Arsenic poisoning is a global health problem. Chronic exposure to arsenic has been associated with the development of a wide range of diseases and health problems in humans. Arsenic exposure induces the generation of intracellular reactive oxygen species (ROS), which mediate multiple changes to cell behavior by altering signaling pathways and epigenetic modifications, or cause direct oxidative damage to molecules. Antioxidants with the potential to reduce ROS levels have been shown to ameliorate arsenic-induced lesions. However, emerging evidence suggests that constructive activation of antioxidative pathways and decreased ROS levels contribute to chronic arsenic toxicity in some cases. This review details the pathways involved in arsenic-induced redox imbalance, as well as current studies on prophylaxis and treatment strategies using antioxidants.

Metformin has been reported to function as the anti-tumor inhibiting the growth of different types of cancers, including bladder cancer. But there are few reports on the roles of Yap1, the key molecule of Hippo pathway, in the metformin induced inhibition of bladder cancer (BLCA). We are wondering if the inhibitory effect of metformin on bladder cancer is fulfilled via Yap1 and exploring the related mechanism. MTS and colony formation assays were used to explore the cellular viabilities and proliferation of BLCA cells challenged by metformin at different concentrations, in vitro. Flow Cytometry (FCM) was used to analyze the cell cycle and the cellular apoptosis of the BLCA cells. Western Blot was performed to detect the expressions of AMPKα, Yap1, CCND1, CCNE1/2 and CDK2/4/6 in the metformin-treated BLCA cell lines. RNAi method was used for the related genetic functional analysis. The relationships among Yap1, TEADs and CCNE1/2 were predicted and evaluated using bioinformatics, dual-luciferase reporter and co-immunoprecipitation (Co-IP) assays. For in vivo experiments, a xenograft model was used to investigate the effects of metformin on the proliferation of BLCA cells. And Immunohistochemistry (IHC) assay was performed to assess the expressions of CCNE1/2 and Yap1 proteins in the tumor tissues from the model. Metformin could inhibit the proliferation of the BLCA cells via inducing the G1 cell cycle arrest without apoptosis. And metformin upregulated the phosphorylated AMPKα and decreased the expressions of Yap1 and CCND1, CCNE1/2 and CDK4/6. AMPK inhibition by compound C (CC) restored the cell proliferation and the G1 cell cycle arrest induced by metformin, in vivo. Knockdown of YAP1 inhibited the proliferation of BLCA cells and caused the cell cycle arrest at G1 phase by decreasing the expressions of CCNE1/2 and other G1 phase related molecules, which has been restored by the Yap 5SA mutant. Bioinformatics analysis showed that trans-factor TEAD4 was highly expressed and positively associated with the expressions of CCNE1 and CCNE2 in BLCA and only TEAD4 was precipitated by Yap1 in the BLCA cells. Further studies demonstrated that Yap1 positively regulated both CCNE1 and CCNE2 expressions via forming complex with TEAD4. Furthermore, we observed that metformin inhibited the cell proliferation by decreasing the expressions of Yap1 and both CCNE1 and CCNE2 in xenograft model. The results of our study reveal a new potential regulatory pathway in which metformin inhibits cell proliferation via AMPKα/Yap1/TEAD4/CCNE1/2 axis in BLCA cells, providing new insights into novel molecular therapeutic targets for BLCA.

Hepatic encephalopathy (HE) is a central nervous system dysfunction syndrome caused by acute and chronic liver failure or various portal systemic shunt disorders. HE arises from metabolic disorder and excludes other known types of encephalopathy. HE is a major cause of death in people with liver disease. Early diagnosis and timely treatment are key to improving HE prognosis. Herein, we established a model of HE and performed metabolomics to identify 50 significantly differential metabolites between the HE group and control group. The main metabolic pathways associated with these differential metabolites were the purine metabolism, pyrimidine metabolism, aminoacyl tRNA biosynthesis, and glucose metabolism. Through proteomics analysis, we identified 226 significantly differential proteins (52 up-regulated and 174 down-regulated). The main (Kyoto Encyclopedia of Genes and Genomes) enrichment pathways were the Staphylococcus aureus infection, vitamin digestion and absorption, and complement and coagulation cascades. Through the conjoint analysis of proteomics and metabolomics, the differentially present proteins and metabolites were found to be involved in vitamin digestion and absorption, and ferroptosis pathways. In HE, malondialdehyde was significantly elevated, but glutathione was significantly diminished, and the redox balance was destroyed, thus leading to changes in proteins’ levels associated with the ferroptosis pathway. In conclusion, this study preliminarily explored the molecular and metabolic mechanisms underlying HE.

Acute liver injury (ALI) is a significant global public health issue that can rapidly develop into acute liver failure, seriously endangering the safety of patients. Eugenol has various pharmacological effects such as antioxidant, anti-inflammatory, antibacterial, and neuroprotective properties. Through pathological section observation, eugenol can alleviate the degree of liver damage caused by thioacetamide. Based on metabolomics, a total of 87 metabolites were found to have differences in content between the control group and the thioacetamide group. Compared with the control group, the contents of 42 metabolites had increased and 45 metabolites had decreased in the thioacetamide group. These differential expressed metabolites mainly indicate inflammatory damage, oxidative damage, and abnormal energy metabolism. There were 269 metabolites with differences in content between the eugenol intervention group and the thioacetamide group. Compared with the thioacetamide group, there were 101 metabolites with increased content and 168 metabolites with decreased content in the eugenol intervention group. These differential expressed metabolites suggest that eugenol intervention can correct inflammation damage, oxidative damage, and energy metabolism abnormalities caused by TAA. This study found through pathological section observation and metabolomics that eugenol has a protective effect on acute liver injury caused by thioacetamide, and the protective mechanism may be related to the antioxidant and anti-inflammatory effects of eugenol.

The reproductive and developmental toxicity of diquat (DQ), a widely used herbicide, during pregnancy remains insufficiently characterized. This study investigated the effects of repeated DQ exposure on fetal development and maternal metabolism in pregnant Sprague–Dawley rats. The rats were administered sublethal doses of DQ (28.88 and 57.57 mg/kg), and maternal serum sex hormones, fetal skeletal development, and serum metabolomic profiles were evaluated. Compared with controls, serum estradiol levels were significantly decreased in the high-dose exposure group, whereas luteinizing hormone and follicle-stimulating hormone levels remained unchanged. Significant alterations in malondialdehyde, superoxide dismutase, and glutathione levels indicated oxidative stress in exposed rats. Severe fetal skeletal ossification deficits and developmental delays were observed, with incomplete or failed ossification of the occipital bone, sternum, caudal vertebrae, and pelvis, with litter-level incidences reaching 100%. Metabolomic analysis identified distinct serum metabolic profiles between DQ-exposed and control groups, suggesting ovarian steroidogenesis, phenylalanine metabolism, and aldosterone synthesis and secretion as key pathways affected by DQ toxicity. These findings suggest that repeated maternal exposure to DQ induces oxidative stress, disrupts metabolic and hormonal homeostasis, and causes delayed fetal skeletal development. This study provides novel evidence for understanding the reproductive and developmental toxicity of DQ and its potential metabolic mechanisms.