Cadmium promoted LPS-induced inflammation through TLR4/IκBα/NFκ-B signaling by increasing ROS-mediated incomplete autophagy.

Cadmium (Cd) exposure is considered as non-infectious stressor to human and animal health. Recent studies suggest that the immunotoxicity of low dose Cd is not directly apparent, but disrupts the immune responses when infected with some bacteria or virus. But how Cd alters the adaptive immunity organ and cells remains unclear. In this study, we applied lipopolysaccharide (LPS, infectious stressor) to induced inflammation in spleen tissues and T cells, and investigated the effects after Cd exposure and the underlying mechanism. Cd exposure promoted LPS-induced the expressions of the inflammatory factors, induced abnormal initiation of autophagy, but blocked autophagic flux. The effects Cd exposure under LPS activation were reversed by the autophagy promoter Rapamycin. Under LPS activation conditions, Cd also induced oxidative stress by increasing the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and reducing total antioxidant capacity (T-AOC) activity. The increased superoxide dismutase (SOD) activity after Cd exposure might be a negative feedback or passive adaptive regulation of oxidative stress. Cd-increased autophagic flux inhibition and TNF-α expression were reversed by ROS scavenger α-tocopherol (TCP). Furthermore, under LPS activation condition, Cd promoted activation of toll-like receptor 4 (TLR4)/IκBα/NFκ-B signaling pathway and increased TLR4 protein stability, which were abolished by the pretreatment of Rapamycin. The present study confirmed that, by increasing ROS-mediated inhibiting autophagic degradation of TLR4, Cd promoted LPS-induced inflammation in spleen T cells. This study identified the mechanism of autophagy in Cd-aggravated immunotoxicity under infectious stress, which could arouse public attention to synergistic toxicity of Cd and bacterial or virus infection.

From ferroptosis to cuproptosis, and calcicoptosis, to find more novel metals-mediated distinct form of regulated cell death.

Regulated cell death (RCD), also known as programmed cell death (PCD), plays a critical role in various biological processes, such as tissue injury/repair, development, and homeostasis. Dysregulation of RCD pathways can lead to the development of many human diseases, such as cancer, neurodegenerative disorders, and cardiovascular diseases. Maintaining proper metal ion homeostasis is critical for human health. However, imbalances in metal levels within cells can result in cytotoxicity and cell death, leading to a variety of diseases and health problems. In recent years, new types of metal overload-induced cell death have been identified, including ferroptosis, cuproptosis, and calcicoptosis. This has prompted us to examine the three defined metal-dependent cell death types, and discuss other metals-induced ferroptosis, cuproptosis, and disrupted Ca2+ homeostasis, as well as the roles of Zn2+ in metals' homeostasis and related RCD. We have reviewed the connection between metals-induced RCD and various diseases, as well as the underlying mechanisms. We believe that further research in this area will lead to the discovery of novel types of metal-dependent RCD, a better understanding of the underlying mechanisms, and the development of new therapeutic strategies for human diseases.

Cadmium induced immunosuppression through TLR-IκBα-NFκB signaling by promoting autophagic degradation.

Environmental and occupational exposure to cadmium (Cd) poses a serious threat to human health. Recent studies indicate that Cd perturbs the immune system and increases the risk of pathogenicity and mortality of bacterial or virus infection. However, the underlying mechanism of Cd-modulated immune responses remains unclear. In this study, we aim to investigate the role of Cd in the immune function of mouse spleen tissues and its primary T cells with Concanavalin A (ConA, a well-known T cell mitogen) activation condition, and elucidate the molecular mechanism. The results showed that Cd exposure inhibited ConA-induced the expressions of tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) in mouse spleen tissues. Furthermore, the transcriptomic profile by RNA-sequence reveals that: (1) Cd exposure can alter immune system process; (2) Cd may affect the NFκB signaling pathway. Both in vitro and in vivo results showed that Cd exposure reduced ConA-activated toll-like receptor 9 (TLR9)-IκBα-NFκB signaling, and the expressions of TLR9, TNF-α and IFN-γ, which were effectively reversed by autophagy-lysosomal inhibitors. All these results confirmedly demonstrated that, by promoting the autophagy-lysosomal degradation of TLR9, Cd suppressed immune response under ConA activation condition. This study provides insight on the mechanism of Cd immunnotoxicity, which might contribute to the prevention of Cd toxicity in the future.

Cadmium Disrupted ER Ca2+ Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells.

Cadmium (Cd2+) exposure induces chronic kidney disease and renal cancers, which originate from injury and cancerization of renal tubular cells. Previous studies have shown that Cd2+ induced cytotoxicity by disrupting the intracellular Ca2+ homeostasis that is physically regulated by the endoplasmic reticulum (ER) Ca2+ store. However, the molecular mechanism of ER Ca2+ homeostasis in Cd2+-induced nephrotoxicity remains unclear. In this study, our results firstly revealed that the activation of calcium-sensing receptor (CaSR) by NPS R-467 could protect against Cd2+ exposure-induced cytotoxicity of mouse renal tubular cells (mRTEC) by restoring ER Ca2+ homeostasis through the ER Ca2+ reuptake channel sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). Cd2+-induced ER stress and cell apoptosis were effectively abrogated by SERCA agonist CDN1163 and SERCA2 overexpression. In addition, in vivo, and in vitro results proved that Cd2+ reduced the expressions of SERCA2 and its activity regulator phosphorylation phospholamban (p-PLB) in renal tubular cells. Cd2+-induced SERCA2 degradation was suppressed by the treatment of proteasome inhibitor MG132, which suggested that Cd2+ reduced SERCA2 protein stability by promoting the proteasomal protein degradation pathway. These results suggested that SERCA2 played pivotal roles in Cd2+-induced ER Ca2+ imbalance and stress to contribute to apoptosis of renal tubular cells, and the proteasomal pathway was involved in regulating SERCA2 stability. Our results proposed a new therapeutic approach targeting SERCA2 and associated proteasome that might protect against Cd2+-induced cytotoxicity and renal injury.

Cadmium perturbed lipid profile and induced liver dysfunction in mice through phosphatidylcholine remodeling and promoting arachidonic acid synthesis and metabolism.

Cadmium ion (Cd2+) exposure has been reported to associate with the prevalence of dyslipidemia, and contribute to the initiation and progression of nonalcoholic fatty liver disease (NAFLD). However, Cd2+ exposure perturbed specific metabolic pathways and underlying mechanisms are still unclear. In the present study, through lipidomics analyses of differential metabolites in serum between the Cd2+-exposed mice and the control group, 179 differential metabolites were identified, among which phosphatidylcholines (PCs) accounted for 49 % metabolites. Moreover, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment assay indicates that PCs participate in the metabolic pathways, including the Arachidonic Acid (AA) metabolism, which also could be potential NAFLD biomarkers. Moreover, in vivo and in vitro results suggested that Cd2+ exposure induced PC synthesis and remodeling, and increased AA level by promoting fatty acid desaturase 1 (FADS1) to catalyze synthesis process instead of cytosolic phospholipase A2 (cPLA2) mediated release pathway. Inhibition of FADS1 by T3364366 could reverse Cd-induced AA, prostaglandin E2 (PGE2) and triglyceride (TAG) levels, and it also reduce cisplatin resistance in HepG2 cells. This study provides new evidence of Cd2+-induced dyslipidemia and reveals underlying molecular mechanism involved in liver dysfunction of Cd2+ exposure.

Blocking stanniocalcin 2 reduces sunitinib resistance in clear cell renal cell carcinoma.

Stanniocalcin 2 (STC2) has been identified as a prognostic marker in renal cell carcinoma. However, the role of STC2 in renal cell carcinoma is still unclear. In this study, we investigated the relationship between high expression of STC2 and sunitinib resistance in cells and the underlying mechanism. Through GEPIA platform analysis based on TCGA database, it showed that the expression of STC2 in kidney renal clear cell carcinoma (KIRC) was significantly higher than that in the normal population. Real-time quantitative PCR and western blotting detected significantly higher expression levels of STC2 in clear cell renal cell carcinoma (ccRCC) cells than that in normal renal cells. Enzyme-linked immunosorbent assay (ELISA) determined whether there is a high secretion of STC2 in ccRCC cells. The sunitinib resistance could be significantly reduced by STC2 neutralizing antibody but aggravated by the addition of recombinant human STC2 in ccRCC cells. Sunitinib suppressed STC2 expression and secretion, destroyed lysosomal acidic pH, and accumulated in the cells. However, STC2 neutralizing antibody can reduce the accumulation of sunitinib in cells to improve the inhibitory efficiency of sunitinib on cell proliferation. This study suggested STC2 could serve as a potential novel target for the treatment of ccRCC, anti-STC2 antibody might be an option of immunotherapy in the future.

Cadmium induces triglyceride levels via microsomal triglyceride transfer protein (MTTP) accumulation caused by lysosomal deacidification regulated by endoplasmic reticulum (ER) Ca2+ homeostasis.

Cadmium (Cd) exposure induced lipid metabolic disorder with changes in lipid composition, as well as triglyceride (TG) levels. Liver is the main organ maintaining body TG level and previous studies suggested that Cd exposure might increase TG synthesis but reduce TG uptake in liver. However, the effects of Cd exposure on TG secretion from liver and underlying mechanism are still unclear. In the present study, the data revealed that Cd exposure increased TG levels in the HepG2 cells and the cultured medium by increasing the expression of microsomal triglyceride transfer protein (MTTP), which was abrogated by siRNA knockdown of MTTP. MTTP was synergistically accumulated after Cd exposure or treated with proteasome inhibitor MG132 and lysosome inhibitor chloroquine (CQ), which suggested the Cd increased MTTP protein stability by inhibiting both the proteasome and the lysosomal protein degradation pathways. In addition, our results demonstrated that Cd exposure inhibited the lysosomal acidic degradation pathway through disrupting endoplastic reticulum (ER) Ca2+ homeostasis. Cd-induced MTTP protein and TG levels were significantly reduced by pretreatments of BAPTA/AM chelation of intracellular Ca2+, 2-APB inhibition of ER Ca2+ release channel inositol 1,4,5-trisphosphate receptor (IP3R) and CDN1163 activation of ER Ca2+ reuptake pump sarcoplasmic reticulum Ca2+-ATPase (SERCA). These results suggest that Cd-induced ER Ca2+ release impaired the lysosomal acidity, which associated with MTTP protein accumulation and contributed to increased TG levels.

Dysregulation of autophagy acts as a pathogenic mechanism of non-alcoholic fatty liver disease (NAFLD) induced by common environmental pollutants.

Non-alcoholic fatty liver disease (NAFLD) has been the most common chronic liver disease in the world, including the developing countries. NAFLD is metabolic disease with significant lipid deposition in the hepatocytes of the liver, which is usually associated with oxidative stress, inflammation and fibrogenesis, and insulin resistance. Progressive NAFLD can develop into non-alcoholic steatohepatitis (NASH) or hepatocellular carcinoma. The current evidence proposes that environmental pollutants promote development and progression of NAFLD, and autophagy plays a vital role but is multifactorial affected in NAFLD. In this review, we analyzed on the regulations of common environmental pollutants on autophagy in NAFLD. To clarify the involved roles of autophagy, we discussed the dysregulation of autophagy by environmental pollutants in adipose tissue and gut, and their interactions with liver, as well as epigenetic regulation on autophagy by environmental pollutants. Furthermore, protective roles of potential therapeutic treatments on the multiple-hits of autophagy in NAFLD were descripted.