Arsenic-induced Oxidative Stress Research Articles

Baicalein Alleviates Arsenic-induced Oxidative Stress through Activation of the Keap1/Nrf2 Signalling Pathway in Normal Human Liver Cells.

Oxidative stress is a key mechanism underlying arsenicinduced liver injury, the Kelch-like epichlorohydrin-related protein 1 (Keap1)/nuclear factor E2 related factor 2 (Nrf2) pathway is the main regulatory pathway involved in antioxidant protein and phase II detoxification enzyme expression. The aim of the present study was to investigate the role and mechanism of baicalein in the alleviation of arsenic-induced oxidative stress in normal human liver cells. Normal human liver cells (MIHA cells) were treated with NaAsO2 (0, 5, 10, 20 μM) to observe the effect of different doses of NaAsO2 on MIHA cells. In addition, the cells were treated with DMSO (0.1%), NaAsO2 (20 μM), or a combination of NaAsO2 (20 μM) and Baicalein (25, 50 or 100 μM) for 24 h to observe the antagonistic effect of Baicalein on NaAsO2. Cell viability was determined using a Cell Counting Kit- 8 (CCK-8 kit). The intervention doses of baicalein in subsequent experiments were determined to be 25, 50 and 100μM. The intracellular content of reactive oxygen species (ROS) was assessed using a 2',7'-dichlorodihydrofluorescein diacetate (DCFHDA) probe kit. The malonaldehyde (MDA), Cu-Zn superoxide dismutase (Cu-Zn SOD) and glutathione peroxidase (GSH-Px) activities were determined by a test kit. The expression levels of key genes and proteins were determined by real-time fluorescence quantitative polymerase chain reaction (qPCR) and Western blotting. Baicalein upregulated the protein expression levels of phosphorylated Nrf2 (p-Nrf2) and nuclear Nrf2, inhibited the downregulation of Nrf2 target genes induced by arsenic, and decreased the production of ROS and MDA. These results demonstrate that baicalein promotes Nrf2 nuclear translocation by upregulating p-Nrf2 and inhibiting the downregulation of Nrf2 target genes in arsenic-treated MIHA cells, thereby enhancing the antioxidant capacity of cells and reducing oxidative stress. Baicalein alleviated arsenic-induced oxidative stress through activation of the Keap1/Nrf2 signalling pathway in normal human liver cells.

Hesperidin and chlorogenic acid mitigate arsenic-induced oxidative stress via redox regulation, photosystems-related gene expression, and antioxidant efficiency in the chloroplasts of Zea mays

The ubiquitous metalloid arsenic (As), which is not essential, can be found extensively in the soil and subterranean water of numerous nations, raising substantial apprehensions due to its impact on both agricultural productivity and sustainability. Plants exposed to As often display morphological, physiological, and growth-related abnormalities, collectively leading to reduced productivity. Polyphenols, operating as secondary messengers within the intricate signaling networks of plants, assume integral functions in the acquisition of resistance to diverse environmental stressors, including but not limited to drought, salinity, and exposure to heavy metals. The pivotal roles played by polyphenols in these adaptive processes underscore their profound significance in plant biology. This study aims to elucidate the impact of hesperidin (HP) and chlorogenic acid (CA), recognized as potent bioactive compounds, on maize plants exposed to As. To achieve this objective, the study examined the physiological and biochemical impacts, including growth parameters, photosynthesis, and chloroplastic antioxidants, of HP (100 μM) and CA (50 μM) on Zea mays plants exposed to arsenate stress (AsV, 100 μM - Na2HAsO4⋅7H2O). As toxicity led to reductions in fresh weight (FW) and dry weight (DW) by 33% and 26%, respectively. However, the application of As+HP and As + CA increased FW by 22% and 40% and DW by 14% and 17%, respectively, alleviating the effects of As stress. As toxicity resulted in the up-regulation of PSII genes (psbA and psbD) and PSI genes (psaA and psaB), indicating a potential response to the re-formation of degraded regions, likely driven by the heightened demand for photosynthesis. Exogenous HP or/and CA treatments effectively counteracted the adverse effects of As toxicity on the photochemical quantum efficiency of PSII (Fv/Fm). H2O2 content showed a 23% increase under As stress, and this increase was evident in guard cells when examining confocal microscopy images. In the presence of As toxicity, the chloroplastic antioxidant capacity can exhibit varying trends, with either a decrease or increase observed. After the application of CA and/or HP, a significant increase was observed in the activity of GR, APX, GST, and GPX enzymes, resulting in decreased levels of H2O2 and MDA. Additionally, the enhanced functions of MDHAR and DHAR have modulated the redox status of ascorbic acid (AsA) and glutathione (GSH). The HP or CA-mediated elevated levels of AsA and GSH content further contributed to the preservation of redox homeostasis in chloroplasts facing stress induced by As. In summary, the inclusion of HP and CA in the growth medium sustained plant performance in the presence of As toxicity by regulating physiological and biochemical characteristics, chloroplastic antioxidant enzymes, the AsA-GSH cycle and photosynthesis processes, thereby demonstrating their significant potential to confer resistance to maize through the mitigation of As-induced oxidative damage and the safeguarding of photosynthetic mechanisms.

N6-methyladenosine promotes aberrant redox homeostasis required for arsenic carcinogenesis by controlling the adaptation of key antioxidant enzymes

N6-methyladenosine (m6A), a high-profile RNA epigenetic modification, responds to oxidative stress and temporal-specifically mediates arsenic carcinogenesis. However, how m6A affects aberrant redox homeostasis required for arsenic carcinogenesis is poorly understood. Here, we established arsenic-carcinogenic models of different stages, including As-treated, As-transformed, and As-tumorigenic cell models. We found that arsenic-induced reactive oxygen species (ROS) elevated m6A levels, thus triggering m6A-dependent antioxidant defenses. During arsenic-induced cell transformation, METTL3-upregulated m6A on the mRNAs of SOD1, SOD2, CAT, TXN, and GPX1 promoted the mRNA translation and protein expressions of these antioxidant enzymes by increasing YTHDF1-mediated mRNA stability. Meanwhile, FTO-downregulated m6A on PRDX5 mRNA increased PRDX5 translation and expression by reducing YTHDF2-mediated mRNA decay. After upregulated antioxidant defenses balanced with high levels of ROS induced by arsenic, the m6A balance formed in mRNAs of six key antioxidant enzymes (SOD1, SOD2, CAT, TXN, GPX1, and PRDX5) and promoted high expressions of these antioxidant enzymes to maintain aberrant redox homeostasis. METTL3 inhibitor STM2457, FTO inhibitor FB23–2, or YTHDF1 knockdown disturbed the aberrant redox homeostasis by breaking the m6A balance, causing cell death in arsenic-induced tumors. Our results demonstrated that m6A promotes the formation and maintenance of aberrant redox homeostasis required for arsenic carcinogenesis by time-dependently orchestrating the adaptive expressions of six key m6A-targeted antioxidant enzymes. This study advances our understanding of arsenic carcinogenicity from the novel aspect of m6A-dependent adaptation to arsenic-induced oxidative stress.

Application of biochar and humic acid improves the physiological and biochemical processes of rice (Oryza sativa L.) in conferring plant tolerance to arsenic-induced oxidative stress.

Biochar (BC) and humic acid (HA) are well-documented in metal/metalloid detoxification, but their regulatory role in conferring plant oxidative stress under arsenic (As) stress is poorly understood. Therefore, we aimed at investigating the role of BC and HA (0.2 and 0.4gkg-1 soil) in the detoxification of As (0.25mM sodium arsenate) toxicity in rice (Oryza sativa L. cv. BRRI dhan75). Arsenic exhibited an increased lipid peroxidation, hydrogen peroxide, electrolyte leakage, and proline content which were 32, 30, 9, and 89% higher compared to control. In addition, the antioxidant defense system of rice consisting of non-enzyme antioxidants (18 and 43% decrease in ascorbate and glutathione content) and enzyme activities (23-50% reduction over control) was decreased as a result of As toxicity. The damaging effect of As was prominent in plant height, biomass acquisition, tiller number, and relative water content. Furthermore, chlorophyll and leaf area also exhibited a decreasing trend due to toxicity. Arsenic exposure also disrupted the glyoxalase system (23 and 33% decrease in glyoxalase I and glyoxalase II activities). However, the application of BC and HA recovered the reactive oxygen species-induced damages in plants, upregulated the effectiveness of the ascorbate-glutathione pool, and accelerated the activities of antioxidant defense and glyoxalase enzymes. These positive roles of BC and HA ultimately resulted in improved plant characteristics with better plant-water status and regulated proline content that conferred As stress tolerance in rice. So, it can be concluded that BC and HA effectively mitigated As-induced physiology and oxidative damage in rice plants. Therefore, BC and HA could be used as potential soil amendments in As-contaminated rice fields.

Preharvest melatonin application mitigates arsenic-induced oxidative stress and improves vase life of tuberose (Polianthes tuberosa L.) cut flowers

Arsenic (As) stress severely hinders the growth of ornamental cut flowers. Melatonin (MLT) as a biostimulant protects plants from various abiotic stresses including As stress. However, its protective roles are not well understood in ornamental cut flowers especially tuberose. This research investigated the effects of exogenous melatonin supplementation on alleviating As stress damage in tuberose plants. In As-treated plants, growth traits and leaf chlorophyll contents markedly decreased, while application of MLT, alleviated the inhibitory effect of As on plant growth and chlorophyll content in As-treated plants. Melatonin application considerably increased the vase life of cut tuberose flowers and also improved the protein as well as proline contents in leaf tissues. Level of oxidative markers including electrolyte leakage (EL), malondialdehyde (MDA) and hydrogen peroxide (H2O2) increased in As-treated plants. Upon application of MLT, this trend was alleviated; however, the activities of enzymatic antioxidants increased when plants were subjected to As stress in combination with MLT. Results obtained in the present study suggest that exogenous MLT could alleviate negative effects of As stress on tuberose plants stimulating of oxidative defense related antioxidants. These results are beneficial to improve ornamental tuberose cut flowers production in heavy metal polluted soils or irrigation water.

A Novel Quinazoline Derivative Prevents and Treats Arsenic-Induced Liver Injury by Regulating the Expression of RecQ Family Helicase.

Arsenic is a carcinogenic metalloid toxicant widely found in the natural environment. Acute or prolonged exposure to arsenic causes a series of damages to the organs, mainly the liver, such as hepatomegaly, liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Therefore, it is imperative to seek drugs to prevent arsenic-induced liver injury. Quinazolines are a class of nitrogen heterocyclic compounds with biological and pharmacological effects in vivo and in vitro. This study was designed to investigate the ameliorating effects of quinazoline derivatives on arsenic-induced liver injury and its molecular mechanism. We investigated the mechanism of the quinazoline derivative KZL-047 in preventing and ameliorating arsenic-induced liver injury in vitro by cell cycle and apoptosis. We performed real-time fluorescence quantitative polymerase chain reaction (qPCR) and Western blotting combined with molecular docking. In vivo, the experiments were performed to investigate the mechanism of KZL-047 in preventing and ameliorating arsenic-induced liver injury using arsenic-infected mice. Physiological and biochemical indices of liver function in mouse serum were measured, histopathological changes in liver tissue were observed, and immunohistochemical staining was used to detect changes in the expression of RecQ-family helicases in mouse liver tissue. The results of in vitro experiments showed that sodium arsenite (SA) inhibited the proliferation of L-02 cells, induced apoptosis, blocked the cell cycle at the G1 phase, and decreased the expression of RecQ family helicase; after KZL-047 treatment in arsenic-induced L-02 cells, the expression of RecQ family helicase was upregulated, and the apoptosis rate was slowed, leading to the restoration of the cell viability level. KZL-047 inhibited arsenic-induced oxidative stress, alleviated oxidative damage and lipid peroxidation in vivo, and ameliorated arsenic toxicity-induced liver injury. KZL-047 restored the expression of RecQ family helicase proteins, which is consistent with the results of in vitro studies. In summary, KZL-047 can be considered a potential candidate for the treatment of arsenic-induced liver injury.

D-Limonene Alleviates Oxidative Stress Injury of the Testis Induced by Arsenic in Rat.

Long-term exposure to arsenic can lead to testicular damage and lower sperm quality in males, which is mediated by increased arsenic-induced oxidative stress and other damage mechanisms. D-Limonene, which is rich in oranges, lemons, oranges, grapes and other natural fruits, can relieve doxorubicin (DOX)-induced kidney injury and CCL4-induced cardiac toxicity by inhibiting oxidative stress and inflammatory response. The antioxidant and anti-inflammatory properties of D-limonene motivate us to further explore whether it can reduce arsenic-induced testicular injury. To verify this scientific hypothesis, testicular pathology, testicular oxidative stress levels and sperm motility were determined after intervention with D-limonene in rats chronically exposed to arsenic. As expected, long-term arsenic exposure caused testicular tissue structure disturbances, increased levels of oxidative stress, and decreased sperm activation, all of which were significantly inhibited due to treatment with D-limonene. In conclusion, our data reveal a previously unproven beneficial effect of D-limonene, namely that D-limonene can inhibit arsenic-induced testicular injury, and also provide theoretical and experimental basis for the application of D-limonene in the treatment of arsenic-induced testicular injury.

Investigating the efficacy of tartaric acid and zinc-mediated endogenous melatonin induction for mitigating arsenic stress in Tagetes patula L.

In order to enhance plant growth and productivity, various chemicals and substances are commonly employed, wherein their effectiveness is influenced by factors such as concentration and growth stage. This study aimed to investigate the impact of arsenic stress on Tagetes patula L. and evaluate the potential alleviating effects of zinc (Zn) and tartaric acid. The findings revealed that low concentrations of Zn and tartaric acid effectively protected Tagetes patula L. from the adverse effects of heavy metal stress. Zinc exhibited a crucial role in plant physiology by stimulating enzyme activity and defense mechanisms. Furthermore, moderate concentrations of Zn and tartaric acid were observed to promote plant growth and increase chlorophyll content. Notably, the combined application of Zn and tartaric acid exhibited the most significant improvements in plant morphology and chlorophyll levels. Additionally, the treatments with low concentrations of Zn and tartaric acid resulted in reduced oxidative stress, as evidenced by decreased levels of hydrogen peroxide and malondialdehyde (MDA) content. Moreover, the application of zinc and tartaric acid positively influenced total soluble protein levels and relative water content. The combined treatment also enhanced the activities of antioxidant enzymes, thereby mitigating oxidative damage induced by arsenic stress. Furthermore, the synergistic effect of the Zn and tartaric acid treatment effectively alleviated arsenic-induced oxidative stress and increased the concentration of melatonin. Proline accumulation exhibited an increase under various treatments, with the combination of Zn and tartaric acid showing the most favorable impact. The resting membrane potential (RMP) of the plants was influenced by different treatments, with consistent effects observed in the combined Zn and tartaric acid treatment. Additionally, the combination of targeted amendments (TA) and Zn treatments proved beneficial in reducing soil pollution indicators. In conclusion, the synergistic application of Zn and tartaric acid demonstrated promising effects in mitigating arsenic-induced stress and optimizing the growth and physiology of Tagetes patula plants.

Supplementation with Ascophyllum nodosum extracts mitigates arsenic toxicity by modulating reactive oxygen species metabolism and reducing oxidative stress in rice

Ascophyllum nodosum extract (ANE) is considered as an effective source of biostimulants that have the potential of ameliorating the negative impact of different abiotic stresses in plants. Considering the growth-promoting ability and other regulatory roles of ANE, the present investigation was executed to evaluate the role of ANE in conferring arsenic (As) tolerance in rice (Oryza sativa L. cv. BRRI dhan89). Rice seedlings (35-d-old) were exposed to two doses of sodium arsenate (As1 − 50 mg As kg–1 soil; As2 − 100 mg As kg–1 soil) at 25 days after transplanting through irrigation, whereas only water was applied to the control. Foliar application of 0.1% ANE was also supplemented under control as well as As-stressed conditions at 7 days intervals for 5 times. Arsenic-induced oxidative stress was evident through a sharp increase in lipid peroxidation, hydrogen peroxide, methylglyoxal, and electrolyte leakage in the As-treated plants. As a consequence, plant growth and biomass, leaf relative water content, as well as yield attributes were reduced noticeably. On the other hand, ANE supplemented plants accumulated enhanced levels of ascorbate and glutathione, their redox balance, and the activities of antioxidant and glyoxalase enzymes viz. ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase, glutathione reductase, catalase, glutathione peroxidase, and activities of glyoxalase I and glyoxalase II, respectively. Furthermore, relative water content, plant growth, yield attributes and yield were increased in the As-treated rice plants with ANE supplementation. The results reflected that foliar spray with ANE alleviated As-induced oxidative stress in rice plants by modulating the antioxidative defense and glyoxalase system.

Responses of individual and combined polystyrene and polymethyl methacrylate nanoplastics on hormonal content, fluorescence/photochemistry of chlorophylls and ROS scavenging capacity in Lemna minor under arsenic-induced oxidative stress.

Nanoplastics alter the adverse impacts of hazardous contaminants such as heavy metals by changing their adsorption and accumulation. Few findings are available on the interaction between nanoplastic and heavy metals in plants. However, there is no report on the mechanisms for removing metal stress-mediated oxidative damage by the combination treatments of nanoplastics. To address this lack of information, polystyrene nanoplastic (PS, 100mgL-1) and polymethyl methacrylate (PMMA, 100mgL-1) were hydroponically applied to Lemna minor exposed to arsenate (As, 100μM) for 7 days. PS or PMMA caused a reduction in the contents of N, P, K, Ca, Mg and Mn, but the improved contents were detected in the presence of PS or PMMA plus As stress. The hormone contents (auxin, gibberellic acid, cytokinin, salicylic acid and jasmonic acid) reduced by stress were re-arranged through PS or PMMA applications. Based on chlorophyll efficiency, fluorescence kinetics and performance of PSII, the impaired photosynthesis by As stress was improved via PS or PMMA applications. This alleviation did not continue under the combined form of PS and PMMA in As-applied plants. All analyzed antioxidant activity (superoxide dismutase (SOD), catalase (CAT), peroxidase (POX), ascorbate peroxidase (APX), glutathione reductase (GR), glutathione S-transferase (GST), glutathione peroxidase (GPX), monodehydroascorbate reductase (MDHAR) and dehydroascorbate reductase (DHAR)) decreased or unchanged under As, PS or PMMA. Due to the inactivation of the defense system, L. minor had high levels of hydrogen peroxide (H2O2) and thiobarbituric acid reactive substances (TBARS), showing lipid peroxidation. After As toxicity, induvial applications of PS or PMMA indicated the activated enzyme capacity (SOD, POX, GST and GPX) and upregulated AsA/DHA, GSH/GSSG and redox state of GSH, which facilitated the removal of radical accumulation. The efficiency of the antioxidant system in As+PS+PMMA-applied L. minor was not enough to remove damage induced by As stress; hereby, TBARS and H2O2 contents were similar to the As-treated group. Our findings from alone or combined application of PS and PMMA provide new information to advance the tolerance mechanism against As exposure in L. minor.

Glutathione Might Attenuate Arsenic-Induced Liver Injury by Modulating the Foxa2-XIAP Axis to Reduce Oxidative Stress and Mitochondrial Apoptosis.

Arsenic (AS) is a metalloid element that widely exists and can cause different degrees of liver damage. The molecular mechanism of arsenic-induced liver injury has yet to be fully elucidated. Clinically, glutathione (GSH) is often used as an antidote for heavy metal poisoning and hepatoprotective drugs. However, the hepatoprotective effect of glutathione remains unknown in arsenic-induced liver injury. The regulatory relationship between Foxa2 and XIAP may play an important role in mitochondrial survival and death. Therefore, we took Foxa2-XIAP as the axis to explore the protective mechanism of GSH. In this study, we first established a mouse model of chronic arsenic exposure and examined liver function as reflected by quantitative parameters such as aspartate aminotransferase and alanine aminotransferase. Also, redox parameters in the liver were measured, including malondialdehyde, superoxide dismutase, 8-hydroxy-2'-deoxyguanosin, and glutathione peroxidase. RT-qPCR and western-blotting were used to detect the levels of related genes and proteins, such as Foxa2, XIAP, Smac, Bax, Bcl2, Caspase9, and Caspase3. Subsequently, GSH was administered at the same time as high arsenic exposure, and changes in the above parameters were observed. After a comprehensive analysis of the above results, we demonstrate that GSH treatment alleviates arsenic-induced oxidative stress and inhibits the mitochondrial pathway of apoptosis, which can be regulated through the Foxa2 and XIAP axis. The present study would be helpful in elucidating the molecular mechanism of arsenic-induced liver injury and identifying a new potential therapeutic target. And we also provided new theoretical support for glutathione in the treatment of liver damage caused by arsenic.

SIRT1/PGC-1α is involved in arsenic-induced male reproductive damage through mitochondrial dysfunction, which is blocked by the antioxidative effect of zinc

Exposure to arsenic poses threats to male reproductive system, including impairing the testes and sperm quality. Although an association regarding arsenic exposure and male reproductive damage has been reported, the undergoing molecular mechanisms and interventions for prevention remain unclear. For the present work, male mice were exposed to 0, 2.5, 5, or 10 ppm sodium arsenite (NaAsO2) for 8 months. The results showed that arsenic-exposed mice had reduced fertility with abnormalities in the testes, epididymides, and sperm. Exposure of mice to arsenic caused a redox imbalance, decreased SIRT1 and PGC-1α levels, and affected mitochondrial biogenesis and proteins related to mitochondrial dynamics. For immortalized spermatogenic (GC-2) cells, arsenic caused apoptosis and oxidative stress, reduced SIRT1/PGC-1α levels and ATP production, inhibited mitochondrial respiration, and changed the mitochondrial membrane potential (MMP). Mitochondrial biogenesis and dynamics were also impaired. However, by reducing mitochondrial damage in GC-2 cells, upregulation of SIRT1 or zinc (Zn) supplementation reversed the apoptosis induced by arsenic. For mice, Zn supplementation blocked arsenic-induced oxidative stress, the decreases of SIRT1 and PGC-1α levels, and the impairment of mitochondrial function, and it reversed the damage to testes, low sperm quality, and low litter size. Collectively, these results suggest that arsenic causes excessive production of ROS, inhibits the SIRT1/PGC-1α pathway, and causing mitochondrial dysfunction by mediating impairment of mitochondrial biogenesis and dynamics, which results in germ cells apoptosis and male reproductive damage, processes that are blocked by Zn via an antioxidative effect. Our study contributes to understanding of the mechanisms for arsenic-induced male reproductive damage and points to the therapeutic significance of Zn.

Arsenic-induced differential inflammatory responses in mouse thymus involves NF-κB/STAT-3 disruption, Treg bias and autophagy activation

AimArsenic contamination in drinking water is a world-wide public health concern. Sustained arsenic ingestion leads to immune alterations and subsequent development of inflammatory and autoimmune diseases; however, the underlying cellular and molecular intricacies of immunotoxicity remains uncharacterized. We aim to understand how exposure to arsenic at different concentrations affects the immune system differentially and whether arsenic-induced differential inflammation dictates altered T-regulatory cell bias and emphasize the role of autophagy in the pathway. Main methodsSwiss albino mice were exposed to environmentally relevant concentrations of arsenic in drinking water for 28 days. Examination of thymic cyto-architecture was done to evaluate thymic damage. ELISA was performed for key cytokines. Flow cytometry, western blotting, and immunostaining were performed for cell surface and intracellular proteins. Co-immunoprecipitation and transfection with siRNA were performed to examine the direct physical interactions between proteins. Key findingsOur study distinctly demonstrates that arsenic-induced oxidative stress instigates NF-κB activation, which not only provokes pro-inflammatory responses, but also exhibits immune-suppressive activity depending on the dose of arsenic. Co-immunoprecipitation of NF-κBp65 and pSTAT-3 reveals that arsenic alters their physical interaction, thereby suppressing IL-6/STAT-3/IL-17A feedback loop. Flow cytometry and silencing studies demonstrate that NF-κB-driven Treg cell differentiation induces immune-suppression through FoxP3 up-regulation at the highest dose of arsenic and such immune-suppression is actively supported by NF-κB-driven autophagy activation. SignificanceCollectively, our findings reveal that exposure to arsenic differentially impacts the immune system and understanding the molecular cascade might provide direction for prevention/treatment of arsenic-induced inflammatory and autoimmune diseases.

Differential Effects of Arsenic in Drinking Water on Mouse Hepatic and Intestinal Heme Oxygenase-1 Expression.

Arsenic exposure has been associated with the risks of various diseases, including cancers and metabolic diseases. The aim of this study was to examine the effects of arsenic exposure via drinking water on the expression of heme oxygenase-1 (HO-1), a major responsive gene to arsenic-induced oxidative stress, in mouse intestinal epithelial cells which is the first site of exposure for ingested arsenic, and the liver, a known target of arsenic toxicity. The expression of HO-1 was determined at mRNA, protein, or enzymic activity levels in mice exposed to sodium arsenite through drinking water, at various doses (0, 2.5, 10, 25, 100 ppm), and for various time periods (1, 3, 7, or 28 days). HO-1 was significantly induced in the intestine, but not liver, at arsenic doses of 25 ppm or lower. The intestinal HO-1 induction was seen in both males and females, plateaued within 1–3 days of exposure, and was accompanied by increases in microsomal HO activity. In mice exposed to 25-ppm of arsenite for 7 days, total arsenic and As(III) levels in intestinal epithelial cells were significantly higher than in the liver. These findings identify intestinal epithelial cells as likely preferential targets for arsenic toxicity and support further studies on the functional consequences of intestinal HO-1 induction.

Nrf2/Keap1 pathway in countering arsenic-induced oxidative stress in mice after chronic exposure at environmentally-relevant concentrations.

Contamination of drinking water by carcinogen arsenic (As) is of worldwide concern as its exposure poses potential threat to human health. As such, it is important to understand the mechanisms associated with As-induced toxicity to humans. The Nrf2/Keap1 signal pathway is one of the most important defense mechanisms in cells to counter oxidative stress; however, limited information is available regarding its role in countering As-induced stress in model animal mouse. In this study, we assessed the responses of Nrf2/keap1 pathway in mice after chronic exposure to As at environmentally-relevant concentrations of 10-200μgL-1 for 30 days via drinking water. Our results indicate that chronic As exposure had limited effect on mouse growth. However, As induced oxidative stress to mice as indicated by increased content of malondialdehyde (MDA; 52-90%), an index of lipid peroxidation. Further, arsenic exposure reduced the activity of superoxide dismutase (SOD; 14-18%), an indication of reduced anti-oxidative activity. Besides, arsenic exposure increased MnSOD mRNA transcription by 25-66%, and decreased the mRNA transcriptions of Cu/ZnSOD by 72-83% and metallothionein by 16-75%, a cysteine-rich protein involved in metal detoxification. To counter arsenic toxicity, the expression of transcription factor for Nrf2 and Keap1 was increased by 2.8-8.9 and 0.2-8.1 fold in mice. To effectively reduce As-induced oxidative stress, the Nrf2/Keap1 transcription factor upregulated several downstream anti-oxidative genes, including heme oxygenase-1 (0.9-2.5 fold), glutamate-cysteine ligase catalytic subunit (0.6-1.7 fold), and NADH quinone dehydrogenase 1 (2.1-4.8 fold). This study shows the importance of Nrf2/Keap1 signaling pathway and associated anti-oxidative enzymes in countering As-toxicity in mice, possibly having implication for human health.

Arsenic, Oxidative Stress and Reproductive System.

Infertility is a severe medical problem and is considered a serious global public health issue affecting a large proportion of humanity. Oxidative stress is one of the most crucial factors involved in infertility. Recent studies indicate that the overproduction of reactive oxygen species (ROS) or reactive nitrogen species (RNS) may cause damage to the male and female reproductive systems leading to infertility. Low amounts of ROS and RNS are essential for the normal functioning of the male and female reproductive systems, such as sperm motility, acrosome reaction, interactions with oocytes, ovulation, and the maturation of follicles. Environmental factors such as heavy metals can cause reproductive dysfunction in men and women through the overproduction of ROS and RNS. It is suggested that oxidative stress caused by arsenic is associated with male and female reproductive disorders such as through the alteration in sperm counts and motility, decreased sex hormones, dysfunction of the testis and ovary, as well as damage to the processes of spermatogenesis and oogenesis. This review paper highlights the relationship between arsenic-induced oxidative stress and the prevalence of infertility, with detailed explanations of potential underlying mechanisms.

Irvingia gabonensis leaf extract scavenges nitric oxide and hydrogen peroxide in vitro and modulates arsenic-induced hepatic oxidative stress in wistar rats

BackgroundArsenic is a carcinogenic heavy metal that contaminates the environment, predisposing the exposed populace to its detrimental health effects. This study investigated the liver protective effect of ethanol leaf extract of Irvingia gabonensis (ELEIG) in sodium arsenite (SA)-exposed Wistar rats and its nitric oxide (NO.) and hydrogen peroxide (H2O2)-scavenging properties in vitro.MethodsEleven experimental groups made up of five (5) rats each (weight range 100 - 161 g) were used in this study. Group 1 (normal control) had normal rat chow and water. Group 2 received 4.1 mg/kg body weight (kgbw) of SA. Groups 3–8 received SA and graded doses of ELEIG and groups 9-11 had varied doses of ELEIG. Treatment, which spanned 14 days, was by oral gavage. Concentrations of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA) as well as activities of liver enzymes (AST, ALT, ALP, and GGT) and concentrations of total bilirubin (TBIL) and direct bilirubin (DBIL) were determined using standard procedures. Standard methods were also used to determine the in vitro NO. and H2O2-scavenging properties of the extract.ResultsExposure to SA orchestrated significant (p ˂ 0.05) increases in CAT, MDA, AST, ALT, ALP and GGT and significant (p ˂ 0.05) decreases in SOD and GPx, relative to control. There were insignificant (p ˃ 0.05) differences in TBIL and DBIL concentrations, compared with control. Simultaneous and post-treatment with ELEIG at graded doses, alleviated the noxious effects of SA. In addition, ELEIG scavenged NO. and H2O2 in concentration-dependent manner.ConclusionThe results suggest that ELEIG possesses potent antioxidant property and combats SA-induced hepatic oxidative stress/toxicity in Wistar rats.

Attenuating effect of Indian mustard (Brassica juncea) seed and its nano formulation on arsenic induced-oxidative stress and associated genotoxicity in rat

ObjectiveArsenic (As) has been in the forefront of toxicological research due to its continual worldwide human exposure and its adverse effects including genotoxicity. The study assessed the potential ameliorative effect of Indian mustard seeds (Brassica juncea) and their nanoparticles against arsenic toxicity. MethodsMale Wistar rats were used for the exposure study. Group I was control and group V was exposed only to the nanoparticles. Groups II, III, and IV were exposed to 10 mg/kg sodium arsenite for two weeks. Groups III and IV were treated with mustard seeds and the nanoparticles (500 mg/kg) respectively. ResultsArsenic intoxication caused a marked increase in the levels of As in the brain. Additionally, oxidative damage was exhibited with significantly enhanced levels of serum 8-OHdG and hepatic p53 and pS15. The pictographs and the analyzed parameters of the COMET assay illustrated DNA damage with significantly increased values of tail moment and length. Treatment with mustard seeds and its nanoparticles markedly reversed the adverse effects of As toxicity, which is attributed to the presence of a gamut of constituent phytocompounds in the mustard seeds. ConclusionTaken together the nano formulation was more efficacious and could be introduced as a potential nutraceutical to combat metal toxicity.

Protective effects of methanolic extract of Andrographis paniculata (Burm.f.) Nees leaves against arsenic-induced damage in rats

BackgroundMedicinal plants are natural sources of antioxidants effective in the treatment of oxidative stress-mediated diseases. This study aims to evaluate the hepato-renal protective efficacy of Andrographis paniculata leaves methanolic extract in arsenic-induced oxidative stress. Animals were divided into four groups of six animals per group. The rats in groups 1 and 2 received normal saline, while rats in groups 3 and 4 received 200 mg/kg body weight of A. paniculata or ascorbic acid per day, respectively, for 7 days orally. The rats in groups 2, 3, and 4 received a single dose of arsenic at 10 mg/kg body weight intraperitoneally on day 7, and 24 h later, rats in all the groups were killed and the blood, liver, and kidney samples were collected for biochemical/histological studies.ResultsAdministration of arsenic to rats induced a significant increase in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, urea, creatinine, and triglycerides in the plasma, while it decreased superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT) activities in the liver and kidney. It also significantly reduced the levels of white blood cells (WBC), red blood cells (RBC), platelet (PLT), and lymphocytes (LYM) in the blood. However, the levels of AST, ALT, cholesterol, urea, creatinine, and triglycerides in the plasma of groups of rats that received A. paniculata extract before administration of arsenic were decreased, while their SOD, GSH, and CAT levels were elevated in the liver and kidney. The values of their WBC, RBC, PLT, and LYM were also significantly increased when compared to the arsenic group rats. Histological observations showed varying degrees of liver damage in the arsenic group rats, while the histoarchitecture of the liver of rats that received A. paniculata extract were significantly improved.ConclusionsThis study demonstrated that A. paniculata extract ameliorates arsenic-induced hepato-renal toxicity and could be exploited in the management of toxicity effects associated with the arsenic.

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.