Chronic cadmium (Cd2+) exposure is epidemiologically linked to metabolic disorders like hypertriglyceridemia, but the precise mechanisms disrupting hepatic lipid metabolism are unclear. Lysosomal function, critical for lipid degradation via autophagy, represents a potential yet unexplored target in Cd2+-induced steatosis. We utilized multi-strain mouse models and human hepatocytes to investigate the effects Cd2+ exposure. Serum metabolomics and biochemical assays were employed to assess lipid profiles. The role of ATP6V0A1, a key subunit of the V-ATPase proton pump, was systematically examined using genetic approaches (knockdown and overexpression) in conjunction with lysosomal pH probes, autophagic flux assays, and protein stability measurements. Cd2+ exposure consistently induced hypertriglyceridemia in mice, accompanied by a significantly altered serum triglyceride metabolomic profile. In the liver, Cd2+ downregulated ATP6V0A1 protein, which impaired lysosomal acidification and thereby blocked autophagic flux. Mechanistically, Cd2+ did not affect ATP6V0A1 mRNA levels but promoted its protein degradation, which could be attenuated by inhibitors of both the proteasome and the autophagy-lysosomal pathway. Functionally, either pharmacological inhibition of lysosomal acidity or genetic knockdown of ATP6V0A1 recapitulated Cd2+-induced intracellular and secreted triglyceride accumulation. Crucially, overexpression of ATP6V0A1 rescued Cd2+-induced lysosomal dysfunction, restored autophagic flux, and normalized triglyceride levels. Our study uncovers a novel molecular pathway wherein Cd2+ post-transcriptionally destabilizes ATP6V0A1, which paradoxically leads to lysosomal dysfunction and autophagic block, ultimately driving hepatic triglyceride accumulation, thereby nominating ATP6V0A1 as a central regulator and potential therapeutic target for chemical-associated fatty liver disease.

Ferroptosis, a unique form of cell death, is characterized by its dependency on iron levels and resulting effects such as antioxidant imbalance, lipid peroxidation, and mitochondrial dysfunction. In immune cells, such as T cells, B cells, and macrophages, ferroptosis can regulate cell function and phenotype. The complex mechanisms of ferroptosis in immune cells are influenced by various factors, including tissue injuries, diseases, tumors, and external stimuli. Given the crucial role of immune cells in immune responses, inflammation, metabolism, and cancer treatment, understanding the role of ferroptosis in immune cells is essential. This article highlights the basic characteristics of ferroptosis, its mechanisms in different immune cell types, and its implications in metabolic diseases, sepsis, autoimmune diseases, and exposure to environmental pollutants like heavy metals and air pollution particles. Further research on immune cell ferroptosis will shed light on disease pathologies and potential therapeutic strategies.

Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, are defined by the progressive loss of neurons through interconnected pathological mechanisms, including oxidative stress, mitochondrial dysfunction, protein aggregation, and neuroinflammation. Accumulating evidence implicates metal dyshomeostasis as a central and multifaceted contributor to these mechanisms, with roles ranging from a primary pathogenic driver in AD and PD, to a secondary amplifier of genetic pathology in HD and ALS, and as a contextual risk modifier in the presence of toxic metals. Essential trace metals such as iron, zinc, copper, manganese, selenium, iodine, and molybdenum are vital for neurotransmission, antioxidant defense, and cellular metabolism. Dysregulation of these metals disrupts redox balance, impairs proteostasis, and activates regulated cell death pathways, including ferroptosis and cuproptosis. Toxic metals, such as lead, cadmium, and mercury, exacerbate neurodegeneration by displacing essential metals, inducing oxidative injury, and promoting protein misfolding and neuroinflammation. This narrative review synthesizes mechanistic, experimental, genetic epidemiological, and clinical evidence to critically evaluate the contributions of both essential and toxic metals to neurodegeneration in AD, PD, HD, and ALS. We examine the genetic, environmental, and physiological determinants of metal homeostasis; the analytical techniques for quantifying metals in clinical samples; and clinical trial data on metal-targeted therapeutic strategies. Notably, iron chelation with deferiprone consistently reduces brain iron on neuroimaging but worsens clinical outcomes in both PD and AD, presenting a translational paradox that requires mechanistic re-evaluation. We also provide methodological recommendations for interpreting Mendelian randomization studies of metal exposures and propose translational priorities to advance metal-targeted diagnostics and therapeutics for neurodegenerative diseases.

Cadmium ion (Cd2+) is a non-essential metal that can increase cancer risk, including potentially renal cell carcinoma (RCC), though this link is not definitive. Cd2+ exposure impairs fatty acid metabolism in the kidneys, particularly affecting arachidonic acid (AA) levels, which are crucial for health. Previous studies have suggested that Cd2+-altered the AA metabolism associates with renal dysfunction. However, the role and mechanism of Cd2+-regulated AA source in promoting RCC progression are still unclear. This study aims to investigate how Cd2+ exposure affects AA levels in renal cancer cells and its role in promoting cell migration. Cd2+ exposure increases AA levels through cPLA2-mediated release. It also induces calcium ion (Ca2+) redistribution from the endoplasmic reticulum (ER) to mitochondria, activating the p38 MAPK/cPLA2 signaling pathway, and epithelial-mesenchymal transition (EMT) of Caki-1 cells. Cd2+-induced ER Ca2+ release, p38 MAPK/cPLA2 signaling activation, AA levels, and EMT of Caki-1 cells were effectively reversed by siRNA knockdown of IP3R. Both exogenous AA treatments and Cd2+-induced AA metabolite PGD2 promoted EMT and cell migration of Caki-1 cells. This study highlights Cd2+'s impact on fatty acid metabolism and organelle function in renal cancer cells, identifying potential therapeutic targets for RCC.

Targeting ferroptosis shows considerable promise for diseases through modulation of immune cell function and phenotype. However, the process is regulated by diverse factors making its role in heavy metal immunotoxicity incompletely understood. In this study, we investigated the effect of Cd2+ on ferroptosis in B cells and underlying mechanism. We demonstrated that Cd2+ induces ferroptosis via iron overload, as supported by rescue with the iron chelator deferoxamine (DFO) and elevated Fe2+ levels detected via Ferro Orange flow cytometry. Cd2+ treatment also increased lipid peroxidation and expression of long-chain acyl-CoA synthetase 4 (ACSL4), while downregulating glutathione peroxidase 4 (GPX4). Functionally, the ferroptosis inducer Erastin pre-sensitized cells to Cd2+, while the specific inhibitor Ferrostatin-1 robustly restored viability. Mechanistically, Cd2+ enhanced protein interaction between nuclear receptor coactivator 4 (NCOA4) and ferritin heavy chain 1 (FTH1). By siRNA knockdown of NCOA4, Cd2+-induced FTH1 degradation, iron overload, and lipid peroxidation were significantly attenuated. Autophagy/lysosome inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) partially reversed Cd2+-mediated suppression of GPX4 and FTH1. Using LysoTracker and acridine orange staining, we found that Cd2+ enhances lysosomal acidification. To further delineate the mechanism of Cd2+-induced ferritinophagy, we employed the transcriptomic analysis of spleen from Cd2+-exposed mice. In vivo analysis revealed a marked upregulation of ATP6V0A1, a crucial element of the vacuolar proton pump. This ATP6V0A1 upregulation was recapitulated in human Ramos B cells following Cd2+ exposure at both the protein and transcriptional levels. Knockdown of ATP6V0A1 mitigated Cd2+-induced lysosomal acidification, FTH1 degradation, iron overload, and lipid peroxidation. These findings, combined murine in vivo screening and in vitro validation in human cells, indicate that Cd2+ upregulates ATP6V0A1 to promote lysosomal acidification, which facilitates NCOA4-mediated ferritinophagy, iron release, and subsequent ferroptosis. This study advances our understanding of heavy metal immunotoxicity and highlights potential therapeutic targets for mitigating Cd2+-induced immune dysfunction.

Epidemiological studies have demonstrated exposure to cadmium ion (Cd2+) is significantly associated with the incidence and aggravation of nonalcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Cd2+ exposure could alter lipid metabolism, and changed lipid metabolites are significantly associated with NASH. Arachidonic acid (ArA) is an omega-6 polyunsaturated fatty acid. Promotion of ArA synthesis and profile changes by Cd2+ exposure potentially to cause NAFLD. ArA metabolism pathway has been identified to enrich in Cd2+ exposure-facilitated NASH. ArA could be generation an impressive metabolic profile through mainly three pathways, including Cyclooxygenases (COX), Lipoxygenases (LOX) and Cytochrome P450 (CYP450) pathway. However, the functions of these metabolites and underlying mechanism in hepatic inflammation are still not clear. In present study, by integrative transcriptomics and metabolomics analysis, we identified that the fatty acid metabolic process and the pro-inflammatory NF-κB signaling pathway were enriched in Cd2+-regulated differentially expressed genes (DEGs) and Cd2+-altered differential metabolites, such as, fatty acid biosynthesis, degradation, and ArA metabolism. The metabolites levels of LOX pathway products 5-HETE and leukotriene C4 (LTC4), and COX catalytic product prostaglandin D2 (PGD2) were significantly elevated in Cd2+ exposed mouse livers. 5-HETE, LTC4, and PGD2 were significantly positive correlated with NF-κB signaling. In addition, the synthase of 20-Hydroxyeicosatetraenoic acid (20-HETE), CYP450 gene 4 family (CYP4A32), was also involved in NF-κB signaling network. Results from both in vitro and in vivo proved that Cd2+ exposure increased ArA metabolite to PGD2 and 20-HETE, and upregulated the mRNA level of their catalytic enzyme PGDS and CYP4A32. Cd2+-induced ArA metabolite to PGD2 and 20-HETE promoted activation of TLR4/IκBα/NF-κB signaling and pro-inflammatory of hepatocytes. Our study explores novel molecular mechanism of Cd2+ exposure-aggravated liver diseases and provides potential novel targets for in hepatic inflammatory treatments and prevention.

OBJECTIVE:To investigate the potential value of exosomes derived from rat ectoderm mesenchymal stem cells (EMSCs-exo) for repairing secondary spinal cord injury.METHODS:EMSCs-exo were obtained using ultracentrifugation from EMSCs isolated from rat nasal mucosa, identified by transmission electron microscope, nanoparticle tracking analysis (NTA), and Western blotting, and quantified using the BCA method. Neonatal rat microglia purified by differential attachment were induced with 100 μg/L lipopolysaccharide (LPS) and treated with 37.5 or 75 mg/L EMSCs-exo. PC12 cells were exposed to 400 μmol/L H2O2 and treated with EMSCs-exo at 37.5 or 75 mg/L. The protein and mRNA expressions of Arg1 and iNOS in the treated cells were determined with Western blotting and qRT- PCR, and the concentrations of IL- 6, IL-10, and IGF-1 in the supernatants were measured with ELISA. The viability and apoptosis of PC12 cells were detected using CCK-8 assay and flow cytometry.RESULTS:The isolated rat EMSCs showed high expressions of nestin, CD44, CD105, and vimentin. The obtained EMSCs-exo had a typical cup-shaped structure under transmission electron microscope with an average particle size of 142 nm and positivity for CD63, CD81, and TSG101 but not vimentin. In LPS-treated microglia, EMSCs-exo treatment at 75 mg/L significantly increased Arg1 protein level and lowered iNOS protein expression (P < 0.05). EMSCs-exo treatment at 75 mg/L, as compared with the lower concentration at 37.5 mg/L, more strongly increased Arg1 mRNA expression and IGF-1 and IL-10 production and decreased iNOS mRNA expression and IL-6 production in LPS-induced microglia, and more effectively promoted cell survival and decreased apoptosis rate of H2O2-induced PC12 cells (P < 0.05).CONCLUSION:EMSCs-exo at 75 mg/L can effectively reduce the proportion of M1 microglia and alleviate neuronal apoptosis under oxidative stress to promote neuronal survival, suggesting its potential in controlling secondary spinal cord injury.

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.

The block copolymer micelles and natural biopolymers were utilized to form layer-by-layer (LbL) films via electrostatic interaction, which were able to effectively load and controllably release favipiravir, a potential drug for the treatment of coronavirus epidemic. The LbL films demonstrated reversible swelling/shrinking behavior along with the manipulation of temperature, which could also maintain the integrity in the structure and the morphology. Due to dehydration of environmentally responsive building blocks, the drug release rate from the films was decelerated by elevating environmental temperature and ionic strength. In addition, the pulsed release of favipiravir was observed from the multilayer films under the trigger of temperature, which ensured the precise control in the content of the therapeutic reagents at a desired time point. The nanoparticle-based LbL films could be used for on-demand in vitro release of chemotherapeutic reagents.

The donor-derived cell-free DNA (ddcfDNA) is found in the plasma and urine of kidney transplant recipients and displays notable potential in diagnosing rejection, specifically antibody-mediated rejection (ABMR). Nonetheless, the quantitative methods of ddcfDNA lacking standardization and diverse detection techniques can impact the test outcomes. Besides, both the fraction and absolute values of ddcfDNA have been reported as valuable markers for rejection diagnosis, but they carry distinct meanings and are special in various pathological conditions. Additionally, ddcfDNA is highly sensitive to kidney transplant injury. The various sampling times and combination with other diseases can indeed impact ddcfDNA detection values. This review comprehensively analyses the various factors affecting ddcfDNA detection in kidney transplantation, including the number of SNPs and sequencing depths. Furthermore, different pathological conditions, distinct sampling time points, and the presence of complex heterologous signals can influence ddcfDNA testing results in kidney transplantation. The review also provides insights into ddcfDNA testing on different platforms along with key considerations.

The silica nanocapsules were functionalized with poly(methacrylic acid)-block-poly(2-acrylamido-2-methylpropanesulfonic acid) (PMAA-b-PAMPS) and assembled with chitosan (CHI) by layer-by-layer deposition and cross-linking to develop lithium electrolyte nanocomposites in the presence of concentrated alkaline solutions. The inorganic/organic nanocapsules and the assembled CHI chains endowed the multilayer films with well-defined structure, great temperature tolerance, and comparable mechanical properties. The films possessed a high loading capacity of alkaline electrolytes. The entrapment of a concentrated alkaline solution in the film matrix led to high ionic conductivity ( 0.73 mS cm−1 at 25 °C) and outstanding temperature-tolerated capacity. The films maintained a constant ionic conductivity and physical strength against mechanical deformations. For the first time, the impact of molecular weight of block copolymers on electrochemical properties of electrolyte-loaded multilayer films was investigated. The lithium-ion batteries built by flexible alkaline electrolytes of nanocapsule-based multilayer films demonstrated excellent ionic conductivity and electrochemical sustainability, possessing discharge capacity of 163.5 mA h g−1 and retaining 97.53

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 Ca 2+ homeostasis, as well as the roles of Zn 2+ 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.