As a critical molecule in the onset and sustainment of inflammatory response, the receptor for advanced glycation end products (RAGE) has a variety of ligands, such as advanced glycation end products (AGEs), S100/calcium granule protein, and high-mobility group protein 1 (HMGB1). Recently, an increasing number studies have shown that RAGE ligand binding can initiate the intracellular signal cascade, affect intracellular signal transduction, stimulate the release of cytokines, and play a vital role in the occurrence and development of immune-related diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Alzheimer’s disease. In addition, other RAGE signaling pathways can play crucial roles in life activities, such as inflammation, apoptosis, autophagy, and endoplasmic reticulum stress. Therefore, the strategy of targeted intervention in the RAGE signaling pathway may have significant therapeutic potential, attracting increasing attention. In this paper, through the systematic induction and analysis of RAGE-related signaling pathways and their regulatory mechanisms in immune-related diseases, we provide theoretical clues for the follow-up targeted intervention of RAGE-mediated diseases.

Inorganic arsenic is a well-established environmental toxicant linked to acute liver injury, fibrosis, and cancer. While oxidative stress, pyroptosis, and ferroptosis are known contributors, the role of PTEN-induced kinase 1 (PINK1)-mediated mitophagy in arsenic-induced hepatic immunotoxicity remains underexplored. Our study revealed that acute arsenic exposure prompts differentiation of hepatic dendritic cells (DCs) and T helper (Th) 1, Th2, Th17, and regulatory T (Treg) cells, alongside increased transcription factors and cytokines. Inorganic arsenic triggered liver redox imbalance, leading to elevated alanine transaminase (ALT), hydrogen peroxide (H₂O₂), malondialdehyde (MDA), and activation of nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) pathway. PINK1-mediated mitophagy was initiated, and its inhibition exacerbates H₂O₂ accumulation while promoting DCs/Th1/Th2/Treg differentiation in the liver of arsenic-exposed mice. Mitoquinone (MitoQ) pretreatment relieved arsenic-induced acute liver injury and immune imbalance by activating Nrf2/HO-1 and PINK1-mediated mitophagy. To our knowledge, this is the first report identifying PINK1-mediated mitophagy as a protective factor against inorganic arsenic-induced hepatic DCs/Th1/Th2 differentiation. This study has provided new insights on the immunotoxicity of inorganic arsenic and established a foundation for exploring preventive and therapeutic strategies targeting PINK1-mediated mitophagy in acute liver injury. Consequently, the application of mitochondrial antioxidant MitoQ may offer a promising treatment for the metalloid-induced acute liver injury.

From the two perspectives of intestinal flora and plasma metabolomics, the mechanism of occurrence and development of pneumoconiosis was explored to provide a new target for the prevention and treatment of pneumoconiosis. In this study, 16S ribosome DNA (16SrDNA) gene sequencing technology was used to analyze the differences in intestinal flora of each research group through operational taxonomic units (OUT) analysis, cluster analysis, principal component analysis (PCA), partial least square discriminant analysis (PLS-DA), Kyoto Encyclopedia of Genes and Genomes (KEGG), and other analytical methods were used to analyze the differences in plasma metabolites between the study groups. Metabonomics analysis showed that the plasma metabolites of pneumoconiosis patients were significantly different from those of normal people. Fold change > 2; vip > 1; p < 0.05 were the screening criteria. In the positive and negative mode, we screened ten types of differential metabolites. These ten metabolites were upregulated to varying degrees in the pneumoconiosis patients. Seven metabolic pathways were obtained by analyzing the metabolic pathways of different metabolites. Among them, the aminoacyl tRNA biosynthesis pathway changed most obviously. The α diversity of two groups of intestinal flora was analyzed using the 16SrDNA technique. The results showed that there was no significant difference in ACE, Chao1, Shannon, or Simpson in the two groups (p > 0.05). Beta diversity analysis showed that there were differences in microbial communities. In pneumoconiosis patients, the abundance of Prevotellaceae increased, and the other nine species decreased. Compared to the control group, the abundance of Prevotellaceae in the intestinal flora of pneumoconiosis increased, and the abundance of the other nine species decreased. Compared to controls, ten substances in the plasma metabolites of pneumoconiosis patients were upregulated. Seven metabolic pathways were obtained by analyzing the metabolic pathways of different metabolites. Among them, the aminoacyl tRNA biosynthesis pathway changed most significantly. This provided a theoretical basis for further study on the pathogenesis, early prevention, and treatment of pneumoconiosis.

Inorganic arsenic is a well-known environmental toxicant and carcinogen, and there is overwhelming evidence for an association between this metalloid poisoning and hepatic diseases. However, the biological mechanism involved is not well characterized. In the present study, we probed how inorganic arsenic modulates the hepatic polarization of macrophages, as well as roles of PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy participates in regulating the metalloid-mediated macrophage polarization. Our results indicate that acute arsenic exposure induced macrophage polarization with up-regulated gene expression of inducible nitric oxide synthase (Inos) and arginase-1 (Arg1), monocyte chemotactic protein-1 (Mcp-1) and macrophage inflammatory protein-2 (Mip-2), tumor necrosis factor (Tnf)-α, interleukin (Il)-1β and Il-6, as well as anti-inflammatory factors Il-4 and Il-10. In parallel, we demonstrated the disrupted hepatic redox balance typically characterized by the up-regulation of hydrogen peroxide (H₂O₂) and glutathione (GSH), and activation of PINK1/Parkin-mediated mitophagy in the livers of acute arsenic-exposed mice. In addition, our results demonstrate that it might be the PINK1/Parkin-mediated mitophagy that renders hepatic macrophage refractory to arsenic-induced up-regulation of the genes Inos, Mcp-1, Mip-2, Tnf-α, Il-1β, Il-6 and Il-4. In this regard, this is the first time the protective effects of PINK1/Parkin-mediated mitophagy in inorganic arsenic-induced hepatic macrophage polarization in vivo have been reported. These findings add novel insights into the arsenical immunotoxicity and provide a basis for the preve.ntive and therapeutic potential of PINK1/Parkin-mediated mitophagy in arsenic poisoning.

Background: Previous studies, predominantly in Western individuals, have reported weight gain or weight loss are related to the increased depressive symptoms at all ages, but no study of depressive symptoms has examined its relation to actual (not just self-reported) weight changes in the middle-aged and older adults. Evidence of the relationship in older Asian individuals remains sparse. The study aimed to examine the relationship between weight changes and incidence of depressive symptoms in a nationally representative sample of community-dwelling older Asians. Method: Data were obtained from the China Health and Retirement Longitudinal Study (CHARLS), which included 17,284 adults aged 45 years. Participants were followed every two years using a face-to-face, computer-aided personal interview (CAPI) and structured questionnaire. We excluded participants with no follow-up data. The numbers of individuals who completed both the baseline and follow-up surveys were 3118 for the short-term (two years from 2011–2013) and the long-term (four years from 2011–2015). Additionally, to associate weight change with subsequent depressive symptoms, we also included 2472 participants without depressive symptom in 2013 and observed the incidence of depressive symptom in 2015 (subsequent term from 2013–2015). Finally, weight changes were classified as loss > -3%, stable-3–3%, gain3-6%, gain6-9%, and gain > 9%. Multivariable-adjusted cox regression in the study were used to assess the hazard ratios (HRs) of each weight change category. Results: The incidence of depressive symptoms was 20.72% in the 2011–2013, 27.04% in the 2011–2015, and 23.02% in 2013–2015. Weight loss > 3% for all intervals was associated with higher depressive symptoms than stable weight during the 2011–2013 [1.305(1.031,1.651)] among the total populations. When stratified by sex, the results in males and females were different from those in the total population [females:1.389(0.997, 1.935); males:1.263(0.902, 1.767)]. Weight loss > 3% for intervals was associated with higher depressive symptoms than stable weight during the 2013–2015[1.643(1.140, 2.368)] among the males and its effect was also stronger for the total in 2011–2013. Moreover, there was no significant association between weight gain and incident depressive symptom, and no significant interaction effect in terms of the sex*weight changes. Conclusion: Our findings could inform health promotion interventions to body-weight management aimed at improving the health of the middle-aged and older adults, particularly in the total people with short-term weight loss and males with subsequent term weight loss.

Silicosis is an occupational lung disease characterized by silicotic nodules and progressive pulmonary fibrosis, caused by long-term excessive inhalation of free silica. So far, no effective methods have been developed to delay or cure silicotic fibrosis. Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-Exos), which possess functions of intercellular communication, tissue repair and regeneration, offering a potential strategy for the treatment of silicosis. In this study, exosomes were extracted from human umbilical cord mesenchymal stem cells (huc-MSCs) using differential centrifugation and characterized for subsequent experiments. A silica-induced silicosis mouse model was established. Lung CT scans were performed to assess pulmonary lesions, while blood oxygenation status was monitored. Histopathological analysis of lung tissues was conducted, and Western blot was used to evaluate inflammatory and fibrotic markers, aiming to investigate the therapeutic effects of hucMSCs and their exosomes on silicotic mice. High-throughput transcriptome sequencing of lung tissues was employed to screen differentially expressed genes and signaling pathways in the two treatment groups, followed by in vitro validation of the proposed mechanisms. Our findings demonstrate that hucMSC-Exos alleviate pulmonary inflammation, slow lung fibrosis, inhibit macrophage pyroptosis, activate the actin cytoskeleton signaling pathway, and maintain plasma membrane integrity in silicotic mice. This study provides possible therapeutic targets and molecular mechanisms for silicosis, establishing a link among silicosis, cytoskeleton, and pyroptosis, while validating the protective effect of hucMSC-Exos on the lungs of silicotic mice.