Quercetin ameliorates cytotoxic effects of zinc oxide nanoparticles on sertoli cells by enhancing autophagy and suppressing oxidative stress.

Previous studies have demonstrated the toxic impacts of zinc oxide nanoparticles (ZO-NPs) on male reproductive cells. The effect of quercetin (QCT) on ZO-NPs-induced mouse Sertoli cell (TM4 cell line) toxicity and its underlying mechanisms were investigated in this study. The TM4 cells were exposed to ZO-NPs or QCT in different groups for 24 hr. The TM4 cells pre-treated with 3MA (3-Methyladenine, an autophagy inhibitor) to evaluate the autophagy role of QCT and ZO-NPs in the TM4 cells. ZO-NPs significantly reduced the viability percentage of the TM4 cells. The apoptosis percentage and Bax/Bcl-2 ratio of the ZO-NPs group were significantly increased, while the expression of autophagy-related genes was considerably downregulated. ZO-NPs also induced oxidative stress in the TM4 cells through increasing malondialdehyde contents and reactive oxygen species levels (ROS) and reducing antioxidant factors including superoxide dismutase, catalase, glutathione and glutathione peroxidase. In QCT + ZO-NPs group, these events were considerably reversed. 3MA could significantly decrease the cell viability of TM4 cells exposed to the QCT and ZO-NPs in comparison with the untreated 3MA groups. According to these results, the protective effects of QCT on ZO-NPs-exposed TM4 cells are related to inducing autophagy, prevention apoptosis and suppressing oxidative stress.

Autophagy regulation and its role in normal and malignant hematopoiesis.

Autophagy, the molecular machinery of self-eating, plays a dual role of a tumor promoter and tumor suppressor. This mechanism affects different clinical responses in cancer cells. Autophagy is targeted for treating patients resistant to chemotherapy or radiation. Limited reports investigate the significance of autophagy in cancer therapy, the regulation of hematopoietic and leukemic stem cells and leukemia formation. In the current review, the role of autophagy is discussed in various stages of hematopoiesis including quiescence, self-renewal, and differentiation.

Diosmin ameliorative effects on oxidative stress and fibrosis in paraquat-induced lung injury in mice.

Paraquat (PQ) induces pulmonary fibrosis, a progressive lung disorder resulting in severe respiratory failure and death. Increased oxidative stress, inflammatory reactions, and multiple fibrotic lesions are major features of PQ-induced lung injury. Diosmin (Dio) is a safe drug that is available for clinical use for vascular disorders. Dio exhibits antioxidant, anti-inflammatory, and antifibrotic activities. Accordingly, the aim of this study was to evaluate the protective effect of diosmin on PQ-induced lung injury in mice and the underlying mechanisms involved. Lung injury was induced by PQ (30 mg/kg, intraperitoneally) in NMRI albino mice and Dio (50 and 100 mg/kg, gavage) was administrated 3 days before PQ and continued for 10 or 24 days. After euthanizing the mice, the biochemical and histopathological markers of lung tissue were determined. PQ significantly increased oxidative stress, inflammatory, and fibrotic markers. PQ increased the level of malonedaldehyde (MDA) and hydroxyproline (HYP) and decreased the level of glutathione (GSH) and catalase activity in the lung. Dio (50 and 100 mg/kg) significantly increased GSH levels and catalase activity and decreased HYP content and MDA levels. In addition, Dio reduced histopathological injuries in hematoxylin and eosin-stained and Masson's trichrome-stained sections. These findings suggest that Dio has protective effects against PQ-induced lung injury, which may be due to its antioxidant, anti-inflammatory, and antifibrotic effects.

Dysregulation of Sqstm1, mitophagy, and apoptotic genes in chronic exposure to arsenic and high-fat diet (HFD).

Arsenic (As) is a toxic and hazardous metalloid. Unfortunately, its presence in drinking water together with wrong nutritional patterns is associated with an increase in the occurrence of metabolic disorders in young people. Degradation of mitochondria is presented by a specific form of autophagy called mitophagy which is an important landmark leading to apoptosis during lipotoxicity. Lipotoxicity and cellular toxicity due to arsenic intake can lead to changes in mitophagy and apoptosis. The protein derived from SQSTM1 gene, also called p62, plays an important role in energy homeostasis in the liver, and it can contribute to the regulation of autophagic responses given its effect on signaling of mTOR, MAPK, and NF-KB. Consequently, changes in Sqstm1, mitophagy (BNIP3), and apoptotic (caspase 3) genes in the livers of NMRI mice were examined with the use of real-time RT-PCR Array followed by exposure to an environmentally relevant and negligible cytotoxic concentration of arsenite (50 ppm) in drinking water while being fed with a high-fat diet (HFD) or low-fat diet (LFD) for 20 weeks (LFD-As and HFD-As groups). While LFD-As and HFD groups showed a decrease in BNIP3 expression, a significant increase was observed in the HFD-As group. P62 gene showed downregulation in LFD-As and HFD groups, and upregeneration was observed in the HFD-As group. Caspase 3 showed increased expression as the key factor associated with apoptotic liver cell death in the three groups, with the highest value in HFD-As group. Overall, the changes observed in the expression of Sqstm1, BNIP3, and caspase 3 in this study can be related to the level of liver damage caused by exposure to arsenic and HFD and probably, BNIP3 pro-apoptotic protein is associated with an increased cell death due to HFD and As.

Autophagy upregulation as a possible mechanism of arsenic induced diabetes.

The key features of type 2 diabetes mellitus (T2DM) caused by high fat diet (HFD) in combination with arsenic (As) exposure (pronounced glucose intolerance despite a significant decrease in insulin resistance) are different from those expected for T2DM. Autophagy has been considered as a possible link between insulin resistance and obesity. Therefore in this study, we utilized autophagy gene expression profiling via real-time RT-PCR array analysis in livers of NMRI mice exposed to an environmentally relevant and minimally cytotoxic concentration of arsenite (50 ppm) in drinking water while being fed with a HFD for 20 weeks. Out of 84 genes associated with autophagy under study, 21 genes were related to autophagy machinery components of which 13 genes were downregulated when HDF diet was applied. In this study, for the first time, it was shown that the exposure to arsenic in the livers of mice chronically fed with HFD along with increased oxidative stress resulted in the restoration of autophagy [upregulation of genes involved in the early phase of phagophore formation, phagophore expansion and autophagosome-lysosome linkage stages]. Considering the role of arsenic in the induction of autophagy; it can be argued that reduced insulin resistance in HFD - As induced diabetes may be mediated by autophagy upregulation.