Mercuric Chloride Induced Ovarian Oxidative Stress by Suppressing Nrf2-Keap1 Signal Pathway and its Downstream Genes in Laying Hens

Over the last decade, there has been an increased concern about the health risks from exposure to arsenic at low doses, because of their neurotoxic effects on the developing brain. The exact mechanism underlying arsenic-induced neurotoxicity during sensitive periods of brain development remains unclear, although enhanced oxidative stresses, leading to mitochondrial dysfunctions might be involved. Here, we highlight the generation of reactive oxygen species (ROS) and oxidative stress which leads to mitochondrial dysfunctions and apoptosis in arsenic-induced developmental neurotoxicity. Here, the administration of sodium arsenite at doses of 2 or 4 mg/kg body weight in female rats from gestational to lactational (GD6-PD21) resulted to increased ROS, led to oxidative stress, and increased the apoptosis in the frontal cortex, hippocampus, and corpus striatum of developing rats on PD22, compared to controls. Enhanced levels of ROS were associated with decreased mitochondrial membrane potential and the activity of mitochondrial complexes, and hampered antioxidant levels. Further, neuronal apoptosis, as measured by changes in the expression of pro-apoptotic (Bax, Caspase-3), anti-apoptotic (Bcl2), and stress marker proteins (p-p38, pJNK) in arsenic-exposed rats, was discussed. The severities of changes were found to more persist in the corpus striatum than in other brain regions of arsenic-exposed rats even after the withdrawal of exposure on PD45 as compared to controls. Therefore, our results indicate that perinatal arsenic exposure leads to abrupt changes in ROS, oxidative stress, and mitochondrial functions and that apoptotic factor in different brain regions of rats might contribute to this arsenic-induced developmental neurotoxicity.     

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Abstract

Arsenic-induced tissue damage is a major concern to the human population. An impaired antioxidant defense mechanism followed by oxidative stress is the major cause of arsenic-induced toxicity, which can lead to reproductive failure. The present study was carried out to investigate the preventive role of arjunolic acid, a triterpenoid saponin isolated from the bark of Terminalia arjuna, against arsenic-induced testicular damage in mice. Administration of arsenic (in the form of sodium arsenite, NaAsO₂, at a dose of 10 mg/kg body weight) for 2 days significantly decreased the intracellular antioxidant power, the activities of the antioxidant enzymes, as well as the levels of cellular metabolites. In addition, arsenic intoxication enhanced testicular arsenic content, lipid peroxidation, protein carbonylation and the level of glutathione disulfide (GSSG). Exposure to arsenic also caused significant degeneration of the seminiferous tubules with necrosis and defoliation of spermatocytes. Pretreatment with arjunolic acid at a dose of 20 mg/kg body weight for 4 days could prevent the arsenic-induced testicular oxidative stress and injury to the histological structures of the testes. Arjunolic acid had free radical scavenging activity in a cell-free system and antioxidant power in vivo. In summary, the results suggest that the chemopreventive role of arjunolic acid against arsenic-induced testicular toxicity may be due to its intrinsic antioxidant property.     

Neuroglobin Involvement in the Course of Arsenic Toxicity in Rat Cerebellar Granule Neurons

Exposure to arsenic in drinking water results in a widespread environmental problem in the world, and the brain is a major target. Neuroglobin is a vertebrate heme protein regarded as playing neuroprotective role in hypoxia or oxidative stress. In this study, we investigated the toxic effects of sodium arsenite (NaAsO₂) on primary cultured rat cerebellar granule neurons (CGNs) and detected neuroglobin (Ngb) expression in rat CGNs exposed to NaAsO₂. Our results show that apoptosis was obviously induced by NaAsO₂ treatment in rat CGNs by annexin V-fluorescein isothiocyanate assay. Intracellular reactive oxygen species generation increased significantly in the cells exposed to NaAsO₂, and the apoptotic effects could be partially reversed by antioxidant N-acetyl-l-cysteine. Ngb protein and mRNA expression were significantly downregulated in rat CGNs shortly after NaAsO₂ exposure and then upregulated after a longer time of exposure. Furthermore, mRNA expression changed more than protein expression and the toxic effect of NaAsO₂ on Ngb expression is dose dependent. Higher Ngb expression was also detected in rat cerebellum, but not in other parts (cerebrum, hippocampus, and midbrain) of the brain exposed to NaAsO₂ for 16 weeks. Taken together, cytotoxic effects of NaAsO₂ on rat CGNs is induced at least partly by oxidative stress and Ngb may influence the course of arsenic toxicity in rat CGNs and rat cerebellum.     

Influence of Age on Arsenic-Induced Oxidative Stress in Rat

Influence of age on arsenic-induced (0.05, 0.1, and 0.2 lethal dose to 50?% population (LD₅₀) given intraperitoneally) oxidative stress was investigated in young, adult, and old rats at days?7 and 14 post-exposure. A significant dose-dependent effect of arsenic on biochemical variables suggestive of oxidative stress was noted at day?7 following exposure in old rats. The parameters which were significantly altered include an increased reactive oxygen species, thiobarbituric acid reactive substances (TBARS), catalase activity accompanied by a decreased glutathione level. At day?14 following arsenic exposure (0.05 and 0.1 LD₅₀ dose), we observed a significant oxidative injury as evident from significant depletion of superoxide dismutase (SOD) and catalase activities in blood and tissues in addition to more pronounced accumulation of arsenic in blood and tissues. Interestingly, the toxicity was pronounced in young and old rats compared with adult rats. Accumulation of arsenic found to be more prominent in old rats compared with young and adult, which might be due to impaired metabolism with ageing. We conclude that young and old animals are more vulnerable to the arsenic-induced oxidative injury which is comparable with arsenic accumulation in blood and tissues and duration of exposure.     

Nanoencapsulation of quercetin enhances its dietary efficacy in combating arsenic-induced oxidative damage in liver and brain of rats

AimsThis study was performed to evaluate the therapeutic efficacy of nanocapsulated flavonoidal quercetin (QC) in combating arsenic-induced reactive oxygen species (ROS)-mediated oxidative damage in hepatocytes and brain cells in a rat model.Main methodsHepatic and neuronal cell damage in rats was made by a single injection (sc) of sodium arsenite (NaAsO₂, 13 mg/kg b. wt. in 0.5 ml of physiological saline). A single dose of 500 µl of quercetin suspension (QC) (QC 8.98 µmol/kg) or 500 µl of nanocapsulated QC (NPQC) (QC 8.98 µmol/kg) was given orally to rats at 90 min prior to the arsenite injection.Key findingsInorganic arsenic depositions (182 ± 15.6 and 110 ± 12.8 ng/g protein) were found in hepatic and neuronal mitochondrial membranes. Antioxidant levels in hepatic and neuronal cells were reduced significantly by arsenic. NPQC prevented the arsenite-induced reduction in antioxidant levels in the liver and brain. Arsenic induced a substantial decrease in liver and brain cell membrane microviscosities, and NPQC treatment resulted in a unique protection against the loss. A significant correlation between mitochondrial arsenic and its conjugated diene level was observed both in liver and brain cells for all experimental rats.SignificanceArsenic-specific antidotes are used against arsenic-induced toxicity. However, the target site is poorly recognized and therefore achieving an active concentration of drug molecules can be a challenge. Thus, our objective was to formulate NPQC and to investigate its therapeutic potential in an oral route against arsenite-induced hepatic and neuronal cell damage in a rat model.     

Prophylactic role of taurine on arsenic mediated oxidative renal dysfunction via MAPKs/ NF-κB and mitochondria dependent pathways

The present study has been designed and carried out to investigate the protective role of taurine (2-aminoethanesulphonic acid) against NaAsO₂ induced nephrotoxicity. Oral administration of arsenic increased the productions of ROS and RNS, enhanced lipid peroxidation, protein carbonylation and decreased intracellular antioxidant defence in the kidney tissue. Investigating the responsible signalling cascades, it was found that NaAsO₂ administration activates mitogen-activated protein kinases (MAPKs) and NF-κB in oxidative stress mediated renal dysfunction and induced apoptotic cell death by the reciprocal regulation of Bcl-2/Bad in association with reducing mitochondrial membrane potential and increased cytosolic cytochrome C as well. Treatment with taurine prior to arsenic administration effectively ameliorated As-induced oxidative renal dysfunctions and apoptotic cell death. Histological studies also support the experimental findings. Combining, results suggest that taurine possesses the ability to ameliorate arsenic-induced oxidative insult and renal damage, probably due to its antioxidant activity and functioning via MAPKs/NF-κB and mitochondria dependent pathways.     

MiADMSA Protects Arsenic-Induced Oxidative Stress in Human Keratinocyte ‘HaCaT’ Cells

Arsenic toxicity may lead to skin manifestations and arsenic accumulation in keratinised tissue. Thus human keratinocytes has been extensively used to study dermal effects of arsenic exposure. The present study was aimed to investigate time and dose-dependent effects of arsenic using HaCaT cell line. Another major focus of the study was to evaluate if treatment with monoisoamyl dimercaptosuccinic acid (MiADMSA) offers protection against arsenic-induced oxidative stress and apoptotic cell death using HaCaT cells. HaCaT cell lines were incubated to three different concentrations of arsenic (10, 30 and 50 μM) for 24 h to identify the toxic dose by measuring oxidative stress variables. Later, MiADMSA pre-incubation for an hour preceded arsenic exposure (30 μM). We evaluated cell morphology, lactate dehydrogenase, glutathione linked enzyme and antioxidant enzyme activities to measure oxidative stress status, while MTT assay and caspase 9 and 3 levels were determined for cell viability and apoptotic status. The present study suggests arsenic-induced toxicity in a concentration-dependant manner. Arsenic also caused a significant increase in lactate dehydrogenase accompanied by an elevated antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase and caspase activity). Interestingly, pre-treatment of cell with MiADMSA elicited significant protection against arsenic-induced oxidative stress and apoptotic cell death. The present findings are of clinical relevance and suggest MiADMSA to be a promising candidate in protecting skin against arsenic-induced toxic effects, which need further exploration using in vivo experimental models.     

Curcumin encapsulated in chitosan nanoparticles: a novel strategy for the treatment of arsenic toxicity

Water-soluble nanoparticles of curcumin were synthesized, characterized and applied as a stable detoxifying agent for arsenic poisoning. Chitosan nanoparticles of less than 50 nm in diameter containing curcumin were prepared. The particles were characterized by TEM, DLS and FT-IR. The therapeutic efficacy of the encapsulated curcumin nanoparticles (ECNPs) against arsenic-induced toxicity in rats was investigated. Sodium arsenite (2mg/kg) and ECNPs (1.5 or 15 mg/kg) were orally administered to male Wistar rats for 4 weeks to evaluate the therapeutic potential of ECNPs in blood and soft tissues. Arsenic significantly decreased blood δ-aminolevulinic acid dehydratase (δ-ALAD) activity, reduced glutathione (GSH) and increased blood reactive oxygen species (ROS). These changes were accompanied by increases in hepatic total ROS, oxidized glutathione, and thiobarbituric acid-reactive substance levels. By contrast, hepatic GSH, superoxide dismutase and catalase activities significantly decreased on arsenic exposure, indicative of oxidative stress. Brain biogenic amines (dopamine, norepinephrine and 5-hydroxytryptamine) levels also showed significant changes on arsenic exposure. Co-administration of ECNPs provided pronounced beneficial effects on the adverse changes in oxidative stress parameters induced by arsenic. The results indicate that ECNPs have better antioxidant and chelating potential (even at the lower dose of 1.5 mg/kg) compared to free curcumin at 15 mg/kg. The significant neurochemical and immunohistochemical protection afforded by ECNPs indicates their neuroprotective efficacy. The formulation provides a novel therapeutic regime for preventing arsenic toxicity.     

Protective Role of Taurine against Arsenic-Induced Mitochondria-Dependent Hepatic Apoptosis via the Inhibition of PKCδ-JNK Pathway

Background

Oxidative stress-mediated hepatotoxic effect of arsenic (As) is mainly due to the depletion of glutathione (GSH) in liver. Taurine, on the other hand, enhances intracellular production of GSH. Little is known about the mechanism of the beneficial role of taurine in As-induced hepatic pathophysiology. Therefore, in the present study we investigated its beneficial role in As-induced hepatic cell death via mitochondria-mediated pathway.

Methodology/Principal Findings

Rats were exposed to NaAsO₂ (2 mg/kg body weight for 6 months) and the hepatic tissue was used for oxidative stress measurements. In addition, the pathophysiologic effect of NaAsO₂ (10 µM) on hepatocytes was evaluated by determining cell viability, mitochondrial membrane potential and ROS generation. As caused mitochondrial injury by increased oxidative stress and reciprocal regulation of Bcl-2, Bcl-xL/Bad, Bax, Bim in association with increased level of Apaf-1, activation of caspase 9/3, cleavage of PARP protein and ultimately led to apoptotic cell death. In addition, As markedly increased JNK and p38 phosphorylation with minimal disturbance of ERK. Pre-exposure of hepatocytes to a JNK inhibitor SP600125 prevented As-induced caspase-3 activation, ROS production and loss in cell viability. Pre-exposure of hepatocytes to a p38 inhibitor SB2035, on the other hand, had practically no effect on these events. Besides, As activated PKCδ and pre-treatment of hepatocytes with its inhibitor, rottlerin, suppressed the activation of JNK indicating that PKCδ is involved in As-induced JNK activation and mitochondrial dependent apoptosis. Oral administration of taurine (50 mg/kg body weight for 2 weeks) both pre and post to NaAsO₂ exposure or incubation of the hepatocytes with taurine (25 mM) were found to be effective in counteracting As-induced oxidative stress and apoptosis.

Conclusions/Significance

Results indicate that taurine treatment improved As-induced hepatic damages by inhibiting PKCδ-JNK signalling pathways. Therefore taurine supplementation could provide a new approach for the reduction of hepatic complication due to arsenic poisoning.     

IRE1α/NOX4 signaling pathway mediates ROS‐dependent activation of hepatic stellate cells in NaAsO2‐induced liver fibrosis

Liver fibrosis is a severe health problem worldwide, and it is characterized by the activation of hepatic stellate cells (HSCs) and excessive deposition of collagen. Prolonged arsenic exposure can induce HSCs activation and liver fibrosis. In the present study, the results showed that chronic NaAsO₂ ingestion could result in liver fibrosis and oxidative stress in Sprague–Dawley rats, along with representative collagen deposition and HSCs activation. In addition, the inositol‐requiring enzyme 1α (IRE1α)–endoplasmic reticulum (ER)‐stress pathway was activated, and the activity of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) was upregulated in rat livers. Simultaneously, the excessive production of reactive oxygen species (ROS) could induce HSCs activation, and NOX4 played an important role in generating ROS in vitro. Moreover, ER stress occurred with HSCs activation at the same time under NaAsO₂ exposure, and during ER stress, the IRE1α pathway was responsible for NOX4 activation. Therefore, inhibition of IRE1α activation could attenuate the HSCs activation induced by NaAsO₂. In conclusion, the present study manifested that inorganic arsenic exposure could activate HSCs through IRE1α/NOX4‐mediated ROS generation.     

Protective effect of naringenin on hepatic and renal dysfunction and oxidative stress in arsenic intoxicated rats

Arsenic has a long history as a potent human poison, chronic exposure over a period of time may result in the manifestation of toxicity in practically all systems of the body. In the present investigation the efficacy of naringenin (NRG), a naturally occurring citrus flavanone against arsenic-induced hepatotoxic and nephrotoxic manifestations have been studied in rats. Arsenic trioxide was administered orally at the dose of 2 mg/kg/day with or without combination of NRG (20 or 50 mg/kg/day) for 28 days. At the end of the experimental period the hepatic and renal dysfunction was evaluated by histological examination, serum biomarkers and markers of oxidative stress; lipid peroxidation (LPO), reduced glutathione (GSH) and antioxidant enzymes. Arsenic intoxication increased serum bilirubin, urea, uric acid and creatinine levels, additionally enhanced the activities of hepatic marker enzymes aspartate transaminase, alanine transaminase and alkaline phosphatase. Also, the hepatic and renal tissues showed a marked elevation in LPO levels with a decrease in GSH content and the activities of antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase on arsenic treatment. Simultaneous treatment with NRG restored the activities of serum biomarkers and antioxidant enzymes in the tissues in a dose-dependent manner. Furthermore, the histopathological studies confirmed the protective effect of NRG co-treatment by reducing the pathological changes due to arsenic intoxication in both liver and kidney. Thus, our present study demonstrates that NRG has a potential to protect arsenic-induced oxidative hepatic and renal dysfunction.     

Pomegranate protects against arsenic-induced p53-dependent ROS-mediated inflammation and apoptosis in liver cells

Molecular mechanisms involved in arsenic-induced toxicity are complex and elusive. Liver is one of the most favored organs for arsenic toxicity as methylation of arsenic occurs mostly in the liver. In this study, we have selected a range of environmentally relevant doses of arsenic to examine the basis of arsenic toxicity and the role of pomegranate fruit extract (PFE) in combating it. Male Swiss albino mice exposed to different doses of arsenic presented marked hepatic injury as evident from histological and electron microscopic studies. Increased activities of enzymes alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and alkaline phosphatase corroborated extensive liver damage. It was further noted that arsenic exposure initiated reactive oxygen species (ROS)-dependent apoptosis in the hepatocytes involving loss of mitochondrial membrane potential. Arsenic significantly increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB), coupled with increase in phosphorylated Iκ-B, possibly as adaptive cellular survival strategies. Arsenic-induced oxidative DNA damage to liver cells culminated in p53 activation and increased expression of p53 targets like miR-34a and Bax. Pomegranate polyphenols are known to possess remarkable antioxidant properties and are capable of protecting normal cells from various stimuli-induced oxidative stress and toxicities. We explored the protective role of PFE in ameliorating arsenic-induced hepatic damage. PFE was shown to reduce ROS generation in hepatocytes, thereby reducing arsenic-induced Nrf2 activation. PFE also inhibited arsenic-induced NF-κB-inflammatory pathway. Data revealed that PFE reversed arsenic-induced hepatotoxicity and apoptosis by modulating the ROS/Nrf2/p53–miR-34a axis. For the first time, we have mapped the possible signaling pathways associated with arsenic-induced hepatotoxicity and its rescue by pomegranate polyphenols.     

Huperzine A Ameliorates Cognitive Deficits and Oxidative Stress in the Hippocampus of Rats Exposed to Acute Hypobaric Hypoxia

Acute exposure to high altitudes can cause neurological dysfunction due to decreased oxygen availability to the brain. In this study, the protective effects of Huperzine A on cognitive deficits along with oxidative and apoptotic damage, due to acute hypobaric hypoxia, were investigated in male Sprague–Dawley rats. Rats were exposed to simulated hypobaric hypoxia at 6,000 m in a specially fabricated animal decompression chamber while receiving daily Huperzine A orally at the dose of 0.05 or 0.1 mg/kg body weight. After exposure to hypobaric hypoxia for 5 days, rats were trained in a Morris Water Maze for 5 consecutive days. Subsequent trials revealed Huperzine A supplementation at a dose of 0.1 mg/kg body weight restored spatial memory significantly, as evident from decreased escape latency and path length to reach the hidden platform, and the increase in number of times of crossing the former platform location and time spent in the former platform quadrant. In addition, after exposure to hypobaric hypoxia, animals were sacrificed and biomarkers of oxidative damage, such as reactive oxygen species, lipid peroxidation, lactate dehydrogenase activity, reduced glutathione, oxidized glutathione and superoxide dismutase were studied in the hippocampus. Expression levels of pro-apoptotic proteins (Bax, caspase-3) and anti-apoptotic protein (Bcl-2) of hippocampal tissues were evaluated by Western blotting. There was a significant increase in oxidative stress along with increased expression of apoptotic proteins in hypoxia exposed rats, which was significantly improved by oral Huperzine A at 0.1 mg/kg body weight. These results suggest that supplementation with Huperzine A improves cognitive deficits, reduces oxidative stress and inhibits the apoptotic cascade induced by acute hypobaric hypoxia.     

Memory and Learning Dysfunction Following Copper Toxicity: Biochemical and Immunohistochemical Basis

The prototype disease of Cu toxicity in human is Wilson disease, and cognitive impairment is the presenting symptom of it. There is no study correlating Cu-induced excitotoxicity, apoptosis, and astrocytic reaction with memory dysfunction. We report excitotoxicity, apoptosis, and astrocytic reaction of the hippocampus and frontal cortex with memory dysfunction in rat model of Cu toxicity. Thirty-six rats were divided into group I (control) and group II (100 mg/kgBwt/day CuSO₄ orally). Y-maze was performed for memory and learning at 0, 30, 60, and 90 days. Frontal and hippocampal free Cu concentration, oxidative stress markers [glutathione (GSH), total antioxidant toxicity (TAC), and malondialdehyde (MDA)], and glutamate were measured by atomic absorption spectroscopy, spectrophotometry, and ELISA, respectively. N-methyl-d-aspartate receptors (NMDARs) NR1, NR2A, and NR2B were done by real-time polymerase chain reaction. Immunohistochemistry for caspase-3 and glial fibrillary acidic protein (GFAP) were done and quantified using the ImageJ software. The glutamate level in hippocampus was increased, and NMDAR expression was decreased at 30, 60, and 90 days in group II compared to group I. In the frontal cortex, glutamate was increased at 90 days, but NMDARs were not significantly different in group II compared to group I. Caspase-3 and GFAP expressions were also higher in group II compared to group I, and these changes were more marked in hippocampus than frontal cortex. These changes correlated with respective free tissue Cu, oxidative stress, and Y-maze attention score. Cu toxicity induces apoptosis and astrocytosis of the hippocampus and frontal cortex through direct or glutamate and oxidative stress pathways, and results in impaired memory and learning.     

Protection of arsenic-induced testicular oxidative stress by arjunolic acid

Arsenic-induced tissue damage is a major concern to the human population. An impaired antioxidant defense mechanism followed by oxidative stress is the major cause of arsenic-induced toxicity, which can lead to reproductive failure. The present study was carried out to investigate the preventive role of arjunolic acid, a triterpenoid saponin isolated from the bark of Terminalia arjuna, against arsenic-induced testicular damage in mice. Administration of arsenic (in the form of sodium arsenite, NaAsO(2), at a dose of 10 mg/kg body weight) for 2 days significantly decreased the intracellular antioxidant power, the activities of the antioxidant enzymes, as well as the levels of cellular metabolites. In addition, arsenic intoxication enhanced testicular arsenic content, lipid peroxidation, protein carbonylation and the level of glutathione disulfide (GSSG). Exposure to arsenic also caused significant degeneration of the seminiferous tubules with necrosis and defoliation of spermatocytes. Pretreatment with arjunolic acid at a dose of 20 mg/kg body weight for 4 days could prevent the arsenic-induced testicular oxidative stress and injury to the histological structures of the testes. Arjunolic acid had free radical scavenging activity in a cell-free system and antioxidant power in vivo. In summary, the results suggest that the chemopreventive role of arjunolic acid against arsenic-induced testicular toxicity may be due to its intrinsic antioxidant property.     

Mitochondrial Decay in the Brains of Old Rats: Ameliorating Effect of Alpha-Lipoic Acid and Acetyl-<Emphasis Type="SmallCaps">l</Emphasis>-carnitine

To investigate the mitochondrial decay and oxidative damage resulting from aging, the activities/kinetics of the mitochondrial complexes were examined in the brains of young and old rats as well as in old rats fed R-α-lipoic acid plus acetyl-l-carnitine (LA/ALC). The brain mitochondria of old rats, compared with young rats, had significantly decreased endogenous antioxidants and superoxide dismutase activity; more oxidative damage to lipids and proteins; and decreased activities of complex I, IV and V. Complex I showed a decrease in binding affinity (increase in K_m) for substrates. Feeding LA/ALC to old rats partially restored age-associated mitochondrial dysfunction to the levels of the young rats. These results indicate that oxidative mitochondrial decay plays an important role in brain aging and that a combination of nutrients targeting mitochondria, such as LA/ALC, could ameliorate mitochondrial decay through preventing mitochondrial oxidative damage. Special issue article in honor of Dr. Akitane Mori.     

Protective Role of Quercetin on PCBs-Induced Oxidative Stress and Apoptosis in Hippocampus of Adult Rats

Polychlorinated biphenyls (PCBs) exposure produces neurodegeneration and induces oxidative stress. Neuroprotective role of quercetin, on PCBs induced apoptosis in hippocampus has not yet been studied. The present study is focused to see whether quercetin supplementation precludes against PCBs induced oxidative stress and hippocampal apoptosis. The results have shown that quercetin at 50 mg/kg bwt/30 days has protected oxidative stress in hippocampus of adult male rats. Quercetin, a free radical scavenger decreased the levels of oxidative stress markers in the hippocampus of simultaneous PCB+quercetin treated rats. The pro-apoptotic and anti-apoptotic molecules such as Bad, Bid, Bax and Bcl2 were altered in the hippocampus of experimental animals. PCBs increased the DNA damage and induced neurodegeneration were assessed by histological studies. PCB induced ROS may be linked to increased hippocampal neuronal apoptosis. Quercetin supplementation decreased the neuronal damage and scavenged the free radicals induced by PCBs and protects PCBs induced apoptosis and oxidative stress.     

Oxidative stress contributes to arsenic-induced telomere attrition,chromosome instability,and apoptosis

The environmental contaminant arsenic causes cancer, developmental retardation, and other degenerative diseases and, thus, is a serious health concern worldwide. Paradoxically, arsenic also may serve as an anti-tumor therapy, although the mechanisms of its antineoplastic effects remain unclear. Arsenic exerts its toxicity in part by generating reactive oxygen species. We show that arsenic-induced oxidative stress promotes telomere attrition, chromosome end-to-end fusions, and apoptotic cell death. An antioxidant, N-acetylcysteine, effectively prevents arsenic-induced oxidative stress, telomere erosion, chromosome instability, and apoptosis, suggesting that increasing the intracellular antioxidant level may have preventive or therapeutic effects in arsenic-induced chromosome instability and genotoxicity. Embryos with shortened telomeres from late generation telomerase-deficient mice exhibit increased sensitivity to arsenic-induced oxidative damage, suggesting that telomere attrition mediates arsenic-induced apoptosis. Unexpectedly, arsenite did not cause chromosome end-to-end fusions in telomerase RNA knockout mouse embryos despite progressively damaged telomeres and disrupting embryo viability. Together, these findings may explain why arsenic can initiate oxidative stress and telomere erosion, leading to apoptosis and anti-tumor therapy on the one hand and chromosome instability and carcinogenesis on the other.     

Lycopene protects against trimethyltin-induced neurotoxicity in primary cultured rat hippocampal neurons by inhibiting the mitochondrial apoptotic pathway

Lycopene is a potent free radicals scavenger with demonstrated protective efficacy in several experimental models of oxidative damage. Trimethyltin (TMT) is an organotin compound with neurotoxic effects on the hippocampus and other limbic structures and is used to model neurodegenerative diseases targeting these brain areas. Oxidative stress is widely accepted as a central pathogenic mechanism of TMT-mediated neurotoxicity. The present study investigated whether the plant carotene lycopene protects against TMT-induced neurotoxicity in primary cultured rat hippocampal neurons. Lycopene pretreatment improved cell viability in TMT-treated hippocampal neurons and inhibited neuronal apoptosis. Microfluorometric imaging revealed that lycopene inhibited the accumulation of mitochondria-derived reactive oxygen species (ROS) during TMT exposure. Moreover, lycopene ameliorated TMT-induced activation of the mitochondrial permeability transition pore (mPTP) and the concomitant depolarization of the mitochondrial membrane potential (ΔΨ_m). Consequently, cytochrome c release from the mitochondria and ensuing caspase-3 activation were markedly reduced. These findings reveal that lycopene protects against TMT-induced neurotoxicity by inhibiting the mitochondrial apoptotic pathway. The anti-apoptotic effect of lycopene on hippocampal neurons highlights the therapeutic potential of plant-derived antioxidants against neurodegenerative diseases.