RESUMO
Ulcerative colitis (UC) is a subtype of inflammatory bowel disease. Previous studies have suggested a link between senescence process and the body's inflammatory reaction, indicating that senescence may exacerbate UC, yet the relation between UC and senescence remains unclear. Tedizolid Phosphate (TED), a novel oxazolidinone antimicrobial, is indicated in acute bacterial skin infections, its impact on senescence is not known. Our research revealed that the UC inducer dextran sulfate sodium (DSS) triggers senescence in both colon epithelial NCM460 cells and colon tissues, and TED that screened from a compound library demonstrated a strong anti-senescence effect on DSS treated NCM460 cells. As an anti-senescence medication identified in this research, TED efficiently alleviated UC and colonic senescence in mice caused by DSS. By proteomic analysis and experimental validation, we found that DSS significantly inhibits the AMPK signaling pathway, while TED counteracts senescence by restoring AMPK activity. This research verified that the development of UC is accompanied with colon tissue senescence, and TED, an anti-senescence medication, can effectively treat UC caused by DSS and alleviate colon senescence. Our work suggests anti-senescence strategy is an effective approach for UC treatment.
Assuntos
Proteínas Quinases Ativadas por AMP , Senescência Celular , Colite Ulcerativa , Colo , Sulfato de Dextrana , Transdução de Sinais , Animais , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Transdução de Sinais/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/patologia , Senescência Celular/efeitos dos fármacos , Humanos , Proteínas Quinases Ativadas por AMP/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Linhagem Celular , Masculino , Oxazolidinonas/farmacologia , Oxazolidinonas/uso terapêutico , Organofosfatos/farmacologia , Organofosfatos/uso terapêutico , Modelos Animais de DoençasRESUMO
OBJECTIVES: This study aims to investigate the impact of mesenchymal stem cell (MSC)-derived exosomes (Exo) on cerebral ischemia and reperfusion (I/R) injury, along with the underlying mechanism. METHODS: An animal model of cerebral ischemia was induced using middle cerebral artery occlusion (MCAO), and a cell model utilizing Neuro-2a cells was established through oxygen-glucose deprivation/reoxygenation (OGD/R). Exosomes isolated from mouse MSCs were administered to mice or used to stimulate Neuro-2a cells. Exosomes from MSCs transfected with miR-NC, miR-486-5p mimics, miR-486-5p inhibitor, or phosphatase and tensin homolog (PTEN) short hairpin RNAs (sh-PTEN) were employed to stimulate Neuro-2a cells. The regulatory axis of miR-486-5p and PTEN was confirmed through rescue experiments. RESULTS: Exo-miR-486-5p mimics alleviated cerebral I/R injury, improving neurological deficits and reducing the infarct ratio. Furthermore, Exo-miR-486-5p mimics attenuated OGD/R-induced defects in cell viability and inhibited apoptosis in Neuro-2a cells. These mimics also reduced levels of lactate dehydrogenase (LDH) and malondialdehyde (MDA) while enhancing superoxide dismutase (SOD) activity, both in brain tissue homogenates of mice and cell supernatants. Mechanistically, PTEN was identified as a target of miR-486-5p, and the downregulation of PTEN notably elevated Exo-miR-486-inhibitor-induced reductions in cell viability while mitigating cell apoptosis. CONCLUSION: The results of this study demonstrate the potential of exosomes derived from MSCs to protect against cerebral I/R injury via the miR-486-5p and PTEN axis.
Assuntos
Isquemia Encefálica , Exossomos , MicroRNAs , Traumatismo por Reperfusão , Animais , Exossomos/genética , MicroRNAs/genética , Traumatismo por Reperfusão/genética , Isquemia Encefálica/genética , Apoptose , ReperfusãoRESUMO
Ulcerative colitis (UC) is a chronic inflammatory disease that is increasing in prevalence globally. Senescence is characterized by a specific chronic, low-grade, "sterile" inflammatory state known as inflammaging, suggesting that senescence may exacerbate the severity of UC. However, the link between UC and senescence remains unclear. Valnemulin (VAL) is a semi-synthetic derivative of a naturally occurring diterpenoid antibiotic (pleuromutilin), which can inhibit peptidyl transferase. Studies investigating the potential of valnemulin to inhibit senescence and alleviate colitis are currently limited. In this study, we revealed that dextran sulfate sodium (DSS), an inducer of UC, induces senescence in both colon epithelial NCM460 cells and colon tissues. Additionally, VAL, identified from a compound library, exhibited robust anti-senescence activity in DSS-treated NCM460 cells. Identified in our study as an anti-senescence agent, VAL effectively mitigated DSS-induced UC and colonic senescence in mice. Through network pharmacology analysis and experimental validation, the potential signaling pathway (AMPK/NF-κB) for VAL in treating UC was identified. We discovered that DSS significantly inhibited the AMPK signaling pathway and activated the NF-κB signaling pathway. However, supplementation with VAL remarkably restored AMPK activity and inhibited the NF-κB signaling pathway, which led to the inhibition of senescence. In summary, our study demonstrated that DSS-induced UC stimulates the senescence of colonic tissues, and VAL can effectively alleviate DSS-induced colonic damage and reduce colonic senescence. Our research findings provide a new perspective for targeting anti-senescence in the treatment of UC.