RESUMO
Aged adults are prone to both short- and long-term complications following sepsis due to ineffective therapy. Phosphatidylserine (PS) is a membrane nutrient supplement known to enhance cognition and brain function, but its potential effects in treating sepsis are not well-documented. Our study aimed to explore the potential of PS in improving outcomes in sepsis and sepsis-associated encephalopathy (SAE). Middle-aged mice were administered PS for two months following induction of sepsis by lipopolysaccharides. The results indicated a significant increase in the survival rate of mice treated with PS after sepsis. Surviving mice underwent open field and shuttle box tests 45 days post-sepsis, revealing potential alleviation of neurobehavioral impairments due to PS pretreatment. Analysis at 60 days post-sepsis euthanasia showed reduced cleaved-caspase 3 in neurons and glial cell markers in the PS-treated group compared to the untreated sepsis group. Furthermore, PS administration effectively reduced proinflammatory cytokine gene expression in the hippocampus of mice with SAE, potentially inhibiting the TBK1/NLRP3/ASC signaling pathway. In the gut, PS pretreatment modulated ß-diversity while maintaining jejunal morphology and colon ZO-1 expression, without significantly affecting α-diversity indices. Our findings suggest that PS administration improves survival rates, modulates the gut microbiome, preserves gut integrity, and ameliorates brain pathology in survived mice after sepsis. Importantly, these findings have significant implications for sepsis treatment and cognitive function preservation in aging individuals, providing new insights and sparking further interest and investigation into the potential of PS in sepsis treatment.
RESUMO
Polyphenols have shown great potential to prevent ulcerative colitis. As a natural plant polyphenol, chicoric acid (CA) has antioxidant and anti-inflammatory properties. This study explored the intervention effects and potential mechanism of CA on dextran sodium sulfate (DSS)-induced colitis mice. The results showed that CA alleviated the symptoms of colitis and maintained the intestinal barrier integrity. CA significantly downregulated the mRNA expression levels of inflammatory factors including IL-6, IL-1ß, TNF-α, IFN-γ, COX-2, and iNOS. In addition, CA modulated the gut microbiota by improving the microbial diversity, reducing the abundance of Gammaproteobacteriaand Clostridium_XI and increasing the abundance ofBarnesiellaandLachnospiraceae. Further fecal microbiota transplantation experiments showed that FM from CA donor mice significantly alleviated the symptoms of colitis, verifying the key role of gut microbiota. These results indicate that CA effectively relieves DSS-induced colitis via targeting gut microbiota along with preserving intestinal barrier function and suppressing inflammatory responses.
Assuntos
Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Succinatos , Animais , Camundongos , Intestinos , Ácidos Cafeicos , Polifenóis , Sulfato de Dextrana , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , ColoRESUMO
To overcome C797S mutation, the latest and most common resistance mechanism in the clinical treatment of third-generation EGFR inhibitor, a novel series of substituted 6-(2-aminopyrimidine)-indole derivatives were designed and synthesized. Through the structure-activity relationship (SAR) study, compound 11eg was identified as a novel and potent EGFR L858R/T790M/C797S inhibitor (IC50 = 0.053 µM) but had a weak effect on EGFRWT (IC50 = 1.05 µM). 11eg significantly inhibited the proliferation of the non-small cell lung cancer (NSCLC) cells harboring EGFRL858R/T790M/C797S with an IC50 of 0.052 µM. 11eg also showed potent inhibitory activity against other NSCLC cell lines harboring main EGFR mutants. Furthermore, 11eg exhibited much superior activity in arresting cell cycle and inducing apoptosis of NSCLC cells with mutant EGFRC797S. It blocked cellular EGFR signaling. Importantly, 11eg markedly suppressed the tumor growth in in vivo xenograft mouse model with good safety. Additionally, 11eg displayed good microsomal stability. These results demonstrated the potential of 11eg with novel scaffold as a promising lead compound targeting EGFRC797S to guide in-depth structural optimization.