Background:Huoxue Tongjiang decoction(HXTJD)is an effective prescription for treating reflux esophagitis(RE).We investigated the effects of HXTJD on esophageal motility and mucosal inflammation in a rat RE model.Metho...Background:Huoxue Tongjiang decoction(HXTJD)is an effective prescription for treating reflux esophagitis(RE).We investigated the effects of HXTJD on esophageal motility and mucosal inflammation in a rat RE model.Methods:Chemical composition of HXTJD was analyzed by ultrahigh-performance liquid chromatography Q-Orbitrap mass spectrometry(MS).The change rates of mean contraction tension forces,mean amplitudes,and mean frequencies for the lower esophageal sphincter(LES)were recorded using the isolated tissue bath system,mechanical tension transducer,and PowerLab physiological recorder.After weighing the stomach,the phenol red labeling method was used to measure the gastric emptying rate.The LES ultrastructure was observed through transmission electron microscopy.Immunofluorescence and western blotting were used to detect the number of interstitial cells of Cajal(ICC)and the expression levels of c-kit protein,connexin43(Cx43),and stem cell factor(SCF).Flow cytometric analysis and enzyme-linked immunosorbent assay were conducted to detect the percentages of T helper 17(Th17)cells and regulatory T(Treg)cells and the serum concentrations of interleukin 6(IL-6),interleukin 17(IL-17),and interleukin 10(IL-10)in the rats.Results:We identified 28 chemical constituents in HXTJD.Regarding esophageal motility,we revealed that HXTJD increased the mean contraction tension forces,mean amplitudes,and mean frequency change rate of LES and the gastric emptying rate;decreased stomach weight;and improved the LES ultrastructure.Additionally,HXTJD increased the number of ICC-positive cells,and c-kit,Cx43,and SCF expression levels.Regarding esophageal inflammation,HXTJD significantly decreased the percentage of Th17 cells,and IL-6 and IL-17 concentrations,and increased the percentage of Treg cells and IL-10 concentration.Conclusion:HXTJD was found to be efficacious in the rat RE model.It may promote esophageal motility and alleviate the inflammatory response by activating the SCF/c-kit/ICC pathway and regulating the Th17/Treg cell balance.展开更多
The etiopathology of inflammatory bowel disease （IBD） remains elusive. Accumulating evidence suggests that the abnormality of innate and adaptive immunity responses plays an important role in intestinal inflam- mati...The etiopathology of inflammatory bowel disease （IBD） remains elusive. Accumulating evidence suggests that the abnormality of innate and adaptive immunity responses plays an important role in intestinal inflam- mation. IBD including Crohn＇s disease （CD） and ulcerative colitis （UC） is a chronic inflammatory disease of the gastrointestinal tract, which is implicated in an inappropriate and overactive mucosal immune response to luminal flora. Traditionally, CD is regarded as a Thl- mediated inflammatory disorder while UC is regarded as a Th2-1ike disease. Recently, Th17 cells were identified as a new subset of T helper cells unrelated to Thl or Th2 cells, and several cytokines [e.g. interleukin （IL）-21, IL-23] are involved in regulating their activation and differentiation. They not only play an important role in host defense against extracellular pathogens, but are also associated with the development of autoimmunity and inflammatory response such as IBD. The identification of Th17 cells helps us to explain some of the anomalies seen in the Thl/Th2 axis and has broadened our understanding of the immunopathological effects of Th17 cells in the development of IBD.展开更多
BACKGROUND The imbalance of Th17/Treg cells and the IL-23/IL-17 axis have been confirmed to be associated with sepsis and various inflammatory diseases. Early enteral nutrition (EEN) can modulate the inflammatory resp...BACKGROUND The imbalance of Th17/Treg cells and the IL-23/IL-17 axis have been confirmed to be associated with sepsis and various inflammatory diseases. Early enteral nutrition (EEN) can modulate the inflammatory response, improve immune dysfunction, and prevent enterogenic infection in critically ill patients;however, the precise mechanisms remain unclear. Considering the important roles of Th17 and Treg lymphocytes in the development of inflammatory and infectious diseases, we hypothesized that EEN could improve the immune dysfunction in sepsis by maintaining a balanced Th17/Treg cell ratio and by regulating the IL- 23/IL-17 axis. AIM To investigate the effects of EEN on the Th17/Treg cell ratios and the IL-23/IL-17 axis in septic patients. METHODS In this prospective clinical trial, patients were randomly divided into an EEN or delayed enteral nutrition (DEN) group. Enteral feeding was started within 48 h in the EEN group, whereas enteral feeding was started on the 4th day in the DEN group. The Th17 and Treg cell percentages and the interleukin levels were tested on days 1, 3, and 7 after admission. The clinical severity and outcome variables were also recorded. RESULTS Fifty-three patients were enrolled in this trial from October 2017 to June 2018. The Th17 cell percentages, Th17/Treg cell ratios, IL-17, IL-23, and IL-6 levels of the EEN group were lower than those of the DEN group on the 7th day after admission (P < 0.05). The duration of mechanical ventilation and of the intensive care unit stay of the EEN group were shorter than those of the DEN group (P <0.05). However, no difference in the 28-d mortality was found between the two groups (P = 0.728). CONCLUSION EEN could regulate the imbalance of Th17/Treg cell ratios and suppress the IL- 23/IL-17 axis during sepsis. Moreover, EEN could reduce the clinical severity of sepsis but did not reduce the 28-d mortality of septic patients.展开更多
· AIM: To determine the effects of rapamycin on experimental autoimmune uveoretinitis(EAU) and investigate of role of rapamycin on T cell subsets in the disease.·METHODS: EAU was induced in rats using peptid...· AIM: To determine the effects of rapamycin on experimental autoimmune uveoretinitis(EAU) and investigate of role of rapamycin on T cell subsets in the disease.·METHODS: EAU was induced in rats using peptides1169 to 1191 of the interphotoreceptor binding protein(IRBP). Rapamycin(0.2 mg/kg/d) was administrated by intraperitoneal injection for a consecutive 7d after immunization. Th1/Th2/Th17 cytokines, TGF-β1, and IL-6produced by lymphocyteswere measured by ELISA, while Th17 cells and CD4 +CD25 + regulatory T cells(Tregs)from rat spleen were detected by flow cytometry.·RESULTS: Intraperitoneal treatment immediately after immunization dramatically ameliorated the clinical course of EAU. Clinical responses were associated with reduced retinal inflammatory cell infiltration and tissue destruction. Rapamycin induced suppression of Th1/Th2/Th17 cytokines, including IFN-γ, IL-2, IL-17, IL-4, and IL-10 release from T lymphocytes of EAU rats, in vitro.Rapamycin also significantly increased TGF-β1production but had no effect on IL-6 productionof T lymphocytes from EAU rats in vitro. Furthermore,rapamycin decreased the ratio of Th17 cells/CD4 +T cells and upregulated Tregs in EAU, as detected by flow cytometry.·CONCLUSION: Rapamycin effectively interferes with T cell mediated autoimmune uveitis by inhibiting antigen-specific T cell functions and enhancing Tregs in EAU.Rapamycin is a promising new alternative as an adjunct corticosteroid-sparing agent for treating uveitis.展开更多
Oral lichen planus （OLP） is considered a T cell-mediated autoimmune disease with unknown aetiology. T helper cells appear to play an important role in the pathogenesis of OLP. We investigated the possible role of T ...Oral lichen planus （OLP） is considered a T cell-mediated autoimmune disease with unknown aetiology. T helper cells appear to play an important role in the pathogenesis of OLP. We investigated the possible role of T helper cells, Th1 and Th17, in the lesions and circulation of patients with OLP. Forty patients with OLP and 15 healthy volunteers were recruited. Double immunofluorescence staining was used to detect Th1 and Th17 cells in the OLP lesions, and intracellular cytokine staining and flow cytometry to evaluate the proportion of Th1 and Th17 cells in peripheral blood. The levels of serum interferon （IFN）-γ and interleukin （IL）-17 were assessed by using an enzyme-linked immunosorbent assay. It was found that Th17 cells, as well as Th1 cells, were present in OLP lesions. The proportion of peripheral Th1 and Th17 cells was significantly increased in patients with OLP. The proportion of Th17 cells in atrophic-erosive OLP was elevated as compared with that in reticular OLP. Serum IL-17 levels in OLP patients were significantly higher than in controls, and those in the atrophic-erosive OLP group were increased as compared with the reticular OLP group. However, the levels of serum IFN-γ were slightly decreased in OLP patients. Our data suggested that Th1 and Th17 cells in the local lesions and peripheral blood may be associated with the pathogenesis of OLP, and that IL-17 may be an important proinflammatory cytokine in OLP. These findings enhance our understanding of OLP pathogenesis.展开更多
Primary sclerosing cholangitis(PSC)is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis,with no curative treatment available,and liver transplantation...Primary sclerosing cholangitis(PSC)is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis,with no curative treatment available,and liver transplantation is inevitable for end-stage patients.Human placentalmesenchymal stem cell(hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis,inhibit collagen production and possess immunomodulatory properties in autoimmune liver disease.Here,we prepared hpMSC-derived exosomes(Exo^(MSC))and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2^(−/−)mice and multicellular organoids established from PSC patients.The results showed that Exo^(MSC) ameliorated liver fibrosis in Mdr2^(−/−)mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis,and the percentage of CD4+IL-17A+T cells was reduced both in Exo^(MSC)-treated Mdr2^(−/−)mice(Mdr2^(−/−)-Exo)in vivo and Exo^(MSC)-treated Th17 differentiation progressed in vitro.Furthermore,Exo^(MSC) improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular organoids.Thus,our data demonstrate the antifibrosis effect of Exo^(MSC) in PSC disease by inhibiting Th17 differentiation,and ameliorating the Th17-induced microenvironment,indicating the promising potential therapeutic role of Exo^(MSC) in liver fibrosis of PSC or Th17-related diseases.展开更多
Objective: To study the correlation between mi R-21 and Treg/Th17 ratio in the microenvironment of rats with hepatocellular carcinoma. Methods: Diethylnitrosamine was used to build the hepatocel ular carcinoma model o...Objective: To study the correlation between mi R-21 and Treg/Th17 ratio in the microenvironment of rats with hepatocellular carcinoma. Methods: Diethylnitrosamine was used to build the hepatocel ular carcinoma model of rats; the content of Treg cells and Th17 cells and the expression of mi R-21 in the peripheral blood of rats with hepatocellular carcinoma were detected. The statistical analysis was performed on the correlation between mi R-21 expression and Treg/Th17 ratio. Results: Hepatocellular carcinoma model of rats was successfully constructed. The proportion of Th17 cells among all CD4+T cells in the peripheral blood of rats with hepatocellular carcinoma was 5.319%, which was higher than the control group; while the proportion of Treg cells was 9.472%, which was higher than the control group. Treg/Th17 ratio in the model group was 1.781, compared with 1.478 in the control group. The expression of mi R-21 was increased in the peripheral blood of rats with hepatocellular carcinoma and it showed a positive correlation with the ratio of Treg/Th17. Conclusions: There is a positive correlation between the expression level of miR-21 and the ratio of Treg/Th17.展开更多
基金supported by the National Natural Science Foundation of China(No.81573737 and 82074213)the science foundation of Tianjin Municipal Health Bureau(No.2023169 and 2021045)the Tianjin Municipal Health Commission Science and Technology Project(No.TJWJ2022QN057).
文摘Background:Huoxue Tongjiang decoction(HXTJD)is an effective prescription for treating reflux esophagitis(RE).We investigated the effects of HXTJD on esophageal motility and mucosal inflammation in a rat RE model.Methods:Chemical composition of HXTJD was analyzed by ultrahigh-performance liquid chromatography Q-Orbitrap mass spectrometry(MS).The change rates of mean contraction tension forces,mean amplitudes,and mean frequencies for the lower esophageal sphincter(LES)were recorded using the isolated tissue bath system,mechanical tension transducer,and PowerLab physiological recorder.After weighing the stomach,the phenol red labeling method was used to measure the gastric emptying rate.The LES ultrastructure was observed through transmission electron microscopy.Immunofluorescence and western blotting were used to detect the number of interstitial cells of Cajal(ICC)and the expression levels of c-kit protein,connexin43(Cx43),and stem cell factor(SCF).Flow cytometric analysis and enzyme-linked immunosorbent assay were conducted to detect the percentages of T helper 17(Th17)cells and regulatory T(Treg)cells and the serum concentrations of interleukin 6(IL-6),interleukin 17(IL-17),and interleukin 10(IL-10)in the rats.Results:We identified 28 chemical constituents in HXTJD.Regarding esophageal motility,we revealed that HXTJD increased the mean contraction tension forces,mean amplitudes,and mean frequency change rate of LES and the gastric emptying rate;decreased stomach weight;and improved the LES ultrastructure.Additionally,HXTJD increased the number of ICC-positive cells,and c-kit,Cx43,and SCF expression levels.Regarding esophageal inflammation,HXTJD significantly decreased the percentage of Th17 cells,and IL-6 and IL-17 concentrations,and increased the percentage of Treg cells and IL-10 concentration.Conclusion:HXTJD was found to be efficacious in the rat RE model.It may promote esophageal motility and alleviate the inflammatory response by activating the SCF/c-kit/ICC pathway and regulating the Th17/Treg cell balance.
基金Supported by Grants From the National Natural Science Foundation of China,No.30770988 and No.30971358
文摘The etiopathology of inflammatory bowel disease （IBD） remains elusive. Accumulating evidence suggests that the abnormality of innate and adaptive immunity responses plays an important role in intestinal inflam- mation. IBD including Crohn＇s disease （CD） and ulcerative colitis （UC） is a chronic inflammatory disease of the gastrointestinal tract, which is implicated in an inappropriate and overactive mucosal immune response to luminal flora. Traditionally, CD is regarded as a Thl- mediated inflammatory disorder while UC is regarded as a Th2-1ike disease. Recently, Th17 cells were identified as a new subset of T helper cells unrelated to Thl or Th2 cells, and several cytokines [e.g. interleukin （IL）-21, IL-23] are involved in regulating their activation and differentiation. They not only play an important role in host defense against extracellular pathogens, but are also associated with the development of autoimmunity and inflammatory response such as IBD. The identification of Th17 cells helps us to explain some of the anomalies seen in the Thl/Th2 axis and has broadened our understanding of the immunopathological effects of Th17 cells in the development of IBD.
基金the National Natural Science Foundation of China,No.81701881the Nanjing Medical Science and Technology Development Foundation,No.YKK15098 and No.YKK17102
文摘BACKGROUND The imbalance of Th17/Treg cells and the IL-23/IL-17 axis have been confirmed to be associated with sepsis and various inflammatory diseases. Early enteral nutrition (EEN) can modulate the inflammatory response, improve immune dysfunction, and prevent enterogenic infection in critically ill patients;however, the precise mechanisms remain unclear. Considering the important roles of Th17 and Treg lymphocytes in the development of inflammatory and infectious diseases, we hypothesized that EEN could improve the immune dysfunction in sepsis by maintaining a balanced Th17/Treg cell ratio and by regulating the IL- 23/IL-17 axis. AIM To investigate the effects of EEN on the Th17/Treg cell ratios and the IL-23/IL-17 axis in septic patients. METHODS In this prospective clinical trial, patients were randomly divided into an EEN or delayed enteral nutrition (DEN) group. Enteral feeding was started within 48 h in the EEN group, whereas enteral feeding was started on the 4th day in the DEN group. The Th17 and Treg cell percentages and the interleukin levels were tested on days 1, 3, and 7 after admission. The clinical severity and outcome variables were also recorded. RESULTS Fifty-three patients were enrolled in this trial from October 2017 to June 2018. The Th17 cell percentages, Th17/Treg cell ratios, IL-17, IL-23, and IL-6 levels of the EEN group were lower than those of the DEN group on the 7th day after admission (P < 0.05). The duration of mechanical ventilation and of the intensive care unit stay of the EEN group were shorter than those of the DEN group (P <0.05). However, no difference in the 28-d mortality was found between the two groups (P = 0.728). CONCLUSION EEN could regulate the imbalance of Th17/Treg cell ratios and suppress the IL- 23/IL-17 axis during sepsis. Moreover, EEN could reduce the clinical severity of sepsis but did not reduce the 28-d mortality of septic patients.
基金Supported by National Natural Science Foundation of China(No.81371005)
文摘· AIM: To determine the effects of rapamycin on experimental autoimmune uveoretinitis(EAU) and investigate of role of rapamycin on T cell subsets in the disease.·METHODS: EAU was induced in rats using peptides1169 to 1191 of the interphotoreceptor binding protein(IRBP). Rapamycin(0.2 mg/kg/d) was administrated by intraperitoneal injection for a consecutive 7d after immunization. Th1/Th2/Th17 cytokines, TGF-β1, and IL-6produced by lymphocyteswere measured by ELISA, while Th17 cells and CD4 +CD25 + regulatory T cells(Tregs)from rat spleen were detected by flow cytometry.·RESULTS: Intraperitoneal treatment immediately after immunization dramatically ameliorated the clinical course of EAU. Clinical responses were associated with reduced retinal inflammatory cell infiltration and tissue destruction. Rapamycin induced suppression of Th1/Th2/Th17 cytokines, including IFN-γ, IL-2, IL-17, IL-4, and IL-10 release from T lymphocytes of EAU rats, in vitro.Rapamycin also significantly increased TGF-β1production but had no effect on IL-6 productionof T lymphocytes from EAU rats in vitro. Furthermore,rapamycin decreased the ratio of Th17 cells/CD4 +T cells and upregulated Tregs in EAU, as detected by flow cytometry.·CONCLUSION: Rapamycin effectively interferes with T cell mediated autoimmune uveitis by inhibiting antigen-specific T cell functions and enhancing Tregs in EAU.Rapamycin is a promising new alternative as an adjunct corticosteroid-sparing agent for treating uveitis.
文摘Oral lichen planus （OLP） is considered a T cell-mediated autoimmune disease with unknown aetiology. T helper cells appear to play an important role in the pathogenesis of OLP. We investigated the possible role of T helper cells, Th1 and Th17, in the lesions and circulation of patients with OLP. Forty patients with OLP and 15 healthy volunteers were recruited. Double immunofluorescence staining was used to detect Th1 and Th17 cells in the OLP lesions, and intracellular cytokine staining and flow cytometry to evaluate the proportion of Th1 and Th17 cells in peripheral blood. The levels of serum interferon （IFN）-γ and interleukin （IL）-17 were assessed by using an enzyme-linked immunosorbent assay. It was found that Th17 cells, as well as Th1 cells, were present in OLP lesions. The proportion of peripheral Th1 and Th17 cells was significantly increased in patients with OLP. The proportion of Th17 cells in atrophic-erosive OLP was elevated as compared with that in reticular OLP. Serum IL-17 levels in OLP patients were significantly higher than in controls, and those in the atrophic-erosive OLP group were increased as compared with the reticular OLP group. However, the levels of serum IFN-γ were slightly decreased in OLP patients. Our data suggested that Th1 and Th17 cells in the local lesions and peripheral blood may be associated with the pathogenesis of OLP, and that IL-17 may be an important proinflammatory cytokine in OLP. These findings enhance our understanding of OLP pathogenesis.
基金supported by grants for National Key Research and Development Program of China(No.2020YFA0113003)Key Research and Development Project of Zhejiang Province(No.2023C03046)+1 种基金Fundamental Research Funds for the Central Universities(No.2022ZFJH003)Research Project of Jinan Microecological Biomedicine Shandong Laboratory(No.JNL-2022026C,JNL-2023003C).
文摘Primary sclerosing cholangitis(PSC)is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis,with no curative treatment available,and liver transplantation is inevitable for end-stage patients.Human placentalmesenchymal stem cell(hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis,inhibit collagen production and possess immunomodulatory properties in autoimmune liver disease.Here,we prepared hpMSC-derived exosomes(Exo^(MSC))and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2^(−/−)mice and multicellular organoids established from PSC patients.The results showed that Exo^(MSC) ameliorated liver fibrosis in Mdr2^(−/−)mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis,and the percentage of CD4+IL-17A+T cells was reduced both in Exo^(MSC)-treated Mdr2^(−/−)mice(Mdr2^(−/−)-Exo)in vivo and Exo^(MSC)-treated Th17 differentiation progressed in vitro.Furthermore,Exo^(MSC) improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular organoids.Thus,our data demonstrate the antifibrosis effect of Exo^(MSC) in PSC disease by inhibiting Th17 differentiation,and ameliorating the Th17-induced microenvironment,indicating the promising potential therapeutic role of Exo^(MSC) in liver fibrosis of PSC or Th17-related diseases.
文摘Objective: To study the correlation between mi R-21 and Treg/Th17 ratio in the microenvironment of rats with hepatocellular carcinoma. Methods: Diethylnitrosamine was used to build the hepatocel ular carcinoma model of rats; the content of Treg cells and Th17 cells and the expression of mi R-21 in the peripheral blood of rats with hepatocellular carcinoma were detected. The statistical analysis was performed on the correlation between mi R-21 expression and Treg/Th17 ratio. Results: Hepatocellular carcinoma model of rats was successfully constructed. The proportion of Th17 cells among all CD4+T cells in the peripheral blood of rats with hepatocellular carcinoma was 5.319%, which was higher than the control group; while the proportion of Treg cells was 9.472%, which was higher than the control group. Treg/Th17 ratio in the model group was 1.781, compared with 1.478 in the control group. The expression of mi R-21 was increased in the peripheral blood of rats with hepatocellular carcinoma and it showed a positive correlation with the ratio of Treg/Th17. Conclusions: There is a positive correlation between the expression level of miR-21 and the ratio of Treg/Th17.
