This study investigates the molecular complexities of non-alcoholic fatty liver disease(NAFLD)-induced brain dysfunction,with a focus on the liver-intestine-brain axis and potential therapeutic interventions.The main ...This study investigates the molecular complexities of non-alcoholic fatty liver disease(NAFLD)-induced brain dysfunction,with a focus on the liver-intestine-brain axis and potential therapeutic interventions.The main objectives include understanding critical microbiota shifts in NAFLD,exploring altered metabolites,and identifying key regulatory molecules influencing brain function.The methods employed encompassed 16S ribosomal RNA(rRNA)sequencing to scrutinize stool microbiota in NAFLD patients and healthy individuals,non-targeted metabolomics using LC-MS to uncover elevated levels of deoxycholic acid(DCA)in NAFLD mice,and single-cell RNA sequencing(scRNA-seq)to pinpoint the pivotal gene Hpgd in microglial cells and its downstream Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway.Behavioral changes and brain function were assessed in NAFLD mice with and without fecal microbiota transplantation(FMT)treatment,utilizing various assays and analyses.The results revealed significant differences in microbiota composition,with increased levels of Bacteroides in NAFLD patients.Additionally,elevated DCA levels were observed in NAFLD mice,and FMT treatment demonstrated efficacy in ameliorating liver function and brain dysfunction.Hpgd inhibition by DCA activated the JAK2/STAT3 pathway in microglial cells,leading to inflammatory activation,inhibition of mitochondrial autophagy,induction of neuronal apoptosis,and reduction in neuronal action potentials.This study elucidates the intricate molecular mechanisms underlying the liver-gut-brain axis in NAFLD,and the identification of increased DCA and the impact of JAK2/STAT3 signaling on microglial cells highlight potential therapeutic targets for addressing NAFLD-induced brain dysfunction.展开更多
A broad spectrum of liver disorders and their associated complications most notably hepatic encephalopathy impact millions of individuals worldwide,including conditions such as non-alcoholic fatty liver disease,alcoho...A broad spectrum of liver disorders and their associated complications most notably hepatic encephalopathy impact millions of individuals worldwide,including conditions such as non-alcoholic fatty liver disease,alcoholic liver injury,viral hepatitis,hepatic fibrosis,cirrhosis,and hepatocellular carcinoma.The underlying pathogenic mechanisms are multifactorial,encompassing oxidative stress,inflammatory cascades,mitochondrial impairment,and disturbances in immune homeostasis.Hepatic encephalopathy patients experience cognitive impairment,mood disturbances,and psychomotor dysfunction,significantly reducing quality of life through mechanisms including oxidative stress,neuroinflammation,and neurotransmitter imbalances.The nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)signaling pathway serves as a critical antioxidative defense mechanism in these conditions.Nrf2 regulates the expression of protective enzymes,while HO-1 exerts anti-inflammatory,anti-apoptotic,and antifibrotic effects through heme degradation products.Natural herbal monomers as Nrf2 activators offer advantages of low toxicity,multi-target actions,and extensive traditional use.Various herbal monomers demonstrate specific effects against different liver diseases:In fatty liver,baicalin alleviates lipid accumulation and inflammation;In alcoholic liver disease,curcumin enhances Nrf2 activity reducing oxidative damage;In drug-induced liver injury,dihydromyricetin mitigates oxidative stress;In viral hepatitis,andrographolide inhibits hepatitis C virus replication;In liver fibrosis,multiple compounds inhibit stellate cell activation.These natural compounds simultaneously alleviate hepatic dysfunction and neuropsychiatric symptoms by modulating the Nrf2/HO-1 pathway,though clinical application still faces challenges such as low bioavailability,requiring further research.展开更多
Background Delirium is a form of acute brain dysfunction and geriatric patients are particularly vulnerable to this health problem.The aim of the study was to assess the incidence of delirium and determine the risk fa...Background Delirium is a form of acute brain dysfunction and geriatric patients are particularly vulnerable to this health problem.The aim of the study was to assess the incidence of delirium and determine the risk factors for delirium in patients≥60 years of age hospitalized due to acute myocardial infarction(AMI).Methods The study included 405 consecutive patients(mean age:73.1±8.5,males:61%)hospitalized due to AMI divided and characterized according to the in-hospital delirium presence.Results Of 405 patients,57(14%,mean age:80.9±7.3,males:58%)experienced delirium.Patients with delirium were older(80.9±7.3 vs.71.82±8.1 years),all of them presented multimorbidity,they more frequently used polypharmacy(96.5 vs.30.2%)and their hospitalization was longer(8.0±1.4 vs.4.6±1.0 days)as compared to the patients without delirium.Patients with delirium more frequently experience periprocedural complications as well as the in-hospital reversible problems:fever(40.4 vs.0.9%),infections(78.9 vs.3.7%),pulmonary oedema(73.7 vs.0.6%),hypoxemia(91.1 vs.98.3%),urinary catheter(96.5 vs.17.2%),dehydration(89.5 vs.6.6%),and insomnia(71.9 vs.0.3%)compared to patients without delirium(P<0.001 for all).Valvular heart disease(OR=4.78;95%CI:1.10-2.70;P<0.001,pulmonary oedema(OR=66.79;95%CI:12.04-370.34,P<0.001),and dehydration(OR=37.26;95%CI:10.50-132.27,P<0.001)were risk factors for delirium occurrence.Conclusions The in-hospital course of AMI is complicated by delirium occurrence in 14%of patients≥60 years old.Recognizing and modification of potential,reversible risk factors associated with AMI can reduce the risk of delirium.展开更多
Cells in the brain are surrounded by extracellular space (ECS), which forms porous nets and interconnected routes for molecule transportation. Our view of brain ECS has changed from a largely static compartment to dyn...Cells in the brain are surrounded by extracellular space (ECS), which forms porous nets and interconnected routes for molecule transportation. Our view of brain ECS has changed from a largely static compartment to dynamic and diverse structures that actively regulate neural activity and brain states. Emerging evidence supports that dysregulation of brain ECS contributes to the pathogenesis and development of many neurological disorders, highlighting the importance of therapeutic modulation of brain ECS function. Here, we aim to provide an overview of the regulation and dysfunction of ECS in healthy and pathological brains, as well as advanced tools to investigate properties of brain ECS. This review emphasizes modulation methods to manipulate ECS with implications to restore their function in brain diseases.展开更多
基金supported by National Natural Science Foundation of China(Grant No.:82200971)China Postdoctoral Science Foundation funded project(Grant No.:2023MD744267)Project of Liaoning Provincial Department of Science and Technology,China(Grant Nos.:2023JH2/20200120 and 2022-MS-180).
文摘This study investigates the molecular complexities of non-alcoholic fatty liver disease(NAFLD)-induced brain dysfunction,with a focus on the liver-intestine-brain axis and potential therapeutic interventions.The main objectives include understanding critical microbiota shifts in NAFLD,exploring altered metabolites,and identifying key regulatory molecules influencing brain function.The methods employed encompassed 16S ribosomal RNA(rRNA)sequencing to scrutinize stool microbiota in NAFLD patients and healthy individuals,non-targeted metabolomics using LC-MS to uncover elevated levels of deoxycholic acid(DCA)in NAFLD mice,and single-cell RNA sequencing(scRNA-seq)to pinpoint the pivotal gene Hpgd in microglial cells and its downstream Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway.Behavioral changes and brain function were assessed in NAFLD mice with and without fecal microbiota transplantation(FMT)treatment,utilizing various assays and analyses.The results revealed significant differences in microbiota composition,with increased levels of Bacteroides in NAFLD patients.Additionally,elevated DCA levels were observed in NAFLD mice,and FMT treatment demonstrated efficacy in ameliorating liver function and brain dysfunction.Hpgd inhibition by DCA activated the JAK2/STAT3 pathway in microglial cells,leading to inflammatory activation,inhibition of mitochondrial autophagy,induction of neuronal apoptosis,and reduction in neuronal action potentials.This study elucidates the intricate molecular mechanisms underlying the liver-gut-brain axis in NAFLD,and the identification of increased DCA and the impact of JAK2/STAT3 signaling on microglial cells highlight potential therapeutic targets for addressing NAFLD-induced brain dysfunction.
基金supported by the First Department of Cardiology,School of Medicine in Katowice,Medical University of Silesia,Katowice,Poland.
文摘Background Delirium is a form of acute brain dysfunction and geriatric patients are particularly vulnerable to this health problem.The aim of the study was to assess the incidence of delirium and determine the risk factors for delirium in patients≥60 years of age hospitalized due to acute myocardial infarction(AMI).Methods The study included 405 consecutive patients(mean age:73.1±8.5,males:61%)hospitalized due to AMI divided and characterized according to the in-hospital delirium presence.Results Of 405 patients,57(14%,mean age:80.9±7.3,males:58%)experienced delirium.Patients with delirium were older(80.9±7.3 vs.71.82±8.1 years),all of them presented multimorbidity,they more frequently used polypharmacy(96.5 vs.30.2%)and their hospitalization was longer(8.0±1.4 vs.4.6±1.0 days)as compared to the patients without delirium.Patients with delirium more frequently experience periprocedural complications as well as the in-hospital reversible problems:fever(40.4 vs.0.9%),infections(78.9 vs.3.7%),pulmonary oedema(73.7 vs.0.6%),hypoxemia(91.1 vs.98.3%),urinary catheter(96.5 vs.17.2%),dehydration(89.5 vs.6.6%),and insomnia(71.9 vs.0.3%)compared to patients without delirium(P<0.001 for all).Valvular heart disease(OR=4.78;95%CI:1.10-2.70;P<0.001,pulmonary oedema(OR=66.79;95%CI:12.04-370.34,P<0.001),and dehydration(OR=37.26;95%CI:10.50-132.27,P<0.001)were risk factors for delirium occurrence.Conclusions The in-hospital course of AMI is complicated by delirium occurrence in 14%of patients≥60 years old.Recognizing and modification of potential,reversible risk factors associated with AMI can reduce the risk of delirium.
基金funded by the start-up funding of Shenzhen Bay Laboratory,Shenzhen,Guangdong Province,China.
文摘Cells in the brain are surrounded by extracellular space (ECS), which forms porous nets and interconnected routes for molecule transportation. Our view of brain ECS has changed from a largely static compartment to dynamic and diverse structures that actively regulate neural activity and brain states. Emerging evidence supports that dysregulation of brain ECS contributes to the pathogenesis and development of many neurological disorders, highlighting the importance of therapeutic modulation of brain ECS function. Here, we aim to provide an overview of the regulation and dysfunction of ECS in healthy and pathological brains, as well as advanced tools to investigate properties of brain ECS. This review emphasizes modulation methods to manipulate ECS with implications to restore their function in brain diseases.
