CD4 T helper(Th) cell differentiation into distinct T cell subsets is critical to the normal function of the immune system. Until recently,the paradigm held that na?ve T cells differentiated into distinct subsets unde...CD4 T helper(Th) cell differentiation into distinct T cell subsets is critical to the normal function of the immune system. Until recently,the paradigm held that na?ve T cells differentiated into distinct subsets under the guidance of environmental cues(e.g.,cytokines) and that once polarized,these cells were committed to a particular functional state. However,the existence of transdifferentiated T cell populations,which express signature transcription factors and cytokines associated with more than one Th subset,challenges the immutability of T helper subsets and suggests that plasticity is a feature of multifaceted immune responses. How this process impacts immune dysregulation in diseases such as inflammatory bowel diseases(IBD) and the machinery that underlies this process is far from fully understood. Interleukin(IL)-17 secreting helper T(Th17) cells have been heavily implicated in tissue-specific immune pathology including murine models of IBD,human Crohn's disease and ulcerative colitis. Plasticity within this subset is suggested by the existence of IL-17 secreting cells,which,can also secrete interferon-γ,the signature cytokine for Th1 cells or,can co-express the anti-inflammatory transcription factor forkhead box p3,a signature transcription factor of regulatory T cells. In this review we mainly discuss evidence for Th17 plasticity,mechanisms,which govern it,and highlight the potential to therapeutically target this process in human IBD.展开更多
Purpose Systemic inflammation has been increasingly implicated in the pathogenesis of polycystic ovary syndrome(PCOS),but the causal nature and direction of this relationship remain uncertain.This study aimed to evalu...Purpose Systemic inflammation has been increasingly implicated in the pathogenesis of polycystic ovary syndrome(PCOS),but the causal nature and direction of this relationship remain uncertain.This study aimed to evaluate the potential causal associations between circulating inflammatory cytokines and the risk of PCOS using a Mendelian randomisation(MR)approach.Methods We conducted a two-sample MR analysis using summary-level data from large-scale genome-wide association studies involving 91 systemic inflammatory markers(n=14824)and PCOS(10074 cases and 103164 controls)among individuals of European ancestry.Genetic variants associated with cytokines at genome-wide significance(p<5×10^(-8))were selected as instrumental variables.The inverse-variance weighted method was used as the primary analytical strategy,supplemented by sensitivity analyses and correction for multiple testing.Results Genetically predicted higher circulating levels of C-X-C motif chemokine ligand 11(CXCL11)were significantly associated with a reduced risk of PCOS(OR=0.740,95%CI 0.625 to 0.871,p<0.001),and this association remained statistically significant after multiple testing correction(adjusted p=0.030).Nominal associations with decreased PCOS risk were also observed for interleukin-13(IL-13),IL-10 and adenosine deaminase(ADA),but these did not withstand correction for multiple comparisons.No evidence of horizontal pleiotropy was detected,and leave-one-out sensitivity analyses supported the robustness of the findings.Conclusion These results support a potential causal role of systemic inflammation in the development of PCOS,with CXCL11 emerging as a promising inflammatory marker and potential therapeutic target.Further studies are needed to validate these findings and explore their clinical relevance in PCOS management.展开更多
Irritable bowel syndrome(IBS)is one of the most common gastrointestinal disorders,characterized by abdominal pain,bloating,and changes in bowel habits.These symptoms cannot be explained by structural abnormalities and...Irritable bowel syndrome(IBS)is one of the most common gastrointestinal disorders,characterized by abdominal pain,bloating,and changes in bowel habits.These symptoms cannot be explained by structural abnormalities and there is no specific laboratory test or biomarker for IBS.Therefore,IBS is classified as a functional disorder with diagnosis dependent on the history taking about manifested symptoms and careful physical examination.Although a great deal of research has been carried out in this area,the pathophysiology of IBS is complex and not completely understood.Multiple factors are thought to contribute to the symptoms in IBS patients;altered gastrointestinal motility,visceral hypersensitivity,and the brain-gut interaction are important classical concepts in IBS pathophysiology.New areas of research in this arena include inflammation,postinfectious low-grade inflammation,genetic and immunologic factors,an altered microbiota,dietary factors,and enteroendocrine cells.These emerging studies have not shown consistent results,provoking controversy in the IBS field.However,certain lines of evidence suggest that these mechanisms are important at least a subset of IBS patients,confirming that IBS symptoms cannot be explained by a single etiological mechanism.Therefore,it is important to keep in mind that IBS requires a more holistic approach to determining effective treatment and understanding the underlying mechanisms.展开更多
Gastric carcinoma (GC) is the 4<sup>th</sup> most prevalent cancer and has the 2<sup>nd</sup> highest cancer-related mortality rate worldwide. Despite the incidence of GC has decreased over the...Gastric carcinoma (GC) is the 4<sup>th</sup> most prevalent cancer and has the 2<sup>nd</sup> highest cancer-related mortality rate worldwide. Despite the incidence of GC has decreased over the past few decades, it is still a serious health problem. Chronic inflammatory status of the stomach, caused by the infection of Helicobacter pylori (H. pylori) and through the production of inflammatory mediators within the parenchyma is suspected to play an important role in the initiation and progression of GC. In this review, the correlation between chronic inflammation and H. pylori infection as an important factor for the development of GC will be discussed. Major components, including tumor-associated macrophages, lymphocytes, cancer-associated fibroblasts, angiogenic factors, cytokines, and chemokines of GC microenvironment and their mechanism of action on signaling pathways will also be discussed. Increasing our understanding of how the components of the tumor microenviroment interact with GC cells and the signaling pathways involved could help identify new therapeutic and chemopreventive targets.展开更多
A large body of experimental and clinical data supports the notion that inflammation in acute pancreatitis has a crucial role in the pathogenesis of local and systemic damage and is a major determinant of clinical sev...A large body of experimental and clinical data supports the notion that inflammation in acute pancreatitis has a crucial role in the pathogenesis of local and systemic damage and is a major determinant of clinical severity. Thus, research has recently focused on molecules that can regulate the inflammatory processes, such as phosphoinositide 3-kinases (PI3Ks), a family of lipid and protein kinases involved in intracellular signal transduction. Studies using genetic ablation or pharmacologic inhibitors of different PI3K isoforms, in particular the class I PI3Kδ and PI3Kγ, have contributed to a greater understanding of the roles of these kinases in the modulation of inflammatory and immune responses. Recent data suggest that PI3Ks are also involved in the pathogenesis of acute pancreatitis. Activation of the PI3K signaling pathway, and in particular of the class IB PI3Kγ isoform, has a significant role in those events which are necessary for the initiation of acute pancreatic injury, namely calcium signaling alteration, trypsinogen activation, and nuclear factor-κB transcription. Moreover, PI3Kγ is instrumental in modulating acinar cell apoptosis, and regulating local neutrophil infiltration and systemic inflammatory responses during the course of experimental acute pancreatitis. The availability of PI3K inhibitors selective for specific isoforms may provide new valuable therapeutic strategies to improve the clinical course of this disease. This article presents a brief summary of PI3K structure and function, and highlights recent advances that implicate PI3Ks in the pathogenesis of acute pancreatitis.展开更多
Alcoholic liver injury represents a progressive process with a range of consequences including hepatic steatosis, steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Targeting key molecular regul...Alcoholic liver injury represents a progressive process with a range of consequences including hepatic steatosis, steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Targeting key molecular regulators involved in the development of alcoholic liver injury may be of great value in the prevention of liver injury. Peroxisome proliferator-activated receptor α (PPARα) plays a pivotal role in modulation of hepatic lipid metabolism, oxidative stress, inflammatory response and fibrogenesis. As such, PPARα may be a potential therapeutic target for the treatment of alcoholic liver disease.展开更多
Defects in intestinal barrier function characterized by an increase in intestinal permeability contribute to intestinal inflammation.Growing evidence has shown that an increase in intestinal permeability has a pathoge...Defects in intestinal barrier function characterized by an increase in intestinal permeability contribute to intestinal inflammation.Growing evidence has shown that an increase in intestinal permeability has a pathogenic role in diseases such as inflammatory bowel disease(IBD)and celiac disease,and functional bowel disorders such as irritable bowel syndrome.Therefore,clarification of the inflammatory responses,the defense pathway and the corresponding regulatory system is essential and may lead to the development of new therapies.MicroRNAs(miRNAs)are small(19-22nt)noncoding RNA molecules that regulate genes at the post-transcriptional level by base-pairing to specific messenger RNAs for degradation to repress translation.Recent studies suggested that miRNAs are important in the immune response and mediate a critical role in multiple immune response-related disorders.Based on these discoveries,attention has been focused on understanding the role of miRNAs in regulating intestinal barrier dysfunction,especially in IBD.Here,we provide a review of the most recent state-of-the-art research on miRNAs in intestinal barrier dysfunction.展开更多
The incidence of Clostridium difficile (C. difficile) infection (CDI) is 1.8%-5.7% in admitted patients with ulcerative colitis (UC). CDI can worsen UC and increase the risk for colectomy or even death, thus necessita...The incidence of Clostridium difficile (C. difficile) infection (CDI) is 1.8%-5.7% in admitted patients with ulcerative colitis (UC). CDI can worsen UC and increase the risk for colectomy or even death, thus necessitating therapy escalation, such as increasing the corticoid therapy or starting a biologic treatment. Several reported cases with infliximab therapy have provided favorable outcomes in UC patients with CDI, suggesting that infliximab treatment may be protective; however, the optimal infliximab treatment regimen for UC patients with CDI remains to be established. Here, we report a case of worsening UC in the presence of recurrent CDI. The patient had received prior ciprofloxacin and immunosuppressive therapy during a prolonged hospital stay. The deterioration in the patient’s condition likely resulted from the ability of C. difficile to promote relapsing of UC by activating the immune response. Ultimately, the patient was treated with a high dose of infliximab after a low trough level of infliximab at week 8 was identified, yielding better clinical results. Infliximab was found to be safe after repetitive episodes of CDI. The trough level of infliximab was therefore a useful indicator to guide therapy and correlated well with the patient’s outcome.展开更多
Objective: to investigate the clinical value of hemodialysis in the treatment of elderly patients with diabetic nephropathy (DN). Methods: 76 elderly patients with DN were studied in this group. The time period for co...Objective: to investigate the clinical value of hemodialysis in the treatment of elderly patients with diabetic nephropathy (DN). Methods: 76 elderly patients with DN were studied in this group. The time period for collecting research data was from May 2018 to March 2020. The patients were randomly divided into control group and observation group, with 38 cases in each group. They were treated with low flux hemodialysis and high flux hemodialysis in turn. The renal function and inflammatory clearance effect of the two groups were compared, the dialysis safety of the patients was evaluated, and the 1-year survival rate was recorded. Results: the levels of renal function indexes (BUN, SCr, etc.) and inflammatory indexes (IL-6 and CRP) in the observation group were significantly lower than those in the control group (P < 0.05). After treatment, the incidence of cardiovascular events and cerebrovascular events in the observation group was lower than that in the control group, and the 1-year survival rate was higher than that in the control group (P < 0.05). Conclusion: high throughput hemodialysis can more effectively promote the clearance of inflammation in elderly DN patients, improve their renal function, reduce adverse cardiovascular and cerebrovascular events and improve the survival rate of patients.展开更多
文摘CD4 T helper(Th) cell differentiation into distinct T cell subsets is critical to the normal function of the immune system. Until recently,the paradigm held that na?ve T cells differentiated into distinct subsets under the guidance of environmental cues(e.g.,cytokines) and that once polarized,these cells were committed to a particular functional state. However,the existence of transdifferentiated T cell populations,which express signature transcription factors and cytokines associated with more than one Th subset,challenges the immutability of T helper subsets and suggests that plasticity is a feature of multifaceted immune responses. How this process impacts immune dysregulation in diseases such as inflammatory bowel diseases(IBD) and the machinery that underlies this process is far from fully understood. Interleukin(IL)-17 secreting helper T(Th17) cells have been heavily implicated in tissue-specific immune pathology including murine models of IBD,human Crohn's disease and ulcerative colitis. Plasticity within this subset is suggested by the existence of IL-17 secreting cells,which,can also secrete interferon-γ,the signature cytokine for Th1 cells or,can co-express the anti-inflammatory transcription factor forkhead box p3,a signature transcription factor of regulatory T cells. In this review we mainly discuss evidence for Th17 plasticity,mechanisms,which govern it,and highlight the potential to therapeutically target this process in human IBD.
文摘AIM: To characterize longitudinally the inflammation and the gut microbiota dynamics in a mouse model of dextran sulfate sodium (DSS)-induced colitis.
基金supported by the Multidisciplinary Clinical Research Innovation Team Project of Beijing Chao-Yang Hospital(grant no.CYDXK202203)。
文摘Purpose Systemic inflammation has been increasingly implicated in the pathogenesis of polycystic ovary syndrome(PCOS),but the causal nature and direction of this relationship remain uncertain.This study aimed to evaluate the potential causal associations between circulating inflammatory cytokines and the risk of PCOS using a Mendelian randomisation(MR)approach.Methods We conducted a two-sample MR analysis using summary-level data from large-scale genome-wide association studies involving 91 systemic inflammatory markers(n=14824)and PCOS(10074 cases and 103164 controls)among individuals of European ancestry.Genetic variants associated with cytokines at genome-wide significance(p<5×10^(-8))were selected as instrumental variables.The inverse-variance weighted method was used as the primary analytical strategy,supplemented by sensitivity analyses and correction for multiple testing.Results Genetically predicted higher circulating levels of C-X-C motif chemokine ligand 11(CXCL11)were significantly associated with a reduced risk of PCOS(OR=0.740,95%CI 0.625 to 0.871,p<0.001),and this association remained statistically significant after multiple testing correction(adjusted p=0.030).Nominal associations with decreased PCOS risk were also observed for interleukin-13(IL-13),IL-10 and adenosine deaminase(ADA),but these did not withstand correction for multiple comparisons.No evidence of horizontal pleiotropy was detected,and leave-one-out sensitivity analyses supported the robustness of the findings.Conclusion These results support a potential causal role of systemic inflammation in the development of PCOS,with CXCL11 emerging as a promising inflammatory marker and potential therapeutic target.Further studies are needed to validate these findings and explore their clinical relevance in PCOS management.
文摘Irritable bowel syndrome(IBS)is one of the most common gastrointestinal disorders,characterized by abdominal pain,bloating,and changes in bowel habits.These symptoms cannot be explained by structural abnormalities and there is no specific laboratory test or biomarker for IBS.Therefore,IBS is classified as a functional disorder with diagnosis dependent on the history taking about manifested symptoms and careful physical examination.Although a great deal of research has been carried out in this area,the pathophysiology of IBS is complex and not completely understood.Multiple factors are thought to contribute to the symptoms in IBS patients;altered gastrointestinal motility,visceral hypersensitivity,and the brain-gut interaction are important classical concepts in IBS pathophysiology.New areas of research in this arena include inflammation,postinfectious low-grade inflammation,genetic and immunologic factors,an altered microbiota,dietary factors,and enteroendocrine cells.These emerging studies have not shown consistent results,provoking controversy in the IBS field.However,certain lines of evidence suggest that these mechanisms are important at least a subset of IBS patients,confirming that IBS symptoms cannot be explained by a single etiological mechanism.Therefore,it is important to keep in mind that IBS requires a more holistic approach to determining effective treatment and understanding the underlying mechanisms.
文摘Gastric carcinoma (GC) is the 4<sup>th</sup> most prevalent cancer and has the 2<sup>nd</sup> highest cancer-related mortality rate worldwide. Despite the incidence of GC has decreased over the past few decades, it is still a serious health problem. Chronic inflammatory status of the stomach, caused by the infection of Helicobacter pylori (H. pylori) and through the production of inflammatory mediators within the parenchyma is suspected to play an important role in the initiation and progression of GC. In this review, the correlation between chronic inflammation and H. pylori infection as an important factor for the development of GC will be discussed. Major components, including tumor-associated macrophages, lymphocytes, cancer-associated fibroblasts, angiogenic factors, cytokines, and chemokines of GC microenvironment and their mechanism of action on signaling pathways will also be discussed. Increasing our understanding of how the components of the tumor microenviroment interact with GC cells and the signaling pathways involved could help identify new therapeutic and chemopreventive targets.
基金Supported by Ministero dell’Universitàe della Ricerca Scientifica e Tecnologica(MURST,ex-60%to GM and EL)
文摘A large body of experimental and clinical data supports the notion that inflammation in acute pancreatitis has a crucial role in the pathogenesis of local and systemic damage and is a major determinant of clinical severity. Thus, research has recently focused on molecules that can regulate the inflammatory processes, such as phosphoinositide 3-kinases (PI3Ks), a family of lipid and protein kinases involved in intracellular signal transduction. Studies using genetic ablation or pharmacologic inhibitors of different PI3K isoforms, in particular the class I PI3Kδ and PI3Kγ, have contributed to a greater understanding of the roles of these kinases in the modulation of inflammatory and immune responses. Recent data suggest that PI3Ks are also involved in the pathogenesis of acute pancreatitis. Activation of the PI3K signaling pathway, and in particular of the class IB PI3Kγ isoform, has a significant role in those events which are necessary for the initiation of acute pancreatic injury, namely calcium signaling alteration, trypsinogen activation, and nuclear factor-κB transcription. Moreover, PI3Kγ is instrumental in modulating acinar cell apoptosis, and regulating local neutrophil infiltration and systemic inflammatory responses during the course of experimental acute pancreatitis. The availability of PI3K inhibitors selective for specific isoforms may provide new valuable therapeutic strategies to improve the clinical course of this disease. This article presents a brief summary of PI3K structure and function, and highlights recent advances that implicate PI3Ks in the pathogenesis of acute pancreatitis.
文摘Alcoholic liver injury represents a progressive process with a range of consequences including hepatic steatosis, steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Targeting key molecular regulators involved in the development of alcoholic liver injury may be of great value in the prevention of liver injury. Peroxisome proliferator-activated receptor α (PPARα) plays a pivotal role in modulation of hepatic lipid metabolism, oxidative stress, inflammatory response and fibrogenesis. As such, PPARα may be a potential therapeutic target for the treatment of alcoholic liver disease.
基金Supported by Grant for Key Clinical Discipline Construction of Shanghai Municipality,China,No.ZK2012B20Phase Ⅱ Outstanding Young Medical Personnel Training Fund of Jinshan District Health Systems,Shanghai,China,No.JWKJ-RCYQ-201207
文摘Defects in intestinal barrier function characterized by an increase in intestinal permeability contribute to intestinal inflammation.Growing evidence has shown that an increase in intestinal permeability has a pathogenic role in diseases such as inflammatory bowel disease(IBD)and celiac disease,and functional bowel disorders such as irritable bowel syndrome.Therefore,clarification of the inflammatory responses,the defense pathway and the corresponding regulatory system is essential and may lead to the development of new therapies.MicroRNAs(miRNAs)are small(19-22nt)noncoding RNA molecules that regulate genes at the post-transcriptional level by base-pairing to specific messenger RNAs for degradation to repress translation.Recent studies suggested that miRNAs are important in the immune response and mediate a critical role in multiple immune response-related disorders.Based on these discoveries,attention has been focused on understanding the role of miRNAs in regulating intestinal barrier dysfunction,especially in IBD.Here,we provide a review of the most recent state-of-the-art research on miRNAs in intestinal barrier dysfunction.
文摘The incidence of Clostridium difficile (C. difficile) infection (CDI) is 1.8%-5.7% in admitted patients with ulcerative colitis (UC). CDI can worsen UC and increase the risk for colectomy or even death, thus necessitating therapy escalation, such as increasing the corticoid therapy or starting a biologic treatment. Several reported cases with infliximab therapy have provided favorable outcomes in UC patients with CDI, suggesting that infliximab treatment may be protective; however, the optimal infliximab treatment regimen for UC patients with CDI remains to be established. Here, we report a case of worsening UC in the presence of recurrent CDI. The patient had received prior ciprofloxacin and immunosuppressive therapy during a prolonged hospital stay. The deterioration in the patient’s condition likely resulted from the ability of C. difficile to promote relapsing of UC by activating the immune response. Ultimately, the patient was treated with a high dose of infliximab after a low trough level of infliximab at week 8 was identified, yielding better clinical results. Infliximab was found to be safe after repetitive episodes of CDI. The trough level of infliximab was therefore a useful indicator to guide therapy and correlated well with the patient’s outcome.
文摘Objective: to investigate the clinical value of hemodialysis in the treatment of elderly patients with diabetic nephropathy (DN). Methods: 76 elderly patients with DN were studied in this group. The time period for collecting research data was from May 2018 to March 2020. The patients were randomly divided into control group and observation group, with 38 cases in each group. They were treated with low flux hemodialysis and high flux hemodialysis in turn. The renal function and inflammatory clearance effect of the two groups were compared, the dialysis safety of the patients was evaluated, and the 1-year survival rate was recorded. Results: the levels of renal function indexes (BUN, SCr, etc.) and inflammatory indexes (IL-6 and CRP) in the observation group were significantly lower than those in the control group (P < 0.05). After treatment, the incidence of cardiovascular events and cerebrovascular events in the observation group was lower than that in the control group, and the 1-year survival rate was higher than that in the control group (P < 0.05). Conclusion: high throughput hemodialysis can more effectively promote the clearance of inflammation in elderly DN patients, improve their renal function, reduce adverse cardiovascular and cerebrovascular events and improve the survival rate of patients.
