Yujing Zhang

Endocrine-disrupting chemicals (EDCs), ubiquitous in the environment, are increasingly recognized for their detrimental effects on human health. Chronic exposure to EDCs disrupts essential physiological systems, particularly those regulating reproductive, neurological, and metabolic homeostasis. Furthermore, growing evidence suggests a correlation between EDCs exposure and tumorigenesis. Endoplasmic reticulum stress (ERS) has emerged as a vital cellular response to toxic stimuli, influencing apoptotic and proliferative pathways. Notably, ERS and autophagy are interconnected stress responses implicated in various pathological conditions. We propose that EDCs exert their toxic effects and facilitate disease progression by disrupting the ERS-autophagy signaling axis. This review critically examines the molecular interactions between ERS and autophagy induced by EDCs exposure, with the aim of advancing mechanistic understanding and identifying novel therapeutic targets for diseases associated with EDCs.

Disclosures. No relevant conflicts of interest to declare.

Cholangiocarcinoma (CCA) is the most recurrent malignant tumor found in the biliary system. It originates from the bile duct epithelial cells characterized by easy metastasis, high intermittent rate, and poor prognosis. Acetaldehyde dehydrogenase 1 (ALDH1), a marker of cancer stem cells, the levels of which are particularly elevated in various of malignant tumors. Additionally, the increased ALDH1 levels are closely related to the degree and prognosis of malignant tumors. This study reviewed the mechanisms underlying the changes in ALDH1 levels in CCA.

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.

The Exosome complex (EXOSC) is a multiprotein complex that was originally discovered as the machinery of RNA degradation. Interestingly, recent studies have reported that EXOSC family members (EXOSCs) are associated with various human diseases, including cancers. It will be interesting to investigate whether EXOSCs are related to the processes of hepatocellular carcinoma (HCC). In this study, multiple public databases and experimental validation were utilized to systemically investigate the role of EXOSCs, especially EXOSC5, in HCC. It is worth considering that the mRNA and protein levels of many EXOSCs were elevated in HCC, although there were some differences in the results from different database analyses. The over-expression of EXOSCs could predict HCC to some extent, as evidenced by the positive correlation between the elevated EXOSCs and alpha fetoprotein (AFP) levels, as well as with a high accuracy, as shown by the receiver operating characteristic curve analysis. Additionally, higher mRNA expressions of specific EXOSCs were significantly related to clinical cancer stage, shorter overall survival and disease-free survival in HCC patients. A moderate mutation rate of EXOSCs was also observed in HCC. Furthermore, a gene functional enrichment analysis indicated that EXOSCs were mainly involved in the metabolism of RNA. Moreover, we revealed that the expression of EXOSCs is remarkably related to immune cell infiltration. Finally, EXOSC5 was upregulated in HCC tissues and cell lines, promoting cell growth and proliferation via activated signal transducer and activator of transcription 3 (STAT3). The bioinformatic analyses, following verification in situ and in vitro, provided a direction for further functions and underlying mechanism of EXOSCs in HCC.

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.

Aging may be the largest factor for a variety of chronic diseases that influence survival, independence, and wellbeing. Evidence suggests that aging could be thought of as the modifiable risk factor to delay or alleviate age-related conditions as a group by regulating essential aging mechanisms. One such mechanism is cellular senescence, which is a special form of most cells that are present as permanent cell cycle arrest, apoptosis resistance, expression of anti-proliferative molecules, acquisition of pro-inflammatory, senescence-associated secretory phenotype (SASP), and others. Most cells cultured in vitro or in vivo may undergo cellular senescence after accruing a set number of cell divisions or provoked by excessive endogenous and exogenous stress or damage. Senescent cells occur throughout life and play a vital role in various physiological and pathological processes such as embryogenesis, wound healing, host immunity, and tumor suppression. In contrast to the beneficial senescent processes, the accumulation of senescent also has deleterious effects. These non-proliferating cells lead to the decrease of regenerative potential or functions of tissues, inflammation, and other aging-associated diseases because of the change of tissue microenvironment with the acquisition of SASP. While it is understood that age-related diseases occur at the cellular level from the cellular senescence, the mechanisms of cellular senescence in age-related disease progression remain largely unknown. Simplified and rapid models such as in vitro models of the cellular senescence are critically needed to deconvolute mechanisms of age-related diseases. Here, we obtained replicative senescent L02 hepatocytes by culturing the cells for 20 weeks. Then, the conditioned medium containing supernatant from replicative senescent L02 hepatocytes was used to induce cellular senescence, which could rapidly induce hepatocytes into senescence. In addition, different methods were used to validate senescence, including senescence-associated β-galactosidase (SA-β-gal), the rate of DNA synthesis using 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, and senescence-related proteins. At last, we provide example results and discuss further applications of the protocol.

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.

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.

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.