it is still unknown whether they involve genetic or epigenetic mechanisms. Low Cbl levels have also been repeatedly observed in the sera and/or CSF of patients with Alzheimer's disease or multiple sclerosis, but whether Cbl deficit plays a role in the pathogenesis of these diseases is still unclear.

Topics: Animals; Disease Models, Animal; Epidermal Growth Factor; Gastrectomy; Humans; Interleukin-6; Models, Biological; Nerve Degeneration; Rats; Tumor Necrosis Factor-alpha; Vitamin B 12; Vitamin B 12 Deficiency

Growing epidemiological evidence of associations between mildly elevated plasma homocysteine with age-related cognitive impairment, neurodegenerative and cerebrovascular disease has stimulated interest in the role of homocysteine in neurological and neuropsychiatric disorders. Homocysteine is an intermediate in the folate, vitamin B12 and B6 dependent pathways of one-carbon and sulfur amino acid metabolism. Impairments of these pathways may cause CNS dysfunction by promoting the intracellular generation of homocysteine, which is postulated to have vasotoxic and neurotoxic properties. It might also inhibit the methylation of myelin basic protein and membrane phospholipids, or disrupt biogenic amine metabolism and many other vital CNS reactions. However, it is unclear which, if any, of these putative mechanisms underlies the epidemiological associations. Genetic mouse models of hyperhomocysteinemia suggest that the primary metabolic disturbances rather than homocysteine per se may be important in determining neurological outcomes. However, severe and early developmental abnormalities in these mice limit their usefulness for understanding the relation of hyperhomocysteinemia to adult CNS disorders. Pharmacologic and dietary studies on homocysteine in rodents have reported heightened neuronal sensitivity to neurotoxic insults, neurochemical abnormalities and cerebrovascular dysfunction. Such studies are consistent with a causal relationship, but they fail to distinguish between effects that might result from a dietary imbalance and those that might be caused by homocysteine per se. Future work should be directed towards refining these models in order to distinguish between the effects of homocysteine and its determinants on neurological and behavioral outcomes that represent different CNS disorders.

Topics: Animals; Central Nervous System; Disease Models, Animal; Folic Acid; Folic Acid Deficiency; Homocystine; Humans; Hyperhomocysteinemia; Methylenetetrahydrofolate Reductase (NADPH2); Vitamin B 12

Homocysteine is an amino acid that plays a key role in methionine- and homocysteine metabolism. Homocystinuria has been described about four decades ago to be an inherited (autosomal recessive) disorder with rapid progressive atherosclerosis. Thus, homocysteine has been investigated intensively with respect to vascular wall injury and atherogenesis. Folic acid and vitamin B12 are cofactors of methioninsynthase, a key enzyme in homocysteine metabolism. Plasma levels of homocysteine are higher in patients with coronary artery disease documented by coronary angiography than in individuals with normal coronary arteries. Supplementation of folic acid is the treatment of choice to lower plasma homocysteine concentrations. Improvement in endothelial function could be documented in patients with folic acid supplementation. Large scaled clinical trials investigating folic acid supplementation in secondary prevention are now in progress. Today, homocysteine and its association with atherosclerosis raise a lot of questions to be answered. A distinct pathophysiological model linking hyperhomocysteinaemia and atherosclerosis is still not available. The presence of hyperhomocysteinemia in atherosclerotic vascular disease as a surrogate with no pathophysiological relevance itself cannot be ruled out. Routine testing of homocysteine levels is not yet recommended. Treatment of patients with folic acid or vitamin B for primary and secondary prevention of atherosclerotic vascular disease cannot be recommended today, because large scaled intervention trials on homocysteine lowering by vitamin B or folic acid are not available yet. Possible effects of these interventions on acute vascular events are not known.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Animals; Arteriosclerosis; Clinical Trials as Topic; Coronary Artery Disease; Disease Models, Animal; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Models, Biological; Vitamin B 12

Topics: Anemia, Pernicious; Animals; Autoantibodies; Autoimmune Diseases; Disease Models, Animal; Gastric Mucosa; Gastritis, Atrophic; H(+)-K(+)-Exchanging ATPase; Humans; Mice; Parietal Cells, Gastric; Vitamin B 12; Vitamin B 12 Deficiency

Neuropathy commonly complicates cobalamin (Cb1) deficiency in humans, monkeys, fruit bats, and pigs. The neuropathy is characterized by demyelination of the posterolateral columns of the spinal cord (subacute combined degeneration). The lesion was thought to arise primarily from impairment of the adenosylcobalamin-dependent methylmalonyl CoA mutase reaction, leading to the formation of abnormal odd-chain and branched-chain fatty acids and their incorporation into myelin with resultant demyelination. Data from recently developed animal models of the Cb1 neuropathy induced by exposure to nitrous oxide do not substantiate this hypothesis, but rather identify impairment of the methylcobalamin-dependent methionine synthetase reaction as the more important basic defect. The key evidence for this hypothesis is the ability of methionine to delay the onset of Cb1 neuropathy in experimental Cb1 deficiency. In the Cb1-deficient pig, adenosylhomocysteine accumulates in neural tissue, presumably owing to the inability to recycle homocysteine via the defective methionine synthetase reaction. Accumulation of adenosylhomocysteine results in a fall in the adenosylmethionine:adenosylhomocysteine methylation ratio, and this change is believed to cause defective methylation and demyelination in the nervous system. However, in the Cb1 neuropathy in the fruit bat, adenosylhomocysteine does not accumulate in the nervous system, the methylation ratio does not change, and no defect can be demonstrated in the methylation of myelin lipid or basic protein. Although a central role for methionine in the pathogenesis of the Cb1 neuropathy has been established, defective methylation attendant upon impairment of the methionine synthetase reaction may not be the universal defect underlying the Cb1 neuropathy. This would suggest that the methionine effect could be mediated via its role in formate metabolism or polyamine synthesis, or by some as yet unidentified pathway.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Animals; Disease Models, Animal; Humans; Methylation; Methylmalonyl-CoA Mutase; Nervous System Diseases; Nitrous Oxide; Vitamin B 12; Vitamin B 12 Deficiency

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Anemia, Megaloblastic; Animals; Central Nervous System; Deoxyuridine; Disease Models, Animal; Drug Interactions; Enzyme Activation; Folic Acid; Folic Acid Deficiency; Histidine; Humans; Liver; Methionine; Methylmalonyl-CoA Mutase; Nitrous Oxide; Oxidation-Reduction; Pteroylpolyglutamic Acids; Purines; Serine; Tetrahydrofolates; Thymidylate Synthase; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia, Pernicious; Animal Nutritional Physiological Phenomena; Animals; Ataxia; Behavior, Animal; Central Nervous System Diseases; Chiroptera; Demyelinating Diseases; Disease Models, Animal; Flight, Animal; Humans; Species Specificity; Spinal Cord Diseases; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Animals; Cobalt Isotopes; Disease Models, Animal; Intestinal Absorption; Intrinsic Factor; Malabsorption Syndromes; Pancreas; Pancreatectomy; Pancreatic Diseases; Rats; Tissue Extracts; Vitamin B 12

Infection with Trypanosoma brucei rhodesiense (T.b.r) causes acute Human African Trypanosomiasis (HAT) in Africa. This study determined the effect of vitamin B12 on T.b.r -driven pathological events in a mouse model. Mice were randomly assigned into four groups; group one was the control. Group two was infected with T.b.r; group three was supplemented with 8 mg/kg vitamin B12 for two weeks; before infection with T.b.r. For group four, administration of vitamin B12 was started from the 4th days post-infection with T.b.r. At 40 days post-infection, the mice were sacrificed to obtain blood, tissues, and organs for various analyses. The results showed that vitamin B12 administration enhanced the survival rate of T.b.r infected mice, and prevented T.b.r-induced disruption of the blood-brain barrier and decline in neurological performance. Notably, T.b.r-induced hematological alteration leading to anaemia, leukocytosis and dyslipidemia was alleviated by vitamin B12. T.b.r-induced elevation of the liver alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin as well as the kidney damage markers urea, uric acid and creatinine were attenuated by vitamin B12. Vitamin B12 blocked T.b.r-driven rise in TNF-α and IFN-γ, nitric oxide and malondialdehyde. T.b.r-induced depletion of GSH levels were attenuated in the presence of vitamin B12 in the brain, spleen and liver tissues; a clear indication of the antioxidant activity of vitamin B12. In conclusion, treatment with vitamin B12 potentially protects against various pathological events associated with severe late-stage HAT and presents a great opportunity for further scrutiny to develop an adjunct therapy for severe late-stage HAT.

Topics: Animals; Blood-Brain Barrier; Disease Models, Animal; Mice; Nitric Oxide; Trypanosoma brucei brucei; Trypanosoma brucei rhodesiense; Trypanosomiasis, African; Vitamin B 12

The interplay between bacterial virulence factors and the host innate immune response in pneumococcal meningitis (PM) can result in uncontrolled neuroinflammation, which is known to induce apoptotic death of progenitor cells and post-mitotic neurons in the hippocampal dentate gyrus, resulting in cognitive impairment. Vitamin B12 attenuates hippocampal damage and reduces the expression of some key inflammatory genes in PM, by acting as an epidrug that promotes DNA methylation, with increased production of S-adenosyl-methionine, the universal donor of methyl.. Eleven-day-old rats were infected with. In this study, adjuvant therapy with B12 was found to modulate the hippocampal transcriptional signature induced by PM in infant rats, mitigating the effects of the disease in canonical pathways related to the recognition of pathogens by immune cells, signaling via NF-kB, production of pro-inflammatory cytokines, migration of peripheral leukocytes into the central nervous system, and production of reactive species. Phenotypic analysis revealed that B12 effectively inhibited microglia activation in the hippocampus and reduced the inflammatory infiltrate in the central nervous system of the infected animals. These pleiotropic transcriptional effects of B12 that lead to neuroprotection are partly regulated by alterations in histone methylation markings. No adverse effects of B12 were predicted or observed, reinforcing the well-established safety profile of this epidrug.. B12 effectively mitigates the impact of PM on pivotal neuroinflammatory pathways. This leads to reduced microglia activation and inflammatory infiltrate within the central nervous system, resulting in the attenuation of hippocampal damage. The anti-inflammatory and neuroprotective effects of B12 involve the modulation of histone markings in hippocampal neural cells.

Topics: Animals; Disease Models, Animal; Histones; Humans; Meningitis, Pneumococcal; Neuroprotective Agents; Rats; Streptococcus pneumoniae; Vitamin B 12

Hippocampus cells, responsible for learning and memory, are disturbed in Alzheimer's disease (AD), resulting in production of several inflammatory markers, such as neurexin 1 -neuroligin, cyclooxygenase-2 (COX-2), and caspase-3 proteins, used in measurement of AD's severity and development. Vitamin B. B. Vitamin B

Topics: Alzheimer Disease; Animals; Caspase 3; Cyclooxygenase 2; Disease Models, Animal; Hippocampus; Neuronal Plasticity; Rats; Scopolamine; Vitamin B 12; Vitamins

Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously observed in cblC, we uncovered reduced expression of target genes that encode ribosome protein subunits. We also identified specific phenotypes that we ascribe to deregulation of ribosome biogenesis impacting normal translation during development. These findings identify HCFC1/RONIN as transcriptional regulators of ribosome biogenesis during development and their mutation results in complex syndromes exhibiting aspects of both cblC and ribosomopathies.

Topics: Amino Acid Metabolism, Inborn Errors; Animals; Disease Models, Animal; Embryo, Mammalian; Female; Gene Expression Regulation, Developmental; Homocystinuria; Host Cell Factor C1; Humans; Male; Mice; Mice, Knockout; Mutation; Organelle Biogenesis; Oxidoreductases; Protein Biosynthesis; Protein Subunits; Repressor Proteins; Ribosomal Proteins; Ribosomes; Vitamin B 12; Vitamin B 12 Deficiency

TBX1 is a key regulator of pharyngeal apparatus (PhAp) development. Vitamin B12 (vB12) treatment partially rescues aortic arch patterning defects of Tbx1+/- embryos. Here, we show that it also improves cardiac outflow tract septation and branchiomeric muscle anomalies of Tbx1 hypomorphic mutants. At the molecular level, in vivo vB12 treatment enabled us to identify genes that were dysregulated by Tbx1 haploinsufficiency and rescued by treatment. We found that SNAI2, also known as SLUG, encoded by the rescued gene Snai2, identified a population of mesodermal cells that was partially overlapping with, but distinct from, ISL1+ and TBX1+ populations. In addition, SNAI2+ cells were mislocalized and had a greater tendency to aggregate in Tbx1+/- and Tbx1-/- embryos, and vB12 treatment restored cellular distribution. Adjacent neural crest-derived mesenchymal cells, which do not express TBX1, were also affected, showing enhanced segregation from cardiopharyngeal mesodermal cells. We propose that TBX1 regulates cell distribution in the core mesoderm and the arrangement of multiple lineages within the PhAp.

Topics: Animals; DiGeorge Syndrome; Disease Models, Animal; Gene Expression Regulation, Developmental; Mesoderm; Mice; T-Box Domain Proteins; Vitamin B 12

Parkinson's disease (PD) is characterized by a range of motor signs, but cognitive dysfunction is also observed. Supplementation with folic acid and vitamin B12 is expected to prevent cognitive impairment. To test this in PD, we promoted a lesion within the substantia nigra

Topics: Animals; Disease Models, Animal; Folic Acid; Parkinson Disease; Rats; Rotenone; Vitamin B 12

To determine whether B vitamin treatment was sufficient to reduce cognitive impairment associated with high-fat diets in rats and to modulate transketolase (TK) expression and activity.. To test this, we separated 50 rats into five groups that were either fed a standard chow diet (controls) or a high-fat diet (experimental groups H0, H1, H2, and H3). H0 group animals received no additional dietary supplementation, while H1 group animals were administered 100 mg/kg body weight (BW) thiamine, 100 mg/kg BW riboflavin, and 250 mg/kg BW niacin each day, and group H2 animals received daily doses of 100 mg/kg BW pyridoxine, 100 mg/kg BW cobalamin, and 5 mg/kg BW folate. Animals in the H3 group received the B vitamin regimens administered to both H1 and H2 each day.. Over time, group H0 exhibited greater increases in BW and fat mass relative to other groups. When spatial and memory capabilities in these animals were evaluated via conditioned taste aversion (CTA) and Morris Water Maze (MWM), we found B vitamin treatment was associated with significant improvements relative to untreated H0 controls. Similarly, B vitamin supplementation was associated with elevated TK expression in erythrocytes and hypothalamus of treated animals relative to those in H0 (P<0.05).. Together, these findings suggest B vitamin can modulate hypothalamic TK activity to reduce the severity of cognitive deficits in a rat model of obesity. As such, B vitamin supplementation may be a beneficial method for reducing cognitive dysfunction in clinical settings associated with high-fat diets.

Topics: Animals; Cognitive Dysfunction; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Folic Acid; Gene Expression Regulation, Enzymologic; Male; Morris Water Maze Test; Niacin; Pyridoxine; Rats; Riboflavin; Thiamine; Transketolase; Vitamin B 12; Vitamin B Complex

Trichinellosis is a zoonosis results from eating raw or semi-cooked meat of infected animals. Medicinal plants have been used lately as alternatives and/or combined therapies to resolve some drawbacks of the current regimens. This work analyzed the effect of albendazole monotherapy on Trichinella spiralis experimental infection (group A), in comparison to P. granatum and amygdalin extracts +cobalamin (group B), plus its combination with albendazole (group C). The study revealed that the extracts alone or combined with albendazole had an inferior effect to albendazole monotherapy regarding number of adult worms (40.83 ±3.82, 18.67 ±1.86 and 16.83 ±2.32, respectively). However, their effect was more obvious in muscle phase combined with albendazole, achieving the lower number of larvae/mL tissue homogenate (22.33 ±3.27 in comparison to 39.67 ±2.58 achieved by albendazole monotherapy). The extracts exerted a significant immunomodulatory effect by reducing the local CD4+ expression in the intestine as well as in muscle phase (1.15 ±0.25 and 3.80 ±0.65 in comparison to 4.97 ±0.37 and 12.20 ±0.87 with albendazole monotherapy, respectively). So, these extracts improved the therapeutic efficacy of albendazole, specifically in muscle phase and counteracted the inflammatory reaction caused by albendazole monotherapy, thus extensively alleviating the resulting myositis.

Topics: Albendazole; Amygdalin; Animals; Disease Models, Animal; Larva; Myositis; Plant Extracts; Pomegranate; Trichinella spiralis; Trichinellosis; Vitamin B 12

Epileptogenesis is a process that includes molecular and cellular events that foster the establishment of hyperexcitable neuronal networks in the brain. Pentylenetetrazole (PTZ)-induced kindling model in rodents has added new information to the knowledge about the pathogenesis of epilepsy and potential targets of novel antiepileptic agents. Evidence from animal and human studies suggests that oxidative and inflammatory events may play important roles in the initiation and maintaining seizure activities. Vitamin B12 has beneficial effects on the nervous system and presents pleiotropic effects with antioxidant and anti-inflammatory aspects. In the present study, we aimed to test the hypothesis that vitamin B12 and their combination with lamotrigine prevents behavioral deficits, hippocampal damage, oxidation, and proinflammatory state during epileptogenesis. Male rats were subjected to PTZ-induced epileptogenesis and pretreated with vitamin B12 (50 µg/kg) or Lamotrigine (LTG) (25 mg/kg) or B12 (50 µg/kg) + LTG (25 mg/kg). Vitamin B12 and its combination with LTG suppressed epileptogenesis and improved the performance of rats in the passive avoidance test. In addition, Vitamin B12 and its combination with LTG decreased levels of total oxidative status (TOS), oxidative stress index (OSI), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and increased total antioxidant status (TAS) levels in the hippocampus and cerebral cortex. Furthermore, it reduced hippocampal neuronal damage. Current findings support the beneficial actions of vitamin B12 due to its antioxidative and anti-inflammatory properties during the course of disease.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Hippocampus; Kindling, Neurologic; Lamotrigine; Male; Oxidative Stress; Pentylenetetrazole; Rats; Vitamin B 12

Despite advances in the understanding of the pathophysiology of ischemic stroke, therapeutic options remain limited. Methylcobalamin is an endogenous vitamin B12 that exhibits anti-inflammatory and antiapoptotic activities in a variety of diseases. In this study, we aimed to explore the neuroprotective effects and mechanism of action of methylcobalamin on cerebral ischemic injury in vitro and in vivo. The oxygen and glucose deprivation/reperfusion model and middle cerebral artery occlusion model were used to simulate cerebral ischemic injury in vitro and in vivo. Cell viability, inflammatory factors, cell apoptosis, and protein expression levels were determined. Further, autophagy flux and the cerebral infarction volume were measured. The modified neurological severity score, Longa score, Rotarod assay, and foot-fault test were used to evaluate behavioral changes and neurological deficits in rats. In vitro, methylcobalamin significantly increased cell viability, decreased lactate dehydrogenase release, attenuated inflammatory cytokine expression, reduced the apoptotic proportion, and enhanced autophagy flux after OGD treatment. In addition, Bcl-2 and Beclin1 expression levels and the LC3 II/I ratio were increased, whereas levels of Bax and cleaved caspase-3 were decreased. In vivo, methylcobalamin significantly reduced the cerebral infarction volume and neurological deficits in the rats. Furthermore, methylcobalamin activated the ERK1/2 pathway, whereas ERK1/2 inhibitors diminished its effects in the in vitro and in vivo models. In conclusion, methylcobalamin may exert a neuroprotective effect on cerebral ischemia and is a promising drug candidate for developing novel neuroprotective therapies.

Topics: Animals; Apoptosis; Autophagy; Brain Ischemia; Cell Line; Cell Survival; Cytokines; Disease Models, Animal; Infarction, Middle Cerebral Artery; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neuroprotective Agents; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Vitamin B 12

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

For peripheral nerve defects, autografting is considered the therapeutic gold-standard treatment. However, this procedure leads to donor-site morbidity. While various artificial conduits have been recently developed, treatment outcome has been demonstrated to be poorer than that with autograft. In our previous study using a rat sciatic nerve crush injury model, we demonstrated that the delivery of electrospun nanofiber sheets incorporating methylcobalamin (MeCbl sheet) to the local site of a peripheral nerve injury promoted peripheral nerve regeneration. In this study, we examined the effects of combination therapy using an MeCbl sheet and a polyglycolic acid tube filled with collagen sponge (PGA-c) in a rat model of a 10-mm sciatic nerve defect.. The rats were divided into 4 groups: (1) sham group (n = 10); (2) PGA-c group (n = 9), in which the gap was bridged using a PGA-c; (3) PGA-c/Sheet group (n = 8), in which the gap was bridged using a PGA-c wrapped in an MeCbl sheet; and (4) autograft group (n = 10), in which the gap was bridged using a reversed autograft. Motor and sensory function were evaluated, electrophysiological analysis was performed, and histomorphological findings were analyzed at 12 weeks postoperatively.. Compared with the PGA-c group, the PGA-c/Sheet group demonstrated significant improvements in the paw-withdrawal threshold expressed as a ratio relative to the contralateral side (mean difference [MD], -1.51; 95% confidence interval [CI], -2.64 to -0.38), terminal latency (MD, -0.86 ms; 95% CI, -1.56 to -0.16 ms), myelinated axon area (MD, 4.97%; 95% CI, 0.14% to 9.80%), proportion of myelinated axons (MD, 8.453%; 95% CI, 0.001% to 16.905%), and g-ratio (MD, -0.018; 95% CI, -0.035 to -0.001). No significant improvements were observed regarding motor function, electrophysiological findings with the exception of terminal latency, and axon numbers.. An MeCbl sheet in combination with a PGA-c significantly accelerated recovery with respect to sensory function, electrophysiology, and histomorphometry.. An MeCbl sheet may represent an effective therapeutic strategy for promoting regeneration across a nerve gap bridged with an artificial conduit.

Topics: Absorbable Implants; Animals; Axons; Collagen; Disease Models, Animal; Guided Tissue Regeneration; Male; Motor Activity; Nanofibers; Nerve Regeneration; Peripheral Nerve Injuries; Polyglycolic Acid; Rats; Sciatic Nerve; Vitamin B 12

Irradiation of food at 50-55 kGy results in a profound, chronic demyelinating-remyelinating disease of the entire central nervous system (CNS) in cats, named Feline Irradiated Diet-Induced Demyelination (FIDID). This study examines the early stages of demyelination and long-term consequences of demyelination and remyelination on axon survival or loss. Myelin vacuolation is the primary defect leading to myelin breakdown, demyelination then prompt remyelination in the spinal cord and brain. There is no evidence of oligodendrocyte death. The spinal cord dorsal column is initially spared yet eventually becomes severely demyelinated with subsequent loss of axons in the core and then surface of the fasciculus gracilis. However remyelination of the sub-pial axons in the dorsal column results in their protection. While there was a lack of biochemical evidence of Vitamin B12 deficiency, the pathological similarities of FIDID with sub-acute combined degeneration (SCD) led us to explore treatment with Vitamin B12. Treatment led to recovery or improvement in some cats and neurologic relapse on cessation of B12 therapy. While the reason that irradiated food is myelinotoxic in the cat remains unresolved, nonetheless the neuropathological changes match exactly what is seen in SCD and its models and provide an ideal model to study the cellular and molecular basis of remyelination.

Topics: Acute Disease; Animals; Axons; Cats; Chronic Disease; Demyelinating Diseases; Diet; Disease Models, Animal; Female; Macrophages; Male; Metabolome; Microglia; Myelin Sheath; Nerve Degeneration; Neuropathology; Radiation; Remyelination; Spinal Cord; Time Factors; Vitamin B 12

Bacterial meningitis (BM) causes apoptotic damage to the hippocampus and homocysteine (Hcy) accumulation to neurotoxic levels in the cerebrospinal fluid of children. The Hcy pathway controls bioavailability of methyl, and its homeostasis can be modulated by vitamin B. Eleven-day old rats were intracysternally infected with Streptococcus pneumoniae serotype 3, or saline, treated with B. B. Hcy is likely to play a central role in hippocampal damage in the infant rat model of BM, and B

Topics: Animals; Apoptosis; Disease Models, Animal; DNA Methylation; Hippocampus; Meningitis, Pneumococcal; Neuroprotective Agents; Promoter Regions, Genetic; Rats; Rats, Wistar; Streptococcus pneumoniae; Vitamin B 12

Peripheral nerve injury (PNI) is a frequent problem among young adults. Hopefully, regeneration can occur in PNI unlike central nervous system. If nerve cut is complete, gold standard treatment is surgery, but incomplete cuts have been tried to be treated by medicines. The aim of the study was to evaluate and compare clinical and histopathological outcomes of independent treatment of each of Vitamin B12 (B12) and Vitamin D3 (D3) and their combination on sciatic nerve injury in an experimental rat model.. Experimental animal study was performed after the approval of BEH Ethics Committee No. 2015/10. 32 rats were grouped into four (n=8) according to treatment procedures, such as Group 1 (controls with no treatment), Group 2 (intraperitoneal 1 mg/kg/day B12), Group 3 (oral 3500 IU/kg/week D3), Group 4 (intraperitoneal 1 mg/kg/day B12+ oral 3500 IU/kg/week D3). Sciatic Functional Index (SFI) and histopathological analysis were performed.. SFIs of Group 2, 3, 4 were statistically significantly higher than controls. Group 2 and 3 were statistically not different, however Group 4 was statistically significantly higher than others according to SFI. Axonal degeneration (AD) in all treatment groups were statistically significantly lower than in Group 1. AD in Group 4 was significantly lower than in Group 2 and 3; there was no significant difference between Group 2 and 3. There was no significant difference between Group 1,2 and 3 in Axonolysis (A). But A of Group 4 was significantly very much lower than all others. Oedema- inflammation (OE-I) in all treatment groups were significantly lower than in Group 1; there was no significant difference between Group 2 and group 4. OE-I in Group 2 and 4 were significantly lower than in Group 3. There were no significant differences between Group 1, 2 and 3 in damage level scores; score of Group 4 was significantly lower than of Group 1.. B12 and D3 were found effective with no statistically significant difference. But combined use of B12 and D3 improve nerve healing synergistically. We recommend combined use of B12 and D3 after PNI as soon as possible.. A perifériás idegsérülés (PNI) gyakori probléma fiatal felnőttek körében. Reménykeltő, hogy a központi idegrendszeri sérülésekkel ellentétben, PNI esetén lehetséges a regeneráció. Teljes idegszakadás esetén sebészi kezelés az aranystandard, részleges PNI esetén gyógy­szeres kezeléssel is érdemes próbálkozni. A vizsgálat célja a B12- és a D3-vitaminnal, illetve kombinációjukkal történő kezelés klinikai és hisztopatológiai eredményének értékelése és összehasonlítása volt kísérleti állatmodell (patkány) csípőidegének sérülése esetén.. Az etikai engedély (No. 2015/10) megszerzése után 32 kísérleti állatot osztottunk be a protokoll szerinti négy csoportba: a kontrollként szolgáló 1. csoport nem részesült kezelésben, a 2. csoport B12-vitamin-kezelésben (1 mg/ttkg/nap intraperitoneali­san), a 3. csoport D3-vitamin-kezelésben (3500 NE/ttkg/hét orálisan), míg a 4. csoport kombinált B12- és D3-vitamin-kezelésben (B12: 1 mg/ttkg/nap intraperitonealisan, D3: 3500 NE/ttkg/hét orálisan) részesült. Mértük a csípő­ideg funkcionális index pontszámot (Sciatic Functional Index, SFI), illetve hisztopatológiai értékelést végeztünk.. Az 1. csoport SFI-értékével összehasonlítva a 2., 3. és 4. csoport SFI-pontszáma szignifikánsan magasabb volt. A 2. és 3. csoport SFI-értékei nem különböztek, a 4. csoporté ezekhez képest szignifikánsan magasabb volt. Az axondegeneráció (AD) mértéke valamennyi kezelt csoport esetében szignifikánsan alacsonyabb volt, mint az 1. csoportnál. A 4. csoport AD-értéke szignifikánsan ala­csonyabb volt, mint a 2. és 3. csoporté. A 2. és 3. csoport AD-értékei nem különböztek. Az axonolysis (A) mértékében az 1., 2. és 3. csoport esetében nem volt szignifikáns kü­lönbség; velük összehasonlítva, a 4. csoport esetében szignifikánsan alacsonyabb volt az axonolysis. Valamennyi kezelt csoport esetében szignifikánsan alacsonyabb volt az oedema-gyulladás (OE-I) mértéke, mint az 1. csoportnál. A 2. és a 4. csoport között az OE-I nem különbözött szignifikánsan, a 2. és 4. csoport OE-I-értékei szignifikánsan alacsonyabbak voltak, mint a 3. csoporté. A sérülés mérté­két tekintve (damage level score) nem volt szignifikáns kü­lönb­ség az 1., 2. és 3. csoport között; a 4. csoport eseté­ben a sérülés mértéke szignifikánsan alacso­nyabb volt, mint az 1. csoport esetén.. A B12- és a D3-vitamin hatása között nem találtunk szignifikáns különbséget. A B12- és a D3-vitamin ideggyógyulást elősegítő hatása együttes alkal­mazás esetén szinergikusan érvényesül, ezért PNI után minél előbbi kombinált alkalmazásukat javasoljuk.

Topics: Animals; Cholecalciferol; Disease Models, Animal; Humans; Neuroprotective Agents; Peripheral Nerve Injuries; Rats; Sciatic Nerve; Vitamin B 12; Young Adult

Topics: Animals; Apoptosis; Brain-Derived Neurotrophic Factor; Cell Line, Tumor; Cerebral Palsy; Disease Models, Animal; Male; Memory; Mice; MicroRNAs; Motor Activity; Neurons; Neuroprotection; Neuroprotective Agents; Phosphatidylinositol 3-Kinase; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; RNA, Long Noncoding; Thiamine; Vitamin B 12

Oxidative stress has significant role in pathophysiology of any kind of depression through actions of free radicals, non-radical molecules, and unbalancing antioxidant systems in body. In the current study, antidepressant responses of fish oil (FO), Neptune krill oil (NKO), vitamin B12 (Vit B12), and also imipramine (IMP) as the reference were studied. Natural light was employed to induce stress in the animals followed by oral administration of the drugs for 14 days. The antidepressant effect was assessed by tail suspension test (TST) and forced swimming test (FST), antioxidant enzymes and oxidative stress markers were then measured in the brain tissue of the animals. The administration of FO and NKO could significantly reduce the immobility of the animals; while, increasing climbing and swimming time compared to the normal saline in CUS-control group in TST and FST, similarly to IMP but not with Vit B12. Vit B12 could not effect on SOD activity and H

Topics: Animals; Antidepressive Agents; Antioxidants; Depression; Depressive Disorder; Dietary Proteins; Disease Models, Animal; Euphausiacea; Fish Oils; Imipramine; Male; Mice; Oxidative Stress; Pilot Projects; Stress, Physiological; Stress, Psychological; Vitamin B 12

Hyperhomocysteinemia (Hhcy) is an independent risk factor for Alzheimer's disease (AD). Visual dysfunction is commonly found and is positively correlated with the severity of cognitive defects in AD patients. Our previous study demonstrated that Hhcy induces memory deficits with AD-like tau and amyloid-β (Aβ) pathologies in the hippocampus, and supplementation with folate and vitamin B12 (FB) prevents the Hhcy-induced AD-like pathologies in the hippocampus. Here, we investigated whether Hhcy also induces AD-like pathologies in the retina and the effects of FB. An Hhcy rat model was produced by vena caudalis injection of homocysteine for 14 days, and the effects of FB were assessed by simultaneous supplementation with FB in drinking water. We found that Hhcy induced vessel damage with Aβ and tau pathologies in the retina, while simultaneous supplementation with FB remarkably attenuated the Hhcy-induced tau hyperphosphorylation at multiple AD-related sites and Aβ accumulation in the retina. The mechanisms involved downregulation of amyloid precursor protein (APP), presenilin-1, beta-site APP-cleaving enzyme 1, and protein phosphatase-2A. Our data suggest that the retina may serve as a window for evaluating the effects of FB on hyperhomocysteinemia-induced Alzheimer-like pathologies.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Dietary Supplements; Disease Models, Animal; Folic Acid; Homocysteine; Hyperhomocysteinemia; Male; Rats, Sprague-Dawley; Retina; Retinal Vessels; tau Proteins; Vitamin B 12

Folate and vitamin B12 deficiency is associated with depletion of the major intracellular antioxidant glutathione, and oxidative stress is emerging as an etiological mechanism for colon cancer. Azoxymethane (AOM), a potent carcinogen, induces colon cancer in rats by causing pathophysiological changes and oxidative stress. We investigated the synergistic effect of folate and vitamin B12 supplementation against AOM-induced carcinogenesis and oxidative stress in rat colon. Adult male rats were distributed into four groups: 1) Basal diet only; 2) AOM injection (15 mg/kg once per week in weeks 5 and 6); 3) Folate and vitamin B12 supplemented diet; 4) Folate and B12 diet with AOM injection. After 16 weeks, rats were sacrificed, colon tissue dissected, indicators of oxidative stress were measured, and immunohistochemical and ultrastructural changes were evaluated. AOM-injected rats showed oxidative stress, evident by glutathione depletion, oxidation of cellular proteins, and DNA oxidative damage. AOM increased mucosal levels of antiapoptotic and proapoptotic proteins Bcl2 and Bax and caused ultrastructure changes in colonic cell organelles. Folate and vitamin B12 supplementation decreased the level of oxidative stress and ameliorated the cytotoxic effects of AOM. In this in vivo experimental model of colon cancer, folate and vitamin B12 supplementation combats carcinogen-induced oxidative stress.

Topics: Animals; Azoxymethane; Carcinogenesis; Colonic Neoplasms; Dietary Supplements; Disease Models, Animal; Folic Acid; Glutathione; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Vitamin B 12

Vitamins B9 (folate) and B12 act as methyl donors in the one-carbon metabolism which influences epigenetic mechanisms. We previously showed that an embryofetal deficiency of vitamins B9 and B12 in the rat increased brain expression of let-7a and miR-34a microRNAs involved in the developmental control of gene expression. This was reversed by the maternal supply with folic acid (3 mg/kg/day) during the last third of gestation, resulting in a significant reduction of associated birth defects. Since the postnatal brain is subject to intensive developmental processes, we tested whether further folate supplementation during lactation could bring additional benefits. Vitamin deficiency resulted in weaned pups (21 days) in growth retardation, delayed ossification, brain atrophy and cognitive deficits, along with unchanged brain level of let-7a and decreased expression of miR-34a and miR-23a. Whereas maternal folic acid supplementation helped restore the levels of affected microRNAs, it led to a reduction of structural and functional defects taking place during the perinatal/postnatal periods, such as learning/memory capacities. Our data suggest that a gestational B-vitamin deficiency could affect the temporal control of the microRNA regulation required for normal development. Moreover, they also point out that the continuation of folate supplementation after birth may help to ameliorate neurological symptoms commonly associated with developmental deficiencies in folate and B12.

Topics: Animals; Behavior, Animal; Dietary Supplements; Disease Models, Animal; Female; Folic Acid; Growth and Development; Homocysteine; Methylation; MicroRNAs; Nervous System; Pregnancy; Rats, Wistar; Vitamin B 12

Missense mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) cause the majority of familial and some sporadic forms of Parkinson's disease (PD). The hyperactivity of LRRK2 kinase induced by the pathogenic mutations underlies neurotoxicity, promoting the development of LRRK2 kinase inhibitors as therapeutics. Many potent and specific small-molecule LRRK2 inhibitors have been reported with promise. However, nearly all inhibitors are ATP competitive-some with unwanted side effects and unclear clinical outcome-alternative types of LRRK2 inhibitors are lacking. Herein we identify 5'-deoxyadenosylcobalamin (AdoCbl), a physiological form of the essential micronutrient vitamin B

Topics: Allosteric Regulation; Animals; Caenorhabditis elegans; Cobamides; Disease Models, Animal; Drosophila melanogaster; Drug Repositioning; HEK293 Cells; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Parkinson Disease; Rats; Vitamin B 12; Vitamin B Complex

This study aims to test the hypothesis that vitamin D deficiency can influence long-chain polyunsaturated fatty acid metabolism through alterations in the one-carbon cycle. Wistar rats (n = 8 per group) were given either a control (1,000 IU D3/kg diet) or a vitamin D deficient (VDD) (0 IU D3/kg diet) diet from pre-pregnancy to delivery. On day 20 of gestation, pregnant female rats were delivered by C-section to collect placenta and blood. VDD group demonstrated high serum parathyroid hormone, low serum phosphate, low plasma folate, higher plasma homocysteine, and higher plasma malondialdehyde levels (P < 0.05 for all) as compared to control. Lower protein levels of placental cystathionine-β-synthase enzyme (P < 0.05) were observed in the VDD group as compared to control. VDD group demonstrated higher placental mRNA levels of the enzymes phospholipase A

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Calcium; Cyclooxygenase 2; Cystathionine beta-Synthase; Disease Models, Animal; Female; Folic Acid; Gene Expression Regulation; Group II Phospholipases A2; Homocysteine; Humans; Malondialdehyde; Parathyroid Hormone; Phosphates; Placenta; Pregnancy; Rats; Rats, Wistar; Signal Transduction; Thromboxane B2; Vitamin B 12; Vitamin D Deficiency

Abnormal phospholipid metabolism is a major component of many neurodevelopmental disorders including autism. Oral administration of propionic acid (PPA) can produce behavioral abnormalities and biochemical features in rodents similar to those observed in autism and can thus be used as a model to understand impaired brain fatty acid metabolism in autism.. The present study was designed to understand alterations in phospholipid metabolism in the brain of a rodent model of autism and to explore omega-3 and vitamin B12 as remedies. Five groups of rats were selected: Group 1 was the control. Group 2 was the rodent model of autism treated with a neurotoxic dose of PPA. Group 3 was given vitamin B12 cobalamin (16.7 mg/kg/day) for 30 days after PPA treatment. Group 4 was given pharmaceutical grade Omega-3 (200 mg cholesterol free-DHA/kg body weight/day), a product of Madre lab, Germany, for 30 days after PPA treatment for 3 days. Group 5 was given a combined dose of ω-3 + Vitamin B12 for the same duration post-PPA treatment. Phospholipid levels and Phospholipase A2 were measured in the brain homogenates of all the groups. ELISA and western blotting were used to detect the cPLA2 protein level.. A significant decrease in phospholipid levels and a significant increase in cPLA2 were found in brain tissue of PPA-treated rats; however, both ω-3 and vitamin B12 were efficient in ameliorating the neurotoxic effect of PPA.. Both ω-3 and vitamin B12 may play a role in ameliorating impaired phospholipid metabolism in autism; however, proper clinical trials are needed.

Topics: Animals; Autistic Disorder; Cholesterol; Dietary Supplements; Disease Models, Animal; Fatty Acids, Omega-3; Humans; Hydrolysis; Lipid Metabolism; Male; Phospholipases A2; Phospholipids; Propionates; Rats; Vitamin B 12

The pathogenesis of multiple sclerosis (MS) begins with an infection by a bacterium from the class of bacteria that produce and utilize adenosylcobalamin (AdoCbl) and possess an adenosyl transferase enzyme (ATR); these bacteria are the exogenous antigens that cause MS. Human ATR is homologous to bacterial ATR and B cells produce anti-ATR antibodies as an autoimmune response thereby reducing the concentration of ATR and thus limiting production of AdoCbl, one of the two bioactive forms of vitamin B12. The next step in MS pathogenesis is a period of subclinical AdoCbl deficiency over a period of many years resulting in production of odd-carbon-number fatty acids that are incorporated into myelin rendering it antigenic. The next step in MS pathogenesis is breach of the blood brain barrier thereby introducing leukocytes into the brain's blood supply resulting in T cell attack of antigenic myelin. All epidemiological clusters are regions wherein the major agricultural products are legumes that produce a high percentage of odd-carbon-number fatty acids and contain symbiotic rhizobia type bacteria in root nodules and in the soil. This novel etiological hypothesis is called "multiple sclerosis due to adenosylcobalamin deficiency" (MS-AdoCbl). Creation of realistic animal models based on the MS-AdoCbl hypothesis is presented. Methods for testing predictions made by the MS-AdoCbl hypothesis are described.

Topics: Adenosine Triphosphate; Animals; Autoimmunity; B-Lymphocytes; Blood-Brain Barrier; Cobamides; Disease Models, Animal; Fatty Acids; Humans; Male; Methionine Adenosyltransferase; Mice; Models, Biological; Multiple Sclerosis; Rhizobium; T-Lymphocytes; Vitamin B 12

PGC-1α, a key regulator of energy metabolism, seems to be a relevant therapeutic target to rectify the energy deficit observed in heart failure (HF). Since our previous work has shown positive effects of cobalamin (Cb) on PGC-1α cascade, we investigate the protective role of Cb in pressure overload-induced myocardial dysfunction. Mice were fed with normal diet (ND) or with Cb and folate supplemented diet (SD) 3weeks before and 4weeks after transverse aortic constriction (TAC). At the end, left ventricle hypertrophy and drop of ejection fraction were significantly lower in SD mice than in ND mice. Alterations in mitochondrial oxidative capacity, fatty acid oxidation and mitochondrial biogenesis transcription cascade were markedly improved by SD. In SD-TAC mice, lower expression level of the acetyltransferase GCN5 and upregulation of the methyltransferase PRMT1 were associated with a lower protein acetylation and a higher protein methylation levels. This was accompanied by a sustained expression of genes involved in mitochondrial biogenesis transcription cascade (Tfam, Nrf2, Cox1 and Cox4) after TAC in SD mice, suggesting a preserved activation of PGC-1α; this could be at least partly due to corrected acetylation/methylation status of this co-activator. The beneficial effect of the treatment would not be due to an effect of Cb and folate on oxidative stress or on homocysteinemia, which were unchanged by SD. These results showed that Cb and folate could protect the failing heart by preserving energy status through maintenance of mitochondrial biogenesis. It reinforces the concept of a metabolic therapy of HF.

Topics: Animals; Biomarkers; Cells, Cultured; Dietary Supplements; Disease Models, Animal; Energy Metabolism; Folic Acid; Heart Failure; Hyperhomocysteinemia; Mice; Mitochondria, Heart; Models, Biological; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Oxidation-Reduction; Oxidative Stress; Vitamin B 12

In the present study, we investigated the effects of microinjection of vitamin B

Topics: Analgesics; Animals; CA1 Region, Hippocampal; Catheters, Indwelling; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Facial Pain; Formaldehyde; Male; Maze Learning; Memory Disorders; Microinjections; Motor Activity; Naloxone; Narcotic Antagonists; Nootropic Agents; Rats, Wistar; Scopolamine; Vibrissae; Vitamin B 12

Foley et al. (2014) published their findings in this journal on the role of prenatal exposure to propionic acid (PPA) and behavioral outcomes in treated rat pups. The authors show that PPA treated pups displayed subtle differences in behavior including nest seeking, novel object recognition, and locomotor activity. Others have previously proposed that PPA infusion in rat could represent a valid animal model of ASD since many of the diagnostic criteria for the disorder spectrum manifest under such conditions. A pathogenic makeover of gut microbiome to facilitate the growth of microbes capable of producing PPA, like Clostridia species, has been proposed as an infectious contributing etiology to the PPA model of ASD, however the reason for this pathogenic microbial overgrowth is not clear. This discussion highlights a previously identified novel environmental factor (i.e., nitrous oxide, N

Topics: Animals; Animals, Newborn; Autism Spectrum Disorder; Disease Models, Animal; Environment; Nitrous Oxide; Propionates; Rats; Vitamin B 12

Reports indicate that during pregnancy hypertension is known to have long term adverse effects both in the mother and offspring. However, the effect of maternal micronutrient supplementation on this association of in utero exposure and risk of non-communicable diseases in the later life remains unclear. The present study examines the effect of maternal micronutrient and omega-3 fatty acid supplementation either individual or in combination on cardiometabolic risk factors both in the mother and offspring using an animal model of hypertension.. Pregnant Wistar rats were randomly assigned to the following groups; control, PIH (Pregnancy induced hypertention) Induced, PIH+vitamin B12, PIH+ folic acid, PIH+omega-3 fatty acids and PIH+combined smicronutrient supplementation (vitamin B12+folic acid + omega-3 fatty acids). The dams and their offspring were shifted to a control diet after delivery and the offspring continued on these diets till 3mo of age. Hypertension during pregnancy was induced using l-Nitroarginine methylester (50mg/kgbody weight/day).. Omega-3 fatty acid supplementation during pregnancy demonstrated lower levels (p<0.05) of plasma cholesterol while a combined supplementation of folic acid, vitamin B12 and omega 3 fatty acids demonstrated lower (p<0.05) triglyceride levels as compared to PIH induced dams. PIH induction increased (p<0.01) the triglyceride levels in the offspring at 3mo of age and maternal supplementation of either individual or combined micronutrients demonstrated lower (p<0.01) triglyceride levels.. Our findings have implications for planning intervention studies in women with pregnancy induced hypertension.

Topics: Animals; Blood Glucose; Cholesterol; Dietary Supplements; Disease Models, Animal; Fatty Acids, Omega-3; Female; Hypertension, Pregnancy-Induced; Pregnancy; Rats; Triglycerides; Vitamin B 12

Hypobaric hypoxia (HH) leads to reduced oxygen delivery to brain. It could trigger cognitive dysfunction and increase the risk of dementia including Alzheimer's disease (AD). The present study was undertaken in order to examine whether B vitamins (B6, B12, folate, and choline) could exert protective effects on hypoxia-induced memory deficit and AD related molecular events in mice. Adult male Kunming mice were assigned to five groups: normoxic control, hypoxic model (HH), hypoxia+vitamin B6/B12/folate (HB), hypoxia+choline (HC), hypoxia+vitamin B6/B12/folate+choline (HBC). Mice in the hypoxia, HB, HC, and HBC groups were exposed to hypobaric hypoxia for 8 h/day for 28 days in a decompression chamber mimicking 5500 meters of high altitude. Spatial and passive memories were assessed by radial arm and step-through passive test, respectively. Levels of tau and glycogen synthase kinase (GSK)-3β phosphorylation were detected by western blot. Homocysteine (Hcy) concentrations were determined using enzymatic cycling assay. Mice in the HH group exhibited significant spatial working and passive memory impairment, increased tau phosphorylation at Thr181, Ser262, Ser202/Thr205, and Ser396 in the cortex and hippocampus, and elevated Hcy levels compared with controls. Concomitantly, the levels of Ser9-phosphorylated GSK-3β were significantly decreased in brain after hypoxic treatment. Supplementations of vitamin B6/B12/folate+choline could significantly ameliorate the hypoxia-induced memory deficits, observably decreased Hcy concentrations in serum, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites through upregulating inhibitory Ser9-phosphorylated GSK-3β. Our finding give further insight into combined neuroprotective effects of vitamin B6, B12, folate, and choline on brain against hypoxia.

Topics: Animals; Avoidance Learning; Cerebral Cortex; Choline; Dietary Supplements; Disease Models, Animal; Folic Acid; Glycogen Synthase Kinase 3 beta; Hippocampus; Homocysteine; Hypoxia; Male; Maze Learning; Memory; Memory Disorders; Mice; Phosphorylation; tau Proteins; Vitamin B 12; Vitamin B 6; Vitamin B Complex

Vitamin B

Topics: Animals; Cerebral Cortex; Dietary Supplements; Disease Models, Animal; Fatty Acids, Omega-3; Gene Expression; Hippocampus; Malondialdehyde; Nerve Growth Factor; Random Allocation; Rats, Wistar; Vascular Endothelial Growth Factor A; Vitamin B 12; Vitamin B 12 Deficiency

Pathological conditions caused by reduced dosage of a gene, such as gene haploinsufficiency, can potentially be reverted by enhancing the expression of the functional allele. In practice, low specificity of therapeutic agents, or their toxicity reduces their clinical applicability. Here, we have used a high throughput screening (HTS) approach to identify molecules capable of increasing the expression of the gene Tbx1, which is involved in one of the most common gene haploinsufficiency syndromes, the 22q11.2 deletion syndrome. Surprisingly, we found that one of the two compounds identified by the HTS is the vitamin B12. Validation in a mouse model demonstrated that vitamin B12 treatment enhances Tbx1 gene expression and partially rescues the haploinsufficiency phenotype. These results lay the basis for preclinical and clinical studies to establish the effectiveness of this drug in the human syndrome.

Topics: Animals; DiGeorge Syndrome; Disease Models, Animal; Gene Expression Regulation, Developmental; Haploinsufficiency; High-Throughput Screening Assays; Mice; Mutation; T-Box Domain Proteins; Vitamin B 12

Nitrous oxide (N₂O) toxicity can result in myelin loss and hyperhomocysteinemia similar to cobalamin (Cbl) deficiency. Studies on N₂O exposure can help in understanding the mechanism of demyelination. In view of paucity of studies on N₂O toxicity in rats this study was undertaken. Six male wistar rats were exposed to 1.5L/min N₂O with 1:1 O₂ for 90 min daily for 1 month. After 1-month exposure blood homocysteine (HCY) and oxidative stress parameters glutathione (GSH) and total antioxidant capacity (TAC) were measured. Brain and spinal cord was subjected to histopathological examination. The neurobehavioral changes, oxidative stress parameters and histopathological changes were correlated with serum B12 and HCY level. After 1-month exposure, the rats appeared sluggish, lethargic and developed predominantly hind limb weakness for 1-1.5h. In the exposed group, the total distance traveled (2001.66 ± 118.27 cm; p=0.037), time moving (80.16 ± 5.7s; p=0.028), number of rearing (10.33 ± 1.45; p=0.014) and grip strength (1042.40 ± 51.3N; p=0.041) were significantly decreased whereas, resting time significantly increased (219.83 ± 5.7s; p=0.030) compared to controls. Serum HCY level was significantly increased (20.56 ± 1.296 μm/ml; p=0.0007) in the exposed group. However, serum B12 and folic acid levels were not significantly different. GSH significantly decreased (2.21 ± 0.60 mg/dl; p=0.018) along with TAC (0.76 ± 0.16 Trolox_Eq_mmol/l; p=0.036). The histopathological studies revealed shrinkage and vacuolation of neurons in cerebral cortex, focal myelin loss, vacuolation in subcortical white matter and spinal cord. N₂O exposure results in behavioral alterations, hyperhomocysteinemia, cortical and spinal cord demyelination which were associated with decrease GSH and TAC highlighting pathophysiological role of oxidative stress.

Topics: Animals; Antioxidants; Behavior, Animal; Brain; Demyelinating Diseases; Disease Models, Animal; Glutathione; Homocysteine; Hyperhomocysteinemia; Male; Motor Activity; Muscle Strength; Nitrous Oxide; Oxidative Stress; Rats, Wistar; Spinal Cord; Time Factors; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Animals; Cardiovascular Diseases; Disease Models, Animal; Folic Acid; Homocysteine; Humans; Hypercholesterolemia; Hyperhomocysteinemia; Methylenetetrahydrofolate Reductase (NADPH2); Oxidative Stress; Risk Factors; Signal Transduction; Vitamin B 12

High-dose of methylcobalamin promotes nerve regeneration in rats with acrylamide neuropathy. A double-blind controlled trial suggested that high-dose methylcobalamin could increase compound muscle action potentials in patients with amyotrophic lateral sclerosis (ALS). A large-scale extended period human trial is now on-going in ALS (Clinicaltrial.govNCT00444613). We attempted to study whether high-dose methylcobalamin can improve symptoms or retard progression of motor dysfunction in the wobbler mouse model of ALS.. After initial diagnosis of the disease at the postnatal age of 3-4 weeks, wobbler mice received methylcobalamin (3 or 30 mg/kg, n=10/group) or vehicle (n=10), daily for 4 weeks by intraperitoneal administration in a blinded fashion. We compared clinical symptoms and pathological changes among all groups. Vitamin B12 concentrations were measured in the serum, the skeletal muscle and the spinal cord of three groups (n=5/group).. In comparison with vehicle, mice treated with ultra-high dose (30 mg/kg) of methylcobalamin significantly inhibited muscle weakness and contracture in the forelimb, and increased the weight of the bicep muscles and the number of musculocutaneous nerves. Methylcobalamin-treated mice significantly elevated vitamin B12 concentrations of the serum, the bicep muscle and the spinal cord compared to vehicle.. Our results suggest that treatment with methylcobalamin could delay progression of motor symptoms and neuropathological changes in wobbler mouse motor neuron disease if very high doses are used.

Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Muscle Strength; Neuroprotective Agents; Vitamin B 12

The antinociceptive effect of cyanocobalamin (Vit B12) has been reported in animal models and human studies. Our previous study showed the effect of Vit B12 on morphine tolerance. The dependence and tolerance were induced in male mice using subcutaneous morphine injections, 3 times a day (50, 50 and 75 mg/kg/day) for 3 days. Mice also received Vit B12 (100, 250 and 500 µg/kg), clonidine, memantine and saline intraperitoneally before morphine administration. On fourth day mice received only 7 mg /kg morphine just before tail-flick test. To determine the expression of morphine dependence and tolerance, all compounds were injected once intraperitoneally on the day of experiment. The tolerance was evaluated by the tail-flick test. The effect of Vit B12 and other agents on dependence were evaluated by counting the number of jumps (induced by naloxone 5 mg/kg). Co-administration of Vit B12 (100-500 µg/kg) and morphine in 3 days reduced the development of tolerance to morphine analgesic effect (8.2±0.5 and 7.83±0.5 s. vs. normal saline, 3.57±0.3 s). Repeated administration of Vit B12, also, diminished the reduced naloxane withdrawal signs of naloxone withdrawal test (100-500 µg/kg: 5±1.9 and 1.2±0.8 jumps vs. normal saline 72.6±12.2). However, Vit B12 had no effect on the expression of morphine tolerance and physical dependence. It is concluded that co-administration of Vit B12 and morphine could reduce tolerance to analgesic effect of morphine chronic administration and also reduce its withdrawal symptoms.

Topics: Analgesics, Opioid; Animals; Clonidine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Male; Memantine; Mice; Morphine; Morphine Dependence; Naloxone; Pain; Vitamin B 12

The membrane receptor (TCblR/CD320) for transcobalamin (TC)-bound cobalamin (Cbl) facilitates the cellular uptake of Cbl. A genetically modified mouse model involving ablation of the CD320 gene was generated to study the effects on cobalamin homeostasis. The nonlethal nature of this knockout and the lack of systemic cobalamin deficiency point to other mechanisms for cellular Cbl uptake in the mouse. However, severe cobalamin depletion in the central nervous system (CNS) after birth (P<0.01) indicates that TCblR is the only receptor responsible for Cbl uptake in the CNS. Metabolic Cbl deficiency in the brain was evident from the increased methylmalonic acid (P<0.01-0.04), homocysteine (P<0.01), cystathionine (P<0.01), and the decreased S-adenosylmethionine/S-adenosyl homocysteine ratio (P<0.01). The CNS pathology of Cbl deficiency seen in humans may not manifest in this mouse model; however, it does provide a model with which to evaluate metabolic pathways and genes affected.

Topics: Animals; Biological Transport, Active; Brain; Central Nervous System Diseases; Disease Models, Animal; Female; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Pregnancy; Receptors, Cell Surface; Vitamin B 12; Vitamin B 12 Deficiency

The lack of small animal models for hepatitis C virus has impeded the discovery and development of anti-HCV drugs. HCV-IRES plays an important role in HCV gene expression, and is an attractive target for antiviral therapy. In this study, we report a zebrafish model with a biscistron expression construct that can co-transcribe GFP and HCV-core genes by human hepatic lipase promoter and zebrafish liver fatty acid binding protein enhancer. HCV core translation was designed mediated by HCV-IRES sequence and gfp was by a canonical cap-dependent mechanism. Results of fluorescence image and in situ hybridization indicate that expression of HCV core and GFP is liver-specific; RT-PCR and Western blotting show that both core and gfp expression are elevated in a time-dependent manner for both transcription and translation. It means that the HCV-IRES exerted its role in this zebrafish model. Furthermore, the liver-pathological impact associated with HCV-infection was detected by examination of gene markers and some of them were elevated, such as adiponectin receptor, heparanase, TGF-β, PDGF-α, etc. The model was used to evaluate three clinical drugs, ribavirin, IFNα-2b and vitamin B12. The results show that vitamin B12 inhibited core expression in mRNA and protein levels in dose-dependent manner, but failed to impact gfp expression. Also VB12 down-regulated some gene transcriptions involved in fat liver, liver fibrosis and HCV-associated pathological process in the larvae. It reveals that HCV-IRES responds to vitamin B12 sensitively in the zebrafish model. Ribavirin did not disturb core expression, hinting that HCV-IRES is not a target site of ribavirin. IFNα-2b was not active, which maybe resulted from its degradation in vivo for the long time. These findings demonstrate the feasibility of the zebrafish model for screening of anti-HCV drugs targeting to HCV-IRES. The zebrafish system provides a novel evidence of using zebrafish as a HCV model organism.

Topics: Animals; Antiviral Agents; Biomarkers; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation, Viral; Genes, Reporter; Green Fluorescent Proteins; Hepacivirus; Hepatitis C; Host-Pathogen Interactions; Humans; Interferon alpha-2; Interferon-alpha; Larva; Liver; Mutant Chimeric Proteins; Recombinant Proteins; Ribavirin; RNA, Messenger; Viral Core Proteins; Vitamin B 12; Zebrafish

Lupus flares occur when genetically predisposed individuals encounter appropriate environmental agents. Current evidence indicates that the environment contributes by inhibiting T cell DNA methylation, causing overexpression of normally silenced genes. DNA methylation depends on both dietary transmethylation micronutrients and ERK-regulated DNA methyltransferase 1 (DNMT-1) levels. We used transgenic mice to study the effect of interactions between diet, DNMT-1 levels, and genetic predisposition on the development and severity of lupus.. A doxycycline-inducible ERK defect was bred into lupus-resistant (C57BL/6) and lupus-susceptible (C57BL/6 × SJL) mouse strains. Doxycycline-treated mice were fed a standard commercial diet for 18 weeks and then switched to a transmethylation micronutrient-supplemented (MS) or -restricted (MR) diet. Disease severity was assessed by examining anti-double-stranded DNA (anti-dsDNA) antibody levels, the presence of proteinuria and hematuria, and by histopathologic analysis of kidney tissues. Pyrosequencing was used to determine micronutrient effects on DNA methylation.. Doxycycline induced modest levels of anti-dsDNA antibodies in C57BL/6 mice and higher levels in C57BL/6 × SJL mice. Doxycycline-treated C57BL/6 × SJL mice developed hematuria and glomerulonephritis on the MR and standard diets but not the MS diet. In contrast, C57BL/6 mice developed kidney disease only on the MR diet. Decreasing ERK signaling and methyl donors also caused demethylation and overexpression of the CD40lg gene in female mice, consistent with demethylation of the second X chromosome. Both the dietary methyl donor content and the duration of treatment influenced methylation and expression of the CD40lg gene.. Dietary micronutrients that affect DNA methylation can exacerbate or ameliorate disease in this transgenic murine lupus model, and contribute to lupus susceptibility and severity through genetic-epigenetic interactions.

Topics: Animals; Antibodies, Antinuclear; Betaine; CD40 Ligand; Choline; Coenzymes; Diet; Disease Models, Animal; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Epigenesis, Genetic; Folic Acid; Gene Silencing; Genetic Predisposition to Disease; Lupus Erythematosus, Systemic; Methionine; Mice; Mice, Inbred C57BL; Mice, Transgenic; Micronutrients; Riboflavin; Vitamin B 12; Vitamin B 6; Zinc

Spinal motoneuron neuroprotection by vitamin B12 was previously reported; the present study was carried out to evaluate neuroprotectivity in the dorsal root ganglion sensory neuron.. In present study thirty-six Wister-Albino rats (aged 8-9 weeks and weighing 200-250 g) were tested. The animals were randomly divided into 6 groups which every group contained 6 rats. Group A: received normal saline (for 42 days); Group B: vitamin B12 was administered (0.5 mg/kg/day for 21 days); Group C: received vitamin B12 (1 mg/kg/day for 21 days); Group D: received vitamin B12 (0.5 mg/kg/day for 42 days); Group E; received vitamin B12 (1 mg/kg/day for 42 days); Group F; received no treatment. The L5 Dorsal Root Ganglion (DRG) neurons count compared to the number of left and right neurons .Furthermore, DRG sensory neurons for regeneration were evaluated 21 or 42 days after injury (each group was analyzed by One-Way ANOVA test).. (1): The comparison of left crushed neurons (LCN) number with right non-crushed neurons in all experimental groups (B, C, D and C), indicating a significant decline in their neurons enumeration (p<0/05). (2): The comparison of test group's LCN with the control group's LCN revealed a significant rise in the number of experimental group neurons (p<0/05). (3): Moreover, comparing the number of right neurons in experimental groups with the number of neurons in crushed neurons indicated that the average number of right neurons showed a significant increase in experimental groups (p<0/05).. Consequently, the probability of nerve regeneration will be increased by the increment of the administered drug dosage and duration. On the other hand, the regeneration and healing in Dorsal Spinal Ganglion will be improved by increase of administration time and vitamin B12 dose, indicating that such vitamin was able to progress recovery process of peripheral nerves damage in experimental rats. Finally, our results have important implications for elucidating the mechanisms of nerve regeneration. Moreover, the results showed that vitamin B12 had a proliferative effect on the dorsal root ganglion sensory neuron.. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7395141841009256.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Ganglia, Spinal; Male; Nerve Crush; Neurogenesis; Neuroprotective Agents; Rats; Rats, Wistar; Sciatic Nerve; Sciatic Neuropathy; Time Factors; Vitamin B 12

The administration of carbon tetrachloride (CCl(4)) has been established as a model of toxin-induced acute and chronic liver injury. In the present study, we investigate the progression of the biochemical response to acute CCl(4)-induced liver injury, capturing metabolic variations during both toxic insult and regeneration using NMR-based metabonomic analysis of liver tissue and plasma. A single dose of CCl(4) (1 mL/kg BW) was intraperitoneally administered to male Wister rats sacrificed every 12h up to 72 h post treatment, while healthy animals served as controls. Acquired (1)H NMR spectra of liver tissue extracts and plasma samples were explored with multivariate analysis and the resulted models were correlated with conventional biochemical and histopathological indices of toxicity for monitoring the progression of experimental injury. The metabonomic analysis resulted in discrimination between the subjects under toxic insult (up to 36 h) and those at the regenerative phase (peaked at 48 h). At 72 h normalization of liver's pathology similar to the controls group was apparent. Principal component analysis (PCA) trajectories highlighted the time points of the greater degree of toxic insult and the regenerative state. A number of metabolites such as glucose, lactate, choline, formate exhibited variations suggesting CCl(4) induced impairment in essential biochemical pathways as energy metabolism, lipid biosynthesis and transmethylation reactions. The latter provides new evidence of B12 and folate pathways deficiency, indicative of new mechanistic implications possibly by direct inhibition of B12 dependent enzymes by the chlorinated radicals of CCl(4) metabolism.

Topics: Acute Lung Injury; Animals; Carbon Tetrachloride; Disease Models, Animal; Energy Metabolism; Folic Acid; Injections, Intraperitoneal; Lipids; Liver Regeneration; Magnetic Resonance Spectroscopy; Male; Metabolomics; Mice; Multivariate Analysis; Principal Component Analysis; Rats; Rats, Wistar; Time Factors; Vitamin B 12

Diets rich in methyl-donating compounds, including folate, can provide protection against neural tube defects, but their role in preventing craniofacial defects is less clear. Mice deficient in Twisted gastrulation (TWSG1), an extracellular modulator of bone morphogenetic protein signaling, manifest both midline facial defects and jaw defects, allowing study of the effects of methyl donors on various craniofacial defects in an experimentally tractable animal model. The goal of this study was to examine the effects of maternal dietary supplementation with methyl donors on the incidence and type of craniofacial defects among Twsg1(-/-) offspring. Nulliparous and primiparous female mice were fed an NIH31 standard diet (control) or a methyl donor supplemented (MDS) diet (folate, vitamin B-12, betaine, and choline). Observed defects in the pups were divided into those derived mostly from the first branchial arch (BA1) (micrognathia, agnathia, cleft palate) and midline facial defects in the holoprosencephaly spectrum (cyclopia, proboscis, and anterior truncation). In the first pregnancy, offspring of mice fed the MDS diet had lower incidence of BA1-derived defects (12.8% in MDS vs. 32.5% in control; P = 0.02) but similar incidence of midline facial defects (6.4% in MDS vs. 5.2% in control; P = 1.0). Increased maternal parity was independently associated with increased incidence of craniofacial defects after adjusting for diet (from 37.7 to 59.5% in control, P = 0.04 and from 19.1 to 45.3% in MDS, P = 0.045). In conclusion, methyl donor supplementation shows protective effects against jaw defects, but not midline facial defects, and increased parity can be a risk factor for some craniofacial defects.

Topics: Animals; Betaine; Choline; Craniofacial Abnormalities; Dietary Supplements; Disease Models, Animal; Face; Female; Folic Acid; Gastrulation; Jaw; Male; Methylation; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Parity; Pregnancy; Proteins; Risk Factors; Vitamin B 12; Vitamin B Complex

Vascular dementia (VaD) is the second leading cause of dementia behind Alzheimer's disease (AD) and is a frequent comorbidity with AD, estimated to occur in as many as 40% of AD patients. The causes of VaD are varied and include chronic cerebral hypoperfusion, microhemorrhages, hemorrhagic infarcts, or ischemic infarcts. We have developed a model of VaD by inducing hyperhomocysteinemia (HHcy) in wild-type mice. By placing wild-type mice on a diet deficient in folate, B6, and B12 and supplemented with excess methionine, we induced a moderate HHcy (plasma level homocysteine 82.93 ± 3.561 μmol). After 11 weeks on the diet, the hyperhomocysteinemic mice showed a spatial memory deficit as assessed by the 2-day radial-arm water maze. Also, magnetic resonance imaging and subsequent histology revealed significant microhemorrhage occurrence. We found neuroinflammation induced in the hyperhomocysteinemic mice as determined by elevated interleukin (IL)-1β, tumor necrosis factor (TNF)α, and IL-6 in brain tissue. Finally, we found increased expression and increased activity of the matrix metalloproteinase 2 (MMP2) and MMP9 systems that are heavily implicated in the pathogenesis of cerebral hemorrhage. Overall, we have developed a dietary model of VaD that will be valuable for studying the pathophysiology of VaD and also for studying the comorbidity of VaD with other dementias and other neurodegenerative disorders.

Topics: Animals; Brain; Cerebral Hemorrhage; Dementia, Vascular; Diet; Disease Models, Animal; Folic Acid; Humans; Hyperhomocysteinemia; Inflammation; Interleukin-1beta; Interleukin-6; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Memory Disorders; Methionine; Mice; Mice, Inbred C57BL; Vitamin B 12; Vitamin B 6

The pathogenesis of cobalamin (Cbl)-deficient (Cbl-D) neuropathy is not clear, nor is the role of prions (PrP(C)) in myelin maintenance. However, as it is known that Cbl deficiency damages myelin by increasing tumor necrosis factor (TNF)-α and decreasing epidermal growth factor (EGF) levels in rat spinal cord (SC), and that TNF-α and EGF regulate PrP(C) expression in vitro, we investigated whether Cbl deficiency modifies SC PrP(C) and PrP(C)-mRNA levels in Cbl-D rats. PrP(C) levels had increased by the time myelin lesions appeared. This increase was mediated by excess myelinotoxic TNF-α and prevented by EGF, which proved to be as effective as Cbl in preventing Cbl deficiency-induced lesions. There were no significant changes in hepatic PrP(C) levels of Cbl-D rats. Anti-octapeptide repeat (OR) region antibodies normalized SC myelin morphology. Cbl deficiency greatly reduced SC PrP(C)-mRNA levels, which were subsequently increased by Cbl and EGF. Cbl deficiency-induced excess OR is myelin-damaging, but new PrP(C) synthesis is a common effect of different myelinotrophic agents.

Topics: Analysis of Variance; Animals; Central Nervous System; Copper; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gastrectomy; Gene Expression Regulation; Laparotomy; Male; Nerve Fibers, Myelinated; Prions; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Tumor Necrosis Factor-alpha; Vitamin B 12; Vitamin B 12 Deficiency

Metanx is a product containing L-methylfolate, pyridoxal 5'-phosphate, and methylcobalamin for management of endothelial dysfunction. Metanx ingredients counteract endothelial nitric oxide synthase uncoupling and oxidative stress in vascular endothelium and peripheral nerve. This study evaluates Metanx on diabetic peripheral neuropathy in ZDF rats, a model of type 2 diabetes. Metanx was administered to 15-week-old ZDF and ZDF lean rats at either 4.87 mg ⋅ kg(-1) ⋅ day(-1) (a body weight-based equivalent of human dose) or 24.35 mg ⋅ kg(-1) ⋅ day(-1) by oral gavage two times a day for 4 weeks. Both doses alleviated hind limb digital sensory, but not sciatic motor, nerve conduction slowing and thermal and mechanical hypoalgesia in the absence of any reduction of hyperglycemia. Low-dose Metanx increased intraepidermal nerve fiber density but did not prevent morphometric changes in distal tibial nerve myelinated fibers. Metanx treatment counteracted endothelial nitric oxide synthase uncoupling, inducible nitric oxide synthase upregulation, and methylglyoxal-derived advanced glycation end product, nitrotyrosine, and nitrite/nitrate accumulation in the peripheral nerve. In conclusion, Metanx, at a body weight-based equivalent of human dose, increased intraepidermal nerve fiber density and improved multiple parameters of peripheral nerve function in ZDF rats. Clinical studies are needed to determine if Metanx finds use in management of diabetic peripheral neuropathy.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Disease Models, Animal; Folic Acid; Hyperalgesia; Male; Nerve Fibers; Neural Conduction; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Pyridoxal Phosphate; Rats; Rats, Zucker; Sciatic Nerve; Tibial Nerve; Tyrosine; Vitamin B 12

Neural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk.. A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case-control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects.. Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003-0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing.. To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive correction. We have produced a ranked list of variants with the strongest association signals. Variants in the highest rank of associations are likely to include true associations and should be high priority candidates for further study of NTD risk.

Topics: Animals; Case-Control Studies; Disease Models, Animal; Female; Folic Acid; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Humans; Ireland; Mice; Neural Tube Defects; Polymorphism, Single Nucleotide; Risk Factors; Vitamin B 12

Late-onset Alzheimer's disease seems to be a multi-factorial disease with both genetic and non-genetic, environmental, possible causes. Recently, epigenomics is achieving a major role in Alzheimer's research due to its involvement in different molecular pathways leading to neurodegeneration. Among the different epigenetic modifications, DNA methylation is one of the most relevant to the disease. We previously demonstrated that presenilin1 (PSEN1), a gene involved in amyloidogenesis, is modulated by DNA methylation in neuroblastoma cells and Alzheimer's mice in an experimental model of nutritionally altered one-carbon metabolism. This alteration, obtained by nutritional deficiency of B vitamins (folate, B12 and B6) hampered S-adenosylmethionine (SAM)-dependent methylation reactions. The aim of the present paper was to investigate the regulation of DNA methylation machinery in response to hypomethylating (B vitamin deficiency) and hypermethylating (SAM supplementation) alterations of the one-carbon metabolism. We found that DNA methylases (DNMT1, 3a and 3b) and a putative demethylase (MBD2) were differently modulated, in line with the previously observed changes of PSEN1 methylation pattern in the same experimental conditions.

Topics: Alzheimer Disease; Analysis of Variance; Animals; Carbon; Cell Line; Disease Models, Animal; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA-Binding Proteins; Epigenomics; Female; Folic Acid; Humans; Male; Methylation; Mice; Mice, 129 Strain; Mice, Transgenic; S-Adenosylmethionine; Vitamin B 12; Vitamin B 6; Vitamin B Complex; Vitamin B Deficiency

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

Elevated plasma levels of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), are associated with osteoporosis. A decrease in bone blood flow is a potential cause of compromised bone mechanical properties. Therefore, we hypothesized that HHcy decreases bone blood flow and biomechanical properties. To test this hypothesis, male Sprague-Dawley rats were treated with Hcy (0.67 g/L) in drinking water for 8 weeks. Age-matched rats served as controls. At the end of the treatment period, the rats were anesthetized. Blood samples were collected from experimental or control rats. Biochemical turnover markers (body weight, Hcy, vitamin B(12), and folate) were measured. Systolic blood pressure was measured from the right carotid artery. Tibia blood flow was measured by laser Doppler flow probe. The results indicated that Hcy levels were significantly higher in the Hcy-treated group than in control rats, whereas vitamin B(12) levels were lower in the Hcy-treated group compared with control rats. There was no significant difference in folate concentration and blood pressure in Hcy-treated versus control rats. The tibial blood flow index of the control group was significantly higher (0.78 ± 0.09 flow unit) compared with the Hcy-treated group (0.51 ± 0.09). The tibial mass was 1.1 ± 0.1 g in the control group and 0.9 ± 0.1 in the Hcy-treated group. The tibia bone density was unchanged in Hcy-treated rats. These results suggest that Hcy causes a reduction in bone blood flow, which contributes to compromised bone biomechanical properties.

Topics: Animals; Biomarkers; Biomechanical Phenomena; Blood Pressure; Bone Density; Bone Remodeling; Disease Models, Animal; Folic Acid; Homocysteine; Hyperhomocysteinemia; Laser-Doppler Flowmetry; Male; Osteoporosis; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Tibia; Time Factors; Up-Regulation; Vitamin B 12

Topics: Animals; Betaine; Choline; Dietary Fats; Dietary Sucrose; Dietary Supplements; Disease Models, Animal; Fatty Liver; Folic Acid; Male; Non-alcoholic Fatty Liver Disease; Rats; Rats, Wistar; Vitamin B 12

Variations in the intake of folate are capable of modulating colorectal tumorigenesis; however, the outcome appears to be dependent on timing. This study sought to determine the effect of altering folate (and related B vitamin) availability during in-utero development and the suckling period on intestinal tumorigenesis.. Female wildtype mice were fed diets either mildly deficient, replete or supplemented with vitamins B(2), B(6), B(12) and folate for 4 weeks before mating to Apc(1638N) males. Females remained on their diet throughout pregnancy and until weaning. After weaning, all Apc(1638N) offspring were maintained on replete diets for 29 weeks.. At 8 months of age tumour incidence was markedly lower among offspring of supplemented mothers (21%) compared with those of replete (59%) and deficient (55%) mothers (p=0.03). Furthermore, tumours in pups born to deficient dams were most likely to be invasive (p=0.03). The expression of Apc, Sfrp1, Wif1 and Wnt5a--all of which are negative regulatory elements of the Wnt signalling cascade--in the normal small intestinal mucosa of pups decreased with decreasing maternal B vitamin intake, and for Sfrp1 this was inversely related to promoter methylation. β-Catenin protein was elevated in offspring of deficient dams.. These changes indicate a de-repression of the Wnt pathway in pups of deficient dams and form a plausible mechanism by which maternal B vitamin intake modulates tumorigenesis in offspring. These data indicate that maternal B vitamin supplementation suppresses, while deficiency promotes, intestinal tumorigenesis in Apc(1638N) offspring.

Topics: Animals; Animals, Newborn; Colorectal Neoplasms; Dietary Supplements; Disease Models, Animal; Female; Folic Acid; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Pregnancy; Prenatal Exposure Delayed Effects; Riboflavin; Vitamin B 12; Vitamin B 6; Vitamin B Complex; Vitamin D Deficiency; Wnt Signaling Pathway

Hyperhomocysteinemia is associated with an increased risk of Alzheimer's disease (AD). Our previous work has demonstrated that combined folate and vitamin B12 (vit-B12) supplementation prevents tau hyperphosphorylation and memory deficits induced by acute administration of homocysteine in young rats. Here, we further investigated whether folate/vit-B12 supplementation is also effective in aged rats with a chronically high level of homocysteine. 18-month-old rats were injected with homocysteine via the vena caudalis with or without a concurrent folate/vit-B12 supplementation for 28 weeks. We found that hyperhomocysteinemia induced tau hyperphosphorylation and accumulation in hippocampus and cortex. Concurrent signaling changes included the activation of glycogen synthase kinases-3β, cyclin-dependent kinase-5, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38MAPK, and inhibition of protein phosphatase 2A. Although the ability to learn was not affected, the aged rats exhibited significant memory deficits. Folate/vit-B12 supplementation attenuated these biochemical and behavioral correlates. These data demonstrate that folate/vit-B12 supplementation is also effective in a chronic hyperhomocysteinemia model in reversing the AD-like tau pathologies and memory deficits.

Topics: Aging; Animals; Chronic Disease; Dietary Supplements; Disease Models, Animal; Drug Therapy, Combination; Folic Acid; Hyperhomocysteinemia; Male; Memory Disorders; Phosphorylation; Rats; Rats, Sprague-Dawley; tau Proteins; Vitamin B 12

We have separated the active polypeptides from aqueous extracts of Achyranthes bidentata Blume (ABPP), a commonly prescribed Chinese medicinal plant with a range of pharmaceutical properties. We investigated the effects of ABPP administration on peripheral nerve regeneration in a mouse sciatic nerve crush injury model. After nerve crush, the mice received daily tail vein injections of 1, 4, and 16 mg/kg of ABPP, 65 microg/kg of methylcobalamin, and vehicle saline, respectively, over a 21-day period. At 1, 3, 6, 9, 12, 15, 18 and 21 days after nerve crush, the animals were subjected to walking track analysis for evaluating the sciatic functional index (SFI) values. At day 21 the animals were anesthetized, and the compound muscle action potential and nerve conduction velocity were respectively recorded. After the animals were killed, the sciatic nerve was examined with immunohistochemistry and electron microscopy, and gastrocnemius muscle was analyzed with Masson trichome staining. The results indicated that treatment with ABPP at a dose range (1-16 mg/kg) promoted histological regeneration and functional recovery of the injured sciatic nerve and its target muscle, yielding a desired efficacy greater than that by vehicle treatment and close to that by methylcobalamin (65 microg/kg). These findings suggest that plant polypeptides, ABPP, may be a potential agent in ameliorating of neuropathy caused by sciatic nerve crush.

Topics: Achyranthes; Animals; Disease Models, Animal; Mice; Mice, Inbred ICR; Muscle, Skeletal; Nerve Crush; Nerve Regeneration; Neuroprotective Agents; Peptides; Phytotherapy; Random Allocation; Recovery of Function; Sciatic Nerve; Time Factors; Vitamin B 12; Walking

Methylcobalamin is a vitamin B12 analog and is necessary for the maintenance of the nervous system. Although some previous studies have referred to the effects of methylcobalamin on neurons, the precise mechanism of this effect remains obscure. Here we show that methylcobalamin at concentrations above 100 nM promotes neurite outgrowth and neuronal survival and that these effects are mediated by the methylation cycle, a metabolic pathway involving methylation reactions. We also demonstrate that methylcobalamin increases Erk1/2 and Akt activities through the methylation cycle. In a rat sciatic nerve injury model, continuous administration of high doses of methylcobalamin improves nerve regeneration and functional recovery. Therefore, methylcobalamin may provide the basis for better treatments of nervous disorders through effective systemic or local delivery of high doses of methylcobalamin to target organs.

Topics: Action Potentials; Animals; Brain-Derived Neurotrophic Factor; Cell Proliferation; Cell Survival; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Electromyography; Enzyme Activation; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Female; Ganglia, Spinal; In Situ Nick-End Labeling; Methylation; Motor Activity; Muscle, Skeletal; Nerve Regeneration; Neurites; Neurons; Oncogene Protein v-akt; Rats; Rats, Wistar; Recovery of Function; Sciatic Neuropathy; Sensation; Tubulin; Vitamin B 12

B vitamins rescue cleft palate induced by glucocorticoids in rodents; however, the mechanism of this effect remains largely unknown. The objective of our study was to assess the effect of dexamethasone and Vitamin B12 on cell proliferation and apoptosis during palatogenesis. In our study, mesenchymal cell proliferation in mouse embryonic palates decreased when the subjects were administered dexamethasone at embryo day 13.5 (E 13.5). However, mesenchymal cell proliferation was increased after dexamethasone exposure at E 14.0 and E 14.5 in comparison with the control group. After Vitamin B12 treatment, proliferation of mesenchymal cells was restored. No apoptosis was detected until bilaterial palatal shelves adhered and formed a medial epithelium seam in the control group and Vitamin B12-treated group. However, the apoptotic cells were detected under the medial edge epithelium before the palate contacted after dexamethasone treatment. The results suggested that Vitamin B12 restored proliferation, which had been reduced by dexamethasone via a delayed cellular cycle and apoptosis. This study implies that Vitamin B12 may be used to prevent or alleviate cleft palate induced by dexamethasone during embryonic palatogenesis.

Topics: Animals; Apoptosis; Cell Proliferation; Cleft Palate; Dexamethasone; Disease Models, Animal; Glucocorticoids; Mice; Mice, Inbred C57BL; Palate; Vitamin B 12; Vitamins

Since hyper-homocysteinemia (HHcy) was recognized as a risk factor for Alzheimer's disease (AD), many studies tried to induce HHcy in animal models to investigate its effect on amyloid-beta protein precursor (AbetaPP) metabolism. Previous reports found that HHcy induced in AD transgenic mouse models, by either feedina a methionine-enriched diet or vitamin Bs deficient diet, is associated with elevation of amyloid-beta (Abeta) levels. However, there is no data available on the effect of dietary intervention which combines both excessive methionine and low levels of vitamin Bs on amyloidogenesis in any of these models. In the current study, we investigated the effect of a combination diet, which was both enriched in methionine and deficient in folate, vitamin B6 and B12, in an AD mouse model, the Tg2576. We found that 7 months treatment of this diet induced severe HHcy in these mice with plasma homocysteine level higher than 150 microM. However, no difference was detected in brain Abeta levels or deposition between the diet-treated and control group. As shown by western blot, severe HHcy did not alter the steady state levels of proteins involved in AbetaPP metabolism, either. These results demonstrate that this combination diet-induced severe HHcy does not influence amyloidogenesis in vivo.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cerebral Cortex; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Hippocampus; Humans; Hyperhomocysteinemia; Methionine; Mice; Mice, Transgenic; Peptide Fragments; Random Allocation; Vitamin B 12

Receptor-mediated endocytosis is responsible for protein reabsorption in the proximal tubule. This process involves two interacting receptors, megalin and cubilin, which form a complex with amnionless. Whether these proteins function in parallel or as part of an integrated system is not well understood. Here, we report the renal effects of genetic ablation of cubilin, with or without concomitant ablation of megalin, using a conditional Cre-loxP system. We observed that proximal tubule cells did not localize amnionless to the plasma membrane in the absence of cubilin, indicating a mutual dependency of cubilin and amnionless to form a functional membrane receptor complex. The cubilin-amnionless complex mediated internalization of intrinsic factor-vitamin B12 complexes, but megalin considerably increased the uptake. Furthermore, cubilin-deficient mice exhibited markedly decreased uptake of albumin by proximal tubule cells and resultant albuminuria. Inactivation of both megalin and cubilin did not increase albuminuria, indicating that the main role of megalin in albumin reabsorption is to drive the internalization of cubilin-albumin complexes. In contrast, cubulin deficiency did not affect urinary tubular uptake or excretion of vitamin D-binding protein (DBP), which binds cubilin and megalin. In addition, we observed cubilin-independent reabsorption of the "specific" cubilin ligands transferrin, CC16, and apoA-I, suggesting a role for megalin and perhaps other receptors in their reabsorption. In summary, with regard to albumin, cubilin is essential for its reabsorption by proximal tubule cells, and megalin drives internalization of cubilin-albumin complexes. These genetic models will allow further analysis of protein trafficking in the progression of proteinuric renal diseases.

Topics: Absorption; Albumins; Animals; Disease Models, Animal; DNA-Binding Proteins; Integrases; Kidney Tubules, Proximal; Low Density Lipoprotein Receptor-Related Protein-2; Mice; Mice, Inbred C57BL; Mice, Knockout; Proteinuria; Receptors, Cell Surface; Transcription Factors; Vitamin B 12

Using ulnar nerve as donor and musculocutaneous nerve as recipient we recently demonstrated that end-to-end neurorrhaphy in young adult male Wistar rats resulted in good recovery following protracted survival. Here we explored whether anti-inflammatory drug- methylprednisolone, regeneration/myelination-enhancing agent- methylcobalamin and neurite growth-enhancing and angiogenic factor- pleiotrophin accelerated its recovery. Methylprednisolone suppressed the perineuronal microglial reaction and periaxonal ED-1 expression while pleiotrophin increased the blood vessel density and nerve fiber densities in the reconnected nerve as expected. Neither methylprednisolone nor methylcobalamin altered the expression of growth associated protein 43 in the neurons examined suggesting that they did not interfere with axonal regeneration attempt. Surprisingly methylcobalamin enhanced the recovery of compound muscle action potentials and motor end plate innervation and the performance on sticker removal grooming test and augmented the diameters and myelin thicknesses of regenerated axons dramatically while enhancing S-100 expression in Schwann cells; remarkable recovery was achieved 1 month following neurorrhaphy. Simultaneous methylcobalamin and pleiotrophin treatment resulted in quick and persistent supernumerary reinnervation but failed to enhance the recovery over that of the former alone. Methylprednisolone transiently suppressed the enumeration of regrowing axons. In conclusion, methylcobalamin may be preferred over methylprednisolone to facilitate the recovery of peripheral nerves following end-to-end neurorrhaphy. The long-term effect of this treatment however remains to be clarified.

Topics: Animals; Anti-Inflammatory Agents; Carrier Proteins; Cytokines; Disease Models, Animal; Forelimb; Male; Methylprednisolone; Muscle, Skeletal; Nerve Growth Factors; Nerve Regeneration; Nerve Transfer; Rats; Recovery of Function; Ulnar Nerve; Vitamin B 12

The Fgf10 signaling pathway plays an important role in early stages of mouse embryonic palatal development, which is associated with cell proliferation and differentiation. The objective of this study was to assess whether dexamethasone and vitamin B(12) affected the Fgf10 signal pathway of mouse embryonic palate.. Immunohistochemical studies were performed for expression of Fgf10, Fgfr2b, and sonic hedgehog and for cell proliferation and apoptosis of mouse embryonic palate.. The expression of Fgf10, Fgfr2b, and sonic hedgehog was changed in mouse embryonic palate after dexamethasone and vitamin B(12) treatment, resulting in reduced and restored proliferation of mesenchymal cells.. Dexamethasone and vitamin B(12) affected the Fgf10 signaling pathway and cell proliferation of mouse embryonic palate. Cell apoptosis was not altered after dexamethasone and vitamin B(12) exposure.

Topics: Animals; Apoptosis; Cell Proliferation; Cleft Palate; Dexamethasone; Disease Models, Animal; Embryonic Development; Female; Fibroblast Growth Factor 10; Gene Expression Regulation, Developmental; Glucocorticoids; Male; Mice; Mice, Inbred C57BL; Palate; Receptor, Fibroblast Growth Factor, Type 1; Signal Transduction; Vitamin B 12

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by selective degeneration of motor neurons. Mutations in copper/zinc superoxide dismutase (SOD1) account for 20% cases of familial ALS (fALS), but the underlying pathogenetic mechanisms are largely unknown. Using SOD1(G93A) mice model of ALS, we demonstrated that mutation in SOD1 caused a significant increase in the level of plasma homocysteine (Hcy). To investigate whether Hcy-lowering therapy is beneficial to this disease, we applied folic acid (FA) and vitamin B12 which are important factors involved in the Hcy metabolism to assess the neuroprotective effect of FA and B12 in the SOD1(G93A) mice. Our results showed FA or FA+B12 treatment significantly delayed the disease onset and prolonged the lifespan, accompanied by the significant reduction of motor neuron loss. Furthermore, we found that FA or FA+B12 treatment significantly attenuated the plasma Hcy level, suppressed the activation of microglia and astrocytes, and inhibited the expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in spinal cord. Moreover, FA or FA+B12 treatment decreased the levels of cleaved caspase-3 and poly(ADP-ribose)polymerase (PARP) but up-regulated the level of anti-apoptotic protein Bcl-2. However, B12 treatment alone did not show any significant benefit to this disease. These results provide evidence to demonstrate that elevated Hcy is involved in the pathogenesis of fALS and FA therapy may have therapeutic potential for the treatment of the disease.

Topics: Amyotrophic Lateral Sclerosis; Animals; Apoptosis; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Folic Acid; Gas Chromatography-Mass Spectrometry; Homocysteine; Inflammation; Mice; Mice, Transgenic; Motor Neurons; Nitric Oxide Synthase Type II; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Rotarod Performance Test; Spinal Cord; Superoxide Dismutase; Vitamin B 12; Vitamin B Complex

Topics: Animals; Arginine; Cardiovascular Diseases; Cystatin C; Cystatins; Disease Models, Animal; Folic Acid; Glomerular Filtration Rate; Homocysteine; Humans; Hyperhomocysteinemia; Kidney Diseases; Risk Factors; Vitamin B 12; Vitamin B 6

Researchers have developed murine lymphopenic, non-lymphopenic, transgenic, spontaneous and infectious agent based models to induce an experimental autoimmune gastritis (EAG) for the study of human organ-specific autoimmune disease. These models result in a chronic inflammatory mononuclear cell infiltrate in the gastric mucosa, destruction of parietal and zymogenic cells with autoantibodies reactive to the gastric parietal cells and the gastric H+/K+ ATPase (ATP4), arguably hallmarks of a human autoimmune gastritis (AIG). In the case of AIG, it is well documented that, in addition to parietal cell antibodies being detected in up to 90% of patients, up to 70% have intrinsic factor antibodies with the later antibodies considered highly specific to patients with pernicious anemia. This is the first report specifically investigating the occurrence of intrinsic factor antibodies, cobalamin deficiency and pernicious anemia in EAG models. We conclude, in contrast to AIG, that, in the three EAG models examined, intrinsic factor is not selected as a critical autoantigen.

Topics: Anemia, Pernicious; Animals; Autoantibodies; Autoantigens; Autoimmune Diseases; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Gastritis; H(+)-K(+)-Exchanging ATPase; Immunoblotting; Intrinsic Factor; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Vitamin B 12; Vitamin B 12 Deficiency

Lead (Pb(2+)) exposure in development induces impairments of synaptic plasticity in the hippocampal dentate gyrus (DG) area of the anesthetized rats in vivo. The common chelating agents have many adverse effects and are incapable of alleviating lead-induced neurotoxicity. Recently, CQ, clioquinol (5-chloro-7-iodo-8-hydroxy-quinoline), which is a transition metal ion chelator and/or ionophore with low affinity for metal ions, has yielded some promising results in animal models and clinical trials related to dysfunctions of metal ions. In addition, CQ-associated side effects are believed to be overcome with vitamin B12 (VB12) supplementation. To determine whether CQ treatment could rescue impairments of synaptic plasticity induced by chronic Pb(2+) exposure, we investigated the input/output functions (I/Os), paired-pulse reactions (PPRs) and long-term potentiation (LTP) of different treatment groups in hippocampal DG area of the anesthetized rat in vivo by recording field potentials and measured hippocampal Pb(2+) concentrations of different treatment groups by PlasmaQuad 3 inductive coupled plasma mass spectroscopy. The results show: CQ alone does not rescue the lead-induced impairments of synaptic plasticity in hippocampal DG area of the anesthetized rats in vivo; VB12 alone partly rescues the lead-induced impairments of LTP; however the co-administration of CQ and VB12 totally rescues these impairments of synaptic plasticity and moreover, the effects of CQ and VB12 co-administration are specific to the lead-exposed animals.

Topics: Analysis of Variance; Anesthesia; Animals; Clioquinol; Dentate Gyrus; Disease Models, Animal; Dose-Response Relationship, Radiation; Electric Stimulation; Lead Poisoning; Long-Term Potentiation; Neuronal Plasticity; Rats; Rats, Wistar; Synapses; Vitamin B 12; Vitamin B Complex

To investigate the effects of folic acid, vitamin B(6) and B(12) on plasma homocysteine and on learning and memory functions in focal cerebral ischemia rats.. Sprague-Dawley rats were randomly divided into four groups. They were sham operation group (Sham OP), middle cerebral artery occlusion model group (MCAO), MCAO + folic acid group (MCAO + FA) and MCAO + compound vitamin (folate, vitamin B(6) and B(12)) group (MCAO + CV). Plasma homocysteine was measured before and after supplementation and after ischemia.. The level of plasma homocysteine in MCAO + FA and MCAO + CV groups were significantly lower than those in Sham OP and MCAO groups after supplementation and ischemia (6.92 +/- 1.04) micromol/L and (5.49 +/- 1.00) micromol/L vs (9.33 +/- 1.11) micromol/L, (10.90 +/- 2.03 micromol/L), P < 0.05. While in MCAO + CV group was lower than that in MCAO + FA group (5.49 +/- 1.00) micromol/L vs (6.92 +/- 1.04) micromol/L, P < 0.05. The neurological deficit scores and shock times in Y-type maze of MCAO + FA and MCAO + CV groups were lower than those in MCAO group (1.75 +/- 0.46 and 1.38 +/- 0.52 vs 2.62 +/- 0.52; 123.50 +/- 39.77 and 86.25 +/- 21.39 vs 173.25 +/- 46.32, P < 0.05). The correct times of MCAO + CV group in Y-type maze was higher than that in MCAO group (3.75 +/- 0.42 vs 2.12 +/- 0.45, P < 0.05).. Folic acid intake could not only reduce plasma homocysteine concentration but also promote the recovery of the learning and memory functions of rats with cerebral ischemia. The effects of folic acid combined with vitamin B(6) and vitamin B(12) on cerebral ischemia rats was better than that of single folate.

Topics: Animals; Brain Ischemia; Disease Models, Animal; Female; Folic Acid; Homocysteine; Infarction, Middle Cerebral Artery; Learning; Male; Memory; Rats; Rats, Sprague-Dawley; Vitamin B 12; Vitamin B 6; Vitamin B Complex

Cobalamin-deficient (Cbl-D) central neuropathy in the rat is associated with a locally increased expression of neurotoxic tumour necrosis factor-alpha (TNF-alpha) and a locally decreased expression of neurotrophic epidermal growth factor (EGF). These recent findings suggest that cobalamin oppositely regulates the expression of TNF-alpha and EGF, and raise the possibility that these effects might be independent of its coenzyme function. Furthermore, adult Cbl-D patients have high levels of TNF-alpha and low levels of EGF in the serum and cerebrospinal fluid. Serum levels of TNF-alpha and EGF of cobalamin-treated patients normalize concomitantly with haematological disease remission. These observations suggest that cobalamin deficiency induces an imbalance in TNF-alpha and EGF levels in biological fluids that might have a role in the pathogenesis of the damage caused by pernicious anaemia.

Topics: Anemia, Pernicious; Animals; Central Nervous System; Disease Models, Animal; Epidermal Growth Factor; Gastrectomy; Humans; Nerve Degeneration; Nerve Growth Factor; Rats; Tumor Necrosis Factor-alpha; Vitamin B 12; Vitamin B 12 Deficiency

Neural tube defects (NTD) are mainly of multifactorial origin. Maternal treatment with valproic acid (VPA) during pregnancy induces NTD in susceptible fetuses. Elevated levels of homocysteine are observed in pregnancies with NTD. The mechanism by which homocysteine might cause NTD is unknown.. The aim of this study was to determine if homocystine would augment VPA-induced exencephaly in an experimental model.. Groups of mice were injected (IP) on gestational day 8 (GD) with a single dose of 75 mg/kg of L: -Homocystine (HC) or a proportionate volume of saline, followed by a single dose of 600 mg/kg of VPA or an equal volume of saline. In a second experiment, mice were treated with a daily dose of 75 mg/kg of HC or an equal volume of saline (IP) from GD 5 and continued through GD 10. These animals had a single exposure to 600 mg/kg of VPA or saline (IP) on GD 8. All animals were killed by cervical dislocation on GD 18. Plasma homocysteine, folate and vitamin B12 were determined on GD 8 and GD 10 from single and multiple dose groups of mice, respectively, from additional experiments.. The VPA and HC+VPA induced significantly higher rates of embryonic resorption and intrauterine growth retardation (IUGR) than HC or saline alone. HC + VPA groups had significantly more numerous fetuses with severe IUGR than HC alone or VPA alone groups. Both single and multiple doses of HC augmented VPA-induced reduction in fetal body weight. Successive doses of HC did not augment the rate of IUGR more significantly than a single dose of HC. Incidence of exencephaly was significantly enhanced in the HC + VPA groups compared to that in the HC or VPA alone groups. HC alone was not teratogenic. Plasma homocysteine levels increased several fold both in HC and HC + VPA groups and the increase was not particularly more marked in multiple dose groups than in the single dose groups. VPA did not elevate homocysteine concentration. Both FA and vitamin B12 concentrations were reduced by VPA, HC and HC + VPA, but HC and VPA when combined did not produce an additive effect on vitamin levels.. These data indicate that HC and VPA interact in neurulation stage embryos, affect fundamental processes of closure of the neural tube and lead to enhanced incidence of NTD.

Topics: Abnormalities, Drug-Induced; Animals; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Female; Fetal Growth Retardation; Folic Acid; Gestational Age; Homocysteine; Homocystine; Mice; Neural Tube Defects; Pregnancy; Random Allocation; Teratogens; Valproic Acid; Vitamin B 12

To evaluate the effects of dietary folic acid supplementation on the cerebral vascular damage induced by hyperhomocysteinemia, rats were fed a diet containing 3.0 g/kg homocystine for 2 wk and then either 3.0 g/kg homocystine or 3.0 g/kg homocystine plus 0.008 g/kg folic acid for 8 wk. Control rats consumed the AIN-93 Maintenance diet throughout the experiment. The cerebral expression of glucose transporter-1 was measured by Western blot analysis and cerebrovascular structural alterations were evaluated by electron microscopy. The homocystine diet significantly increased the plasma levels of homocysteine and TBARS and decreased the cerebral expression of glucose transporter-1 (GLUT-1) with a concomitant increase in the percentage of damaged cerebral vessels. The inclusion of dietary folic acid for 8 wk caused plasma homocysteine levels to be the same as in control rats and it significantly upregulated the cerebral expression of GLUT-1 that was significantly reduced by hyperhomocysteinemia. Folic acid supplementation also significantly decreased the incidence of damaged vessels due to hyperhomocysteinemia. These results and the electron microscopy findings suggested that folic acid supplementation might reduce the detrimental effects on the endothelium caused by experimentally induced hyperhomocysteinemia.

Topics: Animals; Cerebrovascular Circulation; Dietary Supplements; Disease Models, Animal; Endothelium, Vascular; Energy Intake; Folic Acid; Homocysteine; Hyperhomocysteinemia; Male; Microcirculation; Rats; Rats, Sprague-Dawley; Reference Values; Thiobarbituric Acid Reactive Substances; Vitamin B 12; Weight Gain

Newborn mice weaned from mice fed on a B12-deficient diet during pregnancy and lactation were fed on a B12-deficient diet for 90 days after weaning, and the state of B12 deficiency was evaluated. The effect of B12 deficiency on the testicular tissue was also examined. The body weight of the mice fed on a B12-deficient diet for 90 days was slightly lower than that of the control mice administrated CN-B12, and the urinary excretion of methylmalonic acid (MMA) was increased. The B12 concentrations in the liver and testes were markedly depressed by B12 deficiency, being about 13 and 10 pmol/g, respectively, on day 90. The testes weight was clearly reduced by B12 deficiency. The testes weight/100 g body weight was also lowered. Clear morphological changes were observed in the testicular tissue of the B12-deficient mice. These results showed that mice in a severely B12-deficient state could be produced by dietary B12 deprivation. These B12-deficient mice could be useful as model animals not only for elucidating the functions of B12 in vivo, but also for biochemical studies.

Topics: Animals; Body Weight; Diet; Disease Models, Animal; Liver; Male; Maternal Nutritional Physiological Phenomena; Methylmalonic Acid; Mice; Mice, Inbred BALB C; Organ Size; Severity of Illness Index; Testis; Time Factors; Vitamin B 12; Vitamin B 12 Deficiency

Infants of epileptic women treated with valproic acid (VPA) during pregnancy have a higher risk of developing spina bifida than those of the general population. VPA induces exencephaly in experimental animal embryos. But the pathogenetic mechanism remains rather elusive. Antiepileptic drugs (AED) in general accentuate pregnancy-imposed fall in maternal folate levels. Periconceptional folic acid supplementation is reported to protect embryos from developing neural tube defects (NTD). Conflicting results have been reported by experimental studies that attempted to alleviate VPA-induced NTD by folic acid. Our objectives were to determine the critical developmental stages and an effective dose of folic acid for the prevention of VPA-induced exencephaly in mouse fetuses. A single teratogenic dose of 400 mg/kg of VPA was administered to TO mice on gestation day (GD) 7 or 8. It was followed by (1) a single dose of 12 mg/kg of FA (folinic acid) or (2) 3 doses of FA 4 mg/kg each. In experiment (3), FA (4 mg/kg) was administered thrice daily starting on GD 5 and continued through GD 10. These animals received VPA on GD 7 or 8. VPA and B12 concentrations were determined by radioimmunoassay. The single heavy dose of FA had no rescue effect on NTD. Three divided doses of FA on GD 7 and continuous dosing of FA from GD 5 through GD 10 substantially reduced the VPA-induced exencephaly in the fetuses. In the later experiments, the neural folds elevated faster than the non-supplemented group. VPA considerably reduced maternal plasma folate and B12 concentrations. The heavy dose of FA only moderately improved vitamin levels. Three divided doses of FA elevated the vitamin levels slightly better but it was the prolonged dosing of FA that was associated with sustained elevation of plasma levels higher than the control levels and acceleration of neural tube closure thus accounting for the pronounced protection against VPA-induced NTD development. These data suggest that plasma levels of FA and B12 have to be kept substantially elevated and maintained high throughout organogenesis period to protect embryos against VPA-induced NTD in this mouse model.

Topics: Abnormalities, Drug-Induced; Animals; Brain; Dietary Supplements; Disease Models, Animal; Enzyme Inhibitors; Female; Folic Acid; Maternal Exposure; Mice; Neural Tube Defects; Time Factors; Valproic Acid; Vitamin B 12

Topics: Anemia, Macrocytic; Anemia, Megaloblastic; Animals; Biomarkers; Dietary Supplements; Disease Models, Animal; Folic Acid; Folic Acid Deficiency; Vitamin B 12; Vitamin B 12 Deficiency

Hyperhomocysteinemia is associated with increased risk of atherosclerotic and thrombotic vascular disease. In many patients, hyperhomocysteinemia can be treated or prevented by dietary supplementation with B vitamins, but the clinical benefit of B vitamins for the prevention of vascular disease has not been proven.. Using an atherogenic diet that produces both hyperhomocysteinemia and hypercholesterolemia, we tested the hypothesis that dietary supplementation with B vitamins (folic acid, vitamin B(12), and vitamin B(6)) would prevent hyperhomocysteinemia, vascular dysfunction, and atherosclerotic lesions in monkeys. After 17 months, plasma total homocysteine increased from 3.6+/-0.3 to 11.8+/-1.7 micromol/L in monkeys fed an unsupplemented atherogenic diet (P<0.01) but did not increase in monkeys fed an atherogenic diet supplemented with B vitamins (3.8+/-0.3 micromol/L). Serum cholesterol increased from 122+/-7 to 550+/-59 mg/dL in the unsupplemented group (P<0.001) and from 118+/-5 to 492+/-55 mg/dL in the supplemented group (P<0.001). Responses to endothelium-dependent vasodilators, both in resistance vessels in vivo and in the carotid artery ex vivo, were impaired to a similar extent in groups that did and did not receive vitamin supplements. Anticoagulant responses to the infusion of thrombin were also impaired to a similar extent in both groups. Vitamin supplementation failed to prevent intimal thickening in the carotid or iliac arteries.. These findings demonstrate that supplementation with B vitamins prevents hyperhomocysteinemia but is not sufficient to prevent the development of vascular dysfunction or atherosclerotic lesions in monkeys with marked hypercholesterolemia, even in the absence of preexisting atherosclerosis.

Topics: Animals; Arteriosclerosis; Blood Coagulation; Carotid Arteries; Cholesterol; Diet, Atherogenic; Dietary Supplements; Disease Models, Animal; Folic Acid; Hypercholesterolemia; Hyperhomocysteinemia; In Vitro Techniques; Macaca fascicularis; Partial Thromboplastin Time; Pyridoxine; Thrombin; Treatment Outcome; Vascular Diseases; Vasodilation; Vasodilator Agents; Vitamin B 12

Although hyperhomocysteinemia (HHcy) is a well-known risk factor for the development of cardiovascular disease, the underlying molecular mechanisms are not fully elucidated. Here we show that induction of HHcy in apoE-null mice by a diet enriched in methionine but depleted in folate and vitamins B6 and B12 increased atherosclerotic lesion area and complexity, and enhanced expression of receptor for advanced glycation end products (RAGE), VCAM-1, tissue factor, and MMP-9 in the vasculature. These homocysteine-mediated (HC-mediated) effects were significantly suppressed, in parallel with decreased levels of plasma HC, upon dietary supplementation with folate and vitamins B6/B12. These findings implicate HHcy in atherosclerotic plaque progression and stability, and they suggest that dietary enrichment in vitamins essential for the metabolism of HC may impart protective effects in the vasculature.

Topics: Animals; Apolipoproteins E; Arteriosclerosis; Cells, Cultured; Diet; Disease Models, Animal; Folic Acid; Humans; Hyperhomocysteinemia; Immunohistochemistry; Male; Matrix Metalloproteinase 9; Methionine; Mice; Mice, Inbred C57BL; Mice, Knockout; Pyridoxine; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Thromboplastin; Vascular Cell Adhesion Molecule-1; Vasculitis; Vitamin B 12

The effect of some B vitamins in chemical and thermal models of nociception in mice was investigated. The association thiamine/pyridoxine/cyanocobalamin (TPC, 20-200 mg/kg, i.p. or per os), thiamine, pyridoxine (50-200 mg/kg, i.p.) or riboflavin (3-100 mg/kg, i.p) induced an antinociceptive effect, not changed by naloxone (10 mg/kg, i.p.), in the acetic acid writhing model. Treatment for 7 days with thiamine/pyridoxine/cyanocobalamin (100 or 200 mg/kg, i.p.), thiamine (50 or 100 mg/kg) or pyridoxine (50 or 100 mg/kg) or acute treatment with riboflavin (6 or 12 mg/kg, i.p) inhibited the nociceptive response induced by formaldehyde. The B vitamins did not inhibit the nociceptive response in the hot-plate model. Both 7-day thiamine/pyridoxine/cyanocobalamin (100 mg/kg, i.p.) or acute riboflavin (25 or 50 mg/kg, i.p.) treatment partially reduced formaldehyde-induced hindpaw oedema. The B vitamins antinociceptive effect may involve inhibition of the synthesis and/or action of inflammatory mediators since it was not observed in the hot-plate model, was not reversed by naloxone, only the second phase of the formaldehyde-induced nociceptive response was inhibited, and formaldehyde-induced hindpaw oedema was reduced.

Topics: Acetic Acid; Animals; Constriction; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Formaldehyde; Hindlimb; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Motor Activity; Naloxone; Nociceptors; Pain; Pain Measurement; Pyridoxine; Riboflavin; Thiamine; Vitamin B 12; Vitamin B Complex

Vitamin B-12 deficiency and hyperhomocysteinemia alter the metabolism of trace elements. This study tested the hypothesis that there is a reverse relationship in which diets high in iron, copper, nickel and cobalt would influence vitamin B-12 deficiency outcomes including hyperhomocysteinemia. Piglets (German Landrace x Pietrain) were assigned to six groups of 8 and fed one of the following diets for 166 d: a vitamin B-12-adequate and folate-fortified diet (30 microg/kg vitamin B-12 and 0.5 mg/kg folate) with normal trace element concentrations or one of five vitamin B-12-free, folate nonsupplemented diets (0.36 mg/kg), with either normal trace element concentrations or high concentrations of iron (300 mg/kg), copper (30 mg/kg), cobalt (1 mg/kg) or nickel (6 mg/kg). Feed intake and weight gain did not differ significantly among the groups. Vitamin B-12-deficient pigs developed diminished serum and liver concentrations of vitamin B-12 and folate, an accumulation of iron in the liver and hyperhomocysteinemia. The magnitude of changes differed among vitamin B-12-deficient groups. Vitamin B-12-deficient pigs fed 6 mg/kg nickel had distinctly higher vitamin B-12 concentrations in liver and serum and 45% lower serum concentration of homocysteine than the corresponding deficiency group fed 1 mg/kg nickel; iron concentration in liver was completely normalized. Vitamin B-12-deficient pigs fed 1 mg/kg cobalt had 47% lower homocysteine concentrations in serum than the vitamin B-12-deficient group fed 0.13 mg/kg cobalt, but the vitamin B-12 status was unaffected. Supplementation of iron and copper did not affect these variables. The dietary manipulations had no detrimental effects on variables symptomatic of oxidative stress. The findings indicate a collaborative relationship between vitamin B-12 metabolism and the trace elements nickel and cobalt.

Topics: Animal Feed; Animals; Cobalt; Copper; Dietary Supplements; Disease Models, Animal; Female; Folic Acid; Homocysteine; Hyperhomocysteinemia; Iron; Liver; Male; Nickel; Swine; Trace Elements; Vitamin B 12; Vitamin B 12 Deficiency

In the present study, we investigated the peripheral nervous system (PNS) (both in terms of its ultrastructure and in terms of its function) of rats made cobalamin (Cbl)-deficient either through total gastrectomy or through prolonged feeding on a Cbl-deficient diet. In both these types of Cbl-deficient neuropathies we found: (a) ultrastructurally, intramyelin and endoneural edema, with no or minimal axonal damage in the PNS, in dorsal root ganglia, and the ventral and dorsal rootlets of the spinal cord; (b) electrophysiologically, a significant reduction in the nerve conduction velocity, consistent with that reported in (a); (c) morphometrically, a significant reduction in the density of myelinated fibers both in the sciatic nerve and in the peroneal nerve. All these pathological changes were reversed by chronic postoperative administration of Cbl into totally gastrectomized (TGX)-rats, hinting at the specificity of the damage itself in relation to the permanent Cbl-deficient status of the TGX-rats. No signs of segmental demyelination or remyelination were found. We also observed a turning of type I fibers into type II fibers in the soleus muscle of all our Cbl-deficient rats, however the Cbl deficiency had been induced. This muscular change was still present in TGX- and Cbl-treated rats, and it cannot be related to a malnutrition status, since it has been observed also in rats fed a Cbl-deficient diet. All these results demonstrate that Cbl deficiency strongly affects rat PNS within different parameters.

Topics: Animals; Disease Models, Animal; Electrophysiology; Gastrectomy; Male; Muscle, Skeletal; Neural Conduction; Neuromuscular Junction; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Vitamin B 12; Vitamin B 12 Deficiency

The totally gastrectomized (TGX) rat is a new experimental model for studying the pathogenesis of cobalamin (Cbl)-deficient myelopathy, i.e., subacute combined degeneration, total gastrectomy (TG) serving as a surgical paradigm of human pernicious anemia. We determined the serum levels of some biochemical indicators of Cbl deficiency in TGX rats at 2 to 10 months after TG. Methylmalonic acid (MMA) rose within 2 months and progressively increased thereafter until the end of the investigation period. 2-Methylcitric acid (MCA) rose significantly by 6 months and showed a further increment 4 months later. Homocysteine was only clearly elevated much later than the serum MMA, i.e., 10 months after the operation. The concentrations of MMA, MCA, and cystathionine were increased in kidney, liver, and spinal cord (SC) of TGX rats at 10 months. Chronic treatment of TGX rats with Cbl greatly decreased the serum levels of all the metabolic indicators of Cbl deficiency. Chronic peroral administration of the antibiotic lincomycin to TGX rats in an attempt to suppress the enteric flora markedly decreased serum MMA levels. Only Cbl, however, given either for the first 2 months after TG or for the third and fourth postoperative months (i.e., after SC abnormalities had already appeared) significantly decreased the severity of spongy vacuolation in SC white matter, although not completely preventing or repairing the neuropathological damage. Therefore, neither the early impairment in TGX rats of the Cbl-dependent methylmalonyl-coenzyme A mutase reaction nor the more delayed impairment of the Cbl-dependent methionine synthase step, as reflected by changes in serum metabolite levels, seems to be causally related to the TG-induced spongy vacuolation in SC white matter.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Anemia, Pernicious; Animals; Bacteria, Anaerobic; Citrates; Cystathionine; Disease Models, Animal; Erythromycin; Gastrectomy; Homocysteine; Humans; Intestines; Lincomycin; Male; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Postgastrectomy Syndromes; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Diseases; Vacuoles; Vitamin B 12; Vitamin B 12 Deficiency

Many cobalt-deficient sheep develop liver lesions known as ovine "white liver" disease, but the etiology of these changes is controversial. It has been suggested that cofactors are required for development of liver damage in cobalt-deficient sheep. In this study, one group of lambs (n = 5) was fed a diet low in cobalt (4.5 micrograms/kg) while a group of control lambs (n = 4) received the same diet after it had been supplemented with cobalt (1000 micrograms/kg). All cobalt-depleted lambs had reduced growth rate, anorexia, lacrimation, and alopecia, and they eventually became emaciated (mean body weight at end of study: 83% of initial body weight). Plasma concentrations of bilirubin and serum activity of glutamate-oxaloacetate transferase were elevated in these animals, while plasma concentrations of vitamin B12 were reduced (less than 220 pmol/L from day 42). Fatty degeneration of the liver associated with reduced concentrations of vitamin B12 (14.5 pmol/g) was seen in these animals at necropsy at 196 days. Microscopic liver lesions included accumulation of lipid droplets and lipofuscin particles in hepatocytes, dissociation and necrosis of hepatocytes, and sparse infiltration by neutrophils, macrophages, and lymphocytes. Ultrastructural hepatocytic alterations included swelling, condensation and proliferation of mitochondria, hypertrophy of smooth endoplasmic reticulum, vesiculation and loss of arrays of rough endoplasmic reticulum, and accumulation of lipid droplets and lipofuscin granules in cytoplasm of hepatocytes. No liver lesions were seen in control lambs. The results of this study indicate that cofactors are not a prerequisite to development of hepatic damage in cobalt-deficient sheep. Reduced activities of the vitamin B12-dependent enzymes, methylmalonyl CoA mutase and methionine synthase, and lipid peroxidation are of likely pathogenetic importance in the development of the lesions.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Alopecia; Animals; Anorexia; Aspartate Aminotransferases; Bilirubin; Cobalt; Diet; Disease Models, Animal; Endoplasmic Reticulum, Smooth; gamma-Glutamyltransferase; Liver; Liver Diseases; Methylmalonyl-CoA Mutase; Microscopy, Electron; Sheep; Sheep Diseases; Vitamin B 12

Elderly patients with alcoholism often require surgery and receive nitrous oxide (N2O) as a component of their anesthetic. Since aging, ethanol, and N2O may all perturb folate and/or vitamin B12 metabolism, we examined the combined influence of these parameters on vitamin B12/folate status in a rodent model. Aged male Fischer 344 rats (24 months old) were given a liquid ethanol diet (35% of calories as ethanol) and control rats were pair-fed a liquid diet with carbohydrate substituting for the caloric content of ethanol. After receiving liquid diets for 7 weeks, rats were exposed to 60% N2O/40% 0(2) for 6 h. Urinary excretion of formic acid, formiminoglutamic acid (FIGLU), and methylmalonic acid (MMA) were used as indirect markers of folate/vitamin B12 status. In both the aged ethanol-fed and control groups, excretion of formic acid and FIGLU markedly increased the first day after N2O exposure and returned towards background values by the second day. No changes occurred in MMA excretion. Exposure to N2O decreased methionine synthase activities in liver, kidney and brain, and recovery of methionine synthase activities occurred over a period of 4 days in both the aged ethanol-fed and control groups. Ethanol treatment for 7 weeks combined with acute exposure to N2O did not deplete the aged rats of folate or vitamin B12 in blood, liver, kidney or brain. Thus, in this animal model, aging, chronic ethanol administration, and acute N2O exposure did not act synergistically to produce prolonged and severe disturbances in folate and vitamin B12 metabolism.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Aging; Alcoholism; Animals; Disease Models, Animal; Folic Acid; Male; Nitrous Oxide; Rats; Rats, Inbred F344; Vitamin B 12

Jejunoileal bypass operation was originally done to promote weight loss for treatment of morbid obesity. We used such a model to determine if dietary vitamin absorption is compromised by such an operation. Six rats were subjected to a jejunoileal bypass, 6 control rats were pair-fed to bypassed rats; and 6 were fed ad libitum. Vitamin content of folic, B6, riboflavin, nicotinate, pantothenate, thiamin, biotin, B12, vitamins A, E, and carotene in blood and liver was determined after 8 postoperative weeks. Aside from riboflavin, blood vitamin levels were significantly depressed in bypassed rats. The deepest depression was seen for B12, carotene and vitamin E. Liver vitamin stores of folate, riboflavin, thiamin, B12, clearly were significantly depressed in the bypassed animals compared to the pair-fed and ad libitum-fed controls. This model can serve for rapidly studying micronutrient depletion due to malabsorption without dietary manipulation or antibiotics for gut sterilization.

Topics: Animals; Carotenoids; Disease Models, Animal; Jejunoileal Bypass; Malabsorption Syndromes; Rats; Rats, Inbred Strains; Riboflavin; Vitamin B 12; Vitamin E; Vitamins

The streptozotocin-treated diabetic rat was not found to be a suitable animal model for methylmalonic acidaemia as previously described. Urinary methylmalonic acid (MMA) was measured in adult Wistar rats prior to and following injection of streptozotocin (40 mg/kg). Plasma and tissue MMA levels were measured following the induction of diabetes and compared with data from control rats. MMA levels were determined by a gas chromatographic-mass spectrometric method (McMurray et al., 1986). Diabetes was confirmed by the 10 x increase in 24 h urine volume; glycosuria; glycaemia; and weight loss. Urinary MMA excreted did not change during the 11 week diabetic period and there was no difference between the pre- and post-diabetic phases (p less than 0.05). Plasma and tissue MMA concentrations were not elevated in this diabetic animal model. Also in contrast to earlier reports, the vitamin B12 levels of the diabetic rats were not elevated compared to controls (p less than 0.05).

Topics: Animals; Chromatography, Gas; Diabetes Mellitus, Experimental; Disease Models, Animal; Male; Malonates; Methylmalonic Acid; Nutritional Status; Rats; Rats, Inbred Strains; Streptozocin; Vitamin B 12

The effects of carnitine and cobamamide were studied at the unspecific stage of anorexia nervosa treatment. Carnitine and cobamamide accelerated the amelioration of the patients' somatic state (body weight gain, gastrointestinal functions normalization). Experimental psychological technique of involved deciphering discovered that latent fatigue disappeared and mental performance sharply increased under carnitine and cobamamide treatment. Experimental model of anorexia nervosa was used for electron microscopy and morphometry of neocortical tissue structure after starvation period and in feeding rehabilitation with carnitine and cobamamide. These drugs were shown to promote cerebral mass growth, increase in neocortical layers thickness, pyramidal neurons volume, that led to full restoration of normal structure of neocortex. The data provide a basis suitable to recommend carnitineand cobamamide to treat patients with relevant anorexia.

Topics: Animals; Anorexia Nervosa; Body Weight; Carnitine; Cerebral Cortex; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Mice; Mice, Inbred CBA; Microscopy, Electron; Organ Size; Vitamin B 12

Experimental autoimmune gastritis (AIG), defined by the appearance of auto antibodies to parietal cells, was induced by neonatal thymectomy in BALB/c nu/+mice 3 days after birth. Vitamin B12 absorption and intrinsic factor in the stomach extract decreased compared with those in AIG-negative control groups. No decrease of the serum A/G ratio in AIG-bearing mice was observed. Although development of anemia, as evaluated by a decrease in hematocrit value, was poor until 12 mo of age and the gastric mucosa was hypertrophic, the AIG resembled human pernicious anemia rather than Ménétrier's disease. Adoptive transfer of spleen cells, but not sera, of AIG-bearing nu/+ into BALB/c nu/nu mice caused AIG in all animals 1 mo later, indicating the involvement of lymphocytes in the induction mechanism of AIG. Cytofluorometric and immunohistochemical analysis of lymphocytes in the gastric mucosa revealed T-cell infiltration at an early stage (1.5-3 mo) followed by B cell infiltration (6 mo). When the fraction enriched with parietal cells, which were intensively stained with sera of AIG-bearing mice and fluorescent antibody to mouse immunoglobulin G, was injected into the foot pads of AIG-bearing nude mice, typical delayed-type hypersensitivity reaction was observed in all animals. This was not seen in the mice injected with the cell fraction enriched with chief cells, although a few of them were stained by the immunofluorescent technique. Thus, the delayed-type hypersensitivity reaction seems to be directly involved in the mechanism of tissue damage.

Topics: Anemia, Pernicious; Animals; Animals, Newborn; Antigen-Antibody Complex; Autoantibodies; Autoimmune Diseases; Disease Models, Animal; Female; Gastric Mucosa; Gastritis; Hypersensitivity, Delayed; Immunization, Passive; Intrinsic Factor; Lymphocytes; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Parietal Cells, Gastric; Thymectomy; Vitamin B 12

Experiments were performed to investigate the effects of mecobalamin (CH3-B12) on disorders of testicular function. Male rats received subcutaneously an injection of doxorubicin (ADR) three times a week for 3, 5 and 7 weeks. Thereafter, they were periodically sacrificed for the examination of cauda epididymal sperm profiles and the morphology of the testis. ADR treatment caused a decrease in sperm counts, sperm motility and the diameter of the seminiferous tubules, and an increase in the percentage of abnormal sperms. These damaging effects depended on the dosage and period of treatment with ADR. Based on these findings, rats with testicular dysfunction induced by the treatment with ADR at a daily dose of 0.25 mg/kg, three times a week for 5 weeks were prepared to investigate the effects of CH3-B12 on oligozoospermia. CH3-B12 was given intraperitoneally to the oligozoospermic rats six times a week for 5 and 10 weeks. The results obtained indicated that 1,000 micrograms/kg of CH3-B12 caused a significant increase in both the sperm counts and the diameter of the seminiferous tubules. These results suggest that CH3-B12 is a candidate drug for oligozoospermia.

Topics: Animals; Disease Models, Animal; Doxorubicin; Male; Rats; Rats, Inbred Strains; Sperm Count; Sperm Motility; Spermatogenesis; Testicular Diseases; Vitamin B 12

It has been proposed that the biochemical lesion in subacute combined degeneration of the cord due to vitamin B12 deficiency, is impaired methylation of residue 107 (arginine) in myelin basic protein. We have examined myelin basic protein in brains of rats in which vitamin B12 was inactivated by exposure to nitrous oxide for up to 7 days. In addition brains of fruit bats in which vitamin B12 neuropathy had been produced by feeding washed, and hence vitamin B12-free fruit, were examined. There was no difference in the methylation of arginine 107 in myelin basic protein in these animals as compared to healthy control animals. Rats given an inhibitor of transmethylation reactions (cycloleucine) showed the expected fall in methylation of myelin basic protein.

Topics: Animals; Arginine; Brain Diseases; Chiroptera; Cycloleucine; Disease Models, Animal; Liver; Methylation; Myelin Basic Protein; Rats; Rats, Inbred Strains; Vitamin B 12; Vitamin B 12 Deficiency

Four pairs of monkeys were maintained in an atmosphere of nitrous oxide under conditions which had previously been shown to produce subacute combined degeneration (SCD) of the spinal cord. The diet of one of each pair was supplemented with methionine. In every case the monkey with the unsupplemented diet became ataxic at around 10 weeks and the disorder progressed over a period of 2-3 weeks until the animal was moribund. During this period there was no detectable clinical change in the monkeys receiving methionine supplementation. Microscopical examination of the spinal cord and peripheral nerves of the unsupplemented monkeys showed the classical changes of SCD. The histological changes correlated with the clinical observations. Sections form the methionine-supplemented monkeys showed no change or only slight changes. These results suggest that, in these animals, inability to resynthesise methionine from homocysteine leads to SCD. It seems probable that the primary lesion producing SCD in human beings with pernicious anaemia is also inability to maintain methionine biosynthesis.

Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Humans; Macaca fascicularis; Methionine; Nitrous Oxide; Spinal Cord; Spinal Cord Diseases; Tetrahydrofolates; Vitamin B 12

Topics: Animals; Bone Marrow; Deoxyuridine; Disease Models, Animal; DNA; Female; Folic Acid; Formyltetrahydrofolates; Nitrous Oxide; Rats; Thymidine; Vitamin B 12; Vitamin B 12 Deficiency

A comparative experimentation between treatment with large amounts of vitamin B12 alone and associations of intrinsic factor with different concentrations of vitamin B12 in the gastrectomised dog and rat subjected to digestive stress induced by phenylbutazone is reported. This study served to examine the possible therapeutic role of vitamin B12 passive diffusion occurring with large amounts of cyanocobalamine in the digestive tract, and to verify the utility and efficacy of the intrinsic factor contained in the marketed Gastropylore, the composition of which associates an original lyophilisate of suckling lamb gastric mucosa (LLGM) with vitamin B12. Treatments with either of the components alone exerted no protective effect against phenylbutazone-induced ulcerations whereas Gastropylore gave very significant protection (p less than 0.00001). Enhancement of the vitamin did not yield any significant improvement. Weight increase after gastrectomy was clear in the three groups of animals treated with Gastropylore or LLGM containing vitamin B12. Vitamin B12 passive diffusion appears to play no important therapeutic role while the intrinsic factor contained in a lyophilised preparation of lamb gastric mucosa seems to prove useful.

Topics: Animals; Body Weight; Disease Models, Animal; Dogs; Female; Freeze Drying; Gastrectomy; Gastric Mucosa; Intestinal Mucosa; Male; Phenylbutazone; Rats; Sheep; Stomach Ulcer; Tissue Extracts; Vitamin B 12

Topics: Adolescent; Adult; Anemia, Megaloblastic; Animals; Antibody Formation; Child; Disease Models, Animal; DNA Replication; Folic Acid; Folic Acid Deficiency; Humans; Iron; Lectins; Lymphocytes; Middle Aged; Nutrition Disorders; Rats; Spleen; Thymus Gland; Transferrin; Vitamin B 12

Rats with surgically created self-filling jejunal blind loops and the blind loop syndrome manifested gastrointestinal bleeding and hyperabsorption of iron. Although the mean hematocrit and serum iron levels of rats with self-filling blind loops became overtly anemic and manifested low-serum iron levels. It is suggested that the documented gastrointestinal bleeding in these rats with the experimental blind loop syndrome is another manifestation of damage to the intestinal epithelium in conditions of small intestinal bacterial overgrowth.

Topics: Animals; Blind Loop Syndrome; Digestive System Physiological Phenomena; Disease Models, Animal; Feces; Gastrointestinal Hemorrhage; Guaiac; Hematocrit; Intestinal Absorption; Iron; Male; Occult Blood; Rats; Vitamin B 12

Topics: Animal Nutritional Physiological Phenomena; Animals; Body Weight; Bone Marrow Cells; Demyelinating Diseases; Disease Models, Animal; Erythrocyte Count; Erythrocytes; Folic Acid; Haplorhini; Hematocrit; Hemoglobins; Leukocyte Count; Liver; Macaca; Male; Malonates; Nervous System; Spinal Cord Diseases; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Ampicillin; Animals; Azo Compounds; Biopsy; Blood Cell Count; Body Weight; Disease Models, Animal; FIGLU Test; Folic Acid; Glutarates; Growth; Haplorhini; Hematocrit; Hepatectomy; Histidine; Liver; Male; Malonates; Papio; Propionates; Sodium; Valine; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Animals; Disease Models, Animal; Flurothyl; Folic Acid; Folic Acid Deficiency; Male; Phenobarbital; Rats; Seizures; Vitamin B 12

Topics: Animals; Body Weight; Brain; Carbon Radioisotopes; Cobamides; Diet; Disease Models, Animal; Liver; Malonates; Organ Size; Propionates; Rats; Spleen; Vitamin B 12; Vitamin B 12 Deficiency

The effect of partial pancreatectomy (80-90%) on vitamin B(12) absorption was studied in the rat. The absorption of 5 ng of (57)Co-labeled vitamin B(12) was significantly reduced from 70 +/-2.5% (mean +/-SE) in control and sham-operated rats to 32 +/-2.6% in partially pancreatectomized rats. Hog pancreatic extract (0.17 g/kg) improved vitamin B(12) absorption from 30.0 to 61.0% in partially pancreatectomized rats but did not alter vitamin B(12) absorption in control rats. Chloramphenicol did not enhance vitamin B(12) absorption in partially pancreatectomized rats with pancreatic extract-improved vitamin B(12) malabsorption. The partially pancreatectomized rats with pancreatic extract-improved vitamin B(12) malabsorption were sacrificed and the stomach and small bowel studied in vitro to further define the pathogenesis of the vitamin B(12) malabsorption. Rat gastric intrinsic factor stimulated vitamin B(12) uptake by intestinal sacs prepared from partially pancreatectomized rats 3.1-fold. Gastric intrinsic factor prepared from partially pancreatectomized rats was as effective in promoting vitamin B(12) uptake by rat intestinal sacs as intrinsic factor prepared from control rats. These data indicate that partially pancreatectomized rats develop an abnormality in the absorption of labeled vitamin B(12) which can be corrected by pancreatic extract. The vitamin B(12) malabsorption is due to neither an alteration in gastric intrinsic factor activity nor an impairment of the intrinsic factor-vitamin B(12) receptor in the intestine. It is suggested that in the partially pancreatectomized rats the intrinsic factor-vitamin B(12) complex exists in a form which is not available for absorption.

Topics: Animals; Body Weight; Chloramphenicol; Cobalt Isotopes; Disease Models, Animal; Gastric Mucosa; Intestinal Absorption; Intestine, Small; Intrinsic Factor; Malabsorption Syndromes; Male; Pancreas; Pancreatectomy; Rats; Vitamin B 12

Topics: Animals; Cobalt Isotopes; Disease Models, Animal; Dogs; Intestinal Absorption; Intestinal Diseases; Intestinal Obstruction; Intestine, Small; Ischemia; Methods; Molecular Weight; Time Factors; Vitamin B 12

Topics: Animals; Cardiomyopathies; Chlorides; Disease Models, Animal; Electrocardiography; Immobilization; Magnesium; Methods; Myocardium; Necrosis; Potassium Chloride; Rabbits; Vitamin B 12