The mechanism of low-level arsenic exposure-induced hypertension: Inhibition of the activity of the angiotensin-converting enzyme 2.

It is now well-established that arsenic exposure induces hypertension in humans. Although arsenic-induced hypertension is reported in many epidemiological studies, the underlying molecular mechanism of arsenic-induced hypertension is not fully characterized. In the human body, blood pressure is primarily regulated by a well-known physiological system known as the renin-angiotensin system (RAS). Hence, we explored the potential molecular mechanisms of arsenic-induced hypertension by investigating the regulatory roles of the RAS. Adult C57BL/6JJcl male mice were divided into four groups according to the concentration of arsenic in drinking water (0, 8, 80, and 800 ppb) provided for 8 weeks. Arsenic significantly raised blood pressure in arsenic-exposed mice compared to the control group, and significantly raised plasma MDA and Ang II and reduced Ang (1-7) levels. RT-PCR results showed that arsenic significantly downregulated ACE2 and MasR in mice aortas. In vitro studies of endothelial HUVEC cells treated with arsenic showed increased level of MDA and Ang II and lower levels of Ang (1-7), compared with the control. Arsenic significantly downregulated ACE2 and MasR expression, as well as those of Sp1 and SIRT1; transcriptional activators of ACE2, in HUVECs. Arsenic also upregulated markers of endothelial dysfunction (MCP-1, ICAM-1) and inflammatory cytokines (IL-6, TNF-α) in HUVECs. Our findings suggest that arsenic-induced hypertension is mediated, at least in part, by oxidative stress-mediated inhibition of ACE2 as well as by suppressing the vasoprotective axes of RAS, in addition to the activation of the classical axis.

Natural Dietary Compounds in the Treatment of Arsenic Toxicity.

Chronic exposure to arsenic (As) compounds leads to its accumulation in the body, with skin lesions and cancer being the most typical outcomes. Treating As-induced diseases continues to be challenging as there is no specific, safe, and efficacious therapeutic management. Therapeutic and preventive measures available to combat As toxicity refer to chelation therapy, antioxidant therapy, and the intake of natural dietary compounds. Although chelation therapy is the most commonly used method for detoxifying As, it has several side effects resulting in various toxicities such as hepatotoxicity, neurotoxicity, and other adverse consequences. Drugs of plant origin and natural dietary compounds show efficient and progressive relief from As-mediated toxicity without any particular side effects. These natural compounds have also been found to aid the elimination of As from the body and, therefore, can be more effective than conventional therapeutic agents in ameliorating As toxicity. This review provides an overview of the recently updated knowledge on treating As poisoning through natural dietary compounds. This updated information may serve as a basis for defining novel prophylactic and therapeutic formulations.

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.

Environmental arsenic exposure and its contribution to human diseases, toxicity mechanism and management.

Arsenic is a well-recognized environmental contaminant that occurs naturally through geogenic processes in the aquifer. More than 200 million people around the world are potentially exposed to the elevated level of arsenic mostly from Asia and Latin America. Many adverse health effects including skin diseases (i.e., arsenicosis, hyperkeratosis, pigmentation changes), carcinogenesis, and neurological diseases have been reported due to arsenic exposure. In addition, arsenic has recently been shown to contribute to the onset of non-communicable diseases, such as diabetes mellitus and cardiovascular diseases. The mechanisms involved in arsenic-induced diabetes are pancreatic ß-cell dysfunction and death, impaired insulin secretion, insulin resistance and reduced cellular glucose transport. Whereas, the most proposed mechanisms of arsenic-induced hypertension are oxidative stress, disruption of nitric oxide signaling, altered vascular response to neurotransmitters and impaired vascular muscle calcium (Ca2+) signaling, damage of renal, and interference with the renin-angiotensin system (RAS). However, the contributions of arsenic exposure to non-communicable diseases are complex and multifaceted, and little information is available about the molecular mechanisms involved in arsenic-induced non-communicable diseases and also no suitable therapeutic target identified yet. Therefore, in the future, more basic research is necessary to identify the appropriate therapeutic target for the treatment and management of arsenic-induced non-communicable diseases. Several reports demonstrated that a daily balanced diet with proper nutrient supplements (vitamins, micronutrients, natural antioxidants) has shown effective to reduce the damages caused by arsenic exposure. Arsenic detoxication through natural compounds or nutraceuticals is considered a cost-effective treatment/management and researchers should focus on these alternative options. This review paper explores the scenarios of arsenic contamination in groundwater with an emphasis on public health concerns. It also demonstrated arsenic sources, biogeochemistry, toxicity mechanisms with therapeutic targets, arsenic exposure-related human diseases, and onsets of cardiovascular diseases as well as feasible management options for arsenic toxicity.

Amelioration of Metal-Induced Cellular Stress by α-Lipoic Acid and Dihydrolipoic Acid through Antioxidative Effects in PC12 Cells and Caco-2 Cells.

α-Lipoic acid (ALA) and its reduced form dihydrolipoic acid (DHLA) are endogenous dithiol compounds with significant antioxidant properties, both of which have the potential to detoxify cells. In this study, ALA (250 µM) and DHLA (50 µM) were applied to reduce metal (As, Cd, and Pb)-induced toxicity in PC12 and Caco-2 cells as simultaneous exposure. Both significantly decreased Cd (5 µM)-, As (5 µM)-, and Pb (5 µM)-induced cell death. Subsequently, both ALA and DHLA restored cell membrane integrity and intracellular glutathione (GSH) levels, which were affected by metal-induced toxicity. In addition, DHLA protected PC12 cells from metal-induced DNA damage upon co-exposure to metals. Furthermore, ALA and DHLA upregulated the expression of survival-related proteins mTOR (mammalian target of rapamycin), Akt (protein kinase B), and Nrf2 (nuclear factor erythroid 2-related factor 2) in PC12 cells, which were previously downregulated by metal exposure. In contrast, in Caco-2 cells, upon co-exposure to metals and ALA, Nrf2 was upregulated and cleaved PARP-1 (poly (ADP-ribose) polymerase-1) was downregulated. These findings suggest that ALA and DHLA can counterbalance the toxic effects of metals. The protection of ALA or DHLA against metal toxicity may be largely due to an enhancement of antioxidant defense along with reduced glutathione level, which ultimately reduces the cellular oxidative stress.

Binding of collagen gene products with titanium oxide.

Titanium is the only metal to which osteoblasts can adhere and on which they can grow and form bone tissue in vivo, resulting in a strong bond between the implant and living bone. This discovery provides the basis for the universal medical application of Ti. However, the biochemical mechanism of bond formation is still unknown. We aimed to elucidate the mechanism of bond formation between collagen, which constitutes the main organic component of bone, and TiO2, of which the entire surface of pure Ti is composed. We analysed the binding between the soluble collagen and TiO2 by chromatography with a column packed with Ti beads of 45 µm, and we explored the association between collagen fibrils and TiO2 (anatase) powders of 0.2 µm. We ran the column of chromatography under various elution conditions. We demonstrated that there is a unique binding affinity between Ti and collagen. This binding capacity was not changed even in the presence of the dissociative solvent 2M urea, but it decreased after heat denaturation of collagen, suggesting the contribution of the triple-helical structure. We propose a possible role of periodically occurring polar amino acids and the collagen molecules in the binding with TiO2.

Effects of curcumin, D-pinitol alone or in combination in cytotoxicity induced by arsenic in PC12 cells.

Arsenic is a well-known potent toxicant affecting people by causing various human diseases. Long-term exposure to arsenic has strong adverse health effects on liver and kidney disorders, and various forms of cancer. Contrarily, curcumin and D-pinitol are bioactive dietary compounds that have antioxidant properties. Both are used to treat a broad variety of human diseases. Thus, we hypothesized that both may have synergistic effects against arsenic-induced toxicity in PC12 cells. Cells were pretreated with curcumin (1, 2.5, 5 and 10 µM), D-pinitol (1, 2.5, 5 and 10 µM) alone or in combination, then exposed to sodium arsenite (10 µM). The final concentration of curcumin 2.5 µM and D-pinitol 5 µM was selected for combination treatment based on their highest protection at lowest concentration against arsenic toxicity. Results demonstrated that pretreatment of curcumin and D-pinitol and their combined treatment with arsenic rescued PC12 cells. Western blot analysis results showed that pretreatment of curcumin and D-pinitol and their combined treatment with arsenic significantly inhibited arsenic-induced cell death through up-regulation of pro-survival proteins and down-regulation of cell death-related proteins, although these protein expressions were negatively regulated by arsenic. Furthermore, the effect of combined treatment with curcumin and D-pinitol was stronger than individual treatment.

Arsenic intoxication: general aspects and chelating agents.

Arsenic (As) is widely used in the modern industry, especially in the production of pesticides, herbicides, wood preservatives, and semiconductors. The sources of As such as contaminated water, air, soil, but also food, can cause serious human diseases. The complex mechanism of As toxicity in the human body is associated with the generation of free radicals and the induction of oxidative damage in the cell. One effective strategy in reducing the toxic effects of As is the usage of chelating agents, which provide the formation of inert chelator-metal complexes with their further excretion from the body. This review discusses different aspects of the use of metal chelators, alone or in combination, in the treatment of As poisoning. Consideration is given to the therapeutic effect of thiol chelators such as meso-2,3-dimercaptosuccinic acid, sodium 2,3-dimercapto-1-propanesulfonate, 2,3-dimercaptopropanol, penicillamine, ethylenediaminetetraacetic acid, and other recent agents against As toxicity. The review also considers the possible role of flavonoids, trace elements, and herbal drugs as promising natural chelating and detoxifying agents.

Curcumin alleviates arsenic-induced toxicity in PC12 cells via modulating autophagy/apoptosis.

Arsenic is a recognized highly toxic contaminant, responsible for numerous human diseases and affecting many millions of people in different parts of the world. Contrarily, curcumin is a natural dietary polyphenolic compound and the main active ingredient in turmeric. Recently it has drawn great attention due to its diverse biological activities, strong antioxidant properties and therapeutic potential against many human ailments. In this study, we aimed to explore the protective effects and the regulatory role of curcumin on arsenic-induced toxicity and gain insights into biomolecular mechanism/s. Arsenic (10 µM) treatment in PC12 cells for 24 h induced cytotoxicity by decreasing cell viability and intracellular glutathione level and increasing lactate dehydrogenase activity and DNA fragmentation. In addition, arsenic caused apoptotic cell death in PC12 cells, which were confirmed from flow cytometry results. Moreover, arsenic (10 µM) treatment significantly down-regulated the inhibition factors of autophagy/apoptosis; mTOR, Akt, Nrf2, ERK1, Bcl-x, Xiap protein expressions, up-regulated the enhanced factors of autophagy/apoptosis; ULK, LC3, p53, Bax, cytochrome c, caspase 9, cleaved caspase 3 proteins and eventually caused autophagic and apoptotic cell death. However, curcumin (2.5 µM) pretreatment with arsenic (10 µM) effectively saves PC12 cells against arsenic-induced cytotoxicity through increasing cell viability, intracellular GSH level and boosting the antioxidant defense system, and limiting the LDH activity and DNA damage. Furthermore, pretreatment of curcumin with arsenic expressively alleviated arsenic-induced toxicity and cell death by reversing the expressions of proteins; mTOR, Akt, Nrf2, ERK1, Bcl-x, Xiap, ULK, LC3, p53, Bax, cytochrome c, caspase 9 and cleaved caspase 3. Our findings indicated that curcumin showed antioxidant properties through the Nrf2 antioxidant signaling pathway and alleviates arsenic-triggered toxicity in PC12 cells by regulating autophagy/apoptosis.

Interactions between iron and manganese in neurotoxicity.

The essential and naturally occurring transition metal manganese (Mn) is present in the soil, water, air, and various foods. Manganese can accumulate in the brain if the Mn intake or exposure is excessive and this can result in neurotoxic effects. Manganese is important for the proper activation of different metabolic and antioxidant enzymes. There are numerous Mn importers and exporters. However, the exact transport mechanism for Mn is not fully understood. On the other hand, iron (Fe) is another well-known essential metal, which has redox activity in addition to chemical characteristics resembling those of Mn. Existing data show that interactions occur between Fe and Mn due to certain similarities regarding their mechanisms of the absorption and the transport. It has been disclosed that Mn-specific transporters, together with Fe transporters, regulate the Mn distribution in the brain and other peripheral tissues. In PC12 cells, a significant increase of transferrin receptor (TfR) mRNA expression was linked to Mn exposure and accompanied by elevated Fe uptake. In both humans and animals, there is a strong relationship between Fe and Mn metabolism. In the present review, special attention is paid to the interaction between Mn and Fe. In particular, Fe and Mn distribution, as well as the potential molecular mechanisms of Mn-induced neurotoxicity in cases of Fe deficiency, are discussed.

Investigating the protective actions of D-pinitol against arsenic-induced toxicity in PC12 cells and the underlying mechanism.

Arsenic is awfully toxic metalloid responsible for many human diseases all over the world. Contrastingly, D-pinitol is a naturally occurring bioactive dietary compound has antioxidant properties. The objective of this study is to elucidate the protective actions of D-pinitol on arsenic-induced cytotoxicity and explore its controlling role in biomolecular mechanisms in PC12 cells. Obtained results demonstrated that co-exposure of D-pinitol with arsenic increases cell viability, decreases DNA damage and protects PC12 cells from arsenic-induced cytotoxicity by increasing glutathione (GSH) level and glutathione reductase (GR). Protein expression of western blot analysis showed that co-exposure of D-pinitol and arsenic significantly inhibited arsenic-induced autophagy which further suppressed apoptosis through up-regulation of survival factors; mTOR, p-mTOR, Akt, p-Akt, NF-кB, Nrf2, ERK1, GR, Bcl-x and down-regulation of death factors; p53, Bax, cytochrome c, LC3, although arsenic regulated those factors negatively. These results of this study suggested that D-pinitol protects PC12 cells from arsenic-induced cytotoxicity.

Developmental toxicity of arsenic: a drift from the classical dose-response relationship.

Arsenic is a well-known natural environmental contaminant distributed in food, water, air, and soil. The developmental toxicity of arsenic exposure is a significant concern in large parts of the world. Unlike acute toxic exposure, the classical dose-response relationship is not adequate for estimating the possible impact of chronic low-level arsenic exposure. The real-life risk and impact assessments require the consideration of the co-exposure to multiple toxins, individual genetic and nutritional predisposition, and the particularly vulnerable stages of the neurodevelopment. This context shifts the assessment model away from the 'one-exposure-for-one-health-effect.' We underscore the need for a comprehensive risk assessment that takes into account all relevant determinants. We aim to elaborate a model that can serve as a basis for an understanding of complex interacting factors in a long-lasting and ongoing low-level arsenic exposure, to identify, protect, and support the children at risk.

Selenium and zinc protections against metal-(loids)-induced toxicity and disease manifestations: A review.

Metals are ubiquitous in the environment due to huge industrial applications in the form of different chemicals and from extensive mining activities. The frequent exposures to metals and metalloids are crucial for the human health. Trace metals are beneficial for health whereas non-essential metals are dangerous for the health and some are proven etiological factors for diseases including cancers and neurological disorders. The interactions of essential trace metals such as selenium (Se) and zinc (Zn) with non-essential metals viz. lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg) in biological system are very critical and complex. A huge number of studies report the protective role of Se and Zn against metal toxicity, both in animal and cellular levels, and also explain the numerous mechanisms involved. However, it has been considered that a tiny dyshomeostasis in the metals/trace metals status in biological system could induce severe deleterious effects that can manifest to numerous diseases. Thus, in this particular review, we have demonstrated the critical protection mechanism/s of Se and Zn against Cd, Pb, As and Hg toxicity in a one by one manner to clarify the up-to-date findings and perspectives. Furthermore, biomolecular consequences are comprehensively presented in light of particular cellular/biomolecular events which are somehow linked to a subsequent disease. The analyzed reports support significant protection potential of Se and Zn, either alone or in combination with other agents, against each of the abovementioned non-essential metals. However, Se and Zn are still not being used as detoxifying agents due to some unexplained reasons. We hypothesized that Se could be a potential candidate for detoxifying As and Hg regardless of their chemical speciations, but requires intensive clinical trials. However, particularly Zn-Hg interaction warrants more investigations both in animal and cellular level.