Exosomal microRNA-588 from M2 polarized macrophages contributes to cisplatin resistance of gastric cancer cells

World Journal of Gastroenterology · 2021 · 47 citations

• Cancer research
• Medicine
• Biology

BACKGROUND: Gastric cancer is a prevalent malignant cancer with a high incidence and significantly affects the health of modern people globally. Cisplatin (DDP) is one of the most common and effective chemotherapies for patients with gastric cancer, but DDP resistance remains a severe clinical challenge. AIM: To explore the function of M2 polarized macrophages-derived exosomal microRNA (miR)-588 in the modulation of DDP resistance of gastric cancer cells. METHODS: M2 polarized macrophages were isolated and identified by specific markers using flow cytometry analysis. The exosomes from M2 macrophages were identified by transmission electron microscopy and related markers. The uptake of the PKH67-labelled M2 macrophages-derived exosomes was detected in SGC7901 cells. The function and mechanism of exosomal miR-588 from M2 macrophages in the modulation of DDP resistance of gastric cancer cells was analyzed by CCK-8 assay, apoptosis analysis, colony formation assay, Western blot analysis, qPCR analysis, and luciferase reporter assay in SGC7901 and SGC7901/DDP cells, and by tumorigenicity analysis in nude mice. RESULTS: . miR-588 was able to target cylindromatosis (CYLD) in gastric cancer cells. The depletion of CYLD reversed miR-588 inhibition-regulated cell proliferation and apoptosis of gastric cancer cells exposed to DDP. CONCLUSION: In conclusion, we uncovered that exosomal miR-588 from M2 macrophages contributes to DDP resistance of gastric cancer cells by partly targeting CYLD. miR-588 may be applied as a potential therapeutic target for the treatment of gastric cancer.

Bronchial epithelial pyroptosis promotes airway inflammation in a murine model of toluene diisocyanate-induced asthma

Biomedicine & Pharmacotherapy · 2020 · 89 citations

• Immunology
• Medicine
• Chemistry

Airway epithelial injury in response to allergens such as toluene diisocyanate (TDI) leads to persistent airway inflammation. Pyroptosis is recognized as a strong proinflammatory cell death process. However, the role of pyroptosis in bronchial epithelial injury and airway inflammation in TDI-induced asthma remains unknown. In this study, cytotoxic effect of TDI on 16HBE cells (a human bronchial epithelial cell line) was detected. Then a TDI-induced experimental asthma mouse model was established for in vivo study. Here we found that TDI induced pyroptosis in 16HBE cells, as evidenced by enhanced expressions of caspase-1 and elevated levels of LDH, IL-1β and HMGB1. As expected, TDI-induced inflammatory cell death was significantly blocked by a specific NLRP3 inflammasome inhibitor. Intriguingly, in asthmatic mice, the increased cleavages of caspase-1 and pyroptotic executioner gasdermin D (GSDMD) in bronchial epithelial cells were decreased by NLRP3 inflammasome inhibitor. Furthermore, inhibition of NLRP3 inflammasome attenuated airway hyper-responsiveness and airway inflammation, accompanied by lower levels of IL-1β, IgE and Th2-related cytokines. Our data suggest that bronchial epithelial pyroptosis exacerbates airway inflammation and hyper-responsiveness in TDI-induced asthma via NLRP3 inflammasome activation and GSDND cleavage. Therefore, NLRP3 inflammasome-mediated pyroptosis may be a potential treatment target for TDI-induced asthma.

Triphenyl phosphate exposure induces kidney structural damage and gut microbiota disorders in mice under different diets

Environment International · 2020 · 44 citations

• Chemistry
• Internal medicine
• Endocrinology

Exposure of humans to organophosphate flame retardants (OPFRs) and the consequent health risk have increased owing to the latter's widespread application. Although triphenyl phosphate (TPP), an OPFR, is a potential chemical determinant of liver function damage, its effects on kidney function in mice under high fructose/fat (HFF) diet are still unclear. In this study, C57BL/6J mice were fed HFF to generate an obesity model and mice were exposed to low dose (0.01 mg/kg/day; TPP-L) and high dose (1 mg/kg/day; TPP-H) of TPP for 12 weeks. Results showed that TPP-L and TPP-H combined with HFF, as well as TPP-H alone, caused kidney structural damage and gut microbiota disorders in mice. Inflammatory response induced by nuclear factor kappa B (NF-κB p65)/nod-like receptor protein 3 (NLRP3) and caspase-3 promoted kidney structure damage, as well as accumulation of triglyceride and total cholesterol and the protein residues in urine. Although TPP-L did not cause obvious structural damage in the kidneys, 0.01 mg/kg TPP induced significant inflammation and gut microbiota disorders. These findings provide new insights regarding health risk assessment after chronic exposure to TPP and HFF alone, as well as a combination of TPP with HFF in mice.