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 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.

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.

[Clinical effects of percutaneous elastic intramedullary nail assisted by arthrography for the treatment of radial neck fractures in children].

OBJECTIVE: To explore clinical effect of closed reduction percutaneous elastic intramedullary nail assisted by arthrography in the treatment of radial neck fracture in children. METHODS: A retrospective analysis was performed on 23 children with radial neck fracture treated with arthrography assisted closed reduction and percutaneous elastic intramedullary nail internal fixation (arthrography with elastic nail group) from January 2019 to December 2022, including 12 males and 11 females, aged from 2 to 12 years old with an average of (7.36±1.89) years old;According to Judet fracture types, 14 children were type Ⅲ and 9 children were type Ⅳ. In addition, 23 children with radial neck fracture were selected from January 2015 to December 2018 who were treated with closed reduction and percutaneous elastic intramedullary nail fixation (elastic nail group), including 11 males and 12 females, aged from 2 to 14 years old with an average of (7.50±1.91) years old;Judet classification included 15 children were type Ⅲ and 8 children were type Ⅳ. Operative time and intraoperative fluoroscopy times were compared between two groups. Metaizeau evaluation criteria was used to evaluate fracture reduction, and Tibone-Stoltz evaluation criteria was used to evaluate functional recovery of elbow between two groups. RESULTS: Both groups were followed up for 12 to 24 months with an average of (16.56±6.34) months. Operative time and intraoperative fluoroscopy times of elastic nail group were (56.64±19.27) min and (21.13±7.87) times, while those of joint angiography with elastic nail group were (40.33±11.50) min and (12.10±3.52) times;there were difference between two groups (P<0.05). According to Metaizeau evaluation, 11 patients got excellent result, 9 good and 3 fair in joint angiography with elastic nail group, while in elastic nail group, 5 excellent, 13 good, 4 acceptable, and 1 poor;the difference between two groups was statistically significant (P<0.05). According to Tibone-Stoltz criteria, 14 patients got excellent result, 8 good, and 1 fair in joint arthrography with elastic nail group;while in elastic nail group, 12 patients got excellent result, 9 good, 1 fair and 1 poor;there was no significant difference between two groups (P>0.05). CONCLUSION: Compared to percutaneous elastic intramedullary nail fixation, closed reduction assisted by arthrography has advantages of reduced operation time, decreased intraoperative fluoroscopy frequency, and improved fracture reduction. Arthrography enables clear visualization of the anatomical structures of radius, head, neck, bone, and cartilage in children, facilitating comprehensive display of fracture reduction and brachioradial joint alignment. This technique more precisely guides the depth of elastic intramedullary nail implantation in radius neck, thereby enhancing surgical efficiency and success rate.