To investigate the toxic mechanism of hexavalent chromium Cr(VI) and search for an antidote for Cr(VI)-induced cytotoxicity, a study of mitochondrial dysfunction induced by Cr(VI) and cell survival by recovering mitochondrial function was performed. In the present study, we found that the gene expression of electron transfer flavoprotein dehydrogenase (ETFDH) was strongly downregulated by Cr(VI) exposure. The levels of coenzyme 10 (CoQ10) and mitochondrial biogenesis presented by mitochondrial mass and mitochondrial DNA copy number were also significantly reduced after Cr(VI) exposure. The subsequent, Cr(VI)-induced mitochondrial damage and apoptosis were characterized by reactive oxygen species (ROS) accumulation, caspase-3 and caspase-9 activation, decreased superoxide dismutase (SOD) and ATP production, increased methane dicarboxylic aldehyde (MDA) content, mitochondrial membrane depolarization and mitochondrial permeability transition pore (MPTP) opening, increased Ca²⁺ levels, Cyt c release, decreased Bcl-2 expression, and significantly elevated Bax expression. The Cr(VI)-induced deleterious changes were attenuated by pretreatment with CoQ10 in L-02 hepatocytes. These data suggest that Cr(VI) induces CoQ10 deficiency in L-02 hepatocytes, indicating that this deficiency may be a biomarker of mitochondrial dysfunction in Cr(VI) poisoning and that exogenous administration of CoQ10 may restore mitochondrial function and protect the liver from Cr(VI) exposure.

The liver is a highly metabolic organ and plays a crucial role in the transportation, storage, and/or detoxication of xenobiotics. Liver damage induced by xenobiotics (e.g., heavy metal, endocrine disrupting chemicals, Chinese herbal medicine, or nanoparticles) has become a pivotal reason for liver diseases, leading to great clinical challenge and much attention for the past decades. Given that endoplasmic reticulum (ER) is the prominent organelle involved in hepatic metabolism, ER dysfunction, namely, ER stress, is clearly observed in various liver diseases. In response to ER stress, a conserved adaptive signaling pathway known as unfolded protein response (UPR) is activated to restore ER homeostasis. However, the prolonged ER stress with UPR eventually leads to the death of hepatocytes, which is a pathogenic event in many hepatic diseases. Therefore, analyzing the perturbation in the activation or inhibition of ER stress and the UPR signaling pathway is likely an effective marker for investigating the molecular mechanisms behind the toxic effects of xenobiotics on the liver. We review the role of ER stress in hepatic diseases and xenobiotic‐induced hepatotoxicity, which not only provides a theoretical basis for further understanding the pathogenesis of liver diseases and the mechanisms of hepatotoxicity induced by xenobiotics but also presents a potential target for the prevention and treatment of xenobiotic‐related liver diseases.

Stress‐induced premature senescence may be involved in the pathogeneses of acute liver injury. Hexavalent chromium [Cr(VI)], a common environmental pollutant related to liver injury, likely leads to premature senescence in L02 hepatocytes. However, the underlying mechanisms regarding hepatocyte premature senility in Cr(VI) exposure remain poorly understood. In this study, we found that chronic exposure of L02 hepatocytes to Cr(VI) led to premature senescence characterized by increased β‐galactosidase activity, senescence‐associated heterochromatin foci, G1 phase arrest, and decreased cell proliferation. Additionally, Cr(VI)‐induced senescent L02 hepatocytes showed upregulated inflammation‐related factors, such as IL‐6 and fibroblast growth factor 23 (FGF23), which also exhibited reactive oxygen species (ROS) accumulation derived from mitochondria accompanied with increased concentration of intracellular calcium ions (Ca²⁺) and activity of nuclear factor kappa B (NF‐κB). Of note is that ROS inhibition by N‐acetyl‐Lcysteine pretreatment not only alleviated Cr(VI)‐induced premature senescence but also reduced the elevated intracellular Ca²⁺, activated NF‐κB, and secretion of IL‐6/FGF23. Intriguingly, the toxic effect of Cr(VI) upon premature senescence of L02 hepatocytes and increased levels of IL‐6/FGF23 could be partially reversed by the intracellular Ca²⁺ chelator BAPTA‐AM pretreatment. Furthermore, by utilizing the NF‐κB inhibitor pyrrolidine dithiocarbamate (PDTC), we confirmed that NF‐κB mediated IL‐6/FGF23 to regulate the Cr(VI)‐induced L02 hepatocyte premature senescence, whilst the concentration of intracellular Ca²⁺ was not influenced by PDTC. To the best of our knowledge, our data reports for the first time the role of ROS‐Ca²⁺‐NF‐κB signaling pathway in Cr(VI)‐induced premature senescence. Our results collectively shed light on further exploration of innovative intervention strategies and treatment targeting Cr(VI)‐induced chronic liver damage related to premature senescence.

Heparanase, a member of the carbohydrate-active enzyme (CAZy) GH79 family, is an endo-β-glucuronidase capable of degrading the carbohydrate moiety of heparan sulphate proteoglycans, thus modulating and facilitating remodeling of the extracellular matrix. Heparanase activity is strongly associated with major human pathological complications, including but not limited to tumour progress, angiogenesis and inflammation, which make heparanase a valuable therapeutic target. Long-due crystallographic structures of human and bacterial heparanases have been recently determined. Though the overall architecture of human heparanase is generally comparable to that of bacterial glucuronidases, remarkable differences exist in their substrate recognition mode. Better understanding of regulatory mechanisms of heparanase in substrate recognition would provide novel insight into the anti-heparanase inhibitor development as well as potential clinical applications.

PE (preeclampsia) is a heterogeneous disorder with early onset PE (EOPE) and late onset PE (LOPE) subtypes. Associations between maternal miRNAs biosynthesis genes polymorphisms and risk of PE have been previously observed. However, the impact of polymorphisms in DGCR8 which is indispensable in miRNA maturing processing on the susceptibility to preeclampsia (PE) has not been elucidated yet. We, therefore, conducted a case-control study to evaluate the impact of polymorphisms in DGCR8 on the risk of EOPE and LOPE. A total of 66 patients diagnosed with EOPE, 206 with LOPE and 330 healthy controls were recruited. Five SNPs in DGCR8 were genotyped including rs1558496, rs1640299, rs720012, rs720014, and rs9606241. Logistic regression was used to estimate the OR and the 95% CI for the associations. Increased risk of LOPE has been observed among patients with rs1640299 TG genotype (OR = 1.98 (95%CI: 1.38, 2.87), p = 2.32e-4) and rs720014 TC genotype (OR = 2.49 (95%CI: 1.72, 3.60), p = 1.40e-7). The DGCR8 rs1558496/ rs1640299/ rs720012/ rs720014/ rs9606241 haplotype T-G-A-C-A and T-G-A-C-G were associated with increased risk of LOPE (OR = 2.20 (95%CI: 1.49, 3.25), p = 5.90e-5, and 1.58 (95%CI: 1.06, 2.36), p = 0.024, respectively). And the haplotype T-T-G-T-A was associated with lower risk of LOPE (OR = 0.74 (95%CI: 0.58, 0.95), p = 0.018). These significant associations retained after false-positive discovery rate correction. However, none of the tested SNPs or haplotypes in DGCR8 gene is associated with risk of EOPE (p > 0.05). Polymorphisms in DGCR8 might participate in the pathological process of preeclampsia. The rs1640299 T > G and rs720014 T > C polymorphisms are associated with late onset preeclampsia susceptibility.

Hexavalent chromium (Cr(VI)) pollution is a severe public health problem in the world. Although it is believed that mitochondrial fragmentation is a common phenomenon in apoptosis, whether excessive fission is crucial for apoptosis remains controversial. We previously confirmed that Cr(VI) mainly targeted mitochondrial respiratory chain complex I (MRCC I) to induce reactive oxygen species (ROS)-mediated apoptosis, but the related mechanism was unclear. In this study, we found Cr(VI) targeted MRCC I to induce ROS accumulation and triggered mitochondria-related cytotoxicity. Cr(VI)-induced cytotoxicity was alleviated by pretreatment of Glutamate/malate (Glu/Mal; MRCC I substrates), and was aggravated by cotreatment of rotenone (ROT; MRCC I inhibitor). Cr(VI) induced excessive mitochondrial fragmentation and mitochondrial dynamin-related protein 1 (Drp1) translocation, the application of Drp1-siRNA alleviated Cr(VI)-induced apoptosis. The cytotoxicity in the Drp1-si plus Cr(VI) treatment group was alleviated by the application of Glu/Mal, and was aggravated by the application of ROT. Drp1 siRNA promoted the inhibition of Glu/Mal on Cr(VI)-induced cytotoxicity, and alleviated the aggravation of ROT on Cr(VI)-induced cytotoxicity. Taken together, Cr(VI)-induced Drp1 modulation was dependent on MRCC I inhibition-mediated ROS production, and Drp1-mediated mitochondrial fragmentation contributed to Cr(VI)-induced MRCC I-dependent cytotoxicity, which provided the experimental basis for further elucidating Cr(VI)-induced cytotoxicity.