s-allylcysteine and Disease-Models--Animal

The purpose of this review is to discuss the molecular mechanisms underlying the anticancer properties of S-allylcysteine (SAC). Over the decades, evidence derived from in vitro and in vivo studies has shown that this predominant organosulfur component of aged garlic extract has multiple anticancer properties; hence, some potential mechanisms responsible for the anticarcinogenic action have been suggested. These mechanisms include induction of carcinogen detoxification, inhibition of cell proliferation and growth, mediation of cell cycle arrest, induction of cell death, inhibition of epithelial-mesenchymal transition and cell invasion, suppression of metastasis, and induction of immunomodulation in cancer cells. However, the actions and mechanisms are not comprehensive, and important aspects of the anticancer activities of SAC still need to be explored. In light of the current evidence, more specific studies, specifically clinical and epidemiological, are required to advance the promising use of SAC as a chemopreventive and therapeutic agent in cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Proliferation; Cysteine; Disease Models, Animal; Garlic; Humans; Mice; Neoplasms; Rats

Topics: Aging; Animals; Cells, Cultured; Cognitive Dysfunction; Cysteine; Disease Models, Animal; Garlic; Hippocampus; Male; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Plant Extracts

In the present study, we evaluated the therapeutic potentiality of S-allylcysteine (SAC) in streptozotocin (STZ)-nicotinamide (NAD)-induced diabetic nephropathy (DN) in experimental rats.. SAC was orally administered for 45 days to rats with STZ-NAD-induced DN; a metformin-treated group was included for comparison. Effect of SAC on body weight, organ weight, blood glucose, levels of insulin, glycated haemoglobin, and renal biochemical markers was determined. Body composition by total body electrical conductivity (TOBEC) and dual-X ray absorptiometry (DXA), kidney antioxidant analysis, real-time polymerase chain reaction, and western blot analysis of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), nuclear factor kappa B (NF-κB), interleukin (IL)-6, and tumor necrosis factor (TNF)-α; histopathological and scanning electron microscope (SEM) analysis of the kidneys were performed in both control and experimental rats.. SAC treatment showed significantly decreased levels of blood glucose, glycated haemoglobin, creatinine, albumin, AST, ALT, creatinine kinase, lactate dehydrogenase, and expressions of NF-κB, IL-6, and TNF-α compared with DN control rats. Furthermore, SAC administration to DN rats significantly improved body composition and antioxidant defense mechanism which was confirmed by the upregulation of mRNA and protein expressions of antioxidant genes.. Thus, SAC showed adequate therapeutic effect against DN by downregulation of inflammatory factors and attenuation of oxidative stress. Histological and SEM observations also indicated that SAC treatment notably reverses renal damage and protects the kidneys from hyperglycemia-mediated oxidative damage.

Topics: Animals; Antineoplastic Agents; Antioxidants; Cysteine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Inflammation; Male; Niacinamide; Oxidative Stress; Rats; Rats, Wistar; Streptozocin

S-Allyl cysteine (SAC) is an active component in garlic and has various pharmacological effects, such as anti-inflammatory, anti-oxidant, and anti-cancer activities. In this study, we explored the suppressive effects of SAC on allergic airway inflammation induced in an ovalbumin (OVA)-induced asthma mouse model. To induce asthma, BALB/c mice were sensitized to OVA on days 0 and 14 by intraperitoneal injection and exposed to OVA from days 21 to 23 using a nebulizer. SAC was administered to mice by oral gavage at a dose of 10 or 20 mg/kg from days 18 to 23. SAC significantly reduced airway hyperresponsiveness, inflammatory cell counts, and Th2 type cytokines in bronchoalveolar lavage fluid induced by OVA exposure, which was accompanied by reduced serum OVA-specific immunoglobulin E. In histological analysis of the lung tissue, administration of SAC reduced inflammatory cell accumulation into lung tissue and mucus production in airway goblet cells induced by OVA exposure. Additionally, SAC significantly decreased MUC5AC expression and nuclear factor-κB phosphorylation induced by OVA exposure. In summary, SAC effectively suppressed allergic airway inflammation and mucus production in OVA-challenged asthmatic mice. Therefore, SAC shows potential for use in treating allergic asthma.

Topics: Allergens; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Cysteine; Cytokines; Disease Models, Animal; Eosinophilia; Female; Immunoglobulin E; Lung; Mice, Inbred BALB C; Mucus; Ovalbumin

Sepsis is a serious and life-threatening medical condition with a higher rate of patients' morbidity and mortality and with complications such as acute kidney injury (AKI). S-allyl cysteine (SAC) is the active constituent of the medicinal plant garlic (Allium sativum) with multiple beneficial effects including anti-inflammatory and antioxidant properties. In this research, we tried to determine the protective effect of SAC pretreatment in a mouse model of AKI. To induce AKI, lipopolysaccharide (LPS) was injected once (10 mg/kg, i.p.) and SAC was administered at doses of 25, 50, or 100 mg/kg (p.o.) 1 h before LPS. Treatment of LPS-challenged C56BL/6 animals with SAC lowered serum level of creatinine and blood urea nitrogen (BUN), partially restored renal oxidative stress-related biomarkers including malondialdehyde (MDA), glutathione (GSH), and activity of superoxide dismutase (SOD) and catalase in addition to improvement of mitochondrial membrane potential (MMP). Furthermore, SAC was capable to bring renal nuclear factor-kappaB (NF-κB), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), toll-like receptor 4 (TLR4), cyclooxygenase-2 (COX2), tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), Annexin V, and DNA fragmentation partially back to their control levels. Additionally, SAC pretreatment was capable to exert a protective effect, as shown histologically by lower tubular injury and pathologic changes in the kidney. In summary, SAC is capable to alleviate LPS-induced AKI through mitigation of renal oxidative stress, inflammation, and apoptosis in addition to preservation of mitochondrial integrity and its favorable effect exhibits a dose-dependent pattern.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Apoptosis; Creatinine; Cysteine; Disease Models, Animal; Garlic; Humans; Inflammation; Kidney; Lipopolysaccharides; Male; Malondialdehyde; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Oxidative Stress; Sepsis; Signal Transduction

Topics: Animals; Bleomycin; Cell Differentiation; Collagen; Cysteine; Disease Models, Animal; Gene Expression Regulation; Instillation, Drug; Male; Myofibroblasts; Pulmonary Fibrosis; Rats; Transforming Growth Factor beta1

Stroke is a devastating clinical condition for which an effective neuroprotective treatment is currently unavailable. S-allyl cysteine (SAC), the most abundant organosulfur compound in aged garlic extract, has been reported to possess neuroprotective effects against stroke. However, the mechanisms underlying its beneficial effects remain poorly defined. The present study tests the hypothesis that SAC attenuates ischemic neuronal injury by activating the nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent antioxidant response in both in vitro and in vivo models. Our findings demonstrate that SAC treatment resulted in an increase in Nrf2 protein levels and subsequent activation of antioxidant response element pathway genes in primary cultured neurons and mice. Exposure of primary neurons to SAC provided protection against oxygen and glucose deprivation-induced oxidative insults. In wild-type (Nrf2(+/+) ) mice, systemic administration of SAC attenuated middle cerebral artery occlusion-induced ischemic damage, a protective effect not observed in Nrf2 knockout (Nrf2(-/-) ) mice. Taken together, these findings provide the first evidence that activation of the Nrf2 antioxidant response by SAC is strongly associated with its neuroprotective effects against experimental stroke and suggest that targeting the Nrf2 pathway may provide therapeutic benefit for the treatment of stroke. The transcription factor Nrf2 is involved in cerebral ischemic disease and may be a promising target for the treatment of stroke. We provide novel evidence that SAC confers neuroprotection against ischemic stroke by activating the antioxidant Nrf2 signaling pathway. ARE, antioxidant response element; GCLC, glutathione cysteine ligase regulatory subunit; GCLM, glutathione cysteine ligase modulatory subunit; HO-1, heme oxygenase-1; JNK, c-Jun N-terminal kinase; Keap1, Kelch-like ECH-associated protein 1; Maf, musculoaponeurotic fibrosarcoma; Nrf2, nuclear factor erythroid-2-related factor 2; SAC, S-allyl cysteine; ROS, reactive oxygen species.

Topics: Animals; Animals, Newborn; Brain Infarction; Brain Ischemia; Cells, Cultured; Cerebral Cortex; Cysteine; Disease Models, Animal; Embryo, Mammalian; Glucose; Hypoxia; In Situ Nick-End Labeling; L-Lactate Dehydrogenase; Mice; Mice, Transgenic; Neurologic Examination; Neurons; Neuroprotective Agents; NF-E2-Related Factor 2; Signal Transduction

Sepsis is characterized by a severe production of reactive oxygen species (ROS) and other radical species with consequent oxidative stress. S-allyl cysteine (SAC) is a water-soluble organosulfur component present in garlic which is a potent antioxidant and free radical scavenger. In the present study, the purpose was to explore the anti-inflammatory, antioxidant, and anti-apoptotic actions of SAC on lipopolysaccharide (LPS)-induced sepsis in rats. Thirty-two male Wistar rats were separated into 4 groups. These were control, SAC control, sepsis, and sepsis + SAC-induced groups. Sepsis was induced by administration of LPS (5 mg/kg) into 2 groups. SAC (50 mg/kg) was given orally to SAC control and SAC treatment groups per 12 h during 2 days after intraperitoneal LPS injection. Serum AST, ALT, ALP, and hsCRP levels and liver and lung MPO, NO, and DNA fragmentation levels were evaluated. In sepsis group, elevated levels of ALT, AST, ALP, and hsCRP were observed. The abnormal increases were decreased in sepsis + SAC group compared to sepsis group. In lung tissue, MPO and NO levels were increased in sepsis group compared to the control group. MPO activity and NO levels were decreased by SAC application in sepsis + SAC group compared with sepsis group. In liver tissue, DNA fragmentation was significantly higher in sepsis group than that in the control group. In contrast, a decreased level of DNA fragmentation was noted in sepsis + SAC group when compared with the sepsis group. In conclusion, SAC ameliorates LPS-induced indicators of liver damage and suppresses the discharge of NO and MPO in lung tissue via its antioxidant properties.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antioxidants; Aspartate Aminotransferases; C-Reactive Protein; Cysteine; Disease Models, Animal; DNA Fragmentation; Lipopolysaccharides; Liver; Lung; Male; Nitric Oxide; Peroxidase; Rats, Wistar; Sepsis

Retinal ischemia-associated ocular disorders are vision-threatening. The aim of the present study was to examine whether S-allyl l-cysteine (SAC) is able to protect against retina ischemia/reperfusion injury.. In vivo, retinal ischemia in the rat was induced by raising intraocular pressure (IOP) to 120 mmHg for 60 min. In vitro, an ischemic-like insult, namely oxidative stress, was established by incubating retinal ganglion cell-5 (RGC-5) with 500 μM H(2)O(2) for 24 h. The mechanisms involved in these processes were evaluated by electrophysiology, immunohistochemistry, and molecular biological approaches.. The retinal changes caused by the high IOP were characterized by a decrease in electroretinogram b-wave amplitudes, a loss of choline acetyltransferase immunolabeling amacrine cell bodies/neuronal processes, and an upregulation of the mRNA levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelium growth factor (VEGF), and matrix metalloproteinase-9 (MMP-9). The increased protein levels of HIF-1α, VEGF, and MMP-9 were also seen in RGC-5 cells subjected to defined oxidative stress. Of clinical importance, the ischemic/ischemic-like detrimental effects were concentration-dependently (least effect at 25 μM) and/or significantly (50 and/or 100 μM) blunted when SAC was applied 15 min before retinal ischemia or ischemic-like insult, respectively.. SAC would seem to protect against retinal ischemia by acting as an antioxidant and inhibiting the upregulation of HIF-1α, VEGF, and MMP-9.

Topics: Animals; Antioxidants; Cell Line; Cysteine; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Hypoxia-Inducible Factor 1, alpha Subunit; Intraocular Pressure; Ischemia; Matrix Metalloproteinase 9; Oxidative Stress; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reperfusion Injury; Retina; RNA, Messenger; Treatment Outcome; Vascular Endothelial Growth Factor A

Alzheimer's disease (AD) is one of the most common forms of dementia in the elderly. In AD patients, β-amyloid peptide (Aβ) plaques and neurofibrillary tangles are common features observed in the CNS. Aβ deposition results in the production of reactive oxygen species (ROS) leading to the hyperphosphorylation of tau that are associated with neuronal damage. Cholinesterase inhibitors and a partial NMDA receptor antagonist (memantine) have been identified as potential treatment options for AD. However, clinical studies have found that these drugs fail to prevent the disease progression. From ancient times, garlic (Allium sativum) has been used to treat several diseases. By 'aging' of garlic, some adverse reactions of garlic can be eliminated. Recent findings suggest that 'aged garlic extract' (AGE) may be a therapeutic agent for AD because of its antioxidant and Aβ lowering properties. To date, the molecular properties of AGE have been sparsely studied in vitro or in vivo. The present study tested specific biochemical and molecular effects of AGE in neuronal and AD rodent models. Furthermore, we identified S-allyl-L-cysteine (SAC) as one of the most active chemicals responsible for the AGE-mediated effect(s). We observed significant neuroprotective and neurorescue properties of AGE and one of its ingredients, SAC, from ROS (H(2)O(2))-mediated insults to neuronal cells. Treatment of AGE and SAC were found to protect neuronal cells when they were independently co-treated with ROS. Furthermore, a novel neuropreservation effect of AGE was detected in that pre-treatment with AGE alone protected ∼ 80% neuronal cells from ROS-mediated damage. AGE was also found to preserve pre-synaptic protein synaptosomal associated protein of 25 kDa (SNAP25) from ROS-mediated insult. For example, treatment with 2% AGE containing diet and SAC (20 mg/kg of diet) independently increased (∼70%) levels of SNAP25 and synaptophysin in Alzheimer's amyloid precursor protein-transgenic mice, of which the latter was significantly decreased in AD. Taken together, the neuroprotective, including preservation of pre-synaptic proteins by AGE and SAC can be utilized in future drug development in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Cell Line, Transformed; Cysteine; Disease Models, Animal; Exploratory Behavior; Garlic; Gene Expression Regulation; Humans; Hydrogen Peroxide; L-Lactate Dehydrogenase; Memory, Short-Term; Mice; Mice, Transgenic; Neurons; Neuroprostanes; Plant Extracts; Rats; Reactive Oxygen Species; Synapses; Synaptophysin; Synaptosomal-Associated Protein 25; Time Factors

S-allyl cysteine (SAC), a sulfur containing amino acid derived from garlic, has been reported to have antioxidant, anti-cancer, antihepatotoxic and neurotrophic activity. This study was designed to examine the pre-treatment effects of SAC on cognitive deficits and oxidative damage in the hippocampus of intracerebroventricular streptozotocin (ICV-STZ)-infused mice. Mice pre-treated with SAC (30mg/kg) and vehicle (intraperitoneal; once daily for 15days) were bilaterally injected with ICV-STZ (2.57mg/kg body weight), whereas sham rats received the same volume of vehicle. The pre-treatment of this drug to Swiss albino mice has prevented the cognitive and neurobehavioral impairments. An increased latency and path length were observed in lesion, i.e. streptozotocin (STZ) group as compared to sham group and these were protected significantly in STZ group pre-treated with SAC. Levels of reduced glutathione (GSH) and its dependent enzymes (Glutathione peroxidase [GPx] and glutathione reductase [GR]) were decreased in STZ group as compared to sham group and pre-treatment of STZ group with SAC has protected their activities significantly. Conversely, the elevated level of thiobarbituric acid reactive substances (TBARS) in STZ group was attenuated significantly in SAC pre-treated group when compared with STZ lesioned group. Apoptotic parameters like DNA fragmentation, expression of Bcl2 and p53 were protected by the pre-treatment of SAC against STZ induced cognitive impairment. This study concludes that intervention of SAC could prevent free radicals associated deterioration of cognitive functions and neurobehavioral activities.

Topics: Alzheimer Disease; Animals; Antioxidants; Apoptosis; Cysteine; Disease Models, Animal; Immunohistochemistry; Injections, Intraventricular; Maze Learning; Mice; Nerve Degeneration; Neurotoxins; Oxidative Stress; Streptozocin

The neuroprotective effects of s-allyl cysteine, s-ethyl cysteine, and s-propyl cysteine in D-galactose (DG)-treated mice were examined. DG treatment increased the formation of Aβ(1-40) and Aβ(1-42), enhanced mRNA expression of β-amyloid precursor protein (APP) and β-site APP cleavage enzyme 1 (BACE1), and reduced neprilysin expression in brain (P < 0.05); however, the intake of three test compounds significantly decreased the production of Aβ(1-40) and Aβ(1-42) and suppressed the expression of APP and BACE1 (P < 0.05). DG treatments declined brain protein kinase C (PKC) activity and mRNA expression (P < 0.05). Intake of test compounds significantly retained PKC activity, and the expression of PKC-α and PKC-γ (P < 0.05). DG treatments elevated brain activity and mRNA expression of aldose reductase (AR) and sorbitol dehydrogenase as well as increased brain levels of carboxymethyllysine (CML), pentosidine, sorbitol, and fructose (P < 0.05). Test compounds significantly lowered AR activity, AR expression, and CML and pentosidine levels (P < 0.05). DG treatments also significantly increased the formation of reactive oxygen species (ROS) and protein carbonyl and decreased the activity of glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (P < 0.05); however, the intake of test compounds in DG-treated mice significantly decreased ROS and protein carbonyl levels and restored brain GPX, SOD, and catalase activities (P < 0.05). These findings support that these compounds via their anti-Aβ, antiglycative, and antioxidative effects were potent agents against the progression of neurodegenerative disorders such as Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Cysteine; Disease Models, Animal; Galactose; Glycosylation; Humans; Male; Mice; Mice, Inbred C57BL; Oxidative Stress

The functional preservation of nerve endings since the early stages of toxicity in a given damaging insult-either acute or chronic-by means of antioxidant and neuroprotective agents is a primary need to design therapeutic strategies for neurodegenerative disorders, with particular emphasis on those diseases with excitotoxic and depleted energy metabolism components. S-allylcysteine (SAC), a well-known antioxidant agent, was tested as a post-treatment in different in vitro and in vivo neurotoxic models. Quinolinic acid (QUIN) was used as a typical excitotoxic/pro-oxidant inducer, 3-nitropropionic acid (3-NP) was employed as a mitochondrial function inhibitor, and their combination (QUIN + 3-NP) was also evaluated in in vitro studies. For in vitro purposes, increasing concentrations of SAC (10-100 microM) were added to isolated brain synaptosomes at different times (1, 3 and 6 h) after the incubation with toxins (100 microM QUIN, 1 mM 3-NP or the combination of QUIN (21 microM) + 3-NP (166 microM). Thirty minutes later, lipid peroxidation (LP) and mitochondrial dysfunction (MD) were evaluated. For in vivo studies, SAC (100 mg/kg, i.p.) was given to QUIN- or 3-NP-striatally lesioned rats for 7 consecutive days (starting 120 min post-lesion). LP and MD were evaluated 7 days post-lesion in isolated striatal synaptosomes. Circling behavior was also assessed. Our results describe a differential pattern of protection achieved by SAC, mostly expressed in the 3-NP toxic model, in which nerve ending protection was found within the first hours (1 and 3) after the toxic insult started, supporting the concept that the ongoing oxidative damage and energy depletion can be treated during the first stages of neurotoxic events.

Topics: Animals; Antioxidants; Brain; Corpus Striatum; Cysteine; Disease Models, Animal; Dyskinesia, Drug-Induced; Lipid Peroxidation; Male; Mitochondria; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Nitro Compounds; Oxidative Stress; Propionates; Quinolinic Acid; Rats; Rats, Wistar; Synaptosomes; Time Factors

We have recently demonstrated that S-allylcysteine (SAC) induces protection on neurochemical, biochemical and behavioral markers of striatal damage in different neurotoxic animal models - including a murine model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridinium (MPTP) injection to mice - indicating that pro-oxidant reactions underlie neurotoxicity in these models (García et al. 2008). In this work we investigated whether SAC can protect the striatum of mice from the morphological alterations in the MPTP toxic model, and if this response is correlated with a reduction in pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) expressions, and further reduction in astrocyte activation (glial fibrillary acidic protein (GFAP) expression). The striatal tissue from MPTP injected animals (30 mg/kg, i.p., ×5 days) showed a significant degree of cell damage and enhanced immunoreactivities to GFAP, TNF-α and iNOS, as well as an enhanced number of apoptotic nuclei. Treatment of mice with SAC (120 mg/kg, i.p., ×5 days) in parallel to MPTP significantly reduced or prevented all these markers. Our results suggest that MPTP-induced morphological alterations recruit a pro-inflammatory component triggered by cytokine TNF-α release and nitric oxide formation, which is sensitive to the antioxidant properties of SAC. This antioxidant is an effective experimental tool to reduce the brain lesions associated with oxidative damage and inflammatory responses.

Topics: Animals; Antioxidants; Apoptosis; Corpus Striatum; Cysteine; Disease Models, Animal; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; MPTP Poisoning; Neuroprotective Agents; Nitric Oxide Synthase Type II; Tumor Necrosis Factor-alpha

Hepatic fibrosis is a chronic progressive disorder with a poor prognosis for which no definitive treatment exists. S-allylcysteine (SAC), an ingredient of aged garlic extract, is known to have antioxidant and hepatoprotective effects. The aim of this study was to investigate the antifibrotic effects of SAC in the liver.. Hepatic fibrosis was induced in male Wistar rats by porcine serum (PS) intraperitoneal injection. SAC (0.15% of basal diet) or N-acetylcysteine (NAC, 0.45% of basal diet) was orally administered for 12 weeks. Liver damage was assessed by the levels of plasma alanine aminotransferase (ALT), hepatic lipid peroxides (LPO), and hepatic total thiols 12 weeks after first PS injection. Area of fibrosis was examined by Azan-Mallory staining. Hydroxyproline content of liver were assessed as an index of collagen content. Liver was examined for expression of alpha-smooth muscle actin (alpha-SMA) as a marker of hepatic stellate cell (HSC) activation.. There were no significant differences in levels of plasma ALT, hepatic LPO, or hepatic total thiols among the groups. PS significantly increased area of fibrosis and hydroxyproline content in the liver. SAC and NAC each markedly attenuated the development ofhepatic fibrosis. SAC and NAC markedly suppressed the PS-induced increase in alpha-SMA expressions.. Oral administration of SAC reduced PS-induced hepatic fibrosis in rats via inhibition of HSC activation. SAC could provide a new therapeutic strategy for hepatic fibrosis.

Topics: Acetylcysteine; Actins; Alanine Transaminase; Animals; Anticarcinogenic Agents; Chemoprevention; Cysteine; Disease Models, Animal; Hepatic Stellate Cells; Lipid Peroxidation; Liver; Liver Cirrhosis; Male; Rats; Rats, Wistar; Serum; Sulfhydryl Compounds; Swine; Treatment Outcome

Experimental evidence on the protective properties of S-allylcysteine (SAC) was collected from three models exerting striatal toxicity. In the first model, SAC (120 mg kg(-1)x5) prevented lipoperoxidation (LP) and mitochondrial dysfunction (MD) in synaptosomal fractions from 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridinium-treated mice (30 mg kg(-1)), but without complete restoration of dopamine levels. In the second model, SAC (300 mg kg(-1)x 3), prevented LP and MD in synaptosomes from rats infused with 6-hydroxydopamine (8 microg microl(-1)) into the substantia nigra pars compacta, but again, without total reversion of depleted dopamine levels. In the third model, SAC (100 mg kg(-1)x 1) prevented MD in synaptosomes from rats injected with 3-nitropropionic acid (10 mg kg(-1)), but in contrast to the other models, it failed to prevent LP. SAC also prevented the aberrant motor activity patterns evoked by the three toxins. Altogether, the results suggest that the antioxidant properties of SAC are responsible for partial or total preservation of neurochemical, biochemical and behavioural markers, indicating that pro-oxidant reactions underlie the neurotoxicity in these models.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antioxidants; Basal Ganglia; Behavior, Animal; Biomarkers; Cysteine; Disease Models, Animal; Dopamine; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Mitochondria; Motor Activity; MPTP Poisoning; Neuroprotective Agents; Neurotoxicity Syndromes; Nitro Compounds; Oxidative Stress; Oxidopamine; Propionates; Rats; Rats, Wistar; Synaptosomes; Time Factors

Carcinoma of the stomach is reportedly the second most common cancerous condition affecting the general population. Administration of antioxidants is reported to effectively alleviate the risk of gastric carcinoma. Therefore, we assessed the protective role of naringenin, an antioxidant and naturally occurring citrus flavanone, on gastric carcinogenesis induced by MNNG (200 mg/kg body weight) and S-NaCl (1 mL per rat) in Wistar rats (obtained from the Central Animal House Facility, University of Madras, Taramani Campus, Chennai, India). The animals were divided into 5 groups, and the effects of naringenin on simultaneous and posttreated stages of MNNG were tested. Cancer risk was analyzed along with their antioxidant status. The LPO levels in the experimental groups were assessed as an index of oxidative milieu. Altered redox status was subsequently investigated by assaying the superoxide and hydroxyl radicals, the enzymatic antioxidants (SOD, CAT, GPx), and the nonenzymatic antioxidants viz reduced GSH, vitamin C, and vitamin E. In the presence of MNNG, cancer incidence and LPO levels were significantly increased, whereas enzymatic (SOD, CAT, and GPx) and nonenzymatic antioxidant activities (GSH, Vitamins C, and E) were decreased in the treated rats compared with control rats. Administration of naringenin to gastric carcinoma-induced rats largely up-regulated the redox status to decrease the risk of cancer. We conclude that up-regulation of antioxidants by naringenin treatment might be responsible for the anticancer effect in gastric carcinoma.

Topics: Animals; Antineoplastic Agents; Antioxidants; Carcinoma; Cysteine; Disease Models, Animal; Flavanones; Gastric Mucosa; Lipid Peroxidation; Male; Methylnitronitrosoguanidine; Oxidation-Reduction; Random Allocation; Rats; Rats, Wistar; Reactive Oxygen Species; Stomach Neoplasms; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Weight Loss

Garlic has been reported to have chemopreventive effects against a variety of cancers. However, different garlic preparations contain different constituents. We investigated the chemopreventive effect of aged garlic extract (AGE), an odorless product from prolonged extraction of fresh garlic, on colon carcinogenesis and cell proliferation in 1,2-dimethylhydrazine (DMH)-induced colon neoplastic rats. Rats were given weekly subcutaneous injections of DMH (20 mg/kg) for 20 wk, and fed either a basal diet or one containing 4% AGE. Serum from AGE-treated rats contained detectable S-allylcysteine. The AGE diet significantly reduced the number of colon tumors and aberrant crypt foci compared to the basal diet. Cell proliferation of normal-appearing colonic mucosa was assessed by MIB-5 immunohistochemistry. AGE treatment significantly decreased the mean MIB-5-labeling index. These findings suggest AGE has a chemopreventive effect on colon carcinogenesis through suppression of cell proliferation.

Topics: 1,2-Dimethylhydrazine; Animals; Anticarcinogenic Agents; Carcinogens; Colonic Neoplasms; Cysteine; Disease Models, Animal; Garlic; Male; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley

Multiple components present in garlic and various garlic preparations are known to exert pleiotropic protective effects as demonstrated in various in vitro and in vivo model systems. However, garlic pleiotropy in relation to Alzheimer's pathophysiology has not been explored extensively. Current study investigated anti-amyloidogenic, anti-inflammatory and anti-tangle effects of dietary aged garlic extract (AGE) (2%) and compared with its prominent constituents, i.e. S-allyl-cysteine (SAC) (20 mg/kg) and di-allyl-disulfide (DADS) (20 mg/kg) in Alzheimer's Swedish double mutant mouse model (Tg2576). Possible cholesterol-dependent and cholesterol-independent mechanisms of actions of AGE, SAC and DADS in exerting anti-amyloidogenic, anti-inflammatory and anti-tangle effects are discussed. Finally, ameliorative effects of dietary interventions were found to be in the order of AGE>SAC>DADS. If validated pre-clinically, dietary intervention with herbal alternative such as AGE having pleiotropic useful properties and least adverse effects may provide greater therapeutic benefit over a single-ingredient synthetic pharmaceutical drug having serious side effects in treating Alzheimer's disease.

Topics: Allyl Compounds; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Blotting, Western; Brain; Cysteine; Disease Models, Animal; Disulfides; Enzyme-Linked Immunosorbent Assay; Female; Garlic; Humans; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Phosphorylation; Plant Extracts; Protein Processing, Post-Translational; tau Proteins

S-Allyl-L-cysteine (SAC), an active organosulfur compound derived from garlic, was found to reduce mortality with lesser incidence of stroke and also to lower the overall stroke-related behavioral score in stroke-prone spontaneously hypertensive (SHRSP) rats by dietary administration. Consequently, the anti-stroke effect of dietary SAC was demonstrated in SHRSP rats.

Topics: Administration, Oral; Animals; Behavior, Animal; Cysteine; Diet; Disease Models, Animal; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stroke; Survival Rate

Combination chemoprevention by diet-derived agents that induce apoptosis is a promising strategy to control gastric cancer, the second most common malignancy worldwide. The present study was undertaken to investigate the apoptosis-inducing potential of a combination of S-allylcysteine (SAC), an organosulphur constituent of garlic and lycopene, a tomato carotenoid during N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) and saturated sodium chloride (S-NaCl)-induced gastric carcinogenesis in Wistar rats using the apoptosis-associated proteins Bcl-2, Bax, Bim, caspase 8 and caspase 3 as markers. Animals administered MNNG followed by S-NaCl developed squamous cell carcinomas of the stomach associated with increased Bcl-2 expression and decreased expression of Bax, Bim, caspase 8 and caspase 3. Although SAC and lycopene alone significantly suppressed the development of gastric cancer, administration of SAC and lycopene in combination was more effective in inhibiting MNNG-induced stomach tumours and modulating the expression of apoptosis-associated proteins. Our results suggest that induction of apoptosis by SAC and lycopene combination represents one of the possible mechanisms that could account for their synergistic chemopreventive activity against gastric cancer.

Topics: Analysis of Variance; Animals; Apoptosis; bcl-2-Associated X Protein; Biomarkers, Tumor; Blotting, Western; Carotenoids; Caspase 3; Caspases; Chemoprevention; Cysteine; Disease Models, Animal; Drug Therapy, Combination; Lycopene; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Probability; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Rats; Rats, Wistar; Sensitivity and Specificity; Stomach Neoplasms

We investigated the chemopreventive effect of S-allylcysteine (SAC), a water-soluble garlic constituent against gastric carcinogenesis induced in male Wistar rats by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and saturated sodium chloride (S-NaCl). The animals were divided into four groups of six animals. Rats in groups 1 and 2 were administered MNNG (200 mg/kg body weight) on days 0 and 14 as well as S-NaCl (1 mL/rat) three days during weeks 0 to 3, and thereafter placed on basal diet until the end of the experiment. Rats in group 2 in addition received SAC (200 mg/kg body weight) three times per week starting on the day following the first exposure to MNNG and continued until the end of the experimental period. Group 3 animals were given SAC alone as in group 2. Group 4 animals received basal diet and tap water throughout the experiment and served as the untreated control. The animals were sacrificed after an experimental period of 21 weeks. Measurement of lipid peroxidation and antioxidants of the glutathione redox cycle in the stomach tissue, liver and venous blood was used to monitor the chemopreventive potential of SAC. All animals that received MNNG and S-NaCl alone, developed tumours, identified histologically as squamous cell carcinomas. In the tumour tissue, diminished lipid peroxidation was accompanied by increase in reduced glutathione (GSH) and GSH-dependent enzymes, whereas in the liver and circulation, enhanced lipid peroxidation was associated with antioxidant depletion. Administration of SAC suppressed the incidence of MNNG+S-NaCl-induced gastric tumours as revealed by the absence of carcinomas. SAC ameliorated MNNG-induced decreased susceptibility of the gastric mucosa to lipid peroxidation, whilst simultaneously increasing the antioxidant status. In the liver and blood, SAC reduced the extent of lipid peroxidation and significantly enhanced antioxidant activities. We suggest that SAC exerts its chemopreventive effects by modulating lipid peroxidation and enhancing GSH-dependent antioxidants in the target organ as well as in the liver and blood.

Topics: Animals; Antineoplastic Agents; Antioxidants; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cysteine; Disease Models, Animal; Gastric Mucosa; Glutathione; Lipid Peroxidation; Liver; Male; Methylnitronitrosoguanidine; Oxidants; Oxidation-Reduction; Rats; Rats, Wistar; Sodium Chloride; Stomach Neoplasms

The efficacy of S-allylcysteine (SAC) as a free radical scavenger was studied using rat brain ischemia models. In a middle cerebral artery occlusion model, preischemic administration of SAC had the following effects: it improved motor performance and memory impairment and reduced water content and the infarct size. In a transient global ischemia model, the time course of free radical (alkoxyl radical) formation as studied by electron paramagnetic resonance (EPR) spectroscopy and alpha-phenyl-N-tert-butylnitrone (PBN) was biphasic; the first peak occurred at 5 min and the second at 20 min after reperfusion. Although SAC did not attenuate the first peak, it did affect the second peak, which is related to lipid peroxidation. The lipid peroxidation as estimated by thiobarbituric acid reactive substances (TBARS) increased significantly at 20 min after reperfusion. SAC decreased TBARS to the levels found without ischemia. These results suggest that SAC could have beneficial effects in brain ischemia and that the major protective mechanism may be the inhibition of free radical-mediated lipid peroxidation.

Topics: Animals; Antioxidants; Cysteine; Disease Models, Animal; Dose-Response Relationship, Drug; Electron Spin Resonance Spectroscopy; Free Radicals; Ischemic Attack, Transient; Lipid Peroxidation; Male; Memory Disorders; Neurons; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thiobarbituric Acid Reactive Substances; Time Factors; Water

Epidemiological and experimental studies suggest that consumption of garlic may protect against several types of cancer. Moreover, a plausible hypothesis has been proposed that the biological effects of garlic can be attributed to the enhancing action of a variety of organosulfur compounds, present in garlic, on hepatic phase II carcinogen detoxification enzymes. We have used the N-methylnitrosourea (NMU)-induced rat mammary tumor model to test the chemopreventive effects of a water-soluble organosulfur constituent derived from aged garlic, S-allylcysteine (SAC). Rats were fed diets supplemented with 666 and 2,000 ppm SAC beginning seven days before initiation with NMU (55 days of age) to termination (18 wk post-NMU), at which time mammary tumors were enumerated. At neither dose did SAC exert an inhibitory effect on any index of tumor development, including incidence, latency, multiplicity, or volume, compared with untreated controls. Weight gains in all groups were similar. Assay of serum SAC levels in supplemented groups indicated that SAC concentrations were beneath the limits of detection of the high-performance liquid chromatography system used. These results contradict previous animal model studies indicating that SAC acts as an inhibitory agent in experimental mammary tumorigenesis; reasons for this discrepancy include the possibility that SAC may exhibit nonlinear dose effects.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Carcinogens; Chromatography, High Pressure Liquid; Cysteine; Diet; Disease Models, Animal; Disease-Free Survival; Female; Garlic; Mammary Neoplasms, Experimental; Methylnitrosourea; Plants, Medicinal; Random Allocation; Rats; Rats, Sprague-Dawley