Riboflavin recovery of spermatogenic dysfunction via a dual inhibition of oxidative changes and regulation of the PINK1-mediated pathway in arsenic-injured rat model.

Arsenic trioxide (As2O3) poisoning and associated potential lesions are of a global concern. Inversely, riboflavin (vitamin B2, VB2) as a component of flavoproteins could play a vital role in the spermatogenic enzymatic reactions. Thus, this research aimed to explore potential beneficial roles of VB2 during As2O3-injured-toxicity. Rats were randomly allocated into 4 groups (n=8/group) and challenged as follows (for 30 days continuously): Group 1 received normal saline; Group 2 was treated with 3 mg As2O3/L; Group 3 received 40 mg VB2/L; Group 4 received 3 mg As2O3/L + 40 mg VB2/L. Both As2O3 and VB2 were dissolved in deionized water. Malondialdehyde (MDA), Glutathione Peroxidase (GSH-Px), Superoxide dismutase (SOD), and Catalase (CAT) were assessed for the oxidative profile, while TAS (Total Antioxidative Status) levels were evaluated for the antioxidant system, in both serum and testicular tissue. P<0.05 was considered statistically significant. The results show that As2O3 significantly decreased the body weight, testicular weight and testis volume, semen quality and testicular cell count (p<0.05). Furthermore, MDA content in the testicular tissue of the As2O3 group rats was significantly higher in comparison to the vehicle group (p<0.05). Likewise, TAS and the activities of GSH-Px, CAT and SOD were reduced (p<0.05) when compared to the control. As(2)O(3) induced testicular damage and seminiferous tubular atrophy. Monodansylcadaverine assays mirrored the histopathology observations. Meanwhile, As2O3 upregulated the expression of mitophagy-related genes including PINK1, Parkin, USP8, LC3-I, Fis1 and Mfn2. The p38 gene, responsible to stress stimuli, was also upregulated by As2O3 administration. Meanwhile, exposure to VB2 led to a significant decrease of the expression levels of mitophagy related genes. Our study revealed that VB2 supplementation protected testicular structures against As2O3-induced injury via a dual inhibition of oxidative changes and a regulation of the PINK1-mediated pathway.

The protective role of autophagy against arsenic trioxide-induced cytotoxicity and ROS-dependent pyroptosis in NCTC-1469 cells.

Arsenic trioxide (As2O3) is widely used in traditional Chinese medicine to treat tumors. This study investigated the effect of As(III) on pyroptosis in murine hepatocytes in vitro and how this relates to autophagy. NCTC1469-cells were treated with As(III) alone (6, 12 and 18 µM) or in combination with N-acetylcysteine (NAC,1 mM), 3-methyladenine (3-MA, 5 mM) or rapamycin (Rapa,100 nM) for 24 h. The results showed that As(III)-treatment reduced cell viability in a dose-dependent manner, but induced lactic dehydrogenase (LDH) activity. As(III)-treatment also resulted in increased intracellular reactive oxygen species (ROS) levels and decreased mitochondrial membrane potential (MMP), therefore promoting pyroptosis. Moreover, As(III)-treatment upregulated the expression of autophagy and pyroptosis-related genes (LC3-A, LC3-B, P62, Beclin-1, Atg5, Caspase-1, Gasdermin D, IL-18, IL-1ß) and downregulated the expression of m-TOR, NLRP3, ASC genes. Meanwhile the accumulation of light chain 3-B/A (LC3B/LC3A), autophagy-related gene 5 (Atg-5), Bcl-2-interacting protein (Beclin-1), Caspase-1, Gasdermin D, interleukin-1ß (IL-1ß), IL-18 and poptosis-associated speck-like protein (ASC) proteins were upregulated while nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) was downregulated in all As(III)-treatment groups. Furthermore, the inhibition of autophagy by 3-MA aggravated AsIII-induced pyroptosis and cytotoxicity. However, NAC or Rapa markedly alleviated the abovementioned phenomenon under As(III) stress. In addition, we speculate that the protective mechanism of NAC on As(III)-induced pyroptosis in hepatocytes mainly include the elimination of ROS because of the chelation of As(III) in the culture medium. In conclusion, these results provide new insight into the mechanisms underlying AsIII-induced cytotoxicity and pyroptosis in hepatocytes in vitro.

Grape seed proanthocyanidin extract alleviates arsenic-induced lung damage through NF-κB signaling.

IMPACT STATEMENT: Arsenic-induced respiratory inflammatory damage is an important occupational hazard in many areas of the world, particularly in underdeveloped and developing countries. Effective treatments are lacking and expensive. Therefore, the aim of the study was to examine the anti-inflammatory effects of proanthocyanidin (PC) and the molecular mechanisms in vivo and in vitro. The present study showed that PC extracted from grape seed could attenuate the lung damage in a mouse model of arsenic poisoning. The effects were observed at the level of lung histology and inflammasome expression. This study suggests that a natural compound is effective in mitigating the toxic effects of arsenic in the lungs, providing an inexpensive and more readily accessible method for treating arsenic exposure in some parts of the world.

Taurine protected As2O3-induced the activation of hepatic stellate cells through inhibiting PPARα-autophagy pathway.

The activation of hepatic stellate cells (HSCs) is a key event in the development of hepatic fibrosis caused by arsenic. However, it is unclear how arsenic induces the activation of HSCs. In the present study, we found that arsenic trioxide (As2O3) induced liver tissue damage, stimulated autophagy and HSCs activation, and increased collagen accumulation in the liver of mice. Supplemented with taurine (Tau) attenuated the changes mentioned above caused by As2O3. In human hepatic stellate cell line LX-2 cells, we found that As2O3-induced activation of HSCs was autophagy-dependent, and we found that peroxisome proliferator activated receptors alpha (PPARα) played an important role in arsenic-induced HSCs activation. In addition, inhibiting autophagy and PPARα alleviated the activation of HSCs and lipid droplet loss induced by As2O3. Moreover, we found that Tau alleviated As2O3-induced elevation of autophagy and PPARα expression, and activation of the HSCs. Our results indicated that autophagy was regulated by PPARα and was involved in lipid droplet loss during the activation of HSCs. Tau alleviated As2O3-induced HSCs activation by inhibiting the PPARα/autophagy pathway. These findings give an innovative insight into the association of PPARα, autophagy, the activation of HSCs and hepatic fibrosis induced by As2O3.

Evaluation of phyto-medicinal efficacy of thymoquinone against Arsenic induced mitochondrial dysfunction and cytotoxicity in SH-SY5Y cells.

BACKGROUND: It is evaluated that a few million individuals worldwide are experiencing Arsenic (As) harmfulness coming about because of anthropogenic discharges. There is likewise proof to propose that As can affect the peripheral, as well as, the central nervous system (CNS). On the contrary, thymoquinone (TQ), a biologically active ingredient of Nigella sativa has exhibited numerous neuro-pharmacological traits since ancient times. HYPOTHESIS/PURPOSE: In the present study, the neuroprotective efficacy of TQ was explored by primarily studying its antioxidant and anti-apoptotic potential against Arsenic trioxide (As2O3) induced toxicity in SH-SY5Y human neuroblastoma cell lines. STUDY DESIGN: For experimentation, cells were seeded in 96 well tissue culture plates and kept undisturbed for 24 h to attain proper adhesion. After 75-80% confluence, cells were pretreated with 10 µM and 20 µM thymoquinone (TQ) for 1 h After adding 2 µM As, cells were set aside for incubation for 24 h without changing the medium. METHODS: The mitigatory effects of TQ with particular reference to cell viability and cytotoxicity, the generation of reactive oxygen species, DNA damage, and mitochondrial dynamics were studied. RESULTS: Pretreatment of SH-SY5Y cells with TQ (10 and 20 µM) for an hour and subsequent exposure to 2 µM As2O3 protected the SH-SY5Y cells against the neuro-damaging effects of the latter. Also, the SH-SY5Y cells were better preserved with increased viability, repaired DNA, less free radical generation and balanced transmembrane potential than those exposed to As2O3 alone. TQ pretreatment also inhibited As2O3-induced exacerbation in protein levels of BAX and PARP-1 and restored the loss of Bcl2 levels. CONCLUSION: The findings of this study suggest that TQ may prevent neurotoxicity and As2O3-induced apoptosis and cytotoxicity. It is, therefore, worth studying further for its potential to reduce the risks of arsenic-related neurological implications.

Arsenic-induced cardiotoxicity correlates with mitochondrial damage and trace elements imbalance in broiler chickens.

Arsenic-based drugs as food additive were used in poultry. However, excessive arsenic exposure can disturb myocardial cell metabolism, which results in the inhibition of growth and development of chickens. Since disordered mitochondria influences cardiac physiology and pathology, a better understanding of the mechanisms modulating cardiomyocyte mitochondria process is critical for identifying the potent detoxication targets under arsenic exposure in chickens. Male Hy-line chickens (1-day-old) were fed either a basal diet or an arsenic trioxide (As2O3)-supplemented diet containing 7.5, 15, and 30 mg/kg As2O3 for 90 d. The concentrations of ions ([Na, Mg, Al, Si, K, Ca, As, Mn, Fe, Zn] and [Cr, Ni, Cu, Ba]) significantly increased and decreased in the heart of chicken under As2O3 exposure, respectively. Moreover, we observed that As2O3 decreased high-density lipoprotein cholesterol concentrations and increased total cholesterol concentrations in the serum. We also observed arterial wall degeneration, biochemical character of mitochondria undergoing either fission or fusion, typical apoptotic cells, typical DNA fragments and TdT-mediated dUTP nick end labeling positive nuclei under As2O3 exposure in the heart. Further quantitative real-time PCR demonstrated that B cell lymphoma/leukemia 2 (Bcl2) were significantly decreased and dynamin-related protein 1 (Drp1), Optic atrophy 1 (Opa1), mitochondrial fission factor 1 (Mfn1), Mfn2, p53, caspase-8, Bcl-2 associated X protein (Bax), caspase-3, caspase-9 and cytochrome C were significantly increased in all As2O3 group. In conclusion, As2O3 can disturb the trace elements homeostasis, which might favor the development of mitochondrial damage. Moreover, we suspected that As2O3-increased mitochondrial dynamics might trigger the apoptosis to limit cell metabolism. These features might identify the role of the mitochondrial dynamics under arsenic-induced cardiovascular disease in the chickens.

Arsenic trioxide: insights into its evolution to an anticancer agent.

Arsenic and its various forms have been in use in ancient Chinese medicine for more than 2000 years. Arsenicals have gained importance for having remedial effects for various diseases from syphilis to cancer thus highlighting its role as a therapeutic agent even though it has been labelled as a potential 'poison'. The ability of arsenic, specifically arsenic trioxide, to treat acute promyelocytic leukaemia has radically changed the perception of this poison and has been the main factor for the re-emergence of this candidate to Western medicine for the treatment of leukaemia and other solid tumours. This review highlights the glorious history of arsenic and its various forms with major emphasis on arsenic trioxide as a therapeutic agent. The mechanism of action, pathogenesis, pharmacokinetic profile, safety concerns, ongoing clinical trials and various new forms of arsenic trioxide are discussed. The review also outlines the therapeutic ability of this drug, discusses the latest developments and recent investigations and potential advancement of arsenic trioxide as nanoformulations that has made it emerge as a potential remedial agent.