BACKGROUND The development of slow transit constipation(STC)is associated with intestinal barrier damage.Huangqi decoction(HQD)is effective in treating STC,but me-chanisms are unclear.AIM To investigate whether HQD al...BACKGROUND The development of slow transit constipation(STC)is associated with intestinal barrier damage.Huangqi decoction(HQD)is effective in treating STC,but me-chanisms are unclear.AIM To investigate whether HQD alleviates STC by downregulating the nuclear factorκB(NF-κB)signaling pathway and restoring intestinal barrier function.METHODS KM mice were divided into control,model,and HQD treatment groups.Fresh colonic tissues were collected for single-cell RNA sequencing and spatial tra-nscriptome sequencing.The expressions of claudin-1,mucin 2,and NF-κB P65 proteins were detected by immunohistochemistry.In vitro experiments evaluated the effects of HQD on the LS174T cell line.RESULTS HQD improved intestinal motility,restored mucosal epithelium function and morphology.Single-cell RNA sequencing and spatial transcriptome sequencing data showed a reduction in goblet cells,decreased mucin 2 secretion,and activated apoptotic pathways in STC mice.The population of intestinal stem cells was reduced,and proliferation along with Wnt/β-catenin pathways were inhibited.STC also altered the distribution of intestinal cell states,increasing immune-associated Enterocyte_C3.Aberrant NF-κB pathway activation was noted across various cell types.After HQD treatment,NF-κB pathway activity was down-regulated,while cell proliferation pathways were up-regulated,alongside an increase in Enterocyte_C1 related to material transport.Immunocytochemical,Western blot,and immunohistochemistry analyses confirmed NF-κB pathway activation in goblet cells of STC mice,with HQD inhibiting this aberrant activation.CONCLUSION STC involves intestinal mucosal barrier damage.HQD may treat STC by suppressing NF-κB signaling in epithelial cells,restoring intestinal epithelial cell function,and promoting mucosal barrier repair.展开更多
BACKGROUND：Triggering receptor expressed on myeloid cells-1 （TREM-1） in the intestine was upregulated and correlated with disease activity in inflammatory bowel diseases. Membrane- bound TREM-1 protein is increased...BACKGROUND：Triggering receptor expressed on myeloid cells-1 （TREM-1） in the intestine was upregulated and correlated with disease activity in inflammatory bowel diseases. Membrane- bound TREM-1 protein is increased in the pancreas, liver and kidneys of patients with severe acute pancreatitis （SAP）, suggesting that TREM-1 may act as an important mediator of inflammation and subsequent extra-pancreatic organ injury. This study aimed to investigate the relationship between the expression of TREM-1 in intestinal tissue and intestinal barrier dysfunction in SAP. METHODS： Sixty-four male Wistar rats were randomly divided into a sham operation group （SO group, n=32） and a SAP group （n=32）. A SAP model was established by retrograde injection of 5% sodium deoxycholate into the bile-pancreatic duct. Specimens were taken from blood and intestinal tissue 2, 6, 12, and 48 hours after operation respectively. The levels of D-lactate, diamine oxidase （DAO） and endotoxin in serum were measured using an improved spectro-photometric method. The expression levels of TREM-1, interleukin-1β （IL-1β）, and tumor necrosis factor-α （TNF-α） mRNA in terminal ileum were detected by real-time reverse transcription-polymerase chain reaction （RT-PCR）. Specimens of the distal ileum were taken to determine pathological changes by a validated histology score. The serum levels of D-lactate, DAO and endotoxin were significantly increased in each subgroup of SAP compared with the SO group （P〈0.01, P〈0.05）. The expression levels of TREM-1, IL-1β and TNF-a mRNA in the terminal ileum in each subgroup of SAP were significantly higher than those in the SO group （P〈0.01, P〈0.05）. The expression level of TREM-lmRNA was positively correlated with IL-1βand TNF-α mRNA （r=0.956, P=0.044; r=0.986, P=0.015）, but the correlation was not found between IL-1β mRNA and TNF-a mRNA （P=0.133）. Compared to the SO group, the pathological changes were aggravated significantly in the SAP group. CONCLUSIONS： The expression level of TREM-1 in intestinal tissue of rats with SAP was elevated, leading to the release of inflammatory mediators and intestinal mucosal injury. This finding indicates that TREM-I might play an important role in the development of intestinal barrier dysfunction in rats with SAP.展开更多
Defects in intestinal barrier function characterized by an increase in intestinal permeability contribute to intestinal inflammation.Growing evidence has shown that an increase in intestinal permeability has a pathoge...Defects in intestinal barrier function characterized by an increase in intestinal permeability contribute to intestinal inflammation.Growing evidence has shown that an increase in intestinal permeability has a pathogenic role in diseases such as inflammatory bowel disease(IBD)and celiac disease,and functional bowel disorders such as irritable bowel syndrome.Therefore,clarification of the inflammatory responses,the defense pathway and the corresponding regulatory system is essential and may lead to the development of new therapies.MicroRNAs(miRNAs)are small(19-22nt)noncoding RNA molecules that regulate genes at the post-transcriptional level by base-pairing to specific messenger RNAs for degradation to repress translation.Recent studies suggested that miRNAs are important in the immune response and mediate a critical role in multiple immune response-related disorders.Based on these discoveries,attention has been focused on understanding the role of miRNAs in regulating intestinal barrier dysfunction,especially in IBD.Here,we provide a review of the most recent state-of-the-art research on miRNAs in intestinal barrier dysfunction.展开更多
Coronavirus disease 2019(COVID-19)caused by the novel severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has become a major global public health event,resulting in a significant social and economic burden.Alth...Coronavirus disease 2019(COVID-19)caused by the novel severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has become a major global public health event,resulting in a significant social and economic burden.Although COVID-19 was initially characterized as an upper respiratory and pulmonary infection,recent evidence suggests that it is a complex disease including gastrointestinal symptoms,such as diarrhea,nausea,and vomiting.Moreover,it remains unclear whether the gastrointestinal symptoms are caused by direct infection of the gastrointestinal tract by SARS-CoV-2 or are the result of systemic immune activation and subsequent dysregulation of homeostatic mechanisms.This review provides a brief overview of the mechanisms by which SARS-CoV-2 disrupts the integrity of the gastrointestinal barrier including the mechanical barrier,chemical barrier,microbial barrier,and immune barrier.展开更多
Objective To investigate the effect of honokiol(HON)and the role of high-mobility group protein B1(HMGB1)on the pathogenesis of severe acute pancreatitis(SAP).Methods Thirty mice were numbered according to weight,and ...Objective To investigate the effect of honokiol(HON)and the role of high-mobility group protein B1(HMGB1)on the pathogenesis of severe acute pancreatitis(SAP).Methods Thirty mice were numbered according to weight,and randomly divided into 5 groups using a random number table,including control,SAP,SAP and normal saline(SAP+NS),SAP and ethyl pyruvate(SAP+EP),or SAP+HON groups,6 mice in each group.Samples of pancreas,intestine,and blood were collected 12 h after SAP model induction for examination of pathologic changes,immune function alterations by enzyme linked immunosorbent assay(ELISA),and Western blot.In vitro experiments,macrophages were divided into 5 groups,the control,lipopolysaccharide(LPS),LPS+DMSO(DMSO),LPS+anti-HMGB1 monoclonal antibody(mAb),and LPS+HON groups.The tight connection level was determined by transmission electron microscopy and fluorescein isothiocyanate-labeled.The location and acetylation of HMGB1 were measured by Western blot.Finally,pyridone 6 and silencing signal transducer and activator of the transcription 1(siSTAT1)combined with honokiol were added to determine whether the Janus kinase(JAK)/STAT1 participated in the regulation of honokiol on HMGB1.The protein expression levels of HMGB1,JAK,and STAT1 were detected using Western blot.Results Mice with SAP had inflammatory injury in the pancreas,bleeding of intestinal tissues,and cells with disrupted histology.Mice in the SAP+HON group had significantly fewer pathological changes.Mice with SAP also had significant increases in the serum levels of amylase,lipase,HMGB1,tumor necrosis factor-α,interleukin-6,diamine oxidase,endotoxin-1,and procalcitonin.Mice in the SAP+HON group did not show these abnormalities(P<0.01).Studies of Caco-2 cells indicated that LPS increased the levels of occludin and claudin-1 as well as tight junction permeability,decreased the levels of junctional adhesion molecule C,and elevated intercellular permeability(P<0.01).HON treatment blocked these effects.Studies of macrophages indicated that LPS led to low nuclear levels of HMGB1,however,HON treatment increased the nuclear level of HMGB1(P<0.01).HON treatment also inhibited the expressions of JAK1,JAK2,and STAT1(P<0.01)and increased the acetylation of HMGB1(P<0.05).Conclusion HON prevented intestinal barrier dysfunction in SAP by inhibiting HMGB1 acetylation and JAK/STAT1 pathway.展开更多
Anthocyanin,as a typical food bioactive molecule,is capable of reversing inflammatory,oxidative and allergic condition thus contributes to intestinal health.We were wondering whether anthocyanin has influence on the i...Anthocyanin,as a typical food bioactive molecule,is capable of reversing inflammatory,oxidative and allergic condition thus contributes to intestinal health.We were wondering whether anthocyanin has influence on the infiltration of inflammatory cells into the intestinal mucosa and thus help enhancing intestinal barrier which could be damaged in some metabolic diseases.In this study,the influence of anthocyanin(administered orally)on the alterations(including structure and permeability)of the intestinal mucosa in mice in response to a high fat-high cholesterol(HFHC)diet was investigated.Primary T helper 17(Th17)cells were isolated from mouse intestine tissues to observe the modulatory role of anthocyanin through the transcription phosphorylated STAT 3(p-STAT3).The results indicated that anthocyanin significantly alleviated HFHC-induced impairment in the intestinal structures and permeability in a dose-dependent manner;moreover,anthocyanin appeared to inhibit HFHC induced the expression of p-STAT3,thereby disturbing Th17 cell differentiation.In high-fat diet(HFD,cholesterol level non-modified)-challenged mice selective p-STAT3 inhibitor significantly reversed the effects of anthocyanin,which were decreased amount of interleukin(IL)-17A(produced and released from Th17 cells)and the protected intestinal structure/function.In summary,the results of this study suggest that anthocyanin may attenuate the damage of intestinal barrier in HFHC mice through regulating intestinal STAT3-Th17-IL-17A signal transduction pathway.展开更多
Severe burn injury is often accompanied by intestinal barrier dysfunction,which is closely associated with post-burn shock,bacterial translocation,systemic inflammatory response syndrome,hypercatabolism,sepsis,multipl...Severe burn injury is often accompanied by intestinal barrier dysfunction,which is closely associated with post-burn shock,bacterial translocation,systemic inflammatory response syndrome,hypercatabolism,sepsis,multiple organ dysfunction syndrome,and other complications.The intestinal epithelium forms a physical barrier that separates the intestinal lumen from the internal milieu,in which the tight junction plays a principal role.It has been well documented that after severe burn injury,many factors such as stress,ischemia/hypoxia,proinflammatory cytokines,and endotoxins can induce intestinal barrier dysfunction via multiple signaling pathways.Recent advances have provided new insights into the mechanisms and the therapeutic strategies of intestinal epithelial barrier dysfunction associated with severe burn injury.In this review,we will describe the current knowledge of the mechanisms involved in intestinal barrier dysfunction in response to severe burn injury and the emerging therapies for treating intestinal barrier dysfunction following severe burn injury.展开更多
Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly.Although at first it was considered innocuous,small vessel disease is no...Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly.Although at first it was considered innocuous,small vessel disease is nowadays regarded as one of the major vascular causes of dementia.Radiological signs of small vessel disease include small subcortical infarcts,white matter magnetic resonance imaging hyperintensities,lacunes,enlarged perivascular spaces,cerebral microbleeds,and brain atrophy;however,great heterogeneity in clinical symptoms is observed in small vessel disease patients.The pathophysiology of these lesions has been linked to multiple processes,such as hypoperfusion,defective cerebrovascular reactivity,and blood-brain barrier dysfunction.Notably,studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel disease.Therefore,the purpose of this review is to provide a new foundation in the study of small vessel disease pathology.First,we discuss the main structural domains and functions of the blood-brain barrier.Secondly,we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel disease.Finally,we conclude with a discussion on future perspectives and propose potential treatment targets and interventions.展开更多
BACKGROUND Diamine oxidase(DAO)is secreted by epithelial cells in the intestinal villi,and its serum levels are elevated after intestinal mucosal damage.d-lactate(D-LA)is a gut microbial metabolite that can enter the ...BACKGROUND Diamine oxidase(DAO)is secreted by epithelial cells in the intestinal villi,and its serum levels are elevated after intestinal mucosal damage.d-lactate(D-LA)is a gut microbial metabolite that can enter the systemic circulation if intestinal barrier function is impaired.Both DAO and D-LA are serum markers of small bowel mucosal integrity,and can be valuable biomarkers of intestinal barrier damage in inflammatory bowel disease(IBD).Intestinal barrier dysfunction was recently found to contribute to psychological symptoms in IBD patients.However,the correlations among DAO,D-LA,psychological symptoms,and disease activity in IBD remain unexplored.AIM To explore the correlations between serum markers of intestinal barrier dysfunction and psychological symptoms in IBD.METHODS We enrolled of 126 participants in this study.Psychological symptom questionnaires(depression,patient health questionnaire-9;anxiety,generalized anxiety disorder-7;and stress,perceived stress scale)and a quality of life(QOL)questionnaire(IBD questionnaire 32)were collected at the baseline.Serum DAO and D-LA levels were measured to assess intestinal barrier integrity.Receiver operating characteristic(ROC)curves were used to identify candidate markers of psychological symptoms and disease activity in IBD patients.Logistic regression was applied,with DAO as an independent variable for predicting psychological symptoms in IBD.RESULTS Serum DAO levels were significantly higher in IBD patients with moderate-to-severe psychological symptoms than in patients with mild or no psychological symptoms.DAO was positively correlated with depression and negatively correlated with QOL in IBD patients.ROC curves revealed that DAO was independently associated with psychological symptoms and clinical activity in patients with IBD.Additionally,logistic regression analysis revealed that each 1-ng/mL increase in DAO levels was significantly associated with an increased risk of psychological symptoms in IBD patients(OR:1.019,95%CI:1.002-1.037).These results highlight the potential of DAO as a novel biomarker for both depression and disease activity in IBD patients.CONCLUSION This study indicates that DAO may be associated with depression and disease activity in IBD patients;however,prospective studies are required to validate its causal relationship.展开更多
BACKGROUND Ferroptosis is a newly recognized form of regulated cell death characterized by iron-dependent accumulation of lipid reactive oxygen species.It has been extensively studied in various diseases,including can...BACKGROUND Ferroptosis is a newly recognized form of regulated cell death characterized by iron-dependent accumulation of lipid reactive oxygen species.It has been extensively studied in various diseases,including cancer,Parkinson’s disease,and stroke.However,its precise role and underlying mechanisms in ischemia/reperfusion injury,particularly in the intestinal ischemia-reperfusion(IIR),remain unclear.In current work,we aimed to investigate the participation of histone lactylation during IIR progression.AIM To investigate the role of mitochondrial alanyl-tRNA synthetase 2(AARS2)in ferroptosis and its epigenetic regulation of acyl-CoA synthetase long-chain family member 4(ACSL4)through histone lactylation during IIR injury.METHODS We established a mouse model to mimic IIR and conducted AARS2 knockdown as treatment.The expression of AARS2 in intestinal tissues was measured by western blot.The integrity of intestinal tissues was detected by hematoxylin and eosin staining,serum fatty acid-binding protein,protein levels of ZO-1 and occluding.An in vitro hypoxia-reperfusion(H/R)cell model was established,and cell viability was measured by CCK-8.The in vitro and in vivo ferroptosis was determined by the accumulation of Fe2+and malondialdehyde(MDA).The epigenetic regulation of ACSL4 by AARS2 was detected by chromatin immunoprecipitation(ChIP)assay and luciferase reporter assay.RESULTS We observed a notable elevated AARS2 level in intestinal tissue of mice in IIR model group,which was reversed by shAARS2 treatment.Knockdown of AARS2 repressed alleviated intestinal barrier disruption and repressed the accumulation of ferroptosis biomarker Fe2+and MDA during IIR.The in vitro results showed that shAARS2 alleviated impaired cell viability caused by H/R,as well as repressed ferroptosis.Knockdown of AARS2 notably downregulated the RNA and protein expression of ACSL4.Mechanistically,knockdown of AARS2 downregulated the enrichment of H3K18 La modification on AARS2,as well as suppressed its promoter activity.Overexpression of AARS2 could abolish the protective effects of shACSL4 in vitro.CONCLUSION The elevation of AARS2 during IIR led to cell ferroptosis via epigenetically upregulating the expression of ACSL4.Our findings presented AARS2 as a promising therapeutic target for IIR.展开更多
To assess the prevalence of a panel of serologic markers that reflect gut barrier dysfunction in a mixed cohort of pediatric and adult primary sclerosing cholangitis(PSC)patients.METHODSSera of 67 PSC patients[median ...To assess the prevalence of a panel of serologic markers that reflect gut barrier dysfunction in a mixed cohort of pediatric and adult primary sclerosing cholangitis(PSC)patients.METHODSSera of 67 PSC patients[median age(range):32(5-79)years,concomitant IBD:67%and cirrhosis:20%]were assayed for the presence of antibodies against to F-actin(AAA IgA/IgG)and gliadin(AGA IgA/IgG)]and for serum level of intestinal fatty acid-binding protein(I-FABP)by ELISA.Markers of lipopolysaccharide(LPS)exposure[LPS binding protein(LBP)]and various anti-microbial antibodies[anti-OMP Plus IgA and endotoxin core IgA antibody(EndoCAb)]were also determined.Poor disease outcome was defined as orthotopic liver transplantation and/or liver-related death during the follow-up[median:99(14-106)mo].One hundred and fifty-three healthy subjects(HCONT)and 172 ulcerative colitis(UC)patients were the controls.RESULTSA total of 28.4%,28.0%,9%and 20.9%of PSC patients were positive for AAA IgA,AAA IgG,AGA IgA and AGA IgG,respectively.Frequencies of AAA IgA and AAA IgG(P<0.001,for both)and AGA IgG(P=0.01,for both)but not AGA IgA were significantly higher compared to both of the HCONT and the UC groups.In survival analysis,AAA IgA-positivity was revealed as an independent predictor of poor disease outcome after adjusting either for the presence of cirrhosis[HR=5.15(1.27-20.86),P=0.022 or for the Mayo risk score(HR=4.24(0.99-18.21),P=0.052].AAA IgA-positivity was significantly associated with higher frequency of anti-microbial antibodies(P<0.001 for EndoCab IgA and P=0.012 for anti-OMP Plus IgA)and higher level of the enterocyte damage marker(median I-FABP<sub>AAA IgA pos</sub><sub>vs</sub><sub>neg</sub>:365 vs 166 pg/mL,P=0.011),but not with serum LBP level.CONCLUSIONPresence of IgA type AAA identified PSC patients with progressive disease.Moreover,it is associated with enhanced mucosal immune response to various microbial antigens and enterocyte damage further highlighting the importance of the gut-liver interaction in PSC.展开更多
The intestinal mucosa is a highly compartmentalized structure that forms a directbarrier between the host intestine and the environment, and its dysfunction couldresult in a serious disease. As T cells, which are impo...The intestinal mucosa is a highly compartmentalized structure that forms a directbarrier between the host intestine and the environment, and its dysfunction couldresult in a serious disease. As T cells, which are important components of themucosal immune system, interact with gut microbiota and maintain intestinalhomeostasis, they may be involved in the process of intestinal barrier dysfunction.P2X7 receptor (P2X7R), a member of the P2X receptors family, mediates the effectsof extracellular adenosine triphosphate and is expressed by most innate or adaptiveimmune cells, including T cells. Current evidence has demonstrated thatP2X7R is involved in inflammation and mediates the survival and differentiationof T lymphocytes, indicating its potential role in the regulation of T cell function.In this review, we summarize the available research about the regulatory role andmechanism of P2X7R on the intestinal mucosa-derived T cells in the setting ofintestinal barrier dysfunction.展开更多
Objective: To explore and analyze the effect of acupoint application combined with microwave treatment on the intestinal barrier dysfunction with moderately severe acute pancreatitis. Methods: A convenient sample of 9...Objective: To explore and analyze the effect of acupoint application combined with microwave treatment on the intestinal barrier dysfunction with moderately severe acute pancreatitis. Methods: A convenient sample of 90 moderately severe acute pancreatitis was selected from March 2017 to December 2017 in the comprehensive hospital with third grade in Tianjin. The patients were divided into group A (acupoint application combined with microwave treatment), group B (acupoint application) and group C (routine nursing). Thirty patients were included in each group. This study need to get the informed consent of the patients. Acupoint application combined with microwave treatment was used, basing on routine nursing measures in group A. Acupoint application was used by the same way and the same traditional Chinese medicine ,basing on routine nursing measures in group B. Routine nursing used in group C. C-reactive protein and the score of intestinal function were measured on 3 th day, 7 th day and 10 th day, after intervention. To record the effective ratio of the treatment after 10 days of intervention. Results: There are significant statistical difference among the three group after intervention (P < 0.05). Conclusion: In some way, acupoint application combined with microwave treatment are able to decrease the time about the recovery of intestinal barrier dysfunction in moderately severe acute pancreatitis and to alleviate the suffering of patients.展开更多
Disturbances in the microbiota-gut-brain axis may contribute to the development of Alzheimer's disease. Magnesium-L-threonate has recently been found to have protective effects on learning and memory in aged and A...Disturbances in the microbiota-gut-brain axis may contribute to the development of Alzheimer's disease. Magnesium-L-threonate has recently been found to have protective effects on learning and memory in aged and Alzheimer's disease model mice. However, the effects of magnesium-L-threonate on the gut microbiota in Alzheimer's disease remain unknown. Previously, we reported that magnesium-L-threonate treatment improved cognition and reduced oxidative stress and inflammation in a double-transgenic line of Alzheimer's disease model mice expressing the amyloid-β precursor protein and mutant human presenilin 1(APP/PS1). Here, we performed 16S r RNA amplicon sequencing and liquid chromatography-mass spectrometry to analyze changes in the microbiome and serum metabolome following magnesium-Lthreonate exposure in a similar mouse model. Magnesium-L-threonate modulated the abundance of three genera in the gut microbiota, decreasing Allobaculum and increasing Bifidobacterium and Turicibacter. We also found that differential metabolites in the magnesiumL-threonate-regulated serum were enriched in various pathways associated with neurodegenerative diseases. The western blotting detection on intestinal tight junction proteins(zona occludens 1, occludin, and claudin-5) showed that magnesium-L-threonate repaired the intestinal barrier dysfunction of APP/PS1 mice. These findings suggest that magnesium-L-threonate may reduce the clinical manifestations of Alzheimer's disease through the microbiota-gut-brain axis in model mice, providing an experimental basis for the clinical treatment of Alzheimer's disease.展开更多
AIM： To evaluate whether multiple determinations of intramucosal pH （pHi） in acute pancreatitis （AP） patients could provide additional information of the disease severity during early hospitalization. METHODS： T...AIM： To evaluate whether multiple determinations of intramucosal pH （pHi） in acute pancreatitis （AP） patients could provide additional information of the disease severity during early hospitalization. METHODS： Twenty-one patients suffering from acute pancreatitis were monitored by gastric tonometry in the first 72 h after hospital admission. RESULTS： In the survivor group （n = 15） the initially low phi values returned to normal level （pHi ≥ 7.32） within 48 h （median pHi： d 1： 7.21; d 2： 7.32; d 3： 7.33）. In contrast, pHi values in the non-survivor group n = 6） were persistently either below or in the low normal range （median pHi 7.12; 7.12; 7.07 respectively）, but pHi differences between the two groups reached significance only after 24 h （P 〈 0.01）. Mucosal acidosis detected at any time during the monitored period was associated with the emergence of single or multiple organ dysfunction （P 〈 0.01）. CONCLUSION： Prolonged gastric mucosal acidosis was associated with remote organ dysfunction and failure in Acute Pancreatitis, however, correlation with the fatal outcome became significant only 24 h after admission. Due to its non-invasive nature gastric tonometry may supplement the pro-inflammatory markers to achieve a multi-faceted monitoring of the disease.展开更多
Heavy alcohol consumption results in alcoholic liver disease(ALD)with inadequate therapeutic options.Here,we first report the potential beneficial effects of ginsenoside Rk2(Rk2),a rare dehydroprotopanaxadiol saponin ...Heavy alcohol consumption results in alcoholic liver disease(ALD)with inadequate therapeutic options.Here,we first report the potential beneficial effects of ginsenoside Rk2(Rk2),a rare dehydroprotopanaxadiol saponin isolated from streamed ginseng,against alcoholic liver injury in mice.Chronic-plus-single-binge ethanol feeding caused severe liver injury,as manifested by significantly elevated serum aminotransferase levels,hepatic histological changes,increased lipid accumulation,oxidative stress,and inflammation in the liver.These deleterious effects were alleviated by the treatment with Rk2(5 and 30 mg/kg).Acting as an nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3)inhibitor,Rk2 ameliorates alcohol-induced liver inflammation by inhibiting NLRP3 inflammasome signaling in the liver.Meanwhile,the treatment with Rk2 alleviated the alcohol-induced intestinal barrier dysfunction via enhancing NLRP6 inflammasome in the intestine.Our findings indicate that Rk2 is a promising agent for the prevention and treatment of ALD and other NLPR3-driven diseases.展开更多
Due to the worldwide epidemic of allergic disease and a cure nowhere in sight,there is a crucial need to explore its pathophysiological mechanisms.As allergic disease has been associated with gut dysbiosis,we searched...Due to the worldwide epidemic of allergic disease and a cure nowhere in sight,there is a crucial need to explore its pathophysiological mechanisms.As allergic disease has been associated with gut dysbiosis,we searched for a possible mechanism from the perspective of the molecular interface between host and microbiota with concurrent metabolomics and microbiome composition analysis.Sprague-Dawley rats were injected with Artemisia pollen extract to stimulate a hyper reaction to pollen.This hyper reaction decreased the circulation of valine,isoleucine,aspartate,glutamate,glutamine,indole-propionate(IPA),and myo-inositol,and reduced short-chain fatty acids(SCFAs)in feces.Several beneficial genera belonging to Ruminococcaceae,Lachnospiraceae,and Clostridiales declined in the model group,whereas Helicobacter and Akkermansia were only expressed in the model group.Furthermore,the expression of intestinal claudin-3 and liver fatty acid binding protein was downregulated in the model group and associated with metabolic changes and bacteria.Our results suggest that alterations in amino acids as well as their derivatives(especially valine,and IPA which is the reductive product of tryptophan),SCFAs,and the gut microbiome(specifically Akkermansia and Helicobacter)may disrupt the intestinal barrier function by inhibiting the expression of claudin proteins and affecting the mucus layer,which further results in hay fever.展开更多
Diabetes mellitus(DM)and its complications continue to impose a substantial burden on healthcare systems worldwide.Diabetic neuropathy(DN)is one of the most common chronic microvascular and neurodegenerative complicat...Diabetes mellitus(DM)and its complications continue to impose a substantial burden on healthcare systems worldwide.Diabetic neuropathy(DN)is one of the most common chronic microvascular and neurodegenerative complications of DM.It is clinically characterized by allodynia,hyperalgesia,and abnormal or absent nerve fiber sensation,which collectively contribute to poor quality of life,sleep disturbances,depression,and increased mortality.Although several pharmacological agents are available to alleviate DN-related symptoms,their limited long-term efficacy and adverse side effects underscore the urgent need for novel therapeutic approaches.This limitation may be attributed to an incomplete understanding of the underlying mechanisms of DN.Accumulating evidence has highlighted the contribution of glial cells including astrocytes,microglia,and oligodendrocytes to the pathogenesis of DN.However,the specific role of astrocytes remains insufficiently defined.Therefore,this review provides a comprehensive evaluation of current knowledge regarding astrocyte involvement in DN mechanisms,with the goal of clarifying their contribution to disease progression and identifying potential therapeutic targets.展开更多
基金Supported by the Natural Science Foundation of Guangdong Province for Distinguished Young Scholars,No.2022B1515020003the National Natural Science Foundation of China,No.82174369,No.82405397,No.82374442,and No.81973847+2 种基金Postdoctoral Fellowship Program of CPSF No.GZC20233247National Key Clinical Disciplineand the Program of Guangdong Provincial Clinical Research Center for Digestive Diseases,No.2020B1111170004.
文摘BACKGROUND The development of slow transit constipation(STC)is associated with intestinal barrier damage.Huangqi decoction(HQD)is effective in treating STC,but me-chanisms are unclear.AIM To investigate whether HQD alleviates STC by downregulating the nuclear factorκB(NF-κB)signaling pathway and restoring intestinal barrier function.METHODS KM mice were divided into control,model,and HQD treatment groups.Fresh colonic tissues were collected for single-cell RNA sequencing and spatial tra-nscriptome sequencing.The expressions of claudin-1,mucin 2,and NF-κB P65 proteins were detected by immunohistochemistry.In vitro experiments evaluated the effects of HQD on the LS174T cell line.RESULTS HQD improved intestinal motility,restored mucosal epithelium function and morphology.Single-cell RNA sequencing and spatial transcriptome sequencing data showed a reduction in goblet cells,decreased mucin 2 secretion,and activated apoptotic pathways in STC mice.The population of intestinal stem cells was reduced,and proliferation along with Wnt/β-catenin pathways were inhibited.STC also altered the distribution of intestinal cell states,increasing immune-associated Enterocyte_C3.Aberrant NF-κB pathway activation was noted across various cell types.After HQD treatment,NF-κB pathway activity was down-regulated,while cell proliferation pathways were up-regulated,alongside an increase in Enterocyte_C1 related to material transport.Immunocytochemical,Western blot,and immunohistochemistry analyses confirmed NF-κB pathway activation in goblet cells of STC mice,with HQD inhibiting this aberrant activation.CONCLUSION STC involves intestinal mucosal barrier damage.HQD may treat STC by suppressing NF-κB signaling in epithelial cells,restoring intestinal epithelial cell function,and promoting mucosal barrier repair.
基金The study was supported by a grant from the National Natural Science Foundation of China （81070287）.
文摘BACKGROUND：Triggering receptor expressed on myeloid cells-1 （TREM-1） in the intestine was upregulated and correlated with disease activity in inflammatory bowel diseases. Membrane- bound TREM-1 protein is increased in the pancreas, liver and kidneys of patients with severe acute pancreatitis （SAP）, suggesting that TREM-1 may act as an important mediator of inflammation and subsequent extra-pancreatic organ injury. This study aimed to investigate the relationship between the expression of TREM-1 in intestinal tissue and intestinal barrier dysfunction in SAP. METHODS： Sixty-four male Wistar rats were randomly divided into a sham operation group （SO group, n=32） and a SAP group （n=32）. A SAP model was established by retrograde injection of 5% sodium deoxycholate into the bile-pancreatic duct. Specimens were taken from blood and intestinal tissue 2, 6, 12, and 48 hours after operation respectively. The levels of D-lactate, diamine oxidase （DAO） and endotoxin in serum were measured using an improved spectro-photometric method. The expression levels of TREM-1, interleukin-1β （IL-1β）, and tumor necrosis factor-α （TNF-α） mRNA in terminal ileum were detected by real-time reverse transcription-polymerase chain reaction （RT-PCR）. Specimens of the distal ileum were taken to determine pathological changes by a validated histology score. The serum levels of D-lactate, DAO and endotoxin were significantly increased in each subgroup of SAP compared with the SO group （P〈0.01, P〈0.05）. The expression levels of TREM-1, IL-1β and TNF-a mRNA in the terminal ileum in each subgroup of SAP were significantly higher than those in the SO group （P〈0.01, P〈0.05）. The expression level of TREM-lmRNA was positively correlated with IL-1βand TNF-α mRNA （r=0.956, P=0.044; r=0.986, P=0.015）, but the correlation was not found between IL-1β mRNA and TNF-a mRNA （P=0.133）. Compared to the SO group, the pathological changes were aggravated significantly in the SAP group. CONCLUSIONS： The expression level of TREM-1 in intestinal tissue of rats with SAP was elevated, leading to the release of inflammatory mediators and intestinal mucosal injury. This finding indicates that TREM-I might play an important role in the development of intestinal barrier dysfunction in rats with SAP.
基金Supported by Grant for Key Clinical Discipline Construction of Shanghai Municipality,China,No.ZK2012B20Phase Ⅱ Outstanding Young Medical Personnel Training Fund of Jinshan District Health Systems,Shanghai,China,No.JWKJ-RCYQ-201207
文摘Defects in intestinal barrier function characterized by an increase in intestinal permeability contribute to intestinal inflammation.Growing evidence has shown that an increase in intestinal permeability has a pathogenic role in diseases such as inflammatory bowel disease(IBD)and celiac disease,and functional bowel disorders such as irritable bowel syndrome.Therefore,clarification of the inflammatory responses,the defense pathway and the corresponding regulatory system is essential and may lead to the development of new therapies.MicroRNAs(miRNAs)are small(19-22nt)noncoding RNA molecules that regulate genes at the post-transcriptional level by base-pairing to specific messenger RNAs for degradation to repress translation.Recent studies suggested that miRNAs are important in the immune response and mediate a critical role in multiple immune response-related disorders.Based on these discoveries,attention has been focused on understanding the role of miRNAs in regulating intestinal barrier dysfunction,especially in IBD.Here,we provide a review of the most recent state-of-the-art research on miRNAs in intestinal barrier dysfunction.
文摘Coronavirus disease 2019(COVID-19)caused by the novel severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has become a major global public health event,resulting in a significant social and economic burden.Although COVID-19 was initially characterized as an upper respiratory and pulmonary infection,recent evidence suggests that it is a complex disease including gastrointestinal symptoms,such as diarrhea,nausea,and vomiting.Moreover,it remains unclear whether the gastrointestinal symptoms are caused by direct infection of the gastrointestinal tract by SARS-CoV-2 or are the result of systemic immune activation and subsequent dysregulation of homeostatic mechanisms.This review provides a brief overview of the mechanisms by which SARS-CoV-2 disrupts the integrity of the gastrointestinal barrier including the mechanical barrier,chemical barrier,microbial barrier,and immune barrier.
基金Supported by National Natural Science Foundation of China(No.81803920 and 81673789)Key Medical Specialty Construction Project of Shanghai Municipal Health Commission(No.ZK2019B18)Shanghai Putuo District Health Commission Characteristic Disease Construction Project(No.2020TSZB03)。
文摘Objective To investigate the effect of honokiol(HON)and the role of high-mobility group protein B1(HMGB1)on the pathogenesis of severe acute pancreatitis(SAP).Methods Thirty mice were numbered according to weight,and randomly divided into 5 groups using a random number table,including control,SAP,SAP and normal saline(SAP+NS),SAP and ethyl pyruvate(SAP+EP),or SAP+HON groups,6 mice in each group.Samples of pancreas,intestine,and blood were collected 12 h after SAP model induction for examination of pathologic changes,immune function alterations by enzyme linked immunosorbent assay(ELISA),and Western blot.In vitro experiments,macrophages were divided into 5 groups,the control,lipopolysaccharide(LPS),LPS+DMSO(DMSO),LPS+anti-HMGB1 monoclonal antibody(mAb),and LPS+HON groups.The tight connection level was determined by transmission electron microscopy and fluorescein isothiocyanate-labeled.The location and acetylation of HMGB1 were measured by Western blot.Finally,pyridone 6 and silencing signal transducer and activator of the transcription 1(siSTAT1)combined with honokiol were added to determine whether the Janus kinase(JAK)/STAT1 participated in the regulation of honokiol on HMGB1.The protein expression levels of HMGB1,JAK,and STAT1 were detected using Western blot.Results Mice with SAP had inflammatory injury in the pancreas,bleeding of intestinal tissues,and cells with disrupted histology.Mice in the SAP+HON group had significantly fewer pathological changes.Mice with SAP also had significant increases in the serum levels of amylase,lipase,HMGB1,tumor necrosis factor-α,interleukin-6,diamine oxidase,endotoxin-1,and procalcitonin.Mice in the SAP+HON group did not show these abnormalities(P<0.01).Studies of Caco-2 cells indicated that LPS increased the levels of occludin and claudin-1 as well as tight junction permeability,decreased the levels of junctional adhesion molecule C,and elevated intercellular permeability(P<0.01).HON treatment blocked these effects.Studies of macrophages indicated that LPS led to low nuclear levels of HMGB1,however,HON treatment increased the nuclear level of HMGB1(P<0.01).HON treatment also inhibited the expressions of JAK1,JAK2,and STAT1(P<0.01)and increased the acetylation of HMGB1(P<0.05).Conclusion HON prevented intestinal barrier dysfunction in SAP by inhibiting HMGB1 acetylation and JAK/STAT1 pathway.
基金supported by the National Natural Science Foundation of China(81973022 and 81730090)。
文摘Anthocyanin,as a typical food bioactive molecule,is capable of reversing inflammatory,oxidative and allergic condition thus contributes to intestinal health.We were wondering whether anthocyanin has influence on the infiltration of inflammatory cells into the intestinal mucosa and thus help enhancing intestinal barrier which could be damaged in some metabolic diseases.In this study,the influence of anthocyanin(administered orally)on the alterations(including structure and permeability)of the intestinal mucosa in mice in response to a high fat-high cholesterol(HFHC)diet was investigated.Primary T helper 17(Th17)cells were isolated from mouse intestine tissues to observe the modulatory role of anthocyanin through the transcription phosphorylated STAT 3(p-STAT3).The results indicated that anthocyanin significantly alleviated HFHC-induced impairment in the intestinal structures and permeability in a dose-dependent manner;moreover,anthocyanin appeared to inhibit HFHC induced the expression of p-STAT3,thereby disturbing Th17 cell differentiation.In high-fat diet(HFD,cholesterol level non-modified)-challenged mice selective p-STAT3 inhibitor significantly reversed the effects of anthocyanin,which were decreased amount of interleukin(IL)-17A(produced and released from Th17 cells)and the protected intestinal structure/function.In summary,the results of this study suggest that anthocyanin may attenuate the damage of intestinal barrier in HFHC mice through regulating intestinal STAT3-Th17-IL-17A signal transduction pathway.
基金supported by the National Natural Science Foundation of China(81471871,81772081).
文摘Severe burn injury is often accompanied by intestinal barrier dysfunction,which is closely associated with post-burn shock,bacterial translocation,systemic inflammatory response syndrome,hypercatabolism,sepsis,multiple organ dysfunction syndrome,and other complications.The intestinal epithelium forms a physical barrier that separates the intestinal lumen from the internal milieu,in which the tight junction plays a principal role.It has been well documented that after severe burn injury,many factors such as stress,ischemia/hypoxia,proinflammatory cytokines,and endotoxins can induce intestinal barrier dysfunction via multiple signaling pathways.Recent advances have provided new insights into the mechanisms and the therapeutic strategies of intestinal epithelial barrier dysfunction associated with severe burn injury.In this review,we will describe the current knowledge of the mechanisms involved in intestinal barrier dysfunction in response to severe burn injury and the emerging therapies for treating intestinal barrier dysfunction following severe burn injury.
基金supported by China Scholarship Council(202208210093,to RJ)。
文摘Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly.Although at first it was considered innocuous,small vessel disease is nowadays regarded as one of the major vascular causes of dementia.Radiological signs of small vessel disease include small subcortical infarcts,white matter magnetic resonance imaging hyperintensities,lacunes,enlarged perivascular spaces,cerebral microbleeds,and brain atrophy;however,great heterogeneity in clinical symptoms is observed in small vessel disease patients.The pathophysiology of these lesions has been linked to multiple processes,such as hypoperfusion,defective cerebrovascular reactivity,and blood-brain barrier dysfunction.Notably,studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel disease.Therefore,the purpose of this review is to provide a new foundation in the study of small vessel disease pathology.First,we discuss the main structural domains and functions of the blood-brain barrier.Secondly,we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel disease.Finally,we conclude with a discussion on future perspectives and propose potential treatment targets and interventions.
基金Supported by National Natural Science Foundation of China,No.82270581 and No.82270546.
文摘BACKGROUND Diamine oxidase(DAO)is secreted by epithelial cells in the intestinal villi,and its serum levels are elevated after intestinal mucosal damage.d-lactate(D-LA)is a gut microbial metabolite that can enter the systemic circulation if intestinal barrier function is impaired.Both DAO and D-LA are serum markers of small bowel mucosal integrity,and can be valuable biomarkers of intestinal barrier damage in inflammatory bowel disease(IBD).Intestinal barrier dysfunction was recently found to contribute to psychological symptoms in IBD patients.However,the correlations among DAO,D-LA,psychological symptoms,and disease activity in IBD remain unexplored.AIM To explore the correlations between serum markers of intestinal barrier dysfunction and psychological symptoms in IBD.METHODS We enrolled of 126 participants in this study.Psychological symptom questionnaires(depression,patient health questionnaire-9;anxiety,generalized anxiety disorder-7;and stress,perceived stress scale)and a quality of life(QOL)questionnaire(IBD questionnaire 32)were collected at the baseline.Serum DAO and D-LA levels were measured to assess intestinal barrier integrity.Receiver operating characteristic(ROC)curves were used to identify candidate markers of psychological symptoms and disease activity in IBD patients.Logistic regression was applied,with DAO as an independent variable for predicting psychological symptoms in IBD.RESULTS Serum DAO levels were significantly higher in IBD patients with moderate-to-severe psychological symptoms than in patients with mild or no psychological symptoms.DAO was positively correlated with depression and negatively correlated with QOL in IBD patients.ROC curves revealed that DAO was independently associated with psychological symptoms and clinical activity in patients with IBD.Additionally,logistic regression analysis revealed that each 1-ng/mL increase in DAO levels was significantly associated with an increased risk of psychological symptoms in IBD patients(OR:1.019,95%CI:1.002-1.037).These results highlight the potential of DAO as a novel biomarker for both depression and disease activity in IBD patients.CONCLUSION This study indicates that DAO may be associated with depression and disease activity in IBD patients;however,prospective studies are required to validate its causal relationship.
文摘BACKGROUND Ferroptosis is a newly recognized form of regulated cell death characterized by iron-dependent accumulation of lipid reactive oxygen species.It has been extensively studied in various diseases,including cancer,Parkinson’s disease,and stroke.However,its precise role and underlying mechanisms in ischemia/reperfusion injury,particularly in the intestinal ischemia-reperfusion(IIR),remain unclear.In current work,we aimed to investigate the participation of histone lactylation during IIR progression.AIM To investigate the role of mitochondrial alanyl-tRNA synthetase 2(AARS2)in ferroptosis and its epigenetic regulation of acyl-CoA synthetase long-chain family member 4(ACSL4)through histone lactylation during IIR injury.METHODS We established a mouse model to mimic IIR and conducted AARS2 knockdown as treatment.The expression of AARS2 in intestinal tissues was measured by western blot.The integrity of intestinal tissues was detected by hematoxylin and eosin staining,serum fatty acid-binding protein,protein levels of ZO-1 and occluding.An in vitro hypoxia-reperfusion(H/R)cell model was established,and cell viability was measured by CCK-8.The in vitro and in vivo ferroptosis was determined by the accumulation of Fe2+and malondialdehyde(MDA).The epigenetic regulation of ACSL4 by AARS2 was detected by chromatin immunoprecipitation(ChIP)assay and luciferase reporter assay.RESULTS We observed a notable elevated AARS2 level in intestinal tissue of mice in IIR model group,which was reversed by shAARS2 treatment.Knockdown of AARS2 repressed alleviated intestinal barrier disruption and repressed the accumulation of ferroptosis biomarker Fe2+and MDA during IIR.The in vitro results showed that shAARS2 alleviated impaired cell viability caused by H/R,as well as repressed ferroptosis.Knockdown of AARS2 notably downregulated the RNA and protein expression of ACSL4.Mechanistically,knockdown of AARS2 downregulated the enrichment of H3K18 La modification on AARS2,as well as suppressed its promoter activity.Overexpression of AARS2 could abolish the protective effects of shACSL4 in vitro.CONCLUSION The elevation of AARS2 during IIR led to cell ferroptosis via epigenetically upregulating the expression of ACSL4.Our findings presented AARS2 as a promising therapeutic target for IIR.
基金Supported by Research Grant of National Research Development and Innovation Office,No.K115818/2015/1János Bólyai Research Scholarship of Hungarian Academy of Sciences to Papp Mthe New National Excellence Program of the Ministry of Human Capacities,No.úNKP-16-3 to Tornai T
文摘To assess the prevalence of a panel of serologic markers that reflect gut barrier dysfunction in a mixed cohort of pediatric and adult primary sclerosing cholangitis(PSC)patients.METHODSSera of 67 PSC patients[median age(range):32(5-79)years,concomitant IBD:67%and cirrhosis:20%]were assayed for the presence of antibodies against to F-actin(AAA IgA/IgG)and gliadin(AGA IgA/IgG)]and for serum level of intestinal fatty acid-binding protein(I-FABP)by ELISA.Markers of lipopolysaccharide(LPS)exposure[LPS binding protein(LBP)]and various anti-microbial antibodies[anti-OMP Plus IgA and endotoxin core IgA antibody(EndoCAb)]were also determined.Poor disease outcome was defined as orthotopic liver transplantation and/or liver-related death during the follow-up[median:99(14-106)mo].One hundred and fifty-three healthy subjects(HCONT)and 172 ulcerative colitis(UC)patients were the controls.RESULTSA total of 28.4%,28.0%,9%and 20.9%of PSC patients were positive for AAA IgA,AAA IgG,AGA IgA and AGA IgG,respectively.Frequencies of AAA IgA and AAA IgG(P<0.001,for both)and AGA IgG(P=0.01,for both)but not AGA IgA were significantly higher compared to both of the HCONT and the UC groups.In survival analysis,AAA IgA-positivity was revealed as an independent predictor of poor disease outcome after adjusting either for the presence of cirrhosis[HR=5.15(1.27-20.86),P=0.022 or for the Mayo risk score(HR=4.24(0.99-18.21),P=0.052].AAA IgA-positivity was significantly associated with higher frequency of anti-microbial antibodies(P<0.001 for EndoCab IgA and P=0.012 for anti-OMP Plus IgA)and higher level of the enterocyte damage marker(median I-FABP<sub>AAA IgA pos</sub><sub>vs</sub><sub>neg</sub>:365 vs 166 pg/mL,P=0.011),but not with serum LBP level.CONCLUSIONPresence of IgA type AAA identified PSC patients with progressive disease.Moreover,it is associated with enhanced mucosal immune response to various microbial antigens and enterocyte damage further highlighting the importance of the gut-liver interaction in PSC.
基金Supported by The National Natural Science Foundation of China,No. 81801943Shanghai Pujiang Program,No. 21PJD009The Research Grant for Public Health Key Discipline of Shanghai Municipality,China,No. GWV-10.1-XK26
文摘The intestinal mucosa is a highly compartmentalized structure that forms a directbarrier between the host intestine and the environment, and its dysfunction couldresult in a serious disease. As T cells, which are important components of themucosal immune system, interact with gut microbiota and maintain intestinalhomeostasis, they may be involved in the process of intestinal barrier dysfunction.P2X7 receptor (P2X7R), a member of the P2X receptors family, mediates the effectsof extracellular adenosine triphosphate and is expressed by most innate or adaptiveimmune cells, including T cells. Current evidence has demonstrated thatP2X7R is involved in inflammation and mediates the survival and differentiationof T lymphocytes, indicating its potential role in the regulation of T cell function.In this review, we summarize the available research about the regulatory role andmechanism of P2X7R on the intestinal mucosa-derived T cells in the setting ofintestinal barrier dysfunction.
文摘Objective: To explore and analyze the effect of acupoint application combined with microwave treatment on the intestinal barrier dysfunction with moderately severe acute pancreatitis. Methods: A convenient sample of 90 moderately severe acute pancreatitis was selected from March 2017 to December 2017 in the comprehensive hospital with third grade in Tianjin. The patients were divided into group A (acupoint application combined with microwave treatment), group B (acupoint application) and group C (routine nursing). Thirty patients were included in each group. This study need to get the informed consent of the patients. Acupoint application combined with microwave treatment was used, basing on routine nursing measures in group A. Acupoint application was used by the same way and the same traditional Chinese medicine ,basing on routine nursing measures in group B. Routine nursing used in group C. C-reactive protein and the score of intestinal function were measured on 3 th day, 7 th day and 10 th day, after intervention. To record the effective ratio of the treatment after 10 days of intervention. Results: There are significant statistical difference among the three group after intervention (P < 0.05). Conclusion: In some way, acupoint application combined with microwave treatment are able to decrease the time about the recovery of intestinal barrier dysfunction in moderately severe acute pancreatitis and to alleviate the suffering of patients.
基金supported by the National Natural Science Foundation of China,Nos.82101271 (to WL),82171178 (to JL)Basic and Applied Basic Research Foundation of Guangdong Province,Nos.2020A1515110317 (to WL),2021A1515010705 (to WL)+1 种基金Young Talent Support Project of Guangzhou Association for Science and Technology (to WL)Technology Key Project of Shenzhen,No.JCYJ202001091 14612308 (to ZS)。
文摘Disturbances in the microbiota-gut-brain axis may contribute to the development of Alzheimer's disease. Magnesium-L-threonate has recently been found to have protective effects on learning and memory in aged and Alzheimer's disease model mice. However, the effects of magnesium-L-threonate on the gut microbiota in Alzheimer's disease remain unknown. Previously, we reported that magnesium-L-threonate treatment improved cognition and reduced oxidative stress and inflammation in a double-transgenic line of Alzheimer's disease model mice expressing the amyloid-β precursor protein and mutant human presenilin 1(APP/PS1). Here, we performed 16S r RNA amplicon sequencing and liquid chromatography-mass spectrometry to analyze changes in the microbiome and serum metabolome following magnesium-Lthreonate exposure in a similar mouse model. Magnesium-L-threonate modulated the abundance of three genera in the gut microbiota, decreasing Allobaculum and increasing Bifidobacterium and Turicibacter. We also found that differential metabolites in the magnesiumL-threonate-regulated serum were enriched in various pathways associated with neurodegenerative diseases. The western blotting detection on intestinal tight junction proteins(zona occludens 1, occludin, and claudin-5) showed that magnesium-L-threonate repaired the intestinal barrier dysfunction of APP/PS1 mice. These findings suggest that magnesium-L-threonate may reduce the clinical manifestations of Alzheimer's disease through the microbiota-gut-brain axis in model mice, providing an experimental basis for the clinical treatment of Alzheimer's disease.
基金Supported by the Hungarian National Scientific Research Fund (OTKA), No. T 016630, and the Hungarian Ministry of Health(ETT), No. 276/2001
文摘AIM： To evaluate whether multiple determinations of intramucosal pH （pHi） in acute pancreatitis （AP） patients could provide additional information of the disease severity during early hospitalization. METHODS： Twenty-one patients suffering from acute pancreatitis were monitored by gastric tonometry in the first 72 h after hospital admission. RESULTS： In the survivor group （n = 15） the initially low phi values returned to normal level （pHi ≥ 7.32） within 48 h （median pHi： d 1： 7.21; d 2： 7.32; d 3： 7.33）. In contrast, pHi values in the non-survivor group n = 6） were persistently either below or in the low normal range （median pHi 7.12; 7.12; 7.07 respectively）, but pHi differences between the two groups reached significance only after 24 h （P 〈 0.01）. Mucosal acidosis detected at any time during the monitored period was associated with the emergence of single or multiple organ dysfunction （P 〈 0.01）. CONCLUSION： Prolonged gastric mucosal acidosis was associated with remote organ dysfunction and failure in Acute Pancreatitis, however, correlation with the fatal outcome became significant only 24 h after admission. Due to its non-invasive nature gastric tonometry may supplement the pro-inflammatory markers to achieve a multi-faceted monitoring of the disease.
基金supported by grants from the Research Committee of the University of Macao(Grant No.:MYRG2022-00020-ICMS)the Science and Technology Development Fund,Macao SAR,China(File No.:0074/2021/AFJ and 0052/2022/A1).
文摘Heavy alcohol consumption results in alcoholic liver disease(ALD)with inadequate therapeutic options.Here,we first report the potential beneficial effects of ginsenoside Rk2(Rk2),a rare dehydroprotopanaxadiol saponin isolated from streamed ginseng,against alcoholic liver injury in mice.Chronic-plus-single-binge ethanol feeding caused severe liver injury,as manifested by significantly elevated serum aminotransferase levels,hepatic histological changes,increased lipid accumulation,oxidative stress,and inflammation in the liver.These deleterious effects were alleviated by the treatment with Rk2(5 and 30 mg/kg).Acting as an nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3)inhibitor,Rk2 ameliorates alcohol-induced liver inflammation by inhibiting NLRP3 inflammasome signaling in the liver.Meanwhile,the treatment with Rk2 alleviated the alcohol-induced intestinal barrier dysfunction via enhancing NLRP6 inflammasome in the intestine.Our findings indicate that Rk2 is a promising agent for the prevention and treatment of ALD and other NLPR3-driven diseases.
基金supported by the National Natural Science Foundation of China(81971515 and 81973290)CAMS Innovation Fund for Medical Sciences(2016-I2M-3-011 and 2016-I2M-1-003)+4 种基金the Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study(Z141102004414062)the National Megaproject for Innovative Drugs(2018ZX09711001-002-002)Beijing Natural Sciences Fund Key Projects(7181007)the Fundamental Research Fund for Central Universities of Peking Union Medical College(3332020037)Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support(ZYLX201826)。
文摘Due to the worldwide epidemic of allergic disease and a cure nowhere in sight,there is a crucial need to explore its pathophysiological mechanisms.As allergic disease has been associated with gut dysbiosis,we searched for a possible mechanism from the perspective of the molecular interface between host and microbiota with concurrent metabolomics and microbiome composition analysis.Sprague-Dawley rats were injected with Artemisia pollen extract to stimulate a hyper reaction to pollen.This hyper reaction decreased the circulation of valine,isoleucine,aspartate,glutamate,glutamine,indole-propionate(IPA),and myo-inositol,and reduced short-chain fatty acids(SCFAs)in feces.Several beneficial genera belonging to Ruminococcaceae,Lachnospiraceae,and Clostridiales declined in the model group,whereas Helicobacter and Akkermansia were only expressed in the model group.Furthermore,the expression of intestinal claudin-3 and liver fatty acid binding protein was downregulated in the model group and associated with metabolic changes and bacteria.Our results suggest that alterations in amino acids as well as their derivatives(especially valine,and IPA which is the reductive product of tryptophan),SCFAs,and the gut microbiome(specifically Akkermansia and Helicobacter)may disrupt the intestinal barrier function by inhibiting the expression of claudin proteins and affecting the mucus layer,which further results in hay fever.
基金Supported by the Fundamental Research Grant Scheme of the Ministry of Higher Education,Malaysia,No.FRGS/1/2024/SKK10/USM/02/8.
文摘Diabetes mellitus(DM)and its complications continue to impose a substantial burden on healthcare systems worldwide.Diabetic neuropathy(DN)is one of the most common chronic microvascular and neurodegenerative complications of DM.It is clinically characterized by allodynia,hyperalgesia,and abnormal or absent nerve fiber sensation,which collectively contribute to poor quality of life,sleep disturbances,depression,and increased mortality.Although several pharmacological agents are available to alleviate DN-related symptoms,their limited long-term efficacy and adverse side effects underscore the urgent need for novel therapeutic approaches.This limitation may be attributed to an incomplete understanding of the underlying mechanisms of DN.Accumulating evidence has highlighted the contribution of glial cells including astrocytes,microglia,and oligodendrocytes to the pathogenesis of DN.However,the specific role of astrocytes remains insufficiently defined.Therefore,this review provides a comprehensive evaluation of current knowledge regarding astrocyte involvement in DN mechanisms,with the goal of clarifying their contribution to disease progression and identifying potential therapeutic targets.
