BACKGROUND In the biologic era,postoperative recurrence(POR)of Crohn’s disease(CD)remains a significant concern.The underlying cause of this phenomenon remains unclear at present.AIM To examine whether intestinal fib...BACKGROUND In the biologic era,postoperative recurrence(POR)of Crohn’s disease(CD)remains a significant concern.The underlying cause of this phenomenon remains unclear at present.AIM To examine whether intestinal fibrosis increases the likelihood of POR when antitumor necrosis factor biologics are used following ileocecal resection(ICR).METHODS We performed a single-centre,retrospective cohort study of patients with CD who underwent ICR.Recurrence was defined by endoscopy(Rutgeerts score≥i2),radiography(active inflammation in the neoterminal ileum)or surgery(another resection>3 months post-ICR),and patients were categorised by the presence of intestinal fibrosis on histopathological evaluation.RESULTS Among 102 patients with CD who underwent ICR and received infliximab within 3 months,69(67.6%)had intestinal fibrosis.In addition,60 patients(58.8%)experienced POR in various forms:52.6%,41.2%,and 10.8%had endoscopic,radiographic,and surgical recurrence,respectively.Patients with intestinal fibrosis experienced faster radiographic recurrence(log rank P=0.03).After adjusting for risk factors associated with POR,intestinal fibrosis increased the risk of early radiographic recurrence(adjusted hazard ratio=4;95%confidence interval:1.03-15.56;P=0.045).CONCLUSION Despite the limited sample size,our study revealed a strong correlation between radiographic POR and intestinal fibrosis in patients who received postoperative anti-tumor necrosis factorαprophylaxis.展开更多
Objectives:A common side effect of inflammatory bowel disease(IBD)is intestinal fibrosis,which frequently leads to intestinal blockage and stricture formation.Although Thalidomide(THD)has shown anti-fibrotic benefits ...Objectives:A common side effect of inflammatory bowel disease(IBD)is intestinal fibrosis,which frequently leads to intestinal blockage and stricture formation.Although Thalidomide(THD)has shown anti-fibrotic benefits in hepatic and renal models,little is known about how it affects intestinal fibrosis and the underlying processes.The present research examines the molecular targets of THD and its potential as a treatment for intestinal fibrosis brought on by colitis.Methods:Clinical samples from Crohn’s disease(CD)patients with intestinal strictures treated with infliximab(IFX)and THD combined with IFX were collected.Dextran sulfate sodium(DSS)was used to develop a mouse model of intestinal fibrosis in C57BL/6 mice.Anti-tumor necrosis factor-alpha(Anti-TNFα),THD,or a combination of the two were administered to the mice.Body weight,colon length,histology,and disease activity index were used to evaluate the disease’s severity.In vitro,THD was tested on colonic fibroblast lines(CCD-18Co and MPF)to assess its effects on cell proliferation,motility,and transdifferentiation.To examine changes in gene expression and signaling pathway modifications,namely in the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/AKT/mTOR)pathway,RNA sequencing,qRT-PCR,and Western blotting were carried out.Results:In DSS-induced colitis,THD therapy lowered fibrosis,as seen by downregulated fibrotic markers(α-smooth muscle actin(α-SMA),collagen I,and collagen III)and decreased collagen deposition.Mechanistically,THD prevented fibroblasts from transdifferentiating and decreased their vitality.Furthermore,THD inhitited the PI3K/AKT/mTOR pathway in vivo and in vitro.Conclusion:THD inhibits the PI3K/AKT/mTOR signaling cascade and suppresses colonic fibroblast transdifferentiation,which protects against DSS-induced colitis-associated fibrosis,especially when combined with anti-TNFαtherapy.展开更多
Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in s...Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelialand endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic proc-ess, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.展开更多
BACKGROUND Inflammatory bowel disease(IBD) is a complex chronic IBD that is closely associated with risk factors such as environment, diet, medications and lifestyle that may influence the host microbiome or immune re...BACKGROUND Inflammatory bowel disease(IBD) is a complex chronic IBD that is closely associated with risk factors such as environment, diet, medications and lifestyle that may influence the host microbiome or immune response to antigens. At present, with the increasing incidence of IBD worldwide, it is of great significance to further study the pathogenesis of IBD and seek new therapeutic targets. Traditional Chinese medicine(TCM) treatment of diseases is characterized by multiple approaches and multiple targets and has a long history of clinical application in China. The mechanism underlying the effect of zedoary turmerictrisomes on inducing mucosal healing in IBD is not clear.AIM To explore the effective components and potential mechanism of zedoary turmeric-trisomes in the treatment of IBD with intestinal fibrosis using network pharmacology and molecular docking techniques.METHODS The chemical constituents and targets of Rhizoma zedoary and Rhizoma sanarum were screened using the TCMSP database. The GeneCards database was searched to identify targets associated with intestinal fibrosis in IBD. The intersection of chemical component targets and disease targets was obtained using the Venny 2.1 online analysis platform, and the common targets were imported into the STRING 11.0 database to construct a protein interaction regulatory network. A “zedoary turmeric-trisomes-chemical composition-target-disease” network diagram was subsequently constructed using Cytoscape 3.7.2 software, and the topological properties of the network were analyzed using the “Network Analysis” plug-in. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses of the common targets were performed using the DAVID 6.8 database to elucidate the mechanism of zedoary turmeric-trisomes in the treatment of IBD. Subsequently, molecular docking of the compounds and targets with the highest intermediate values in the “zedoary turmeric-trisomes-chemical composition-target-disease” network was performed using Sybyl-x 2.1.1 software.RESULTS A total of 5 chemical components with 60 targets were identified, as well as 3153 targets related to IBD and 44 common targets. The protein-protein interaction network showed that the core therapeutic targets included JUN, MAPK14, CASP3, AR, and PTGS2. The GO enrichment analysis identified 759 items, and the KEGG enrichment analysis yielded 52 items, including the cancer pathway, neuroactive ligand-receptor interaction, hepatitis B, and the calcium signaling pathway, reflecting the complex biological processes of the multicomponent, multitarget and multipathway treatment of diseases with zedoary turmeric-trisomes. Molecular docking showed that the compound bonded with the target through hydrogen bond interactions and exhibited good docking activity.CONCLUSION This study identified the potential mechanism of action of zedoary turmeric-trisomes in the treatment of inflammatory bowel fibrosis using network pharmacology and molecular docking technology, providing a scientific basis for further expansion of their clinical use.展开更多
Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases,but no effective anti-fibrotic therapy is currently available.Glucagon receptor(GCGR)and glucagon-like peptide 1 receptor(GLP1R)ar...Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases,but no effective anti-fibrotic therapy is currently available.Glucagon receptor(GCGR)and glucagon-like peptide 1 receptor(GLP1R)are both peptide hormone receptors involved in energy metabolism of epithelial cells.However,their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored.Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn’s disease as well as in the fibrotic colon of mice with chronic colitis.The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate,resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition(EMT).Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo.We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation.Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.展开更多
Intestinal fibrosis is a major complication of inflammatory bowel disease(IBD),leading to a high incidence of surgical interventions and significant disability.Despite its clinical relevance,no targeted pharmacologica...Intestinal fibrosis is a major complication of inflammatory bowel disease(IBD),leading to a high incidence of surgical interventions and significant disability.Despite its clinical relevance,no targeted pharmacological therapies are currently available.This review aims to explore the underlying mechanisms driving intestinal fibrosis and address unresolved scientific questions,offering insights into potential future therapeutic strategies.We conducted a literature review using data from PubMed up to October 2024,focusing on studies related to IBD and fibrosis.Intestinal fibrosis results from a complex network involving stromal cells,immune cells,epithelial cells,and the gut microbiota.Chronic inflammation,driven by factors such as dysbiosis,epithelial injury,and immune activation,leads to the production of cytokines like interleukin(IL)-1β,IL-17,and transforming growth factor(TGF)-β.These mediators activate various stromal cell populations,including fibroblasts,pericytes,and smooth muscle cells.The activated stromal cells secrete excessive extracellular matrix components,thereby promoting fibrosis.Additionally,stromal cells influence the immune microenvironment through cytokine production.Future research would focus on elucidating the temporal and spatial relationships between immune cell-driven inflammation and stromal cell-mediated fibrosis.Additionally,investigations are needed to clarify the differentiation origins of excessive extracellular matrix-producing cells,particularly fibroblast activation protein(FAP)+fibroblasts,in the context of intestinal fibrosis.In conclusion,aberrant stromal cell activation,triggered by upstream immune signals,is a key mechanism underlying intestinal fibrosis.Further investigations into immune–stromal cell interactions and stromal cell activation are essential for the development of therapeutic strategies to prevent,alleviate,and potentially reverse fibrosis.展开更多
Objective: The objective of the study was to explore the potential signaling mechanism of Aconitum tanguticum(Maxim.) Stapf(ATS) and its impact on intestinal fibrosis in vitro. Methods: Network pharmacology was used t...Objective: The objective of the study was to explore the potential signaling mechanism of Aconitum tanguticum(Maxim.) Stapf(ATS) and its impact on intestinal fibrosis in vitro. Methods: Network pharmacology was used to screen the active components of ATS and predict their potential targets in intestinal fibrosis. The protein–protein interaction network graph was constructed using drug–disease intersection targets retrieved from the Search Tool for Retrieval of Interacting Genes/Proteins database. The network diagram was analyzed using Cytoscape 3.6.1'stopology function. The gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted using the database for annotation, visualization, and integrated discovery platform. Intestinal fibroblast model in vitro was constructed using transforming growth factor-β1(TGF-β1)-induced CCD-18Co cells. Quantitative reverse transcription polymerase chain reaction(qRT-PCR)was used to verify the network pharmacology-predicted antifibrotic signaling pathway of ATS and the traditional antifibrotic signaling pathway. Results: Network pharmacology revealed that there were 19 active components in ATS, suggesting that ATS could be involved in the regulation of mitogen-activated protein kinase 1(MAPK1), PIK3CA, MAPK3, and other important targets that are present in cancer pathways, including proteoglycans, infiuenza A, and phosphatidylinositol-3-kinase(PI3K)-protein kinase B(Akt) signaling pathways. The results of quantitative reverse transcription-polymerase chain reaction(qRT-PCR) demonstrated that 0.1–1 μg/mL ATS may suppress tissue inhibitor of metalloproteinase 1, collagen I, and alpha-smooth muscle actin expression levels. The expression of the TGF-β/suppressor of the mother against decapentaplegic(Smad) and PI3K/Akt signaling pathways was controlled by ATS. In addition, ATS inhibited the PI3K/Akt pathway by reducing the expression of MAPK1, HSP90AA1, and PIK3CA. Conclusions: It has been confirmed that ATS is a multipathway and multitarget treatment for intestinal fibrosis. This study suggested that ATS might alleviate intestinal fibrosis by blocking both the TGF-β/Smad and the PI3K/Akt pathway.展开更多
Ulcerative colitis(UC)is an idiopathic,relapsing,and etiologically complicated chronic inflammatory bowel disease.Despite substantial progress in the management of UC,the outcomes of mucosal barrier repair are unsatis...Ulcerative colitis(UC)is an idiopathic,relapsing,and etiologically complicated chronic inflammatory bowel disease.Despite substantial progress in the management of UC,the outcomes of mucosal barrier repair are unsatisfactory.In this study,phillygenin(PHI)treatment alleviated the symptoms of chronic colitis in mice,including body weight loss,severe disease activity index scores,colon shortening,splenomegaly,oxidative stress,and inflammatory response.In particular,PHI treatment ameliorated the tight junction proteins(TJs)reduction,fibrosis,apoptosis,and intestinal stem cell activity,indicating that PHI exerted beneficial effects on the intestinal mucosal barrier in mice with chronic colitis.In the NCM460 cells damage model,dextran sulfate sodium triggered the sequential induction of TJs reduction,fibrosis,and apoptosis.Takeda G protein-coupled receptor-5(TGR5)dysfunction mediated NCM460 cell injury.Moreover,PHI treatment enhanced TJs and suppressed fibrosis and apoptosis to maintain NCM460 cell function,depending on TGR5 activation.PHI promoted TGR5 activation and elevated intracellular cyclic adenosine monophosphate levels in HEK 293T cells transfected with TGR5 expression plasmids.Cellular thermal shift assay and molecular docking studies confirmed that PHI directly binds to TGR5,indicating that PHI is an agonist of TGR5.The process of PERK-eIF2α pathway-mediated endoplasmic reticulum Ca^(2+) release was involved in NCM460 cell injury as well,which was associated with TGR5 dysfunction.When NCM460 cells were pretreated with PHI,the PERK-eIF2α pathway and elevated Ca^(2+) levels were blocked.In conclusion,our study demonstrated a novel mechanism that PHI inhibited the PERK-eIF2α-Ca^(2+) pathway through TGR5 activation to against DSS-induced TJs reduction,fibrosis,and apoptosis.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
BACKGROUND Inflammatory bowel disease,particularly Crohn’s disease(CD),has been associated with alterations in mesenteric adipose tissue(MAT)and the phenomenon termed“creeping fat”.Histopathological evaluations sho...BACKGROUND Inflammatory bowel disease,particularly Crohn’s disease(CD),has been associated with alterations in mesenteric adipose tissue(MAT)and the phenomenon termed“creeping fat”.Histopathological evaluations showed that MAT and intestinal tissues were significantly altered in patients with CD,with these tissues characterized by inflammation and fibrosis.AIM To evaluate the complex interplay among MAT,creeping fat,inflammation,and gut microbiota in CD.METHODS Intestinal tissue and MAT were collected from 12 patients with CD.Histological manifestations and protein expression levels were analyzed to determine lesion characteristics.Fecal samples were collected from five recently treated CD patients and five control subjects and transplanted into mice.The intestinal and mesenteric lesions in these mice,as well as their systemic inflammatory status,were assessed and compared in mice transplanted with fecal samples from CD patients and control subjects.RESULTS Pathological examination of MAT showed significant differences between CDaffected and unaffected colons,including significant differences in gut microbiota structure.Fetal microbiota transplantation(FMT)from clinically healthy donors into mice with 2,4,6-trinitrobenzene sulfonic acid(TNBS)-induced CD ameliorated CD symptoms,whereas FMT from CD patients into these mice exacerbated CD symptoms.Notably,FMT influenced intestinal permeability,barrier function,and levels of proinflammatory factors and adipokines.Furthermore,FMT from CD patients intensified fibrotic changes in the colon tissues of mice with TNBS-induced CD.CONCLUSION Gut microbiota play a critical role in the histopathology of CD.Targeting MAT and creeping fat may therefore have potential in the treatment of patients with CD.展开更多
We would like to present some new thoughts on the publication in the journalpublished in August 2024 in World Journal of Gastroenterology.We specificallyfocused on the alterations in the intestinal tract,mesenteric ad...We would like to present some new thoughts on the publication in the journalpublished in August 2024 in World Journal of Gastroenterology.We specificallyfocused on the alterations in the intestinal tract,mesenteric adipose tissue(MAT),and systemic inflammatory changes in mice following fecal flora transplantationinto a mouse model of Crohn's disease(CD).Accumulating evidence suggests thatthe occurrence of CD is influenced by environmental factors,host immune status,genetic susceptibility,and flora imbalance.One microbiota-based intervention,fecal microbiota transplantation,has emerged as a potential treatment option forCD.The MAT is considered a"second barrier"around the inflamed intestine.Theinteraction between gut microbes and inflammatory changes in MAT has attractedconsiderable interest.In the study under discussion,the authors transplantedfetal fecal microorganisms from patients with CD and clinically healthy donors,respectively,into 2,4,6-trinitrobenzene sulfonic acid-induced CD mice.Theresearch explored the complex interplay between MAT,creeping fat,inflammation,and intestinal flora in CD by evaluating intestinal and mesenteric lesions,along with the systemic inflammatory state in the mice.This article providesseveral important insights.First,the transplantation of intestinal flora holdssignificant potential as a therapeutic strategy for CD,offering hope for patientswith CD.Second,it presents a novel approach to the diagnosis and treatment ofCD:The inflammatory response in CD could potentially be assessed throughpathological or imaging changes in the MAT,and CD could be treated bytargeting the inflammation of the MAT.展开更多
Simultaneous management of intestinal mucosal barrier dysfunction and gut microbiota dysregulation represents a significant challenge in the treatment of inflammatory bowel disease(IBD).Herein,we report a novel system...Simultaneous management of intestinal mucosal barrier dysfunction and gut microbiota dysregulation represents a significant challenge in the treatment of inflammatory bowel disease(IBD).Herein,we report a novel system that integrates multi-enzyme mimicking cerium single-atom nanocatalysts(CeSACs)with Lactobacillus reuteri probiotics(LR@CeSACs)for multipronged management of IBD.In this system,CeSACs demonstrate robust multi-enzyme activities across a broad pH range,effectively scavenging elevated reactive oxygen species,downregulating pro-inflammatory cytokines,and suppressing the expression of fibrosis-related genes.Moreover,probiotics promote the targeting and retention of the CeSACs for sustained catalytic antioxidant therapy.In turn,the inflammation relief enabled by CeSACs promotes bacterial viability,allowing for the rapid reshaping of intestinal barrier function and the restoration of gut microbiota.Therefore,LR@CeSACs exhibit excellent catalytic anti-inflammatory and anti-fibrotic therapeutic effects,as well as a certain prophylactic effect,as demonstrated in several murine models.展开更多
Background This study explored the diagnostic performance of visceral adiposity to predict the degree of intestinal inflammation and fibrosis.Methods The patients with Crohn’s disease(CD)who underwent surgical small ...Background This study explored the diagnostic performance of visceral adiposity to predict the degree of intestinal inflammation and fibrosis.Methods The patients with Crohn’s disease(CD)who underwent surgical small bowel resection at the First Affiliated Hospital of Sun Yat-sen University(Guangzhou,China)between January 2007 and December 2017 were enrolled.We evaluated the intestinal imaging features of computed tomography enterography(CTE),including mesenteric inflammatory fat stranding,the target sign,mesenteric hypervascularity,bowel wall thickening,lymphadenopathy,stricture diameter,and maximal upstream diameter.We used A.K.software(Artificial Intelligence Kit,version 1.1)to calculate the visceral fat(VF)and subcutaneous fat(SF)volumes at the third lumbar vertebra level.Pathological tissue information was recorded.Diagnostic models were established based on the multivariate regression analysis results,and their effectiveness was evaluated by area under the curve(AUC)and decision curve analyses.Results Overall,48 patients with CD were included in this study.The abdominal VF/SF volume ratio(odds ratio,1.20;95%confidence interval,1.05–1.38;P=0.009)and the stenosis diameter/upstream intestinal dilatation diameter(ND)ratio(odds ratio,0.90;95%confidence interval,0.82–0.99;P=0.034)were independent risk factors for the severe fibrosis of the small intestine.The AUC values of the VF/SF ratio,the ND ratio,and their combination were 0.760,0.673,and 0.804,respectively.The combination of the VS/SF volume ratio and ND ratio achieved the highest net benefit on the decision curve.Conclusion The VF volume on CTE can reflect intestinal fibrosis.The combination of the VF/SF volume ratio and ND ratio of CD patients assessed using CTE can help predict severe fibrosis stenosis of the small intestine.展开更多
基金Supported by the National Natural Science Foundation of China,No.82200621the Original Research Projects,Shanghai Ninth People’s Hospital,No.2022LHA08 and No.YBKB202220.
文摘BACKGROUND In the biologic era,postoperative recurrence(POR)of Crohn’s disease(CD)remains a significant concern.The underlying cause of this phenomenon remains unclear at present.AIM To examine whether intestinal fibrosis increases the likelihood of POR when antitumor necrosis factor biologics are used following ileocecal resection(ICR).METHODS We performed a single-centre,retrospective cohort study of patients with CD who underwent ICR.Recurrence was defined by endoscopy(Rutgeerts score≥i2),radiography(active inflammation in the neoterminal ileum)or surgery(another resection>3 months post-ICR),and patients were categorised by the presence of intestinal fibrosis on histopathological evaluation.RESULTS Among 102 patients with CD who underwent ICR and received infliximab within 3 months,69(67.6%)had intestinal fibrosis.In addition,60 patients(58.8%)experienced POR in various forms:52.6%,41.2%,and 10.8%had endoscopic,radiographic,and surgical recurrence,respectively.Patients with intestinal fibrosis experienced faster radiographic recurrence(log rank P=0.03).After adjusting for risk factors associated with POR,intestinal fibrosis increased the risk of early radiographic recurrence(adjusted hazard ratio=4;95%confidence interval:1.03-15.56;P=0.045).CONCLUSION Despite the limited sample size,our study revealed a strong correlation between radiographic POR and intestinal fibrosis in patients who received postoperative anti-tumor necrosis factorαprophylaxis.
文摘Objectives:A common side effect of inflammatory bowel disease(IBD)is intestinal fibrosis,which frequently leads to intestinal blockage and stricture formation.Although Thalidomide(THD)has shown anti-fibrotic benefits in hepatic and renal models,little is known about how it affects intestinal fibrosis and the underlying processes.The present research examines the molecular targets of THD and its potential as a treatment for intestinal fibrosis brought on by colitis.Methods:Clinical samples from Crohn’s disease(CD)patients with intestinal strictures treated with infliximab(IFX)and THD combined with IFX were collected.Dextran sulfate sodium(DSS)was used to develop a mouse model of intestinal fibrosis in C57BL/6 mice.Anti-tumor necrosis factor-alpha(Anti-TNFα),THD,or a combination of the two were administered to the mice.Body weight,colon length,histology,and disease activity index were used to evaluate the disease’s severity.In vitro,THD was tested on colonic fibroblast lines(CCD-18Co and MPF)to assess its effects on cell proliferation,motility,and transdifferentiation.To examine changes in gene expression and signaling pathway modifications,namely in the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/AKT/mTOR)pathway,RNA sequencing,qRT-PCR,and Western blotting were carried out.Results:In DSS-induced colitis,THD therapy lowered fibrosis,as seen by downregulated fibrotic markers(α-smooth muscle actin(α-SMA),collagen I,and collagen III)and decreased collagen deposition.Mechanistically,THD prevented fibroblasts from transdifferentiating and decreased their vitality.Furthermore,THD inhitited the PI3K/AKT/mTOR pathway in vivo and in vitro.Conclusion:THD inhibits the PI3K/AKT/mTOR signaling cascade and suppresses colonic fibroblast transdifferentiation,which protects against DSS-induced colitis-associated fibrosis,especially when combined with anti-TNFαtherapy.
文摘Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelialand endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic proc-ess, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.
基金Supported by General Research of Xi’an Science and Technology Planning Project,No. 2022JH-YBYJ-0265Shaanxi Province Natural Science Basic Research Program-General Project,No:2019JM-580 and 2021SF-314+1 种基金Project of Shaanxi Administration of Traditional Chinese Medicine,No. 2019-ZZ-JC010Shaanxi Provincial Hospital of Traditional Chinese Medicine,No. 2021-07, 2018-04
文摘BACKGROUND Inflammatory bowel disease(IBD) is a complex chronic IBD that is closely associated with risk factors such as environment, diet, medications and lifestyle that may influence the host microbiome or immune response to antigens. At present, with the increasing incidence of IBD worldwide, it is of great significance to further study the pathogenesis of IBD and seek new therapeutic targets. Traditional Chinese medicine(TCM) treatment of diseases is characterized by multiple approaches and multiple targets and has a long history of clinical application in China. The mechanism underlying the effect of zedoary turmerictrisomes on inducing mucosal healing in IBD is not clear.AIM To explore the effective components and potential mechanism of zedoary turmeric-trisomes in the treatment of IBD with intestinal fibrosis using network pharmacology and molecular docking techniques.METHODS The chemical constituents and targets of Rhizoma zedoary and Rhizoma sanarum were screened using the TCMSP database. The GeneCards database was searched to identify targets associated with intestinal fibrosis in IBD. The intersection of chemical component targets and disease targets was obtained using the Venny 2.1 online analysis platform, and the common targets were imported into the STRING 11.0 database to construct a protein interaction regulatory network. A “zedoary turmeric-trisomes-chemical composition-target-disease” network diagram was subsequently constructed using Cytoscape 3.7.2 software, and the topological properties of the network were analyzed using the “Network Analysis” plug-in. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses of the common targets were performed using the DAVID 6.8 database to elucidate the mechanism of zedoary turmeric-trisomes in the treatment of IBD. Subsequently, molecular docking of the compounds and targets with the highest intermediate values in the “zedoary turmeric-trisomes-chemical composition-target-disease” network was performed using Sybyl-x 2.1.1 software.RESULTS A total of 5 chemical components with 60 targets were identified, as well as 3153 targets related to IBD and 44 common targets. The protein-protein interaction network showed that the core therapeutic targets included JUN, MAPK14, CASP3, AR, and PTGS2. The GO enrichment analysis identified 759 items, and the KEGG enrichment analysis yielded 52 items, including the cancer pathway, neuroactive ligand-receptor interaction, hepatitis B, and the calcium signaling pathway, reflecting the complex biological processes of the multicomponent, multitarget and multipathway treatment of diseases with zedoary turmeric-trisomes. Molecular docking showed that the compound bonded with the target through hydrogen bond interactions and exhibited good docking activity.CONCLUSION This study identified the potential mechanism of action of zedoary turmeric-trisomes in the treatment of inflammatory bowel fibrosis using network pharmacology and molecular docking technology, providing a scientific basis for further expansion of their clinical use.
基金supported by the National Key R&D Program of China(2023YFC2507300)the National Natural Science Foundation of China(82273761,81970483,82170537 and 82222010)the Medical Innovation and Development Project of Lanzhou University(lzuyxcx-2022-156,China).
文摘Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases,but no effective anti-fibrotic therapy is currently available.Glucagon receptor(GCGR)and glucagon-like peptide 1 receptor(GLP1R)are both peptide hormone receptors involved in energy metabolism of epithelial cells.However,their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored.Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn’s disease as well as in the fibrotic colon of mice with chronic colitis.The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate,resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition(EMT).Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo.We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation.Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.
基金supported by grants from the National Natural Science Foundation of China(Nos.82341221,82100538,and 82370549).
文摘Intestinal fibrosis is a major complication of inflammatory bowel disease(IBD),leading to a high incidence of surgical interventions and significant disability.Despite its clinical relevance,no targeted pharmacological therapies are currently available.This review aims to explore the underlying mechanisms driving intestinal fibrosis and address unresolved scientific questions,offering insights into potential future therapeutic strategies.We conducted a literature review using data from PubMed up to October 2024,focusing on studies related to IBD and fibrosis.Intestinal fibrosis results from a complex network involving stromal cells,immune cells,epithelial cells,and the gut microbiota.Chronic inflammation,driven by factors such as dysbiosis,epithelial injury,and immune activation,leads to the production of cytokines like interleukin(IL)-1β,IL-17,and transforming growth factor(TGF)-β.These mediators activate various stromal cell populations,including fibroblasts,pericytes,and smooth muscle cells.The activated stromal cells secrete excessive extracellular matrix components,thereby promoting fibrosis.Additionally,stromal cells influence the immune microenvironment through cytokine production.Future research would focus on elucidating the temporal and spatial relationships between immune cell-driven inflammation and stromal cell-mediated fibrosis.Additionally,investigations are needed to clarify the differentiation origins of excessive extracellular matrix-producing cells,particularly fibroblast activation protein(FAP)+fibroblasts,in the context of intestinal fibrosis.In conclusion,aberrant stromal cell activation,triggered by upstream immune signals,is a key mechanism underlying intestinal fibrosis.Further investigations into immune–stromal cell interactions and stromal cell activation are essential for the development of therapeutic strategies to prevent,alleviate,and potentially reverse fibrosis.
基金supported by grants provided by the National Natural Science Foundation of China (81873090)funding from the Research on Identification and Support Innovation and Development of Enterprise Technology Projects in Hubei Province (2021BLB174)the Modern Transmission and Innovation Research Team of Traditional Chinese Medicine at South Central Minzu University
文摘Objective: The objective of the study was to explore the potential signaling mechanism of Aconitum tanguticum(Maxim.) Stapf(ATS) and its impact on intestinal fibrosis in vitro. Methods: Network pharmacology was used to screen the active components of ATS and predict their potential targets in intestinal fibrosis. The protein–protein interaction network graph was constructed using drug–disease intersection targets retrieved from the Search Tool for Retrieval of Interacting Genes/Proteins database. The network diagram was analyzed using Cytoscape 3.6.1'stopology function. The gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted using the database for annotation, visualization, and integrated discovery platform. Intestinal fibroblast model in vitro was constructed using transforming growth factor-β1(TGF-β1)-induced CCD-18Co cells. Quantitative reverse transcription polymerase chain reaction(qRT-PCR)was used to verify the network pharmacology-predicted antifibrotic signaling pathway of ATS and the traditional antifibrotic signaling pathway. Results: Network pharmacology revealed that there were 19 active components in ATS, suggesting that ATS could be involved in the regulation of mitogen-activated protein kinase 1(MAPK1), PIK3CA, MAPK3, and other important targets that are present in cancer pathways, including proteoglycans, infiuenza A, and phosphatidylinositol-3-kinase(PI3K)-protein kinase B(Akt) signaling pathways. The results of quantitative reverse transcription-polymerase chain reaction(qRT-PCR) demonstrated that 0.1–1 μg/mL ATS may suppress tissue inhibitor of metalloproteinase 1, collagen I, and alpha-smooth muscle actin expression levels. The expression of the TGF-β/suppressor of the mother against decapentaplegic(Smad) and PI3K/Akt signaling pathways was controlled by ATS. In addition, ATS inhibited the PI3K/Akt pathway by reducing the expression of MAPK1, HSP90AA1, and PIK3CA. Conclusions: It has been confirmed that ATS is a multipathway and multitarget treatment for intestinal fibrosis. This study suggested that ATS might alleviate intestinal fibrosis by blocking both the TGF-β/Smad and the PI3K/Akt pathway.
基金supported by the National Natural Science Fund of China(Grant Nos.:31800293 and 32370422)Project of Standard for TCM(Grant No.:ZYBZH-Y-JIN-34).
文摘Ulcerative colitis(UC)is an idiopathic,relapsing,and etiologically complicated chronic inflammatory bowel disease.Despite substantial progress in the management of UC,the outcomes of mucosal barrier repair are unsatisfactory.In this study,phillygenin(PHI)treatment alleviated the symptoms of chronic colitis in mice,including body weight loss,severe disease activity index scores,colon shortening,splenomegaly,oxidative stress,and inflammatory response.In particular,PHI treatment ameliorated the tight junction proteins(TJs)reduction,fibrosis,apoptosis,and intestinal stem cell activity,indicating that PHI exerted beneficial effects on the intestinal mucosal barrier in mice with chronic colitis.In the NCM460 cells damage model,dextran sulfate sodium triggered the sequential induction of TJs reduction,fibrosis,and apoptosis.Takeda G protein-coupled receptor-5(TGR5)dysfunction mediated NCM460 cell injury.Moreover,PHI treatment enhanced TJs and suppressed fibrosis and apoptosis to maintain NCM460 cell function,depending on TGR5 activation.PHI promoted TGR5 activation and elevated intracellular cyclic adenosine monophosphate levels in HEK 293T cells transfected with TGR5 expression plasmids.Cellular thermal shift assay and molecular docking studies confirmed that PHI directly binds to TGR5,indicating that PHI is an agonist of TGR5.The process of PERK-eIF2α pathway-mediated endoplasmic reticulum Ca^(2+) release was involved in NCM460 cell injury as well,which was associated with TGR5 dysfunction.When NCM460 cells were pretreated with PHI,the PERK-eIF2α pathway and elevated Ca^(2+) levels were blocked.In conclusion,our study demonstrated a novel mechanism that PHI inhibited the PERK-eIF2α-Ca^(2+) pathway through TGR5 activation to against DSS-induced TJs reduction,fibrosis,and apoptosis.
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,No.82270590.
文摘BACKGROUND Inflammatory bowel disease,particularly Crohn’s disease(CD),has been associated with alterations in mesenteric adipose tissue(MAT)and the phenomenon termed“creeping fat”.Histopathological evaluations showed that MAT and intestinal tissues were significantly altered in patients with CD,with these tissues characterized by inflammation and fibrosis.AIM To evaluate the complex interplay among MAT,creeping fat,inflammation,and gut microbiota in CD.METHODS Intestinal tissue and MAT were collected from 12 patients with CD.Histological manifestations and protein expression levels were analyzed to determine lesion characteristics.Fecal samples were collected from five recently treated CD patients and five control subjects and transplanted into mice.The intestinal and mesenteric lesions in these mice,as well as their systemic inflammatory status,were assessed and compared in mice transplanted with fecal samples from CD patients and control subjects.RESULTS Pathological examination of MAT showed significant differences between CDaffected and unaffected colons,including significant differences in gut microbiota structure.Fetal microbiota transplantation(FMT)from clinically healthy donors into mice with 2,4,6-trinitrobenzene sulfonic acid(TNBS)-induced CD ameliorated CD symptoms,whereas FMT from CD patients into these mice exacerbated CD symptoms.Notably,FMT influenced intestinal permeability,barrier function,and levels of proinflammatory factors and adipokines.Furthermore,FMT from CD patients intensified fibrotic changes in the colon tissues of mice with TNBS-induced CD.CONCLUSION Gut microbiota play a critical role in the histopathology of CD.Targeting MAT and creeping fat may therefore have potential in the treatment of patients with CD.
文摘We would like to present some new thoughts on the publication in the journalpublished in August 2024 in World Journal of Gastroenterology.We specificallyfocused on the alterations in the intestinal tract,mesenteric adipose tissue(MAT),and systemic inflammatory changes in mice following fecal flora transplantationinto a mouse model of Crohn's disease(CD).Accumulating evidence suggests thatthe occurrence of CD is influenced by environmental factors,host immune status,genetic susceptibility,and flora imbalance.One microbiota-based intervention,fecal microbiota transplantation,has emerged as a potential treatment option forCD.The MAT is considered a"second barrier"around the inflamed intestine.Theinteraction between gut microbes and inflammatory changes in MAT has attractedconsiderable interest.In the study under discussion,the authors transplantedfetal fecal microorganisms from patients with CD and clinically healthy donors,respectively,into 2,4,6-trinitrobenzene sulfonic acid-induced CD mice.Theresearch explored the complex interplay between MAT,creeping fat,inflammation,and intestinal flora in CD by evaluating intestinal and mesenteric lesions,along with the systemic inflammatory state in the mice.This article providesseveral important insights.First,the transplantation of intestinal flora holdssignificant potential as a therapeutic strategy for CD,offering hope for patientswith CD.Second,it presents a novel approach to the diagnosis and treatment ofCD:The inflammatory response in CD could potentially be assessed throughpathological or imaging changes in the MAT,and CD could be treated bytargeting the inflammation of the MAT.
基金support from National Natural Science Foundation of China(Grant Nos.82402302,82022033,and 52402353)Sichuan Science and Technology Program(2024NSFSC1776,China)+1 种基金Chengdu Science and Technology Program(Grant No.2024-YF0501722-SN,China)Shanghai Sailing Program(Grant No.3YF1454500,China).
文摘Simultaneous management of intestinal mucosal barrier dysfunction and gut microbiota dysregulation represents a significant challenge in the treatment of inflammatory bowel disease(IBD).Herein,we report a novel system that integrates multi-enzyme mimicking cerium single-atom nanocatalysts(CeSACs)with Lactobacillus reuteri probiotics(LR@CeSACs)for multipronged management of IBD.In this system,CeSACs demonstrate robust multi-enzyme activities across a broad pH range,effectively scavenging elevated reactive oxygen species,downregulating pro-inflammatory cytokines,and suppressing the expression of fibrosis-related genes.Moreover,probiotics promote the targeting and retention of the CeSACs for sustained catalytic antioxidant therapy.In turn,the inflammation relief enabled by CeSACs promotes bacterial viability,allowing for the rapid reshaping of intestinal barrier function and the restoration of gut microbiota.Therefore,LR@CeSACs exhibit excellent catalytic anti-inflammatory and anti-fibrotic therapeutic effects,as well as a certain prophylactic effect,as demonstrated in several murine models.
基金supported by the National Natural Science Foundation of China[grant numbers 81772699,81472999,81272350]the Guangzhou People’s Livelihood Science and Technology Project[grant number 201803010052].
文摘Background This study explored the diagnostic performance of visceral adiposity to predict the degree of intestinal inflammation and fibrosis.Methods The patients with Crohn’s disease(CD)who underwent surgical small bowel resection at the First Affiliated Hospital of Sun Yat-sen University(Guangzhou,China)between January 2007 and December 2017 were enrolled.We evaluated the intestinal imaging features of computed tomography enterography(CTE),including mesenteric inflammatory fat stranding,the target sign,mesenteric hypervascularity,bowel wall thickening,lymphadenopathy,stricture diameter,and maximal upstream diameter.We used A.K.software(Artificial Intelligence Kit,version 1.1)to calculate the visceral fat(VF)and subcutaneous fat(SF)volumes at the third lumbar vertebra level.Pathological tissue information was recorded.Diagnostic models were established based on the multivariate regression analysis results,and their effectiveness was evaluated by area under the curve(AUC)and decision curve analyses.Results Overall,48 patients with CD were included in this study.The abdominal VF/SF volume ratio(odds ratio,1.20;95%confidence interval,1.05–1.38;P=0.009)and the stenosis diameter/upstream intestinal dilatation diameter(ND)ratio(odds ratio,0.90;95%confidence interval,0.82–0.99;P=0.034)were independent risk factors for the severe fibrosis of the small intestine.The AUC values of the VF/SF ratio,the ND ratio,and their combination were 0.760,0.673,and 0.804,respectively.The combination of the VS/SF volume ratio and ND ratio achieved the highest net benefit on the decision curve.Conclusion The VF volume on CTE can reflect intestinal fibrosis.The combination of the VF/SF volume ratio and ND ratio of CD patients assessed using CTE can help predict severe fibrosis stenosis of the small intestine.
