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.

Zinc-pretreatment triggers glutathione and Nrf2-mediated protection against inorganic mercury-induced cytotoxicity and intrinsic apoptosis in PC12 cells.

Mercury (Hg) is a hazardous metal, poses environmental problems with severe human health effects; whereas zinc (Zn) is an essential micronutrient with antioxidant properties. The purpose of this research was to investigate the effect of Zn on inorganic Hg-induced cytotoxicity in the PC12 cells. The cells were treated with HgCl2 (5 µM) for 48 h with/without 1 h prior ZnCl2-treatment (100 µM) and deliberated for further analysis. After 48 h of incubation with only Hg2+, the cell showed reduced cell viability, compromised cell membrane, DNA degradation, depleted glutathione level, ROS generation and drastically increased apoptosis. Subsequently, Hg2+-treated cells demonstrated a significant downregulation of akt, mTOR, ERK1, Nrf2, HO1, Bcl-2, Bcl-xL, and upregulation of p53, Bax, cytochrome c and cleaved caspase 3, indicating intrinsic apoptosis induction. However, cells pretreated with Zn2+ before Hg2+-exposure showed a significant improvement in cell viability, cell membrane, DNA damage, glutathione level, ROS amount and apoptotic cells, with a significant upregulation in mTOR, akt, ERK1, Nrf2, HO1, Bcl-2 and Bcl-xL, and downregulation in p53, Bax, cytochrome c and cleaved caspase 3, indicating inhibition of apoptosis. The findings suggested that Zn2+-pretreatment not only improves glutathione content but also induces activation of Nrf2-HO1 pathway, which would tend to suppress Hg-cytotoxicity.

Green Synthesized Silver Nanoparticles-Mediated Cytotoxic Effect in Colorectal Cancer Cells: NF-κB Signal Induced Apoptosis Through Autophagy.

Green synthesized silver nanoparticles (Ag-NPs) have demonstrated promising effects, including cytotoxicity and anticancer potential, in different cell lines. Therefore, in our previous study, Ag-NPs were synthesized from the reduction of AgNO3 using Brassica rapa var. japonica (Bj) leaf extract as a reducing and stabilizing agent. The synthesized Ag-NPs were spherical in shape, with a size range of 15-30 nm. They had phase-centered cubic structure with strong growth inhibition potential against some bacteria. In continuation with our previous study, in the present study, we aimed to investigate the autophagy-regulated cytotoxic effect of Ag-NPs against human epithelial colorectal adenocarcinoma cells (Caco-2 cells). We found that the Bj leaf aqueous extract facilitated Brassica silver nanoparticles (Brassica Ag-NPs)-induced NF-κB mediated autophagy in Caco-2 cells. Results showed that Ag-NPs reduced cell viability of Caco-2 cells by inducing oxidative stress and DNA damage. Therefore, to understand the mechanism underlying the death-promoting activity of Ag-NPs in Caco-2 cells, western blotting was performed. Western blot analysis showed decreased expression of NFκB and increased expression of IκB, which is a sign of autophagy initiation. In addition, autophagosome formation was accelerated by the activity of p53 and light chain 3 (LC3) II. In addition, inhibition of Akt and mTOR also played a pivotal role in autophagy formation. Finally, excessive expansion of autophagy promoted apoptosis, which subsequently resulted in necrosis. These findings support a novel cell death-promoting function of autophagy by Ag-NPs in Caco-2 cells.

Dietary supplementation of garlic, propolis, and wakame improves recuperation in cadmium exposed Japanese medaka fish (Oryzias latipes).

Cadmium (Cd) toxic effects can overwhelm endogenous antioxidants and affect recuperation in fish. Thus, this study assessed antioxidative properties and ameliorating potentials of dietary supplemented garlic (D1), propolis (D2), and wakame (D3) on i) Cd bioconcentration, and ii) Cd induced toxicity during recuperation in Cd exposed Japanese medaka. In a 21-day exposure, control (0.0 mg Cd/L in water-C1) or Cd-treatment (0.3 mg Cd/L in water-T1) fish were fed medaka diets. Surviving fish in T1 were further depurated for 21-days and fed D1, D2, D3, or medaka diet (C2). Gill, liver, and muscle tissues were assessed weekly for Cd bioconcentration, metallothionein, (MT), superoxide dismutase (SOD), total glutathione (GSH), and lipid peroxidation (LPO). Results showed reduced antioxidant activity by significantly increasing tissue Cd and LPO, and significantly reducing SOD activity and GSH content in gill and muscle upon Cd exposure. In contrast, D1, D2, and D3 diets significantly reduced tissue Cd and LPO, while increasing contents of MT and GSH, and SOD activity, significantly. Other condition indices in D1, D2 and D3 groups were also significantly higher than those in C2 groups. In conclusion, dietary supplementation significantly increased recuperation and tissue functions in fish, in the order D1 > D2 > D3> C2.

Selenium modulates inorganic mercury induced cytotoxicity and intrinsic apoptosis in PC12 cells.

Mercury (Hg) in its all forms, including inorganic Hg (iHg) is an environmental contaminant due to toxicity and diseases in human. However, a little is known about the underlying mechanisms responsible for iHg toxicity. Selenium (Se) is an essential trace element, recognized as an antioxidant and protective agent against metal toxicities. The purpose of this research was to investigate ameliorations of Se counter to iHg-mediated toxicity in PC12 cells. Cytotoxic assays have been shown that iHg (5 µM) caused oxidative stress and intrinsic apoptosis via ROS generation, oxidizing glutathione, damaging DNA, degrading cell membrane integrity, down-regulating mTOR, p-mTOR, akt and ERK1, and up-regulating cleaved caspase 3 and cytochrome c release in PC12 cells 48 h after incubation. Co-treatment of Se (5 µM) inhibited intrinsic apoptosis and oxidative stress induced by iHg (5 µM) via inhibiting ROS formation, boosting GPx contents, increasing reduced glutathione, limiting DNA degradation, improving cell membrane integrity, up-regulating mTOR, p-mTOR, akt, ERK1 and caspase 3, and down-regulating cleaved caspase 3 and cytochrome c leakage in PC12 cells. In conclusion, these results recommended that excessive ROS generation acts a critical role in iHg-influenced oxidative stress and co-treatment of Se attenuates iHg-cytotoxicity through its antioxidant properties.

Amelioration of butylated hydroxytoluene against inorganic mercury induced cytotoxicity and mitochondrial apoptosis in PC12 cells via antioxidant effects.

Mercury (Hg) is a toxic metal, well-known for its dangerous health effects on human. Butylated hydroxytoluene (BHT) is a phenolic component generally consumed as a food additive as an antioxidant. However, BHT induced antioxidant properties against heavy metals-influenced toxicity are little studied. We hypothesized that BHT has a regulatory effect on Hg-induced cytotoxicity. The objective of this research was to assess the protecting effects of BHT against inorganic Hg (iHg)-toxicity in PC12 cells, where cells were treated with/without HgCl2 (Hg2+) (5 µM) and BHT (100 µM) for 48 h and analyzed further. Cells treated by Hg caused a significant cell viability reduction, membrane damage, glutathione reduction, DNA fragmentation, ROS generation, with suppressed expressions of akt, mTOR, ERK1, Nrf2 and HO1; and elevated apoptotic expressions of p53, Bax, cytochrome c and active caspase 3. However, BHT and Hg2+ co-exposure showed prevention against Hg2+-toxicity by improving GSH content and inhibiting ROS generation and oxidative stress mediated damages. Additionally, BHT co-treatment inverted the pro-apoptotic proteins by augmenting pro-survival regulatory proteins akt, mTOR, ERK1, Nrf2 and HO1. These findings proved that BHT inhibits Hg2+-toxicity, hindering ROS generation and intrinsic apoptosis, via enhancing glutathione and antioxidants; and suggested BHT implications as therapeutic.

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.

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.

Zweigelt and Niagara skin extracts suppress cyclobutane pyrimidine dimer formation due to UV irradiation in NHEK cells: first attempt.

The grape skins after pressing the juice are a major problem for winery. However, because it contains a large amount of polyphenols, development of effective usages are expected to construct sustainable waste use. In this study, we examined whether grape skin extract is effective for recovery of DNA damage caused by UV irradiation. Extract from Zweigelt and Niagara skin was prepared by methanol, and UV irradiation was performed at 10 mJ/cm2 (250 nm) and 15 mJ/cm2 (290 nm) using human normal skin cells. As results, the decreased cell viability due to UV irradiation was improved by adding Niagara or Zweigelt skin extract. On the other hand, cyclobutane pyrimidine dimer production due to UV irradiation decreased significantly by Niagara or Zweigelt extract. In addition, the effects of grape skin extracts on the expression of sirtuin gene were also examined.

Analysis of Cadmium, Epigallocatechin Gallate, and Vitamin C Co-exposure on PC12 Cellular Mechanisms.

Exposure to cadmium (Cd) is a risk factor to health impairments, wherein its cytotoxicity is attributed to induction of oxidative stress. Usage of anti-oxidants, however, can help lessen the damaging effects of Cd. The effect of Cd interaction with low concentration of dietary anti-oxidants, L-ascorbic acid and (-)-epigallocatechin gallate (EGCG), to PC12 cellular mechanisms was examined. The expected toxicity of Cd was observed on PC12 cells but addition of L-ascorbic acid ameliorated this effect. On the other hand, addition of EGCG was able to increase the cytotoxicity of Cd and to decrease the protective effect of L-ascorbic acid against Cd. Increase in LDH activity and decrease in free sulfhydryl levels indicated cell membrane damage and oxidative stress, respectively, in Cd- and EGCG-Cd-treated cells. Downregulation of pro-apoptotic proteins (pro-caspase-9, p53, and ERK1) was observed in cells treated with Cd alone and EGCG-Cd, while upregulation of autophagy-linked proteins (p62 and pBeclin1) was found on L-ascorbic acid-Cd combination treatments. These findings indicate that Cd causes cells to undergo an autophagy-enhanced cell death; low-concentration EGCG and L-ascorbic acid promotes cell survival individually; however, interaction of EGCG with Cd showed enhancement of Cd toxicity and antagonism of L-ascorbic acid efficiency.

Phosphorylated chitin increased bone formation when implanted into rat calvaria with the Ti-device.

BACKGROUND: Previously we found that a group of phosphorylated proteins (SIBLINGs) in bone binds with the Ti-device, and increases the early bone formation around the Ti-implants remarkably. From these results, we explained the biochemical mechanism of a strong bond between living bone and Ti, which was discovered by Brånemark and colleagues. For the clinical application of our findings, we need a large amount of these proteins or their substitutes. OBJECTIVE: We aimed to create a new molecule that equips with essential functions of SIBLINGs, Ti-binding, and bone enhancement around the Ti implant. METHODS: We chemically phosphorylated chitin and obtained a soluble form of phosphorylated chitin (P-chitin). In this solution, we immersed the Ti-devices of web-form (TW) which we previously developed and obtained the P-chitin coated TWs. Then we tested the P-chitin coated TWs for their calcification ability in vitro, and bone enhancing ability in vivo, by implanting them into rat calvaria. We compared the P-chitin coated TW and the non-coated TW in regard to their calcification and bone enhancing abilities. RESULTS: Ti-devices coated with phosphorylated-chitin induced a ten times higher calcification in vitro at 20 days, and four times more elevated amount of bone formation in vivo at two weeks than the uncoated Ti-device. CONCLUSIONS: Phosphorylated chitin could be a partial substitute of bone SIBLING proteins and are clinically applicable to accelerate bone formation around the Ti implants, thereby achieving the strong bond between living bone and Ti.

Regulatory effects of dihydrolipoic acid against inorganic mercury-mediated cytotoxicity and intrinsic apoptosis in PC12 cells.

Mercury (Hg) is an extremely dangerous environmental contaminant, responsible for human diseases including neurological disorders. However, the mechanisms of inorganic Hg (iHg)-induced cell death and toxicity are little known. Dihydrolipoic acid (DHLA) is the reduced form of a naturally occurring compound lipoic acid, which act as a potent antioxidant through multiple mechanisms. So we hypothesized that DHLA has an inhibitory role on iHg-cytotoxicity. The purposes of this research were to investigate mechanism/s of cytotoxicity of iHg, as well as, the cyto-protection of DHLA against iHg induced toxicity using PC12 cells. Treatment of PC12 cells with HgCl2 (Hg2+) (0-2.5 µM) for 48 h resulted in significant toxic effects, such as, cell viability loss, high level of lactate dehydrogenase (LDH) release, DNA damage, cellular glutathione (GSH) level decrease and increased Hg accumulation. In addition, protein level expressions of akt, p-akt, mTOR, GR, NFkB, ERK1, Nrf2 and HO-1 in cells were downregulated; and cleaved caspase 3 and cytochrome c release were upregulated after Hg2+ (2.5 µM) exposure and thus inducing apoptosis. Hg2+induced apoptosis was also confirmed by flow cytometry. However, pretreatment with DHLA (50 µM) for 3 h before Hg2+ (2.5 µM) exposure showed inhibition against iHg2+-induced cytotoxicity by reversing cell viability loss, LDH release, DNA damage, GSH decrease and inhibiting Hg accumulation. Moreover, DHLA pretreatment reversed the protein level expressions of akt, p-akt, mTOR, GR, NFkB, ERK1, Nrf2, HO-1, cleaved caspase 3 and cytochrome c. In conclusion, results showed that DHLA could attenuate Hg2+-induced cytotoxicity via limiting Hg accumulation, boosting up of antioxidant defense, and inhibition of apoptosis in cells.

Maternal green tea extract intake during lactation attenuates hepatic lipid accumulation in adult male rats exposed to a continuous high-fat diet from the foetal period.

BACKGROUND: Maternal lipid intake in the early postnatal period has a long-term effect on the possibility of fatty liver formation in children; besides, the importance of lipid consumption during lactation for children's health has been suggested. Green tea extract (GTE) contains abundant catechins, and it has been reported to improve lipid metabolism and prevent fatty liver. OBJECTIVE: The aim of this study was to examine the effects of maternal GTE intake during lactation on hepatic lipid accumulation in adult male rats exposed to a continuous high-fat (HF) diet from the foetal period. METHODS: Pregnant Wistar rats received diets containing 13% (control-fat, CON) or 45% (high-fat, HF) fat. CON-fed mothers received the same diet during lactation, whereas HF-fed mothers received either HF diet alone or HF diet supplemented with 0.24% GTE. At weaning, male offspring were divided into three groups, i.e. CON/CON/CON, HF/HF/HF (HF-offspring) or HF/HF+GTE/HF (GTE-offspring), and were fed until 51 weeks. RESULTS: A significant hepatic triglyceride (Tg) accumulation was observed in the HF-offspring when compared with the other offspring. This is presumed to be caused by the promotion of Tg synthesis derived from exogenous fatty acid due to a significant increase in diacylglycerol O-acyltransferase 1 and a decrease in Tg expenditure caused by decreasing microsomal triglyceride transfer protein (MTTP) and long-chain acyl-CoA dehydrogenase. On the other hand, attenuated hepatic Tg accumulation was observed in the GTE-offspring. The levels of the hepatic lipid metabolism-related enzymes were improved to the same level as the CON-offspring, and particularly, MTTP was significantly increased as compared with the HF-offspring. CONCLUSION: This study indicates the potential protective effects of maternal GTE intake during lactation on HF diet-induced hepatic lipid accumulation in adult male rat offspring and the possible underlying mechanisms.

Long-term effects of maternal resveratrol intake during lactation on cholesterol metabolism in male rat offspring.

Resveratrol (RSV) can protect against non-communicable diseases by improving cholesterol metabolism. However, it is unclear that effects of maternal RSV intake on health of adult offspring. In this study, we examined effects of maternal RSV intake during lactation on cholesterol metabolism in adult male rat offspring. Female Wistar rats were fed a control diet (CON) supplemented with or without RSV (20 mg/kg body weight/day) during their lactation period. Male offspring were weaned onto a standard diet and maintained on this diet for 36 weeks. As a result, plasma cholesterol level significantly decreased in RSV offspring compared to CON offspring. Furthermore, a decrease in hepatic 3-hydroxy-3-methylglutaryl-CoA reductase level and an increase in hepatic LDL-receptor level were observed in the RSV offspring. These results indicate that maternal RSV intake causes long-term decrease in plasma cholesterol level in the offspring through suppression of hepatic cholesterol biosynthesis and promotion of hepatic cholesterol uptake.

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.

Carvacrol inhibits cadmium toxicity through combating against caspase dependent/independent apoptosis in PC12 cells.

Carvacrol is a monoterpenic phenol found in essential oils, is considered a safe food additive, and possesses various therapeutic properties. Numerous studies have also deciphered the protective role of carvacrol on various cytotoxicities. We clarify the effects of carvacrol on cadmium-induced apoptosis in PC12 cells. Carvacrol while co-exposed with cadmium for 48 h raised PC12 cell viability in comparison to only cadmium exposed group. The co-exposure increased the cellular glutathione levels and promoted the expression of glutathione reductase. The magnitude of DNA fragmentation caused by cadmium was also ameliorated by carvacrol. Flow cytometry exhibited the apoptosis rate augmented by cadmium was reduced by carvacrol. Western blotting revealed that cadmium and carvacrol co-exposure alleviated the cadmium-induced down-regulations of mammalian target of rapamycin (mTOR), protein kinase B (Akt), nuclear factor kappa-light-chain-enhancer of activated B cells (NFКB), extracellular signal-regulated kinase-1 (ERK-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) expressions. The co-exposure also reversed action of cadmium by suppressing the cleavage of caspase 3 and reducing the cytosolic levels of cytochrome c and apoptosis inducing factor (AIF). Moreover, carvacrol upon co-exposure significantly increased the intracellular metallothionein content. In conclusion, carvacrol strongly reduced cadmium-triggered oxidative stress and caspase-dependent and caspase-independent apoptosis in PC12 cells.

Polyphenol-enriched azuki bean (Vina angularis) extract reduces the oxidative stress and prevents DNA oxidation in the hearts of streptozotocin-induced early diabetic rats.

We examined the changes in the heart of rats at the early stages of streptozotocin (STZ)-induced diabetes, and whether azuki bean extract (ABE) could influence these changes. The experimental diabetic rats received 0 or 40 mg/kg of ABE orally for 4 weeks, whereas the control group rats received distilled water. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and expression of proteins associated with peroxisomal FA ß-oxidation as well as oxidative stress markers were examined. The levels of peroxisomal ACOX1 and catalase of the diabetic groups were significantly higher than those in the control group. The levels of p62, phosphorylated-p62 (p-p62) and HO-1 in the STZ group were significantly higher than those in the control group, and the levels of p-p62, HO-1, and 8-OHdG were significantly lower by ABE administration. The STZ-induced early diabetes increases the levels of proteins related to peroxisomal FA ß-oxidation and oxidative stress markers in hearts. ABE protects diabetic hearts from oxidative damage.

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.