Objective To reveal the effects and related mechanisms of chlorogenic acid(CGA)on intestinal glucose homeostasis.Methods Forty male Sprague-Dawley rats were randomly and equally divided into four groups:normal chow(NC...Objective To reveal the effects and related mechanisms of chlorogenic acid(CGA)on intestinal glucose homeostasis.Methods Forty male Sprague-Dawley rats were randomly and equally divided into four groups:normal chow(NC),high-fat diet(HFD),HFD with low-dose CGA(20 mg/kg,HFD-LC),and HFD with high-dose CGA(90 mg/kg,HFD-HC).The oral glucose tolerance test was performed,and fast serum insulin(FSI)was detected using an enzyme-linked immunosorbent assay.The m RNA expression levels of glucose transporters(Sglt-1 and Glut-2)and proglucagon(Plg)in different intestinal segments(the duodenum,jejunum,ileum,and colon)were analyzed using quantitative real-time polymerase chain reaction.SGLT-1 protein and the morphology of epithelial cells in the duodenum and jejunum was localized by using immunofluorescence.Results At both doses,CGA ameliorated the HFD-induced body weight gain,maintained FSI,and increased postprandial 30-min glucagon-like peptide 1 secretion.High-dose CGA inhibited the HFD-induced elevation in Sglt-1 expression.Both CGA doses normalized the HFD-induced downregulation of Glut-2 and elevated the expression of Plg in all four intestinal segments.Conclusion An HFD can cause a glucose metabolism disorder in the rat intestine and affect body glucose homeostasis.CGA can modify intestinal glucose metabolism by regulating the expression of intestinal glucose transporters and Plg,thereby controlling the levels of blood glucose and insulin to maintain glucose homeostasis.展开更多
Background As an essential source of nutrients for young mammals,milk possesses a variety of biological functions.Recently identified milk-derived small extracellular vesicles(sEV)have shown potential regulatory effec...Background As an essential source of nutrients for young mammals,milk possesses a variety of biological functions.Recently identified milk-derived small extracellular vesicles(sEV)have shown potential regulatory effects on intestinal health.Current studies have highlighted the functional roles of milk-derived sEV and their RNA cargo in promoting intestinal health.However,there is a paucity of research demonstrating how milk-derived sEV influence intestinal barrier function through the transport of circRNAs.Results In this study,we aimed to investigate the effects of porcine milk sEV(PM-sEV)circRNA on intestinal barrier function.We systematically identified the circRNAs involved in this process and analyzed the miRNAs through which PM-sEV deliver circRNAs to regulate intestinal barrier function.Our findings revealed that PM-sEV promote the expression of the intestinal tight junction proteins ZO-1 and Occludin,both in vivo(mice)and in vitro(IPEC-J2).When PMsEV RNA was reduced using ultrasound treatment,their ability to enhance intestinal barrier function was significantly reduced.Bioinformatics analysis showed that circ-0000197,present in PM-sEV,can target miR-429,while miR-429 has the ability to target the 3’-UTR of ZO-1 and Occludin.Furthermore,experiments involving the overexpression or inhibition of the relevant non-coding RNAs(ncRNAs)demonstrated that circ-0000197 significantly enhances intestinal barrier function,whereas miR-429 exerts an inhibitory effect on this function.Overall,our findings identify circ-0000197 in PM-sEV as a crucial circRNA that regulates intestinal barrier function by inhibiting miR-429.Circ-0000197 carried by PM-sEV acts as a competing endogenous RNA(ceRNA)that regulates the expression of ZO-1 and Occludin by sponging miR-429,thereby promoting intestinal barrier function at both the cellular and in vivo levels.Conclusions These findings emphasize the vital role of circRNAs transported through milk-derived sEV in regulating intestinal health,offering new avenues for developing innovative functional milk components.This mechanism also underscores the importance of PM-sEV carrying circ-0000197 in preserving intestinal barrier integrity.Collectively,this study enhances our understanding of the complex regulatory networks involving PM-sEV carrying circRNAs and their impact on intestinal health.展开更多
Recent advances in understanding type 1 diabetes(T1D)highlight the complexity of managing hypoglycemia,a frequent and perilous complication of diabetes therapy.This letter delves into a novel study by Jin et al,which ...Recent advances in understanding type 1 diabetes(T1D)highlight the complexity of managing hypoglycemia,a frequent and perilous complication of diabetes therapy.This letter delves into a novel study by Jin et al,which elucidates the role of intestinal glucagon-like peptide-1(GLP-1)in the counterregulatory response to hypoglycemia in T1D models.The study employed immunofluorescence,Western blotting,and enzyme-linked immunosorbent assay to track changes in GLP-1 and its receptor expression in diabetic mice subjected to recurrent hypoglycemic episodes.Findings indicate a significant increase in intestinal GLP-1 and GLP-1 receptor expression,correlating with diminished adrenal and glucagon responses,crucial for glucose stabilization during hypoglycemic events.This letter aims to explore the implications of these findings for future therapeutic strategies and the broader understanding of T1D management.展开更多
Background AflatoxinB1(AFB_(1))is a prevalent contaminant in agricultural products,presenting significant risks to animal health.CotA laccase from Bacillus licheniformis has shown significant efficacy in degrading myc...Background AflatoxinB1(AFB_(1))is a prevalent contaminant in agricultural products,presenting significant risks to animal health.CotA laccase from Bacillus licheniformis has shown significant efficacy in degrading mycotoxins in vitro test.The efficacy of Bacillus CotA laccase in animals,however,remains to be confirmed.A 2×2 factorial design was used to investigate the effects of Bacillus CotA laccase level(0 or 1 U/kg),AFB_(1) challenge(challenged or unchal-lenged)and their interactions on ducks.The purpose of this study was to evaluate the efficacy of Bacillus CotA laccase in alleviatingAFB_(1) toxicosis of ducks.Results Bacillus CotA laccase alleviatedAFB_(1)-induced declines in growth performance of ducks accompanied by improved average daily gain(ADG)and lower feed/gain ratio(F/G).Bacillus CotA laccase amelioratedAFB_(1)-induced gut barrier dysfunctions and inflammation testified by increasing the jejunal villi height/crypt depth ratio(VH/CD)and the mRNA expression of tight junction protein 1(TJP1)and zonula occluden-1(ZO-1)as well as decreasing the expression of inflammation-related genes in the jejunum of ducks.Amino acid metabolome showed that Bacillus CotA laccase amelioratedAFB_(1)-induced amino acid metabolism disorders evidenced by increasing the level of glu-tamic acid in serum and upregulating the expression of amino acid transport related genes in jejunum of ducks.Bacil-lus CotA laccase amelioratedAFB_(1)-induced liver injury testified by suppressing oxidative stress,inhibiting apoptosis,and downregulating the expression of hepatic metabolic enzyme related genes of ducks.Moreover,Bacillus CotA laccase degradedAFB_(1) in digestive tract of ducks,resulting in the reduced absorption level ofAFB_(1) across intestinal epithelium testified by the decreased level ofAFB_(1)-DNA adduct in the liver,and the reduced content ofAFB_(1) residues in liver and feces of ducks.Conclusions Bacillus CotA laccase effectively improved the growth performance,intestinal health,amino acid metabolism and hepatic aflatoxin metabolism of ducks fedAFB_(1) diets,highlighting its potential as an efficient and safe feed enzyme forAFB_(1) degradation in animal production.展开更多
BACKGROUND External factors in ulcerative colitis(UC)exacerbate colonic epithelial permea-bility and inflammatory responses.Keratin 1(KRT1)is crucial in regulating these alterations,but its specific role in the progre...BACKGROUND External factors in ulcerative colitis(UC)exacerbate colonic epithelial permea-bility and inflammatory responses.Keratin 1(KRT1)is crucial in regulating these alterations,but its specific role in the progression of UC remains to be fully eluci-dated.AIM To explore the role and mechanisms of KRT1 in the regulation of colonic epithelial permeability and inflammation in UC.METHODS A KRT1 antibody concentration gradient test,along with a dextran sulfate sodium(DSS)-induced animal model,was implemented to investigate the role of KRT1 in modulating the activation of the kallikrein kinin system(KKS)and the cleavage of bradykinin(BK)/high molecular weight kininogen(HK)in UC.RESULTS Treatment with KRT1 antibody in Caco-2 cells suppressed cell proliferation,induced apoptosis,reduced HK expression,and increased BK expression.It further downregulated intestinal barrier proteins,including occludin,zonula occludens-1,and claudin,and negatively impacted the coagulation factor XII.These changes led to enhanced activation of BK and HK cleavage,thereby intensifying KKS-mediated inflammation in UC.In the DSS-induced mouse model,administration of KRT1 antibody mitigated colonic injury,increased colon length,alleviated weight loss,and suppressed inflammatory cytokines such as interleukin(IL)-1,IL-6,tumor necrosis factor-α.It also facilitated repair of the intestinal barrier,reducing DSS-induced injury.CONCLUSION KRT1 inhibits BK expression,suppresses inflammatory cytokines,and enhances markers of intestinal barrier function,thus ameliorating colonic damage and maintaining barrier integrity.KRT1 is a viable therapeutic target for UC.展开更多
Mast cells(MCs)under stress conditions contribute to the development of irritable bowel syndrome(IBS),yet their precise mechanisms in IBS remain unclear.AIM To investigate the role of MC-derived thymosinβ4(Tβ4)in st...Mast cells(MCs)under stress conditions contribute to the development of irritable bowel syndrome(IBS),yet their precise mechanisms in IBS remain unclear.AIM To investigate the role of MC-derived thymosinβ4(Tβ4)in stress-induced intestinal barrier dysfunction.METHODS The colonic mucus Tβ4 levels in IBS patients were determined and their effects on the epithelial barrier were assessed in vitro and in vivo.Specifically,rats genetically deficient in Tβ4(Tβ4^(-/-))or mice deficient in MCs(Kit^(w-sh/w-sh))were used to observe the effects of reintroducing Tβ4 or wild-type peritoneal MCs(wt-PMCs)into these animals.Additionally,the regulatory mechanism underlying Tβ4 secretion in MCs was investigated.RESULTS We demonstrated that high levels of Tβ4 in IBS mucus and intestinal MCs mediate stress-associated disruptive changes to the epithelial barrier.Moreover,Tβ4 treatment of wild-type or MC-deficient Kit^(w-sh/w-sh)mice caused a reduction in tight junction proteins and the interleukin 22 receptor A1(IL22RA1)/Reg3γcascade,but an increase in myosin light chain kinase.Furthermore,Tβ4^(-/-)rats were resistant to stress,though reintroduction of Tβ4 or wt-PMCs restored stress or corticotropin-releasing hormone(CRH)-induced barrier disturbance.Consistently,Tβ4 release from MCs was dependent on the CRH receptor 1,but not degranulation.The effect of Tβ4 was accompanied by IL22RA1/Janus kinase 1(JAK1)/signal transducer and activation of transcription 3(STAT3)pathway inhibition,suggesting a mechanism for physical and immune barrier suppression.CONCLUSION Collectively,these results suggest that Tβ4,which is abundant in IBS mucus and the secretome of MCs,plays a crucial role in the pathogenesis of IBS via IL22RA1/JAK1/STAT3 signaling,with potential implications for diagnostic and therapeutic targeting.展开更多
BACKGROUND Sirtuin 1(SIRT1)is a nicotinamide adenine dinucleotide(NAD+)-dependent protein deacetylase that is involved in various diseases,including cancers,metabolic diseases,and inflammation-associated diseases.Howe...BACKGROUND Sirtuin 1(SIRT1)is a nicotinamide adenine dinucleotide(NAD+)-dependent protein deacetylase that is involved in various diseases,including cancers,metabolic diseases,and inflammation-associated diseases.However,the role of SIRT1 in ulcerative colitis(UC)is still confusing.AIM To investigate the role of SIRT1 in intestinal epithelial cells(IECs)in UC and further explore the underlying mechanisms.METHODS We developed a coculture model using macrophages and Caco-2 cells.After treatment with the SIRT1 activator SRT1720 or inhibitor nicotinamide(NAM),the expression of occludin and zona occludens 1(ZO-1)was assessed by Western blot analysis.Annexin V-APC/7-AAD assays were performed to evaluate Caco-2 apoptosis.Dextran sodium sulfate(DSS)-induced colitis mice were exposed to SRT1720 or NAM for 7 d.Transferase-mediated dUTP nick-end labeling(TUNEL)assays were conducted to assess apoptosis in colon tissues.The expression levels of glucose-regulated protein 78(GRP78),CCAAT/enhancerbinding protein homologous protein(CHOP),caspase-12,caspase-9,and caspase-3 in Caco-2 cells and the colon tissues of treated mice were examined by quantitative real-time PCR and Western blot.RESULTS SRT1720 treatment increased the protein levels of occludin and ZO-1 and inhibited Caco-2 apoptosis,whereas NAM administration caused the opposite effects.DSS-induced colitis mice treated with SRT1720 had a lower disease activity index(P<0.01),histological score(P<0.001),inflammatory cytokine levels(P<0.01),and apoptotic cell rate(P<0.01),while exposure to NAM caused the opposite effects.Moreover,SIRT1 activation reduced the expression levels of GRP78,CHOP,cleaved caspase-12,cleaved caspase-9,and cleaved caspase-3 in Caco-2 cells and the colon tissues of treated mice.CONCLUSION SIRT1 activation reduces apoptosis of IECs via the suppression of endoplasmic reticulum stress-mediated apoptosis-associated molecules CHOP and caspase-12.SIRT1 activation may be a potential therapeutic strategy for UC.展开更多
AIM: To investigate the effect of bone-marrow mesenchymal stem cells (BM MSCs) on the intestinal mucosa barrier in ischemia/reperfusion (I/R) injury. METHODS: BM MSCs were isolated from male Sprague-Dawley rats by den...AIM: To investigate the effect of bone-marrow mesenchymal stem cells (BM MSCs) on the intestinal mucosa barrier in ischemia/reperfusion (I/R) injury. METHODS: BM MSCs were isolated from male Sprague-Dawley rats by density gradient centrifugation, cultured, and analyzed by flow cytometry. I/R injury was induced by occlusion of the superior mesenteric artery for 30 min. Rats were treated with saline, BM MSCs (via intramucosal injection) or tumor necrosis factor (TNF)-α blocking antibodies (via the tail vein). I/R injury was assessed using transmission electron microscopy, hematoxylin and eosin (HE) staining, immunohistochemistry, western blotting and enzyme linked immunosorbent assay.RESULTS: Intestinal permeability increased, tight junctions (TJs) were disrupted, and zona occludens 1 (ZO-1) was downregulated after I/R injury. BM MSCs reduced intestinal mucosal barrier destruction, ZO-1 downregulation, and TJ disruption. The morphological abnormalities after intestinal I/R injury positively correlated with serum TNF-α levels. Administration of anti-TNF-α IgG or anti-TNF-α receptor 1 antibodies attenuated the intestinal ultrastructural changes, ZO-1 downregulation, and TJ disruption. CONCLUSION: Altered serum TNF-α levels play an important role in the ability of BM MSCs to protect against intestinal I/R injury.展开更多
BACKGROUND: Emodin, a traditional Chinese medicine, has a therapeutic effect on severe acute pancreatitis (SAP), whereas the underlying mechanism is still unclear. Studies showed that the intestinal mucosa impairment,...BACKGROUND: Emodin, a traditional Chinese medicine, has a therapeutic effect on severe acute pancreatitis (SAP), whereas the underlying mechanism is still unclear. Studies showed that the intestinal mucosa impairment, and subsequent release of endotoxin and proinflammatory cytokines such as IL-1 beta, which further leads to the dysfunction of multiple organs, is the potentially lethal mechanism of SAP. Caspase-1, an IL-1 beta converting enzyme, plays an important role in this cytokine cascade process. Investigation of the effect of emodin on regulating the caspase-1 expression and the release proinflammatory cytokines will help to reveal mechanism of emodin in treating SAP. METHODS: Eighty Sprague-Dawley rats were randomly divided into four groups (n=20 each group): SAP, sham-operated (SO), emodin-treated (EM) and caspase-1 inhibitor-treated (ICE-I) groups. SAP was induced by retrograde infusion of 3.5% sodium taurocholate into the pancreatic duct. Emodin and caspase-1 inhibitor were given 30 minutes before and 12 hours after SAP induction. Serum levels of IL-1 beta, IL-18 and endotoxin, histopathological alteration of pancreas tissues, intestinal mucosa, and the intestinal caspase-1 mRNA and protein expressions were assessed 24 hours after SAP induction. RESULTS: Rats in the SAP group had higher serum levels of IL-1 beta and IL-18 (P<0.05), pancreatic and gut pathological scores (P<0.05), and caspase-1 mRNA and protein expressions (P<0.05) compared with the SO group. Compared with the SAP group, rats in the EM and ICE-I groups had lower IL-1 beta and IL-18 levels (P<0.05), lower pancreatic and gut pathological scores (P<0.05), and decreased expression of intestine caspase-1 mRNA (P<0.05). Ultrastructural analysis by transmission electron microscopy found that rats in the SAP group had vaguer epithelial junctions, more disappeared intercellular joints, and more damaged intracellular organelles compared with those in the SO group or the EM and ICE-I groups. CONCLUSIONS: Emodin alleviated pancreatic and intestinal mucosa injury in experimental SAP. Its mechanism may partly be mediated by the inhibition of caspase-1 and its downstream inflammatory cytokines, including IL-1 beta and IL-18. Our animal data may be applicable in clinical practice.展开更多
AIM: To investigate whether resveratrol (3,4,5-trihydroxy-trans-stilbene) inhibits collagen I synthesis induced by insulin growth factor-1 (IGF-1) in intestinal fibroblasts, and to explore the ...AIM: To investigate whether resveratrol (3,4,5-trihydroxy-trans-stilbene) inhibits collagen I synthesis induced by insulin growth factor-1 (IGF-1) in intestinal fibroblasts, and to explore the possible molecular mechanisms.展开更多
Houttuynia cordata polysaccharide(HCP) is extracted from Houttuynia cordata, a key traditional Chinese medicine. The study was to investigate the effects of HCP on intestinal barrier and microbiota in H1N1 virus infec...Houttuynia cordata polysaccharide(HCP) is extracted from Houttuynia cordata, a key traditional Chinese medicine. The study was to investigate the effects of HCP on intestinal barrier and microbiota in H1N1 virus infected mice. Mice were infected with H1N1 virus and orally administrated HCP at a dosage of 40 mg×kg^(–1)×d^(–1). H1N1 infection caused pulmonary and intestinal injury and gut microbiota imbalance. HCP significantly suppressed the expression of hypoxia inducible factor-1α and decreased mucosubstances in goblet cells, but restored the level of zonula occludens-1 in intestine. HCP also reversed the composition change of intestinal microbiota caused by H1N1 infection, with significantly reduced relative abundances of Vibrio and Bacillus, the pathogenic bacterial genera. Furthermore, HCP rebalanced the gut microbiota and restored the intestinal homeostasis to some degree. The inhibition of inflammation was associated with the reduced level of Toll-like receptors and interleukin-1β in intestine, as well as the increased production of interleukin-10. Oral administration of HCP alleviated lung injury and intestinal dysfunction caused by H1N1 infection. HCP may gain systemic treatment by local acting on intestine and microbiota. This study proved the high-value application of HCP.展开更多
AIM: To characterize high-mobility group protein 1-toll-like receptor 4(HMGB1-TLR4) and downstream signaling pathways in intestinal ischemia/reperfusion(I/R) injury.METHODS: Forty specific-pathogen-free male C57BL/6 m...AIM: To characterize high-mobility group protein 1-toll-like receptor 4(HMGB1-TLR4) and downstream signaling pathways in intestinal ischemia/reperfusion(I/R) injury.METHODS: Forty specific-pathogen-free male C57BL/6 mice were randomly divided into five groups(n = 8 per group): sham, control, anti-HMGB1, anti-myeloid differentiation gene 88(My D88), and anti-translocatingchain-associating membrane protein(TRIF) antibody groups. Vehicle with the control Ig G antibody, antiHMGB1, anti-My D88, or anti-TRIF antibodies(all 1 mg/kg, 0.025%) were injected via the caudal vein 30 min prior to ischemia. After anesthetization, the abdominal wall was opened and the superior mesenteric artery was exposed, followed by 60 min mesenteric ischemia and then 60 min reperfusion. For the sham group, the abdominal wall was opened for 120 min without I/R. Levels of serum nuclear factor(NF)-κB p65, interleukin(IL)-6, and tumor necrosis factor(TNF)-α were measured, along with myeloperoxidase activity in the lung and liver. Inaddition,morphologic changes that occurred in the lung and intestinal tissues were evaluated. Levels of m RNA transcripts encoding HMGB1 and NF-κB were measured by real-time quantitative PCR, and levels of HMGB1 and NF-κB protein were measured by Western blot. Results were analyzed using one-way analysis of variance.RESULTS: Blocking HMGB 1, MyD 8 8, and TRIF expression by injecting anti-HMGB1, anti-My D88, or anti-TRIF antibodies prior to ischemia reduced the levels of inflammatory cytokines in serum; NF-κB p65: 104.64 ± 11.89, 228.53 ± 24.85, 145.00 ± 33.63, 191.12 ± 13.22, and 183.73 ± 10.81(P < 0.05); IL-6: 50.02 ± 6.33, 104.91 ± 31.18, 62.28 ± 6.73, 85.90 ± 17.37, and 78.14 ± 7.38(P < 0.05); TNF-α, 43.79 ± 4.18, 70.81 ± 6.97, 52.76 ± 5.71, 63.19 ± 5.47, and 59.70 ± 4.63(P < 0.05) for the sham, control, anti-HMGB1, anti-My D88, and anti-TRIF groups, respectively(all in pg/m L).Antibodies also alleviated tissue injury in the lung and small intestine compared with the control group in the mouse intestinal I/R model. The administration of antiHMGB1, anti-My D88, and anti-TRIF antibodies markedly reduced damage caused by I/R, for which anti-HMGB1 antibody had the most obvious effect.CONCLUSION: HMGB1 and its downstream signaling pathway play important roles in the mouse intestinal I/R injury, and the effect of the TRIF-dependent pathway is slightly greater.展开更多
BACKGROUND It is challenging to distinguish intestinal tuberculosis from Crohn’s disease due to dynamic changes in epidemiology and similar clinical characteristics. Recent studies have shown that polymorphisms in ge...BACKGROUND It is challenging to distinguish intestinal tuberculosis from Crohn’s disease due to dynamic changes in epidemiology and similar clinical characteristics. Recent studies have shown that polymorphisms in genes involved in the interleukin (IL)- 23/IL-17 axis may affect intestinal mucosal immunity by affecting the differentiation of Th17 cells. AIM To investigate the specific single-nucleotide polymorphisms (SNPs) in genes involved in the IL-23/IL-17 axis and possible pathways that affect susceptibility to intestinal tuberculosis and Crohn's disease. METHODS We analysed 133 patients with intestinal tuberculosis, 128 with Crohn’s disease, and 500 normal controls. DNA was extracted from paraffin-embedded specimens or whole blood. Four SNPs in the IL23/Th17 axis (IL22 rs2227473, IL1β rs1143627, TGFβ rs4803455, and IL17 rs8193036) were genotyped with TaqMan assays. The transcriptional activity levels of different genotypes of rs2227473 were detected by dual luciferase reporter gene assay. The expression of IL-22R1 in different intestinal diseases was detected by immunohistochemistry. RESULTS The A allele frequency of rs2227473 (P = 0.030, odds ratio = 0.60, 95% confidence interval: 0.37-0.95) showed an abnormal distribution between intestinal tuberculosis and healthy controls. The presence of the A allele was associated with a higher IL-22 transcriptional activity (P < 0.05). In addition, IL-22R1 was expressed in intestinal lymphoid tissues, especially under conditions of intestinal tuberculosis, and highly expressed in macrophage-derived Langhans giant cells. The results of immunohistochemistry showed that the expression of IL-22R1 in patients with Crohn's disease and intestinal tuberculosis was significantly higher than that in patients with intestinal polyps and colon cancer (P < 0.01). CONCLUSION High IL-22 expression seems to be a protective factor for intestinal tuberculosis. IL-22R1 is expressed in Langhans giant cells, suggesting that the IL-22/IL-22R1 system links adaptive and innate immunity.展开更多
AIM： To investigate the role of nuclear factor kappa B （NF-κB） in the pathogenesis of lung injury induced by intestinal ischemia/reperfusion （I/R）, and its effect on intercellular adhesion molecule-1 （ICAM-1） ...AIM： To investigate the role of nuclear factor kappa B （NF-κB） in the pathogenesis of lung injury induced by intestinal ischemia/reperfusion （I/R）, and its effect on intercellular adhesion molecule-1 （ICAM-1） expression and neutrophil infiltration. METHODS： Twenty-four Wistar rats were divided randomly into control, I/R and pyrrolidine dithiocarbamate （PDTC） treatment groups, n = 8 in each. I/R group and PDTC treatment group received superior mysenteric artery （SMA） occluding for 1 h and reperfusion for 2 h. PDTC group was administrated with intraperitoneal injection of 2% 100 mg/kg PDTC 1 h before surgery. Lung histology and bronchia alveolus lung fluid （BALF） protein were assayed. Serum IL-6, lung malondialdehyde （MDA） and myeloperoxidase （MPO） as well as the expression level of NF-κB and ICAM-1 were measured.RESULTS： Lung injury induced by intestinal I/R, was characterized by edema, hemorrhage and neutrophil infiltration as well as by the significant rising of BALF protein. Compared to control group, the levels of serum IL-6 and lung MDA and MPO increased significantly in I/R group （P=0.001）. Strong positive expression of NF-κB p65 and ICAM-1 was observed. After the administration of PDTC, the level of serum IL-6, lung MDA and MPO as well as NF-κB and ICAM-1 decreased significantly （P〈 0.05） when compared to I/R group.CONCLUSION： The activation of NF-κB plays an important role in the pathogenesis of lung injury induced by intestinal I/R through upregulating the neutrophil infiltration and lung ICAM-1 expression. PDTC as an inhibitor of NF-κB can prevent lung injury induced by intestinal I/R through inhibiting the activity of NF-κB.展开更多
Background Myocardial infarction （MI） has likely contributed to the increased prevalence of heart failure （HF）. As a result of re- duced cardiac function, splanchnic blood flow decreases, causing ischemia in villi...Background Myocardial infarction （MI） has likely contributed to the increased prevalence of heart failure （HF）. As a result of re- duced cardiac function, splanchnic blood flow decreases, causing ischemia in villi and damage to the intestinal barrier. The induction of heme oxygenase-1 （HO-1） could prevent, or lessen the effects of stress and inflammation. Thus, the effect and mechanism thereof of HO-1 on the intestines of rats with HF was investigated. Methods Male Wistar rats with heart failure through ligation of the left coronary artery were identified with an left ventricular ejection fraction of 〈 45% through echocardiography and then divided into various experimental groups based on the type of peritoneal injection they received [MI： saline; MI ＋ Cobalt protoporphyrin （CoPP）： CoPP solution; and MI ＋ Tin mesoporphyrin IX dichloride （SnMP）： SnMP solution]. The control group was comprised of rats without coronary ligation. Echocardiogra- phy was performed before ligation for a baseline and eight weeks after ligation in order to evaluate the cardiac function of the rats. The bac- terial translocation （BT） incidence, mesenteric microcirculation, amount of endotoxins in the vein serum, ileum levels of HO- 1, carbon oxide （CO）, nitric oxide （NO）, intedeuldn （IL）-10, turnour necrosis factor-et （TNF-ct）, and the ileum morphology were determined eight weeks after the operation. Results The rats receiving MI ＋ CoPP injections exhibited a recovery in cardiac function, an amelioration of mesenteric microcirculation and change in morphology, a lower BT incidence, a reduction in serum and ileac NO and TNF-ct levels, and an elevation in ileac HO-1, CO, and interleukin-10 （[L-10） levels compared to the MI group （P 〈 0.05）. The rats that received the MI ＋ SnMP injections exhibited results inverse to the MI （P 〈 0.05） group. Conclusions HO-1 exerted a protective effect on the intestines of rats with HF by inhibiting the inflammation and amelioration of microcirculation through the CO pathway. This protective effect could be independent from the recovery of cardiac function.展开更多
AIM To investigate the anti-fibrotic effects of the traditional oriental herbal medicine Daikenchuto(DKT) associated with transient receptor potential ankyrin 1(TRPA1) channels in intestinal myofibroblasts. METHODS In...AIM To investigate the anti-fibrotic effects of the traditional oriental herbal medicine Daikenchuto(DKT) associated with transient receptor potential ankyrin 1(TRPA1) channels in intestinal myofibroblasts. METHODS Inflammatory and fibrotic changes were detected in a2,4,6-trinitrobenzenesulfonic acid(TNBS) chronic colitis model of wild-type and TRPA1-knockout(TRPA1-KO) mice via pathological staining and immunoblotting analysis.Ca^(2+) imaging experiments examined the effects of DKT and its components/ingredients on intestinal myofibroblast(In Myo Fib) cell TRPA1 channel function.Profibrotic factors and transforming growth factor (TGF) -β1-associated signaling were tested in an In Myo Fib cell line by q PCR and immunoblotting experiments.Samples from non-stenotic and stenotic regions of the intestines of patients with Crohn’s disease (CD) were used for pathological analysis. RESULTS Chronic treatment with TNBS caused more severe inflammation and fibrotic changes in TRPA1-KO than in wild-type mice.A one-week enema administration of DKT reduced fibrotic lesions in wild-type but not in TRPA1-KO mice.The active ingredients of DKT,i.e.,hydroxyα-sanshool and 6-shogaol,induced Ca^(2+) influxes in In Myo Fib,and this was antagonized by co-treatment with a selective TRPA1 channel blocker,HC-030031.DKT counteracted TGF-β1-induced expression of TypeⅠcollagen andα-smooth muscle actin (α-SMA) ,which were accompanied by a reduction in the phosphorylation of Smad-2 and p38-mitogen-activated protein kinase (p38-MAPK) and the expression of myocardin.Importantly,24-h incubation with a DKT active component Japanese Pepper increased the m RNA and protein expression levels of TRPA1 in In Myo Fibs,which in turn negatively regulated collagen synthesis.In the stenotic regions of the intestines of CD patients,TRPA1 expression was significantly enhanced.CONCLUSION The effects of DKT on the expression and activation of the TRPA1 channel could be advantageous for suppressing intestinal fibrosis,and benefit inflammatory bowel disease treatment.展开更多
AIM: Nuclear factor kappa B (NF-κB) regulates a large number of genes involved in the inflammatory response to critical illnesses, but it is not known if and how NF-KB is activated and intercellular adhesion molecule...AIM: Nuclear factor kappa B (NF-κB) regulates a large number of genes involved in the inflammatory response to critical illnesses, but it is not known if and how NF-KB is activated and intercellular adhesion molecule-1 (ICAM-1) expressed in the gut following traumatic brain injury (TBI). The aim of current study was to investigate the temporal pattern of intestinal NF-κB activation and ICAM-1 expression following TBI. METHODS: Male Wistar rats were randomly divided into six groups (6 rats in each group) including controls with sham operation and TBI groups at hours 3, 12, 24, and 72, and on d 7. Parietal brain contusion was adopted using weight-dropping method. All rats were decapitated at corresponding time point and mid-jejunum samples were taken. NF-KB binding activity in jejunal tissue was measured using EMSA. Immunohistochemistry was used for detection of ICAM-1 expression in jejunal samples. RESULTS: There was a very low NF-κB binding activity and little ICAM-1 expression in the gut of control rats after sham surgery. NF-KB binding activity in jejunum significantly increased by 160% at 3 h following TBI (P<0.05 vs control), peaked at 72 h (500% increase) and remained elevated on d 7 post-injury by 390% increase. Compared to controls, ICAM-1 was significantly up-regulated on the endothelia of microvessels in villous interstitium and lamina propria by 24 h following TBI and maximally expressed at 72 h post-injury (P<0.001). The endothelial ICAM-1 immunoreactivity in jejunal mucosa still remained strong on d 7 post-injury. The peak of NF-κB activation and endothelial ICAM-1 expression coincided in time with the period during which secondary mucosal injury of the gut was also at their culmination following TBI. CONCLUSION: TBI could induce an immediate and persistent up-regulation of NF-κB activity and subsequent up-regulation of ICAM-1 expression in the intestine. Inflammatory response mediated by increased NF-κB activation and ICAM-1 expression may play an important role in the pathogenesis of acute gut mucosal injury following TBI.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
AIM To evaluate whether fish oil(FO) can protect liver injury induced by intestinal ischemia/reperfusion(I/R) via the AMPK/SIRT-1/autophagy pathway.METHODS Ischemia in wistar rats was induced by superior mesenteric ar...AIM To evaluate whether fish oil(FO) can protect liver injury induced by intestinal ischemia/reperfusion(I/R) via the AMPK/SIRT-1/autophagy pathway.METHODS Ischemia in wistar rats was induced by superior mesenteric artery occlusion for 60 min and reperfusion for 240 min. One milliliter per day of FO emulsion or normal saline was administered by intraperitoneal injection for 5 consecutive days to each animal. Animals were sacrificed at the end of reperfusion. Blood andtissue samples were collected for analyses. AMPK, SIRT-1, and Beclin-1 expression was determined in lipopolysaccharide(LPS)-stimulated HepG2 cells with or without FO emulsion treatment.RESULTS Intestinal I/R induced significant liver morphological changes and increased serum alanine aminotransferase and aspartate aminotransferase levels. Expression of p-AMPK/AMPK, SIRT-1, and autophagy markers was decreased whereas tumor necrosis factor-α(TNF-α) and malonaldehyde(MDA) were increased. FO emulsion blocked the changes of the above indicators effectively. Besides, in LPS-stimulated HepG2 cells, small interfering RNA(siRNA) targeting AMPK impaired the FO induced increase of p-AMPK, SIRT-1, and Beclin-1 and decrease of TNF-α and MDA. SIRT-1 siRNA impaired the increase of SIRT-1 and Beclin-1 and the decrease of TNF-α and MDA.CONCLUSION Our study indicates that FO may protect the liver against intestinal I/R induced injury through the AMPK/SIRT-1/autophagy pathway.展开更多
Ischemic stroke causes brain inflammation and multi-organ injury,which is closely associated with the peroxisome proliferator-activated receptor-gamma(PPARγ)signaling pathway.Recent studies have indicated that ginsen...Ischemic stroke causes brain inflammation and multi-organ injury,which is closely associated with the peroxisome proliferator-activated receptor-gamma(PPARγ)signaling pathway.Recent studies have indicated that ginsenoside Rb1(GRb1)can protect the integrity of the blood-brain barrier after stroke.In the current study,a mouse model of middle cerebral artery occlusion/reperfusion(MCAO/R)was established to determine whether GRb1 can ameliorate brain/lung/intestinal barrier damage via the PPARγsignaling pathway.Staining(2,3,5-triphenyltetrazolium chloride,hematoxylin,and eosin)and Doppler ultrasonography were employed to detect pathological changes.Endothelial breakdown was investigated with the leakage of Evans Blue dye and the expression of TJs(tight junctions)and AJs(adherent junctions).Western blot and immunofluorescence were used to determine the levels of cell junction proteins,PPARγand NF-κB.Results showed that GRb1 significantly mitigated multi-organ injury and increased the expression of cerebral microvascular,pulmonary vascular,and intestinal epithelial connexins.In brain,lung,and intestinal tissues,GRb1 activated PPARγ,decreased the levels of phospho-NF-κB p65,and inhibited the production of proinflammatory cytokines,thereby maintaining barrier permeability.However,co-treatment with GRb1 and the PPARγantagonist GW9662 reversed the barrier-protective effect of GRb1.These findings indicated that GRb1 can improve stroke-induced brain/lung/intestinal barrier damagevia the PPARγpathway.展开更多
基金supported by the National Natural Science foundation of China(No.31071531)the Scientific Research Fund of the Hunan Provincial Education Department(No.14A071)the China National Tobacco Corp Hunan Branch(15-17Aa04)
文摘Objective To reveal the effects and related mechanisms of chlorogenic acid(CGA)on intestinal glucose homeostasis.Methods Forty male Sprague-Dawley rats were randomly and equally divided into four groups:normal chow(NC),high-fat diet(HFD),HFD with low-dose CGA(20 mg/kg,HFD-LC),and HFD with high-dose CGA(90 mg/kg,HFD-HC).The oral glucose tolerance test was performed,and fast serum insulin(FSI)was detected using an enzyme-linked immunosorbent assay.The m RNA expression levels of glucose transporters(Sglt-1 and Glut-2)and proglucagon(Plg)in different intestinal segments(the duodenum,jejunum,ileum,and colon)were analyzed using quantitative real-time polymerase chain reaction.SGLT-1 protein and the morphology of epithelial cells in the duodenum and jejunum was localized by using immunofluorescence.Results At both doses,CGA ameliorated the HFD-induced body weight gain,maintained FSI,and increased postprandial 30-min glucagon-like peptide 1 secretion.High-dose CGA inhibited the HFD-induced elevation in Sglt-1 expression.Both CGA doses normalized the HFD-induced downregulation of Glut-2 and elevated the expression of Plg in all four intestinal segments.Conclusion An HFD can cause a glucose metabolism disorder in the rat intestine and affect body glucose homeostasis.CGA can modify intestinal glucose metabolism by regulating the expression of intestinal glucose transporters and Plg,thereby controlling the levels of blood glucose and insulin to maintain glucose homeostasis.
基金supported by the National key research and development program(2022YFD1300401)Natural Science Foundation of Guangdong Province(2023 A1515012127,2024 A1515010510,2025 A1515011832)+1 种基金National Natural Science Foundation of China(32372958)Visiting Scholar Fund by China Scholarship Council(202008440191).
文摘Background As an essential source of nutrients for young mammals,milk possesses a variety of biological functions.Recently identified milk-derived small extracellular vesicles(sEV)have shown potential regulatory effects on intestinal health.Current studies have highlighted the functional roles of milk-derived sEV and their RNA cargo in promoting intestinal health.However,there is a paucity of research demonstrating how milk-derived sEV influence intestinal barrier function through the transport of circRNAs.Results In this study,we aimed to investigate the effects of porcine milk sEV(PM-sEV)circRNA on intestinal barrier function.We systematically identified the circRNAs involved in this process and analyzed the miRNAs through which PM-sEV deliver circRNAs to regulate intestinal barrier function.Our findings revealed that PM-sEV promote the expression of the intestinal tight junction proteins ZO-1 and Occludin,both in vivo(mice)and in vitro(IPEC-J2).When PMsEV RNA was reduced using ultrasound treatment,their ability to enhance intestinal barrier function was significantly reduced.Bioinformatics analysis showed that circ-0000197,present in PM-sEV,can target miR-429,while miR-429 has the ability to target the 3’-UTR of ZO-1 and Occludin.Furthermore,experiments involving the overexpression or inhibition of the relevant non-coding RNAs(ncRNAs)demonstrated that circ-0000197 significantly enhances intestinal barrier function,whereas miR-429 exerts an inhibitory effect on this function.Overall,our findings identify circ-0000197 in PM-sEV as a crucial circRNA that regulates intestinal barrier function by inhibiting miR-429.Circ-0000197 carried by PM-sEV acts as a competing endogenous RNA(ceRNA)that regulates the expression of ZO-1 and Occludin by sponging miR-429,thereby promoting intestinal barrier function at both the cellular and in vivo levels.Conclusions These findings emphasize the vital role of circRNAs transported through milk-derived sEV in regulating intestinal health,offering new avenues for developing innovative functional milk components.This mechanism also underscores the importance of PM-sEV carrying circ-0000197 in preserving intestinal barrier integrity.Collectively,this study enhances our understanding of the complex regulatory networks involving PM-sEV carrying circRNAs and their impact on intestinal health.
文摘Recent advances in understanding type 1 diabetes(T1D)highlight the complexity of managing hypoglycemia,a frequent and perilous complication of diabetes therapy.This letter delves into a novel study by Jin et al,which elucidates the role of intestinal glucagon-like peptide-1(GLP-1)in the counterregulatory response to hypoglycemia in T1D models.The study employed immunofluorescence,Western blotting,and enzyme-linked immunosorbent assay to track changes in GLP-1 and its receptor expression in diabetic mice subjected to recurrent hypoglycemic episodes.Findings indicate a significant increase in intestinal GLP-1 and GLP-1 receptor expression,correlating with diminished adrenal and glucagon responses,crucial for glucose stabilization during hypoglycemic events.This letter aims to explore the implications of these findings for future therapeutic strategies and the broader understanding of T1D management.
基金National Key Research and Development Program of China(2021YFC2103003)National Natural Science Foundation of China(31972604)+1 种基金Jinan Introductory Innovation Team Project(No.202228037)China Postdoctoral Science Foundation(2023M730998).
文摘Background AflatoxinB1(AFB_(1))is a prevalent contaminant in agricultural products,presenting significant risks to animal health.CotA laccase from Bacillus licheniformis has shown significant efficacy in degrading mycotoxins in vitro test.The efficacy of Bacillus CotA laccase in animals,however,remains to be confirmed.A 2×2 factorial design was used to investigate the effects of Bacillus CotA laccase level(0 or 1 U/kg),AFB_(1) challenge(challenged or unchal-lenged)and their interactions on ducks.The purpose of this study was to evaluate the efficacy of Bacillus CotA laccase in alleviatingAFB_(1) toxicosis of ducks.Results Bacillus CotA laccase alleviatedAFB_(1)-induced declines in growth performance of ducks accompanied by improved average daily gain(ADG)and lower feed/gain ratio(F/G).Bacillus CotA laccase amelioratedAFB_(1)-induced gut barrier dysfunctions and inflammation testified by increasing the jejunal villi height/crypt depth ratio(VH/CD)and the mRNA expression of tight junction protein 1(TJP1)and zonula occluden-1(ZO-1)as well as decreasing the expression of inflammation-related genes in the jejunum of ducks.Amino acid metabolome showed that Bacillus CotA laccase amelioratedAFB_(1)-induced amino acid metabolism disorders evidenced by increasing the level of glu-tamic acid in serum and upregulating the expression of amino acid transport related genes in jejunum of ducks.Bacil-lus CotA laccase amelioratedAFB_(1)-induced liver injury testified by suppressing oxidative stress,inhibiting apoptosis,and downregulating the expression of hepatic metabolic enzyme related genes of ducks.Moreover,Bacillus CotA laccase degradedAFB_(1) in digestive tract of ducks,resulting in the reduced absorption level ofAFB_(1) across intestinal epithelium testified by the decreased level ofAFB_(1)-DNA adduct in the liver,and the reduced content ofAFB_(1) residues in liver and feces of ducks.Conclusions Bacillus CotA laccase effectively improved the growth performance,intestinal health,amino acid metabolism and hepatic aflatoxin metabolism of ducks fedAFB_(1) diets,highlighting its potential as an efficient and safe feed enzyme forAFB_(1) degradation in animal production.
基金Supported by the National Natural Science Foundation of China,No.82160113the“Xingdian Talents”Support Project of Yunnan Province,No.RLMY20220007+1 种基金the Yunnan Province Clinical Research Center for Digestive Diseases,No.202102AA100062the Applied Basic Research Projects of Yunnan Province,No.2019FE001-039.
文摘BACKGROUND External factors in ulcerative colitis(UC)exacerbate colonic epithelial permea-bility and inflammatory responses.Keratin 1(KRT1)is crucial in regulating these alterations,but its specific role in the progression of UC remains to be fully eluci-dated.AIM To explore the role and mechanisms of KRT1 in the regulation of colonic epithelial permeability and inflammation in UC.METHODS A KRT1 antibody concentration gradient test,along with a dextran sulfate sodium(DSS)-induced animal model,was implemented to investigate the role of KRT1 in modulating the activation of the kallikrein kinin system(KKS)and the cleavage of bradykinin(BK)/high molecular weight kininogen(HK)in UC.RESULTS Treatment with KRT1 antibody in Caco-2 cells suppressed cell proliferation,induced apoptosis,reduced HK expression,and increased BK expression.It further downregulated intestinal barrier proteins,including occludin,zonula occludens-1,and claudin,and negatively impacted the coagulation factor XII.These changes led to enhanced activation of BK and HK cleavage,thereby intensifying KKS-mediated inflammation in UC.In the DSS-induced mouse model,administration of KRT1 antibody mitigated colonic injury,increased colon length,alleviated weight loss,and suppressed inflammatory cytokines such as interleukin(IL)-1,IL-6,tumor necrosis factor-α.It also facilitated repair of the intestinal barrier,reducing DSS-induced injury.CONCLUSION KRT1 inhibits BK expression,suppresses inflammatory cytokines,and enhances markers of intestinal barrier function,thus ameliorating colonic damage and maintaining barrier integrity.KRT1 is a viable therapeutic target for UC.
基金Supported by the National Natural Science Foundation of China,No.81270465the Sichuan Science and Technology Program,No.2024NSFSC0631,No.2023JDRC0088,and No.MZGC20240097+4 种基金the Basic Research Cultivation Support Program of Fundamental Research Funds for the Central Universities,No.2682023ZTPY071the Baiqiuen Public Welfare Foundation Program,No.BCF-LX-XH-20221014-12the Third People’s Hospital of Chengdu Clinical Research Program,No.CSY-YN-01-2023-012the Yibin Science and Technology Program,No.2021ZYY009and the Chengdu Medical Research Project Foundation,No.2022284.
文摘Mast cells(MCs)under stress conditions contribute to the development of irritable bowel syndrome(IBS),yet their precise mechanisms in IBS remain unclear.AIM To investigate the role of MC-derived thymosinβ4(Tβ4)in stress-induced intestinal barrier dysfunction.METHODS The colonic mucus Tβ4 levels in IBS patients were determined and their effects on the epithelial barrier were assessed in vitro and in vivo.Specifically,rats genetically deficient in Tβ4(Tβ4^(-/-))or mice deficient in MCs(Kit^(w-sh/w-sh))were used to observe the effects of reintroducing Tβ4 or wild-type peritoneal MCs(wt-PMCs)into these animals.Additionally,the regulatory mechanism underlying Tβ4 secretion in MCs was investigated.RESULTS We demonstrated that high levels of Tβ4 in IBS mucus and intestinal MCs mediate stress-associated disruptive changes to the epithelial barrier.Moreover,Tβ4 treatment of wild-type or MC-deficient Kit^(w-sh/w-sh)mice caused a reduction in tight junction proteins and the interleukin 22 receptor A1(IL22RA1)/Reg3γcascade,but an increase in myosin light chain kinase.Furthermore,Tβ4^(-/-)rats were resistant to stress,though reintroduction of Tβ4 or wt-PMCs restored stress or corticotropin-releasing hormone(CRH)-induced barrier disturbance.Consistently,Tβ4 release from MCs was dependent on the CRH receptor 1,but not degranulation.The effect of Tβ4 was accompanied by IL22RA1/Janus kinase 1(JAK1)/signal transducer and activation of transcription 3(STAT3)pathway inhibition,suggesting a mechanism for physical and immune barrier suppression.CONCLUSION Collectively,these results suggest that Tβ4,which is abundant in IBS mucus and the secretome of MCs,plays a crucial role in the pathogenesis of IBS via IL22RA1/JAK1/STAT3 signaling,with potential implications for diagnostic and therapeutic targeting.
基金Supported by the National Nature Science Foundation of China,No.81600414the Natural Science Foundation of Zhejiang Province,No.LQ16H030001Zhejiang TCM Science and Technology Project,No.2016ZA123 and No.2018ZA013
文摘BACKGROUND Sirtuin 1(SIRT1)is a nicotinamide adenine dinucleotide(NAD+)-dependent protein deacetylase that is involved in various diseases,including cancers,metabolic diseases,and inflammation-associated diseases.However,the role of SIRT1 in ulcerative colitis(UC)is still confusing.AIM To investigate the role of SIRT1 in intestinal epithelial cells(IECs)in UC and further explore the underlying mechanisms.METHODS We developed a coculture model using macrophages and Caco-2 cells.After treatment with the SIRT1 activator SRT1720 or inhibitor nicotinamide(NAM),the expression of occludin and zona occludens 1(ZO-1)was assessed by Western blot analysis.Annexin V-APC/7-AAD assays were performed to evaluate Caco-2 apoptosis.Dextran sodium sulfate(DSS)-induced colitis mice were exposed to SRT1720 or NAM for 7 d.Transferase-mediated dUTP nick-end labeling(TUNEL)assays were conducted to assess apoptosis in colon tissues.The expression levels of glucose-regulated protein 78(GRP78),CCAAT/enhancerbinding protein homologous protein(CHOP),caspase-12,caspase-9,and caspase-3 in Caco-2 cells and the colon tissues of treated mice were examined by quantitative real-time PCR and Western blot.RESULTS SRT1720 treatment increased the protein levels of occludin and ZO-1 and inhibited Caco-2 apoptosis,whereas NAM administration caused the opposite effects.DSS-induced colitis mice treated with SRT1720 had a lower disease activity index(P<0.01),histological score(P<0.001),inflammatory cytokine levels(P<0.01),and apoptotic cell rate(P<0.01),while exposure to NAM caused the opposite effects.Moreover,SIRT1 activation reduced the expression levels of GRP78,CHOP,cleaved caspase-12,cleaved caspase-9,and cleaved caspase-3 in Caco-2 cells and the colon tissues of treated mice.CONCLUSION SIRT1 activation reduces apoptosis of IECs via the suppression of endoplasmic reticulum stress-mediated apoptosis-associated molecules CHOP and caspase-12.SIRT1 activation may be a potential therapeutic strategy for UC.
基金Supported by Natural Science Foundation of China, No.81270528the Natural Science Foundation of Tianjin, No. 08JCYBJC08400, No. 11JCZDJC27800 and No. 12JCZDJC25200the Technology Foundation of Health Bureau in Tianjin, No.2011KY11
文摘AIM: To investigate the effect of bone-marrow mesenchymal stem cells (BM MSCs) on the intestinal mucosa barrier in ischemia/reperfusion (I/R) injury. METHODS: BM MSCs were isolated from male Sprague-Dawley rats by density gradient centrifugation, cultured, and analyzed by flow cytometry. I/R injury was induced by occlusion of the superior mesenteric artery for 30 min. Rats were treated with saline, BM MSCs (via intramucosal injection) or tumor necrosis factor (TNF)-α blocking antibodies (via the tail vein). I/R injury was assessed using transmission electron microscopy, hematoxylin and eosin (HE) staining, immunohistochemistry, western blotting and enzyme linked immunosorbent assay.RESULTS: Intestinal permeability increased, tight junctions (TJs) were disrupted, and zona occludens 1 (ZO-1) was downregulated after I/R injury. BM MSCs reduced intestinal mucosal barrier destruction, ZO-1 downregulation, and TJ disruption. The morphological abnormalities after intestinal I/R injury positively correlated with serum TNF-α levels. Administration of anti-TNF-α IgG or anti-TNF-α receptor 1 antibodies attenuated the intestinal ultrastructural changes, ZO-1 downregulation, and TJ disruption. CONCLUSION: Altered serum TNF-α levels play an important role in the ability of BM MSCs to protect against intestinal I/R injury.
基金supported by grants from Zhejiang Province Traditional Chinese Medicine Scientific Research Fund(2011-ky1-001-164 and 2016ZB066)Public Welfare Projects of Ministry of Science of Zhejiang Province(20130101120016)
文摘BACKGROUND: Emodin, a traditional Chinese medicine, has a therapeutic effect on severe acute pancreatitis (SAP), whereas the underlying mechanism is still unclear. Studies showed that the intestinal mucosa impairment, and subsequent release of endotoxin and proinflammatory cytokines such as IL-1 beta, which further leads to the dysfunction of multiple organs, is the potentially lethal mechanism of SAP. Caspase-1, an IL-1 beta converting enzyme, plays an important role in this cytokine cascade process. Investigation of the effect of emodin on regulating the caspase-1 expression and the release proinflammatory cytokines will help to reveal mechanism of emodin in treating SAP. METHODS: Eighty Sprague-Dawley rats were randomly divided into four groups (n=20 each group): SAP, sham-operated (SO), emodin-treated (EM) and caspase-1 inhibitor-treated (ICE-I) groups. SAP was induced by retrograde infusion of 3.5% sodium taurocholate into the pancreatic duct. Emodin and caspase-1 inhibitor were given 30 minutes before and 12 hours after SAP induction. Serum levels of IL-1 beta, IL-18 and endotoxin, histopathological alteration of pancreas tissues, intestinal mucosa, and the intestinal caspase-1 mRNA and protein expressions were assessed 24 hours after SAP induction. RESULTS: Rats in the SAP group had higher serum levels of IL-1 beta and IL-18 (P<0.05), pancreatic and gut pathological scores (P<0.05), and caspase-1 mRNA and protein expressions (P<0.05) compared with the SO group. Compared with the SAP group, rats in the EM and ICE-I groups had lower IL-1 beta and IL-18 levels (P<0.05), lower pancreatic and gut pathological scores (P<0.05), and decreased expression of intestine caspase-1 mRNA (P<0.05). Ultrastructural analysis by transmission electron microscopy found that rats in the SAP group had vaguer epithelial junctions, more disappeared intercellular joints, and more damaged intracellular organelles compared with those in the SO group or the EM and ICE-I groups. CONCLUSIONS: Emodin alleviated pancreatic and intestinal mucosa injury in experimental SAP. Its mechanism may partly be mediated by the inhibition of caspase-1 and its downstream inflammatory cytokines, including IL-1 beta and IL-18. Our animal data may be applicable in clinical practice.
基金Supported by the National Natural Science Foundation of China,No.81270462the International Cooperation Project of Jiangsu Province Department of Health,No.SBZ201100103
文摘AIM: To investigate whether resveratrol (3,4,5-trihydroxy-trans-stilbene) inhibits collagen I synthesis induced by insulin growth factor-1 (IGF-1) in intestinal fibroblasts, and to explore the possible molecular mechanisms.
基金supported by the National Natural Science Foundation of China(Nos.81330089,8167365881274165 and 81673713)the State Key Program for New Drugsfrom the Ministry of Science and Technology,China(No2018ZX0935003-002)
文摘Houttuynia cordata polysaccharide(HCP) is extracted from Houttuynia cordata, a key traditional Chinese medicine. The study was to investigate the effects of HCP on intestinal barrier and microbiota in H1N1 virus infected mice. Mice were infected with H1N1 virus and orally administrated HCP at a dosage of 40 mg×kg^(–1)×d^(–1). H1N1 infection caused pulmonary and intestinal injury and gut microbiota imbalance. HCP significantly suppressed the expression of hypoxia inducible factor-1α and decreased mucosubstances in goblet cells, but restored the level of zonula occludens-1 in intestine. HCP also reversed the composition change of intestinal microbiota caused by H1N1 infection, with significantly reduced relative abundances of Vibrio and Bacillus, the pathogenic bacterial genera. Furthermore, HCP rebalanced the gut microbiota and restored the intestinal homeostasis to some degree. The inhibition of inflammation was associated with the reduced level of Toll-like receptors and interleukin-1β in intestine, as well as the increased production of interleukin-10. Oral administration of HCP alleviated lung injury and intestinal dysfunction caused by H1N1 infection. HCP may gain systemic treatment by local acting on intestine and microbiota. This study proved the high-value application of HCP.
基金Supported by National Natural Science Foundation of China,No.30940069the Natural Sciences Foundation of Beijing,No.7102127
文摘AIM: To characterize high-mobility group protein 1-toll-like receptor 4(HMGB1-TLR4) and downstream signaling pathways in intestinal ischemia/reperfusion(I/R) injury.METHODS: Forty specific-pathogen-free male C57BL/6 mice were randomly divided into five groups(n = 8 per group): sham, control, anti-HMGB1, anti-myeloid differentiation gene 88(My D88), and anti-translocatingchain-associating membrane protein(TRIF) antibody groups. Vehicle with the control Ig G antibody, antiHMGB1, anti-My D88, or anti-TRIF antibodies(all 1 mg/kg, 0.025%) were injected via the caudal vein 30 min prior to ischemia. After anesthetization, the abdominal wall was opened and the superior mesenteric artery was exposed, followed by 60 min mesenteric ischemia and then 60 min reperfusion. For the sham group, the abdominal wall was opened for 120 min without I/R. Levels of serum nuclear factor(NF)-κB p65, interleukin(IL)-6, and tumor necrosis factor(TNF)-α were measured, along with myeloperoxidase activity in the lung and liver. Inaddition,morphologic changes that occurred in the lung and intestinal tissues were evaluated. Levels of m RNA transcripts encoding HMGB1 and NF-κB were measured by real-time quantitative PCR, and levels of HMGB1 and NF-κB protein were measured by Western blot. Results were analyzed using one-way analysis of variance.RESULTS: Blocking HMGB 1, MyD 8 8, and TRIF expression by injecting anti-HMGB1, anti-My D88, or anti-TRIF antibodies prior to ischemia reduced the levels of inflammatory cytokines in serum; NF-κB p65: 104.64 ± 11.89, 228.53 ± 24.85, 145.00 ± 33.63, 191.12 ± 13.22, and 183.73 ± 10.81(P < 0.05); IL-6: 50.02 ± 6.33, 104.91 ± 31.18, 62.28 ± 6.73, 85.90 ± 17.37, and 78.14 ± 7.38(P < 0.05); TNF-α, 43.79 ± 4.18, 70.81 ± 6.97, 52.76 ± 5.71, 63.19 ± 5.47, and 59.70 ± 4.63(P < 0.05) for the sham, control, anti-HMGB1, anti-My D88, and anti-TRIF groups, respectively(all in pg/m L).Antibodies also alleviated tissue injury in the lung and small intestine compared with the control group in the mouse intestinal I/R model. The administration of antiHMGB1, anti-My D88, and anti-TRIF antibodies markedly reduced damage caused by I/R, for which anti-HMGB1 antibody had the most obvious effect.CONCLUSION: HMGB1 and its downstream signaling pathway play important roles in the mouse intestinal I/R injury, and the effect of the TRIF-dependent pathway is slightly greater.
基金Supported by Key R&D Plan of Science and Technology Department of Jiangxi Province,No.20171BBG70087
文摘BACKGROUND It is challenging to distinguish intestinal tuberculosis from Crohn’s disease due to dynamic changes in epidemiology and similar clinical characteristics. Recent studies have shown that polymorphisms in genes involved in the interleukin (IL)- 23/IL-17 axis may affect intestinal mucosal immunity by affecting the differentiation of Th17 cells. AIM To investigate the specific single-nucleotide polymorphisms (SNPs) in genes involved in the IL-23/IL-17 axis and possible pathways that affect susceptibility to intestinal tuberculosis and Crohn's disease. METHODS We analysed 133 patients with intestinal tuberculosis, 128 with Crohn’s disease, and 500 normal controls. DNA was extracted from paraffin-embedded specimens or whole blood. Four SNPs in the IL23/Th17 axis (IL22 rs2227473, IL1β rs1143627, TGFβ rs4803455, and IL17 rs8193036) were genotyped with TaqMan assays. The transcriptional activity levels of different genotypes of rs2227473 were detected by dual luciferase reporter gene assay. The expression of IL-22R1 in different intestinal diseases was detected by immunohistochemistry. RESULTS The A allele frequency of rs2227473 (P = 0.030, odds ratio = 0.60, 95% confidence interval: 0.37-0.95) showed an abnormal distribution between intestinal tuberculosis and healthy controls. The presence of the A allele was associated with a higher IL-22 transcriptional activity (P < 0.05). In addition, IL-22R1 was expressed in intestinal lymphoid tissues, especially under conditions of intestinal tuberculosis, and highly expressed in macrophage-derived Langhans giant cells. The results of immunohistochemistry showed that the expression of IL-22R1 in patients with Crohn's disease and intestinal tuberculosis was significantly higher than that in patients with intestinal polyps and colon cancer (P < 0.01). CONCLUSION High IL-22 expression seems to be a protective factor for intestinal tuberculosis. IL-22R1 is expressed in Langhans giant cells, suggesting that the IL-22/IL-22R1 system links adaptive and innate immunity.
基金Supported by The Natural Science Foundation of Liaoning Province,No.20042135
文摘AIM： To investigate the role of nuclear factor kappa B （NF-κB） in the pathogenesis of lung injury induced by intestinal ischemia/reperfusion （I/R）, and its effect on intercellular adhesion molecule-1 （ICAM-1） expression and neutrophil infiltration. METHODS： Twenty-four Wistar rats were divided randomly into control, I/R and pyrrolidine dithiocarbamate （PDTC） treatment groups, n = 8 in each. I/R group and PDTC treatment group received superior mysenteric artery （SMA） occluding for 1 h and reperfusion for 2 h. PDTC group was administrated with intraperitoneal injection of 2% 100 mg/kg PDTC 1 h before surgery. Lung histology and bronchia alveolus lung fluid （BALF） protein were assayed. Serum IL-6, lung malondialdehyde （MDA） and myeloperoxidase （MPO） as well as the expression level of NF-κB and ICAM-1 were measured.RESULTS： Lung injury induced by intestinal I/R, was characterized by edema, hemorrhage and neutrophil infiltration as well as by the significant rising of BALF protein. Compared to control group, the levels of serum IL-6 and lung MDA and MPO increased significantly in I/R group （P=0.001）. Strong positive expression of NF-κB p65 and ICAM-1 was observed. After the administration of PDTC, the level of serum IL-6, lung MDA and MPO as well as NF-κB and ICAM-1 decreased significantly （P〈 0.05） when compared to I/R group.CONCLUSION： The activation of NF-κB plays an important role in the pathogenesis of lung injury induced by intestinal I/R through upregulating the neutrophil infiltration and lung ICAM-1 expression. PDTC as an inhibitor of NF-κB can prevent lung injury induced by intestinal I/R through inhibiting the activity of NF-κB.
文摘Background Myocardial infarction （MI） has likely contributed to the increased prevalence of heart failure （HF）. As a result of re- duced cardiac function, splanchnic blood flow decreases, causing ischemia in villi and damage to the intestinal barrier. The induction of heme oxygenase-1 （HO-1） could prevent, or lessen the effects of stress and inflammation. Thus, the effect and mechanism thereof of HO-1 on the intestines of rats with HF was investigated. Methods Male Wistar rats with heart failure through ligation of the left coronary artery were identified with an left ventricular ejection fraction of 〈 45% through echocardiography and then divided into various experimental groups based on the type of peritoneal injection they received [MI： saline; MI ＋ Cobalt protoporphyrin （CoPP）： CoPP solution; and MI ＋ Tin mesoporphyrin IX dichloride （SnMP）： SnMP solution]. The control group was comprised of rats without coronary ligation. Echocardiogra- phy was performed before ligation for a baseline and eight weeks after ligation in order to evaluate the cardiac function of the rats. The bac- terial translocation （BT） incidence, mesenteric microcirculation, amount of endotoxins in the vein serum, ileum levels of HO- 1, carbon oxide （CO）, nitric oxide （NO）, intedeuldn （IL）-10, turnour necrosis factor-et （TNF-ct）, and the ileum morphology were determined eight weeks after the operation. Results The rats receiving MI ＋ CoPP injections exhibited a recovery in cardiac function, an amelioration of mesenteric microcirculation and change in morphology, a lower BT incidence, a reduction in serum and ileac NO and TNF-ct levels, and an elevation in ileac HO-1, CO, and interleukin-10 （[L-10） levels compared to the MI group （P 〈 0.05）. The rats that received the MI ＋ SnMP injections exhibited results inverse to the MI （P 〈 0.05） group. Conclusions HO-1 exerted a protective effect on the intestines of rats with HF by inhibiting the inflammation and amelioration of microcirculation through the CO pathway. This protective effect could be independent from the recovery of cardiac function.
基金MEXT,KAKENHI,No.15K08978,No.22790677 and No.25860571a MEXT-Supported Program supporting research activities of female researchers+1 种基金the Clinical Research Foundationthe Central Research Institute of Fukuoka University,No.151045 and No.147104
文摘AIM To investigate the anti-fibrotic effects of the traditional oriental herbal medicine Daikenchuto(DKT) associated with transient receptor potential ankyrin 1(TRPA1) channels in intestinal myofibroblasts. METHODS Inflammatory and fibrotic changes were detected in a2,4,6-trinitrobenzenesulfonic acid(TNBS) chronic colitis model of wild-type and TRPA1-knockout(TRPA1-KO) mice via pathological staining and immunoblotting analysis.Ca^(2+) imaging experiments examined the effects of DKT and its components/ingredients on intestinal myofibroblast(In Myo Fib) cell TRPA1 channel function.Profibrotic factors and transforming growth factor (TGF) -β1-associated signaling were tested in an In Myo Fib cell line by q PCR and immunoblotting experiments.Samples from non-stenotic and stenotic regions of the intestines of patients with Crohn’s disease (CD) were used for pathological analysis. RESULTS Chronic treatment with TNBS caused more severe inflammation and fibrotic changes in TRPA1-KO than in wild-type mice.A one-week enema administration of DKT reduced fibrotic lesions in wild-type but not in TRPA1-KO mice.The active ingredients of DKT,i.e.,hydroxyα-sanshool and 6-shogaol,induced Ca^(2+) influxes in In Myo Fib,and this was antagonized by co-treatment with a selective TRPA1 channel blocker,HC-030031.DKT counteracted TGF-β1-induced expression of TypeⅠcollagen andα-smooth muscle actin (α-SMA) ,which were accompanied by a reduction in the phosphorylation of Smad-2 and p38-mitogen-activated protein kinase (p38-MAPK) and the expression of myocardin.Importantly,24-h incubation with a DKT active component Japanese Pepper increased the m RNA and protein expression levels of TRPA1 in In Myo Fibs,which in turn negatively regulated collagen synthesis.In the stenotic regions of the intestines of CD patients,TRPA1 expression was significantly enhanced.CONCLUSION The effects of DKT on the expression and activation of the TRPA1 channel could be advantageous for suppressing intestinal fibrosis,and benefit inflammatory bowel disease treatment.
基金Supported by Scientific Research Foundation of the Chinese PLA Key Medical Programs During the 10th Five-Year Plan Period, No. 01Z011
文摘AIM: Nuclear factor kappa B (NF-κB) regulates a large number of genes involved in the inflammatory response to critical illnesses, but it is not known if and how NF-KB is activated and intercellular adhesion molecule-1 (ICAM-1) expressed in the gut following traumatic brain injury (TBI). The aim of current study was to investigate the temporal pattern of intestinal NF-κB activation and ICAM-1 expression following TBI. METHODS: Male Wistar rats were randomly divided into six groups (6 rats in each group) including controls with sham operation and TBI groups at hours 3, 12, 24, and 72, and on d 7. Parietal brain contusion was adopted using weight-dropping method. All rats were decapitated at corresponding time point and mid-jejunum samples were taken. NF-KB binding activity in jejunal tissue was measured using EMSA. Immunohistochemistry was used for detection of ICAM-1 expression in jejunal samples. RESULTS: There was a very low NF-κB binding activity and little ICAM-1 expression in the gut of control rats after sham surgery. NF-KB binding activity in jejunum significantly increased by 160% at 3 h following TBI (P<0.05 vs control), peaked at 72 h (500% increase) and remained elevated on d 7 post-injury by 390% increase. Compared to controls, ICAM-1 was significantly up-regulated on the endothelia of microvessels in villous interstitium and lamina propria by 24 h following TBI and maximally expressed at 72 h post-injury (P<0.001). The endothelial ICAM-1 immunoreactivity in jejunal mucosa still remained strong on d 7 post-injury. The peak of NF-κB activation and endothelial ICAM-1 expression coincided in time with the period during which secondary mucosal injury of the gut was also at their culmination following TBI. CONCLUSION: TBI could induce an immediate and persistent up-regulation of NF-κB activity and subsequent up-regulation of ICAM-1 expression in the intestine. Inflammatory response mediated by increased NF-κB activation and ICAM-1 expression may play an important role in the pathogenesis of acute gut mucosal injury following TBI.
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 the National Natural Science Foundation of China,No.81600446Natural Science Foundation of Liaoning Province,China,No.201102048Natural Science Foundation of Dalian Medical Association,No.w SJ/KJC-01-JL-01
文摘AIM To evaluate whether fish oil(FO) can protect liver injury induced by intestinal ischemia/reperfusion(I/R) via the AMPK/SIRT-1/autophagy pathway.METHODS Ischemia in wistar rats was induced by superior mesenteric artery occlusion for 60 min and reperfusion for 240 min. One milliliter per day of FO emulsion or normal saline was administered by intraperitoneal injection for 5 consecutive days to each animal. Animals were sacrificed at the end of reperfusion. Blood andtissue samples were collected for analyses. AMPK, SIRT-1, and Beclin-1 expression was determined in lipopolysaccharide(LPS)-stimulated HepG2 cells with or without FO emulsion treatment.RESULTS Intestinal I/R induced significant liver morphological changes and increased serum alanine aminotransferase and aspartate aminotransferase levels. Expression of p-AMPK/AMPK, SIRT-1, and autophagy markers was decreased whereas tumor necrosis factor-α(TNF-α) and malonaldehyde(MDA) were increased. FO emulsion blocked the changes of the above indicators effectively. Besides, in LPS-stimulated HepG2 cells, small interfering RNA(siRNA) targeting AMPK impaired the FO induced increase of p-AMPK, SIRT-1, and Beclin-1 and decrease of TNF-α and MDA. SIRT-1 siRNA impaired the increase of SIRT-1 and Beclin-1 and the decrease of TNF-α and MDA.CONCLUSION Our study indicates that FO may protect the liver against intestinal I/R induced injury through the AMPK/SIRT-1/autophagy pathway.
基金supported by the National Natural Science Foundation of China(Nos.81773971,82074058,82104438,and 82104437)the China Postdoctoral Science Foundation(Nos.2021M693518 and 2021M693519)+2 种基金the Natural Science Foundation of Jiangsu Province(Nos.SBK20210432 and SBK20210431)the National Science Foundation for the Third Batch of Special Funding for Postdoctoral Fellows(No.2021TQ0367)the“Double First-Class”University Project(No.CPU2018GF07)。
文摘Ischemic stroke causes brain inflammation and multi-organ injury,which is closely associated with the peroxisome proliferator-activated receptor-gamma(PPARγ)signaling pathway.Recent studies have indicated that ginsenoside Rb1(GRb1)can protect the integrity of the blood-brain barrier after stroke.In the current study,a mouse model of middle cerebral artery occlusion/reperfusion(MCAO/R)was established to determine whether GRb1 can ameliorate brain/lung/intestinal barrier damage via the PPARγsignaling pathway.Staining(2,3,5-triphenyltetrazolium chloride,hematoxylin,and eosin)and Doppler ultrasonography were employed to detect pathological changes.Endothelial breakdown was investigated with the leakage of Evans Blue dye and the expression of TJs(tight junctions)and AJs(adherent junctions).Western blot and immunofluorescence were used to determine the levels of cell junction proteins,PPARγand NF-κB.Results showed that GRb1 significantly mitigated multi-organ injury and increased the expression of cerebral microvascular,pulmonary vascular,and intestinal epithelial connexins.In brain,lung,and intestinal tissues,GRb1 activated PPARγ,decreased the levels of phospho-NF-κB p65,and inhibited the production of proinflammatory cytokines,thereby maintaining barrier permeability.However,co-treatment with GRb1 and the PPARγantagonist GW9662 reversed the barrier-protective effect of GRb1.These findings indicated that GRb1 can improve stroke-induced brain/lung/intestinal barrier damagevia the PPARγpathway.
