Hydrogen-rich water alleviates constipation by attenuating oxidative stress through the sirtuin1/nuclear factor-erythroid-2-related factor 2/heme oxygenase-1 signaling pathway

BACKGROUND Constipation,a highly prevalent functional gastrointestinal disorder,induces a significant burden on the quality of patients'life and is associated with substantial healthcare expenditures.Therefore,identifying efficient therapeutic modalities for constipation is of paramount importance.Oxidative stress is a pivotal contributor to colonic dysmotility and is the underlying pathology responsible for constipation symptoms.Consequently,we postulate that hydrogen therapy,an emerging and promising intervention,can serve as a safe and efficacious treatment for constipation.AIM To determine whether hydrogen-rich water(HRW)alleviates constipation and its potential mechanism.METHODS Constipation models were established by orally loperamide to Sprague-Dawley rats.Rats freely consumed HRW,and were recorded their 24 h total stool weight,fecal water content,and charcoal propulsion rate.Fecal samples were subjected to 16S rDNA gene sequencing.Serum non-targeted metabolomic analysis,malondialdehyde,and superoxide dismutase levels were determined.Colonic tissues were stained with hematoxylin and eosin,Alcian blue-periodic acid-Schiff,reactive oxygen species(ROS)immunofluorescence,and immunohistochemistry for cell growth factor receptor kit(c-kit),PGP 9.5,sirtuin1(SIRT1),nuclear factor-erythroid-2-related factor 2(Nrf2),and heme oxygenase-1(HO-1).Quantitative real-time PCR and western blot analysis were conducted to determine the expression level of SIRT1,Nrf2 and HO-1.A rescue experiment was conducted by intraperitoneally injecting the SIRT1 inhibitor,EX527,into constipated rats.NCM460 cells were induced with H2O2 and treated with the metabolites to evaluate ROS and SIRT1 expression.RESULTS HRW alleviated constipation symptoms by improving the total amount of stool over 24 h,fecal water content,charcoal propulsion rate,thickness of the intestinal mucus layer,c-kit expression,and the number of intestinal neurons.HRW modulated intestinal microbiota imbalance and abnormalities in serum metabolism.HRW could also reduce intestinal oxidative stress through the SIRT1/Nrf2/HO-1 signaling pathway.This regulatory effect on oxidative stress was confirmed via an intraperitoneal injection of a SIRT1 inhibitor to constipated rats.The serum metabolites,β-leucine(β-Leu)and traumatic acid,were also found to attenuate H2O2-induced oxidative stress in NCM460 cells by up-regulating SIRT1.CONCLUSION HRW attenuates constipation-associated intestinal oxidative stress via SIRT1/Nrf2/HO-1 signaling pathway,modulating gut microbiota and serum metabolites.β-Leu and traumatic acid are potential metabolites that upregulate SIRT1 expression and reduce oxidative stress.

Predicting colorectal cancer prognosis based on long noncoding RNAs of disulfidptosis genes

BACKGROUND A recently hypothesized cause of cell death called disulfidptosis has been linked to the expansion,emigration,and vascular rebuilding of cancer cells.Cancer can be treated by targeting the pathways that trigger cell death.AIM To discover the long non-coding RNA of the disulfidaptosis-related lncRNAs(DRLs),prognosis clinical survival,and treat patients with colorectal cancer with medications.METHODS Initially,we queried the Cancer Genome Atlas database to collect transcriptome,clinical,and genetic mutation data for colorectal cancer(CRC).Training and testing sets for CRC patient transcriptome data were generated randomly.Key long non-coding RNAs(lncRNAs)related to DRLs were then identified and evaluated using a least absolute shrinkage and selection operator procedure,as well as univariate and multivariate Cox regression models.A prognostic model was then created after risk scoring.Also,Immune infiltration analysis,immune checkpoint analysis,and medication susceptibility analysis were used to investigate the causes of the different prognoses between high and low risk groups.Finally,we validated the differential expression and biomarker potential of riskpredictive lncRNAs through induction using both NCM460 and HT-29 cell lines,as well as a disulfidptosis model.RESULTS In this work,eight significant lncRNAs linked to disulfidptosis were found.Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of differentially expressed genes between high-and low-risk groups from the prognostic model showed a close relationship with the immune response as well as significant enrichment in neutrophil extracellular trap formation and the IL-17 signaling pathway.Furthermore,significant immune cell variations between the high-risk and low-risk groups were seen,as well as a higher incidence of immunological escape risk in the high-risk group.Finally,Epirubicin,bortezomib,teniposide,and BMS-754807 were shown to have the lowest sensitivity among the four immunotherapy drugs.CONCLUSION Our findings emphasizes the role of disulfidptosis in regulating tumor development,therapeutic response,and patient survival in CRC patients.For the clinical treatment of CRC,these important LncRNAs could serve as viable therapeutic targets.

克罗恩病肛管直肠狭窄的外科治疗进展

肛管直肠狭窄是肛周克罗恩病最具挑战的并发症,严重影响患者生存质量。受肛管直肠周围狭小解剖空间的限制,如何在解决狭窄症状的同时保留括约肌功能并避免复杂性手术是外科医生面临的临床难题之一。目前关于克罗恩病肛管直肠狭窄的相关研究较少,如何为患者提供最佳的临床评估和治疗方案是目前亟待解决的问题。本文就克罗恩病肛管直肠狭窄的内镜和外科治疗方法作一总结,以期为专科医生临床决策提供参考。