Gestational α-ketoglutarate supplementation ameliorates arsenic-induced hepatic lipid deposition via epigenetic reprogramming of ß-oxidation process in female offspring.

Inorganic trivalent arsenic (iAsⅢ) at environmentally relevant levels has been found to cause developmental toxicity. Maternal exposure to iAsⅢ leads to enduring hepatic lipid deposition in later adult life. However, the exact mechanism in iAsⅢ induced hepatic developmental hazards is still unclear. In this study, we initially found that gestational exposure to iAsⅢ at an environmentally relevant concentration disturbs lipid metabolism and reduces levels of alpha-ketoglutaric acid (α-KG), an important mitochondrial metabolite during the citric acid cycle, in fetal livers. Further, gestational supplementation of α-KG alleviated hepatic lipid deposition caused by early-life exposure to iAsⅢ. This beneficial effect was particularly pronounced in female offspring. α-KG partially restored the ß-oxidation process in hepatic tissues by hydroxymethylation modifications of carnitine palmitoyltransferase 1a (Cpt1a) gene during fetal development. Insufficient ß-oxidation capacities probably play a crucial role in hepatic lipid deposition in adulthood following in utero arsenite exposure, which can be efficiently counterbalanced by replenishing α-KG. These results suggest that gestational administration of α-KG can ameliorate hepatic lipid deposition caused by iAsⅢ in female adult offspring partially through epigenetic reprogramming of the ß-oxidation pathway. Furthermore, α-KG shows potential as an interventive target to mitigate the harmful effects of arsenic-induced hepatic developmental toxicity.

Study on the mechanism of arsenic-induced renal injury based on SWATH proteomics technology.

BACKGROUND: Arsenic (As) poisoning is a worldwide endemic disease affecting thousands of people. As is excreted mainly through the renal system, and arsenic has toxic effects on the kidneys, but the mechanism has not been elucidated. In this study, the molecular basis of arsenic's nephrotoxicity was studied by using a high-throughput proteomics technique. METHODS: Eight SD (Sprague-Dawley) rats, half male and half female, were fed an As diet containing 50 mg/kg NaAsO2. Age- and sex-matched rats fed with regular chow were used as controls. At the end of the experiment (90 days), kidney tissue samples were collected and assessed for pathological changes using hematoxylin-eosin staining. Proteomic methods were used to identify alterations in protein expression levels in kidney tissues, and bioinformatic analyses of differentially expressed proteins between arsenic-treated and control groups were performed. The expression of some representative proteins was validated by Western blot analysis. RESULTS: NaAsO2 could induce renal injury. Compared with the control group, 112 proteins were up-regulated, and 46 proteins were down-regulated in the arsenic-treated group. These proteins were associated with the electron transport chain, oxidative phosphorylation, mitochondrial membrane, apoptosis, and proximal tubules, suggesting that the mechanisms associated with them were related to arsenic-induced kidney injury and nephrotoxicity. The expressions of Atp6v1f, Cycs and Ndufs1 were verified, consistent with the results of omics. CONCLUSION: These results provide important evidence for arsenic-induced kidney injury and provide new insights into the molecular mechanism of arsenic-induced kidney injury.

Toxicity of inorganic arsenic to animals and its treatment strategies.

In nature, arsenic is mostly found in the form of inorganic compounds. Inorganic arsenic compounds have a variety of uses and are currently used in the manufacture of pesticides, preservatives, pharmaceuticals, etc. While inorganic arsenic is widely used, arsenic pollution is increasing worldwide. Public hazards caused by arsenic contamination of drinking water and soil are becoming increasingly evident. Epidemiological and experimental studies have linked inorganic arsenic exposure to the development of many diseases, including cognitive impairment, cardiovascular failure, cancer, etc. Several mechanisms have been proposed to explain the effects caused by arsenic, such as oxidative damage, DNA methylation, and protein misfolding. Understanding the toxicology and potential molecular mechanisms of arsenic can help mitigate its harmful effects. Therefore, this paper reviews the multiple organ toxicity of inorganic arsenic in animals, focusing on the various toxicity mechanisms of arsenic-induced diseases in animals. In addition, we have summarized several drugs that can have therapeutic effects on arsenic poisoning in pursuit of reducing the harm of arsenic contamination from different pathways.

Mechanisms of Arsenic Exposure-Induced Hypertension and Atherosclerosis: an Updated Overview.

Arsenic is an abundant element in the earth's crust. In the environment and within the human body, this toxic element can be found in both organic and inorganic forms. Chronic exposure to arsenic can predispose humans to cardiovascular diseases including hypertension, stroke, atherosclerosis, and blackfoot disease. Oxidative damage induced by reactive oxygen species is a major player in arsenic-induced toxicity, and it can affect genes expression, inflammatory responses, and/or nitric oxide homeostasis. Exposure to arsenic in drinking water can lead to vascular endothelial dysfunction which is reflected by an imbalance between vascular relaxation and contraction. Arsenic has been shown to inactivate endothelial nitric oxide synthase leading to a reduction of the generation and bioavailability of nitric oxide. Ultimately, these effects increase the risk of vascular diseases such as hypertension and atherosclerosis. The present article reviews how arsenic exposure contributes to hypertension and atherosclerosis development.

Glucogallin Attenuates RAW 264.7 Cells from Arsenic Trioxide Induced Toxicity via the NF-Ò¡B/NLRP3 Pathway.

Chronic arsenic (As) poisoning is mostly due to subsoil water contaminated with As and its salts. Exposure to As has been found to cause an elevation in reactive oxygen species (ROS), leading to the damage of DNA and proteins, and it also causes immunotoxicity. Treatment regimens are primarily based on chelation therapy and amino acid and vitamin supplementations. Recent studies have established that natural products display effective and progressive relief from arsenicosis without any side effects. ß-glucogallin (BGG), a gallo-tannin natural product, is reported to possess anti-oxidant and anti-inflammatory properties. In the present study, we aim to observe the protective role of BGG against As-induced cytotoxicity, apoptosis, mitochondrial dysfunction, and the underlying mechanisms in RAW 264.7 macrophage cells. We found that BGG alleviates As-induced ROS, apoptosis, and mitochondrial dysfunction in RAW 264.7 macrophage cells. Thus, BGG can be used therapeutically to prevent As-induced toxicity.

Potential value and mechanism of Rosa roxburghii tratt juice on pro-inflammatory responses in peripheral blood of patients with arsenic poisoning.

Increasing evidence supports the role of arsenic in dysregulated immune and inflammation responses, while, safe and effective treatments have not been fully examined. Rosa roxburghii Tratt (RRT), a traditional Chinese edible fruit with potential immunoregulatory activities, was considered as a dietary supplement to explore its protective effects and possible mechanism in arsenic-induced dysregulated inflammation responses. We enrolled 209 arsenicosis patients and 41 controls to obtain baseline data, including the degree of arsenic poisoning prior to the RRT juice (RRTJ) intervention. Then, based on criteria of inclusion and exclusion and the principle of voluntary participation, 106 arsenicosis patients who volunteered to receive treatment were divided into RRTJ (n = 53) and placebo (n = 53) groups randomly. After three months follow-up, 89 subjects (46 and 43 of the RRTJ and placebo groups, respectively) completed the study and were examined for the effects and possible mechanisms of RRTJ on the Th17 cells-related pro-inflammatory responses in peripheral blood mononuclear cells (PBMCs). The PBMCs had higher levels of Th17 and Th17-related inflammatory cytokines IL-17, IL-6, and RORγt. Furthermore, the gene expressions of STAT3 and SOCS3 in PBMCs increased and decreased, respectively. Conversely, RRTJ decreased the number of Th17 cells, secretion of IL-17, IL-6, RORγt, and relative mRNA levels of STAT3, and increased the transcript levels of SOCS3. This study provides limited evidence that possible immunomodulatory effects of RRTJ on the critical regulators, IL-6 and STAT3, of the Th17 cells in arsenicosis patients, which indicated that IL-6/STAT3 pathway might appear as a potential therapeutic target in arsenicosis.

Assessing the Role of Nrf2/GPX4-Mediated Oxidative Stress in Arsenic-Induced Liver Damage and the Potential Application Value of Rosa roxburghii Tratt [Rosaceae].

Arsenic poisoning is a geochemical disease that seriously endangers human health. The liver is one of the important target organs for arsenic poisoning, several studies have shown that oxidative stress plays an important role in arsenic-induced liver damage. However, the specific mechanism of arsenic-induced oxidative stress has not yet been fully elucidated, and currently, there are no effective intervention measures for the prevention and treatment of arsenic-induced liver damage. In this study, the effect of the Nrf2/GPX4 signaling pathway and oxidative stress in the arsenic-induced liver damage was first evaluated. The results show that arsenic can activate the Nrf2/GPX4 signaling pathway and increase the oxidative stress, which in turn promotes arsenic-induced liver damage in MIHA cells. Moreover, when we applied the Nrf2 inhibitor, the promoting effect of arsenic on liver damage was alleviated by inhibiting the activation of the Nrf2/GPX4 signaling pathway. Subsequently, the Rosa roxburghii Tratt [Rosaceae] (RRT) intervention experiments in cells and arsenic poisoning population were designed. The results revealed that RRT can inhibit Nrf2/GPX4 signaling pathway to reduce oxidative stress, thereby alleviates arsenic-induced liver damage. This study provides some limited evidence that arsenite can activate Nrf2/GPX4 signaling pathway to induce oxidative stress, which in turn promotes arsenic-induced liver damage in MIHA cells. The second major finding was that Kaji-ichigoside F1 may be a potential bioactive compound of RRT, which can inhibit Nrf2/GPX4 signaling pathway to reduce oxidative stress, thereby alleviates arsenic-induced liver damage. Our study will contribute to a deeper understanding of the mechanisms in arsenic-induced liver damage, these findings will identify a possible natural medicinal food dual-purpose fruit, RRT, as a more effective prevention and control strategies for arsenic poisoning.

Phytochemicals in the Management of Arsenic Toxicity.

Arsenic toxicity is a major concern due to its deleterious consequences for human health. Rapid industrialization also has weakened the quality of the environment by introducing pollutants that may disrupt balanced ecosystems, adversely and irreversibly impacting humans, plants, and animals. Arsenic, an important toxicant among all environmental hazards, can lead to several detrimental effects on cells and organs, impacting the overall quality of life. Nevertheless, arsenic also has a rich history as a chemotherapeutic agent used in ancient days for the treatment of diseases such as malaria, cancer, plague, and syphilis when other chemotherapeutic agents were yet to be discovered. Arsenicosis-mediated disorders remain a serious problem due to the lack of effective therapeutic options. Initially, chelation therapy was used to metabolically eliminate arsenic by forming a complex, but adverse effects limited their pharmacological use. More recently, plant-based products have been found to provide significant relief from the toxic effects of arsenic poisoning. They act by different mechanisms affecting various cellular processes. Phytoconstituents such as curcumin, quercetin, diallyl trisulfide, thymoquinone, and others act via various molecular pathways, primarily by attenuating oxidative damage, membrane damage, DNA damage, and proteinopathies. Nonetheless, most of the phytochemicals reviewed here protect against the adverse effects of metal or metalloid exposure, supporting their consideration as alternatives to chelation therapy. These agents, if used prophylactically and in conjunction with other chemotherapeutic agents, may provide an effective approach for management of arsenic toxicity. In a few instances, such strategies like coadministration of phytochemicals with a known chelating agent have led to more pronounced elimination of arsenic from the body with lesser off-site adverse effects. This is possible because combination treatment ensures the use of a reduced dose of chelating agent with a phytochemical without compromising treatment. Thus, these therapies are more practical than conventional therapeutic agents in ameliorating arsenic-mediated toxicity. This review summarizes the potential of phytochemicals in alleviating arsenic toxicity on the basis of available experimental and clinical evidence.

Metabolic characteristics related to the hazardous effects of environmental arsenic on humans: A metabolomic review.

Arsenic (As) is a toxic metalloid exist ubiquitously in environment. Epidemiological studies and laboratory animal studies have verified that As damages multiple organs or tissues in the body and is associated with a variety of diseases. Changes in metabolites usually indicate disturbances in metabolic pathways and specific metabolites are considered as biomarkers of diseases or drugs/toxins or environmental effects. Metabolomics is the quantitative measurement of the dynamic multi-parameter metabolic responses of biological systems due to pathophysiological or genetic changes. Current years, some metabolomic studies on the hazardous effect of environmental As on humans have been reported. In this paper, we first overviewed the metabolomics studies of environmental As exposure in humans since 2011, emphasizing on the data mining process of metabolic characteristics related to the hazardous effects of environmental As on humans. Then, the relationship between metabolic characteristics and the toxic mechanism of environmental As exposure in humans were discussed, and finally, the prospects of metabolomics studies on populations exposed to environmental As were put forward. Our paper may shed light on the study of mechanisms, prevention and individualized treatment of As poisoning.

Polyphenolics with Strong Antioxidant Activity from Acacia nilotica Ameliorate Some Biochemical Signs of Arsenic-Induced Neurotoxicity and Oxidative Stress in Mice.

Neurotoxicity is a serious health problem of patients chronically exposed to arsenic. There is no specific treatment of this problem. Oxidative stress has been implicated in the pathological process of neurotoxicity. Polyphenolics have proven antioxidant activity, thereby offering protection against oxidative stress. In this study, we have isolated the polyphenolics from Acacia nilotica and investigated its effect against arsenic-induced neurotoxicity and oxidative stress in mice. Acacia nilotica polyphenolics prepared from column chromatography of the crude methanol extract using diaion resin contained a phenolic content of 452.185 ± 7.879 mg gallic acid equivalent/gm of sample and flavonoid content of 200.075 ± 0.755 mg catechin equivalent/gm of sample. The polyphenolics exhibited potent antioxidant activity with respect to free radical scavenging ability, total antioxidant activity and inhibition of lipid peroxidation. Administration of arsenic in mice showed a reduction of acetylcholinesterase activity in the brain which was counteracted by Acacia nilotica polyphenolics. Similarly, elevation of lipid peroxidation and depletion of glutathione in the brain of mice was effectively restored to normal level by Acacia nilotica polyphenolics. Gallic acid methyl ester, catechin and catechin-7-gallate were identified in the polyphenolics as the major active compounds. These results suggest that Acacia nilotica polyphenolics due to its strong antioxidant potential might be effective in the management of arsenic induced neurotoxicity.

Mitochondrial Dysfunction in Arsenic-Induced Hepatotoxicity: Pathogenic and Therapeutic Implications.

Mitochondria are vital cellular organelles associated with energy production as well as cell signaling pathways. These organelles, responsible for metabolism, are highly abundant in hepatocytes that make them key players in hepatotoxicity. The literature suggests that mitochondria are targeted by various environmental pollutants. Arsenic, a toxic metalloid known as an environmental pollutant, readily contaminates drinking water and exerts toxic effects. It is toxic to various cellular organs; among them, the liver seems to be most affected. A growing body of evidence suggests that within cells, arsenic is highly toxic to mitochondria and reported to cause oxidative stress and alter an array of signaling pathways and functions. Hence, it is imperative to highlight the mechanisms associated with altered mitochondrial functions and integrity in arsenic-induced liver toxicity. This review provides the details of mechanistic aspects of mitochondrial dysfunction in arsenic-induced hepatotoxicity as well as various ameliorative measures undertaken concerning mitochondrial functions.

Oxidative stress induced by realgar in neurons: p38 MAPK and ERK1/2 perturb autophagy and induce the p62-Keap1-Nrf2 feedback loop to activate the Nrf2 signalling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Due to the modernization of traditional Chinese medicine (TCM) and the influence of traditional medication habits (TCM has no toxicity or side effects), arsenic poisoning incidents caused by the abuse of realgar and realgar-containing Chinese patent medicines have occurred occasionally. However, the potential mechanism of central nervous system toxicity of realgar remains unclear. AIM OF THE STUDY: This study aimed to clarify the specific mechanism of realgar-induced neurotoxicity. MATERIALS AND METHODS: In this study, the roles of ERK1/2 and p38 MAPK in realgar-induced neuronal autophagy and overactivation of the nuclear factor erythroid-derived factor 2-related factor (Nrf2) signalling pathways was investigated in vivo and in vitro. RESULTS: The arsenic in realgar passed through the blood-brain barrier and accumulated in the brain, resulting in damage to neurons, synapses and myelin sheaths in the cerebral cortex and a decrease in the total antioxidant capacity. The specific mechanism is that the excessive activation of Nrf2 is regulated by the upstream signalling molecules ERK1/2 and p38MAPK. At the same time, p38 MAPK and ERK1/2 interfere with autophagy, thereby promoting autophagy initiation but causing subsequent dysfunctional autophagic degradation and inducing the p62-Keap1-Nrf2 feedback loop to promote Nrf2 signalling pathway activation and nerve cell apoptosis. CONCLUSIONS: This study confirmed the role of the signalling molecules p38 MAPK and ERK1/2 in perturbing autophagy and inducing the p62-Keap1-Nrf2 feedback loop to activate the Nrf2 signalling pathway in realgar-induced neurotoxicity.

Arsenic-protein interactions as a mechanism of arsenic toxicity.

Millions of people worldwide are exposed to arsenic, a metalloid listed as one of the top chemical pollutants of concern to human health. Epidemiological and experimental studies link arsenic exposure to the development of cancer and other diseases. Several mechanisms have been proposed to explain the effects induced by arsenic. Notably, arsenic and its metabolites interact with proteins by direct binding to individual cysteine residues, cysteine clusters, zinc finger motifs, and RING finger domains. Consequently, arsenic interactions with proteins disrupt the functions of proteins and may lead to the development and progression of diseases. In this review, we focus on current evidence in the literature that implicates the interaction of arsenic with proteins as a mechanism of arsenic toxicity. Data show that arsenic-protein interactions affect multiple cellular processes and alter epigenetic regulation, cause endocrine disruption, inhibit DNA damage repair mechanisms, and deregulate gene expression, among other adverse effects.

Melatonin: a pleiotropic hormone as a novel potent therapeutic candidate in arsenic toxicity.

BACKGROUND: Arsenic is a natural element which exists in the environment in inorganic and organic forms. In humans, the main reason for the toxicity of arsenic is its uptake via water sources. As polluted water and the problems associated with it can be found in many countries. Therefore, considering all these positive effects of melatonin, this review is aimed at melatonin supplementation therapy on arsenic toxicity which seems to be a suitable therapeutic agent to eliminate the adverse effects of arsenic. METHODS AND RESULTS: It is seen in previous studies that chronic exposure to arsenic could cause serious dys functions of organs and induce different degrees of toxicities that is one of the first hazardous materials in the classification of substances by the United States Environmental Protection Agency so leads to costly cleanup operations burdening the economy. Arsenic harmfulness degree depends on the bioavailability, chemical form, valence state, detoxification, and metabolism of human body. The oxidative stress has a major role in arsenic-induced toxicity; on the other hand, it was discovered that melatonin is a powerful scavenger for free radical and it's an extensive-spectrum antioxidant. CONCLUSION: Due to its highly lipophilic and small size properties, melatonin accesses all intracellular organs by easily passing via the cell membrane and prevents protein, DNA damage, and lipid peroxidation. In particular, melatonin, by protecting and reducing oxidative stress in mitochondria, can normalize homeostasis and mitochondrial function and ultimately prevent apoptosis and cell death.

Arsenic methylation - Lessons from three decades of research.

Between 1990 and 2020, our understanding of the significance of arsenic biomethylation changed in remarkable ways. At the beginning of this period, the conversion of inorganic arsenic into mono- and di-methylated metabolites was viewed primarily as a process that altered the kinetic behavior of arsenic. By increasing the rate of clearance of arsenic, the formation of methylated metabolites reduced exposure to this toxin; that is, methylation was detoxification. By 2020, it was clear that at least some of the toxic effects associated with As exposure depended on formation of methylated metabolites containing trivalent arsenic. Because the trivalent oxidation state of arsenic is associated with increased potency as a cytotoxin and clastogen, these findings were consistent with methylation-related changes in the dynamic behavior of arsenic. That is, methylation was activation. Our current understanding of the role of methylation as a modifier of kinetic and dynamic behaviors of arsenic is the product of research at molecular, cellular, organismic, and population levels. This information provides a basis for refining our estimates of risk associated with long term exposure to inorganic arsenic in environmental media, food, and water. This report summarizes the growth of our knowledge of enzymatically catalyzed methylation of arsenic over this period and considers the prospects for new discoveries.

Coenzyme Q10 protected against arsenite and enhanced the capacity of 2,3-dimercaptosuccinic acid to ameliorate arsenite-induced toxicity in mice.

BACKGROUND: Arsenic poisoning affects millions of people. The inorganic forms of arsenic are more toxic. Treatment for arsenic poisoning relies on chelation of extracellularly circulating arsenic molecules by 2,3-dimecaptosuccinic acid (DMSA). As a pharmacological intervention, DMSA is unable to chelate arsenic molecules from intracellular spaces. The consequence is continued toxicity and cell damage in the presence of DMSA. A two-pronged approach that removes extracellular arsenic, while protecting from the intracellular arsenic would provide a better pharmacotherapeutic outcome. In this study, Coenzyme Q10 (CoQ10), which has been shown to protect from intracellular organic arsenic, was administered separately or with DMSA; following oral exposure to sodium meta-arsenite (NaAsO2) - a very toxic trivalent form of inorganic arsenic. The aim was to determine if CoQ10 alone or when co-administered with DMSA would nullify arsenite-induced toxicity in mice. METHODS: Group one represented the control; the second group was treated with NaAsO2 (15 mg/kg) daily for 30 days, the third, fourth and fifth groups of mice were given NaAsO2 and treated with 200 mg/kg CoQ10 (30 days) and 50 mg/kg DMSA (5 days) either alone or in combination. RESULTS: Administration of CoQ10 and DMSA resulted in protection from arsenic-induced suppression of RBCs, haematocrit and hemoglobin levels. CoQ10 and DMSA protected from arsenic-induced alteration of WBCs, basophils, neutrophils, monocytes, eosinophils and platelets. Arsenite-induced dyslipidemia was nullified by administration of CoQ10 alone or in combination with DMSA. Arsenite induced a drastic depletion of the liver and brain GSH; that was significantly blocked by CoQ10 and DMSA alone or in combination. Exposure to arsenite resulted in significant elevation of liver and kidney damage markers. The histological analysis of respective organs confirmed arsenic-induced organ damage, which was ameliorated by CoQ10 alone or when co-administered with DMSA. When administered alone, DMSA did not prevent arsenic-driven tissue damage. CONCLUSIONS: Findings from this study demonstrate that CoQ10 and DMSA separately or in a combination, significantly protect against arsenic-driven toxicity in mice. It is evident that with further pre-clinical and clinical studies, an adjunct therapy that incorporates CoQ10 alongside DMSA may find applications in nullifying arsenic-driven toxicity.

Comparative efficacy of Nano and Bulk Monoisoamyl DMSA against arsenic-induced neurotoxicity in rats.

Chelation therapy is considered as a safe and effective strategy to combat metal poisoning. Arsenic is known to cause neurological dysfunctions such as impaired memory, encephalopathy, and peripheral neuropathy as it easily crosses the blood-brain barrier. Oxidative stress is one of the mechanisms suggested for arsenic-induced neurotoxicity. We prepared Solid Lipid nanoparticles loaded with Monoisoamyl 2, 3-dimercaptosuccinic acid (Nano-MiADMSA), and compared their efficacy with bulk MiADMSA for treating arsenic-induced neurological and other biochemical effects. Solid lipid nanoparticles entrapping MiADMSA were synthesized and particle characterization was carried out by transmission electron microscopy (TEM) and dynamic light scattering (DLS). An in vivo study was planned to investigate the therapeutic efficacy of MiADMSA-encapsulated solid lipid nanoparticles (Nano-MiADMSA; 50 mg/kg orally for 5 days) and compared it with bulk MiADMSA against sodium meta-arsenite exposed rats (25 ppm in drinking water, for 12 weeks) in male rats. The results suggested the size of Nano-MiADMSA was between 100-120 nm ranges. We noted enhanced chelating properties of Nano-MiADMSA compared with bulk MiADMSA as evident by the reversal of oxidative stress variables like blood δ-aminolevulinic acid dehydratase (δ-ALAD), Reactive Oxygen Species (ROS), Catalase activity, Superoxide Dismutase (SOD), Thiobarbituric Acid Reactive Substances (TBARS), Reduced Glutathione (GSH) and Oxidized Glutathione (GSSG), Glutathione Peroxidase (GPx), Glutathione-S-transferase (GST) and efficient removal of arsenic from the blood and tissues. Recoveries in neurobehavioral parameters further confirmed nano-MiADMSA to be more effective than bulk MiADMSA. We conclude that treatment with Nano-MiADMSA is a better therapeutic strategy than bulk MiADMSA in reducing the effects of arsenic-induced oxidative stress and associated neurobehavioral changes.

Activation of Lrrk2 and α-Synuclein in substantia nigra, striatum, and cerebellum after chronic exposure to arsenite.

Arsenic is a neurotoxin and environmental exposure to it correlates with an incidence of neurodegenerative diseases. Considering that arsenic has the potential to inhibit autophagic flux, it was hypothesized that arsenite (NaAsO2) may interplay with LRRK2 and α-Synuclein, affecting their phosphorylation in brain regions prone to neurodegeneration. After 15 weeks of chronic exposure to arsenite, a reduction in grip strength of C57BL/6 male mice was observed. Thirty minutes exposure to arsenite increased phosphorylation of Lrrk2 and α-Synuclein in organotypic brain slice cultures from the cerebellum and striatum, respectively. Chronic exposure of mice to a wide-range of concentrations of arsenite led to a significant induction of Lrrk2 phosphorylation in substantia nigra and cerebellum and α-Synuclein phosphorylation in substantia nigra and striatum. Strong correlations between phosphorylated forms of Lrrk2 and α-Synuclein in substantia nigra, Lrrk2 levels between substantia nigra and striatum, and between Lrrk2 in striatum and α-Synuclein in substantia nigra observed in control animals were completely disrupted by arsenic exposure at 50, 500, and 5000 ppb. A transcriptome analysis identified specific genes and canonical pathways that distinguish striatum, substantia nigra, and cerebellum from each other in control animals and compare individual brain regions to arsenite exposed animals. Chronic arsenite exposure altered transcripts of glutathione redox reactions and serotonin receptor signaling in striatum, axonal guidance signaling, NF-κB and androgen signaling in substantia nigra and mitochondrial dysfunction, oxidative phosphorylation, apoptosis and sirtuin signaling in the cerebellum. These data suggest that arsenite affects processes associated with neurodegenerative diseases in brain region specific manner.

An appraisal on molecular and biochemical signalling cascades during arsenic-induced hepatotoxicity.

Arsenic is a ubiquitous metalloid compound commonly found in the environment, and it is usually found in combination with sulphur and metals. Arsenic is considered as a therapeutic as well as poisoning agent since ancient times. It causes toxic effects on different organs, mainly the liver. In this review, we focused on the molecular mechanism of arsenic-induced hepatotoxicity. Here we envisaged the bridge between arsenic and hepatotoxicity with particular focus on the level of hepatic enzymes such as ALT, AST, and ALP. Here, we attempted to elucidate the role of arsenic in redox imbalance on increased oxidative stress (elevated level of ROS, MDA and NO) and decreased antioxidant levels such as reduced GSH, catalase, and SOD. Oxidative stress induces mitochondrial dysfunction via apoptosis (AKT-PKB, MAPK, PI3/AKT, PKCδ-JNK, AKT/ERK, p53 pathways), fibrosis (TGF-ß/Smad pathway), and necrosis and inflammation (TNF-α, NF-ĸB, IL-1, and IL-6). Along with that, arsenic activates caspases and Bax, decreases Bcl2 through mitochondrial dysfunction, and induces apoptosis regulatory mechanism. We believe the alteration of all these pathways leads to arsenic-induced hepatotoxicity.