Sepsis remains a challenge in critical care worldwide，with intestinal microbiome dysbiosis implicated in its onset，progression，and organ dysfunction. Germ-free （GF） and human microbiota-colonized animals，by eliminating confounding from resident microbiota and combining induction methods such as CLP/LPS/live-bacterial challenge with fecal microbiota transplantation （FMT） and mono- or combined colonization，enable causal tests and dissection of microbiota-host interactions and drug mechanisms. This review summarizes the application of GF and related models in sepsis research. At the immune level，TLR-related signaling and pathogen community-induced suppression of IRF3-dependent defense affect innate immunity and pathogen clearance. At the barrier level，reprogramming of tight junction proteins and increased permeability drive gut-derived amplification. At the metabolic level，short-chain fatty acids and bile acids function as metabolic valves influencing GPR/HDAC signaling. At the epigenetic level，EZH2 and histone deacetylation emerge as druggable targets. We further synthesize anti-sepsis evidence for traditional Chinese medicine （TCM），mainly from conventional animals and clinical studies，discussing how formulae （e.g.，Xuebijing，Shenfu，and Huanglian Jiedu Tang） and active constituents （e.g.，berberine，luteolin，ginsenosides，and resveratrol） may act through microbiota-related and direct host pathways，with FMT/metabolite replenishment enabling further causal testing. Finally，we propose a closed-loop GF-humanized-clinical stratification paradigm for integrated evaluation of microecology，epigenetics，immunity，and organ outcomes，providing a translational path for precision prevention and treatment based on TCM and the microbiome.

Increasing evidence shows that the early lesions of Parkinson's disease (PD) originate from gut, and correction of microbiota dysbiosis is a promising therapy for PD. FLZ is a neuroprotective agent on PD, which has been validated capable of alleviating microbiota dysbiosis in PD mice. However, the detailed mechanisms still need elucidated. Through metabolomics and 16S rRNA analysis, we identified glycoursodeoxycholic acid (GUDCA) was the most affected differential microbial metabolite by FLZ treatment, which was specially and negatively regulated by Clostridium innocuum, a differential microbiota with the strongest correlation to GUDCA production, through inhibiting bile salt hydrolase (BSH) enzyme. The protection of GUDCA on colon and brain were also clarified in PD models, showing that it could activate Nrf2 pathway, further validating that FLZ protected dopaminergic neurons through promoting GUDCA production. Our study uncovered that FLZ improved PD through microbiota-gut-brain axis, and also gave insights into modulation of microbial metabolites may serve as an important strategy for treating PD.

Although enteric glial cell (EGC) abnormal activation is reported to be involved in the pathogenesis of Parkinson's disease (PD), and inhibition of EGC gliosis alleviated gut and dopaminergic neuronal dysfunction was verified in our previous study, the potential role of gut microbiota on EGC function in PD still need to be addressed. In the present study, fecal microbiota transplantation revealed that EGC function was regulated by gut microbiota. By employing 16S rRNA and metabolomic analysis, we identified that 3-indolepropionic acid (IPA) was the most affected differential microbial metabolite that regulated EGC gliosis. The protective effects of IPA on PD were validated in rotenone-stimulated EGCs and rotenone (30 mg/kg i.g. for 4 weeks)-induced PD mice, as indicated by decreased inflammation, improved intestinal and brain barrier as well as dopaminergic neuronal function. Mechanistic study showed that IPA targeted pregnane X receptor (PXR) in EGCs, and inhibition of IL-13Rα1 involved cytokine-cytokine receptor interaction pathway, leading to inactivation of downstream JAK1-STAT6 pathway. Our data not only provided evidence that EGC gliosis was critical in spreading intestinal damage to brain, but also highlighted the potential role of microbial metabolite IPA in alleviating PD pathological damages through gut-brain axis.

[This corrects the article DOI: 10.1016/j.apsb.2025.02.029.].

Objective:To analyze the effect of panax notoginseng saponins(PNS)on mTORC1-HIF1α signaling pathway,and to explore its effect and mechanisms on the differentiation balance of Th17/Treg cells in CD4+T cells.Methods:Isolate the spleens of C57BL/6 mice,then select CD4+T cells by magnetic beads and cultured in vitro.The optimal concentration of PNS was screened by the CCK-8,and then these cells were divided into control group and PNS treatment group(5,10 and 20 μg/ml),each gives correspond-ing drug treatment after 48 h.Afterwards,flow cytometry was used to detect differentiation of Th17/Treg cells.Real-time quantitative fluorescent PCR was used to detect the expressions of RORγt,Foxp3,mTOR,Raptor,HIF1α mRNA.ELISA was used to detect the levels of IL-17A and IL-10 in the supernatant of cell culture.Western blot was used to detect the expressions and phosphorylation levels of 4EBP1,S6K and HIF1α proteins.Results:5,10,20 μg/ml PNS could significantly inhibit Th17 cells differentiation and promote Treg cells differentiation;5,10,20 μg/ml PNS could significantly reduce the expression of RORγt mRNA,and then reduce the level of IL-17A;20 μg/ml PNS could significantly promote the expression of Foxp3 mRNA and increase the level of IL-10;10,20 μg/ml PNS could significantly decrease the phosphorylation of 4EBP1 and S6K;5,10,20 μg/ml PNS could significantly reduce the expression of HIF1α mRNA and inhibit the expression of HIF1α protein.Conclusion:Certain concentrations of PNS can inhibit the differentiation of Th17 cells in CD4+T cells,and promote the differentiation of Treg cells,which is related with modulating mTORC1-HIF1α signaling pathway.

Arsenic compounds are widely used for the therapeutic intervention of multiple diseases.Ancient pharmacologists discovered the medicinal utility of these highly toxic substances,and modern phar-macologists have further recognized the specific active ingredients in human diseases.In particular,Arsenic trioxide(ATO),as a main component,has therapeutic effects on various tumors(including leukemia,hepatocellular carcinoma,lung cancer,etc.).However,its toxicity limits its efficacy,and con-trolling the toxicity has been an important issue.Interestingly,recent evidence has pointed out the pivotal roles of arsenic compounds in phase separation and membraneless organelles formation,which may determine their toxicity and therapeutic efficacy.Here,we summarize the arsenic compounds-regulating phase separation and membraneless organelles formation.We further hypothesize their potential involvement in the therapy and toxicity of arsenic compounds,highlighting potential mecha-nisms underlying the clinical application of arsenic compounds.

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-

Parkinson's disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota-gut-brain axis. However, the explicit mechanisms of microbiota dysbiosis in PD development have not been well elucidated yet. FLZ, a novel squamosamide derivative, has been proved to be effective in many PD models and is undergoing the phase I clinical trial to treat PD in China. Moreover, our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ

Objective To investigate the expression of CD26 (dipeptidyl peptidase 4) in the kidney tissues of diabetic rats and the effects of mycophenolate mofetil (MMF) on the renal CD26 expression.Methods Wistar rats were randomly divided into three groups:normal control group (NC group,n=7),diabetic model group (DM group,n=7) and MMF-treated group (MMF group,n=7).Wistar rats were fed with high-sucrose-high-fat diet and injected with streptozotocin into abdominal cavity to induce diabetes.Sixteen weeks later,blood glucose (BG),blood urea nitrogen (BUN),serum creatinine (Scr),renal hypertrophy index (kidney weight]body weight) and 24 hour urinary protein (24Upro) were measured.The number of CD37CD4+ T cells in renal tissues were measured through flow cytometry.The expression of CD26 in kidney was examined by using Western blotting and immunohistochemistry.Results Compared with NC group,BG,BUN,Scr,kidney weight/body weight,24Upro were significantly increased in DM group (P ＜ 0.05).Except BG and kidney weight] body weight,the above-mentioned parameters were lower in MMF group compared with that in DM group (P ＜ 0.05).Intrarenal CD37CD4+ T cells were significantly up-regulated in DM group compared with that in NC group (P ＜ 0.01).CD26 in renal tissue was mainly expressed in T lymphocytes of renal interstitium.CD26 expression in DM group was significantly higher than that in NC group,and also higher than that in MMF group (P ＜ 0.05).In DM group,CD26+ T lymphocytes infiltration of renal interstitium was positively correlated with 24Upro (r2=0.770,P ＜ 0.05).Conclusions CD26 is related with diabetic nephropathy.MMF maybe inhibit T lymphocytes infiltration to reduce the expression of CD26 in renal interstitium,thus protecting the kidney function.