Inflammatory bowel diseases are characterised by inflammation that compromises the integrity of the epithelial barrier. The intestinal epithelium is not only a static barrier but has evolved complex mechanisms to cont...Inflammatory bowel diseases are characterised by inflammation that compromises the integrity of the epithelial barrier. The intestinal epithelium is not only a static barrier but has evolved complex mechanisms to control and regulate bacterial interactions with the mucosal surface. Apical tight junction proteins are critical in the maintenance of epithelial barrier function and control of paracellular permeability. The characterisation of alterations in tight junction proteins as key players in epithelial barrier function in inflammatory bowel diseases is rapidly enhancing our understanding of critical mechanisms in disease pathogenesis as well as novel therapeutic opportunities. Here we give an overview of recent literature focusing on the role of tight junction proteins, in particular claudins, in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer.展开更多
AIM: To investigate the effect of emodin on expression of claudin4, claudin5 and occludin, as well as the alveolar epithelial barrier in rats with pancreatitis induced by sodium taurocholate. METHODS: Experimental pan...AIM: To investigate the effect of emodin on expression of claudin4, claudin5 and occludin, as well as the alveolar epithelial barrier in rats with pancreatitis induced by sodium taurocholate. METHODS: Experimental pancreatitis was induced by retrograde injection of 5% sodium taurocholate into the biliopancreatic duct. Emodin was injected via the external jugular vein 3 h after induction of acute pancreatitis. Rats from sham operation group and acute pancreatitis group were injected with normal saline (an equivalent volume as emodin) at the same time point. Samples of lung and serum were obtained 6 h after drug administration. Pulmonary morphology was examined with HE staining. Pulmonary edema was estimated by measuring water content in lung tissue samples. Tumor necrosis factorα (TNFα) and interleukin6 (IL6) level were measured by enzymelinked immunospecific assay. Serum amylase and pulmonary myeloperoxidase (MPO) activity were detected by spectrophotometry. Alveolar epithelial barrier was assessed by pulmonary dye extravasation. Expression of claudin4, claudin5 and occludin in lung tissue samples was examined by immunohistology, quantitative realtime reverse transcription polymerase chain reaction and Western blotting analysis, respectively.RESULTS: Pancreatitis-associated lung injury was char-acterized by pulmonary edema, leukocyte infiltration, alveolar collapse, and elevated serum amylase level. The pulmonary damage, pulmonary pathological scores, serum amylase and MPO activity, TNF-α and IL-6 levels, and wet/dry ratio were decreased in rats after treatment with emodin. Immunostaining of claudin-4, claudin-5 and occludin was detected in lung tissue samples from rats in sham operation group, which was distributed in alveolar epithelium, vascular endothelium, and bron-chial epithelium, respectively. The mRNA and protein expression levels of claudin-4, claudin-5 and occludin in lung tissue samples were markedly decreased, the expression level of claudin-4, claudin-5 and occluding was increased, and the pulmon展开更多
Claudin 18.2(CLDN18.2)is a tight-junction protein.CLDN18.2-targeting strategy has cut a striking figure in CLDN18.2 positive patients with advanced gastric cancer.Zolbetuximab,the CLDN18.2 antibody,obtained a better c...Claudin 18.2(CLDN18.2)is a tight-junction protein.CLDN18.2-targeting strategy has cut a striking figure in CLDN18.2 positive patients with advanced gastric cancer.Zolbetuximab,the CLDN18.2 antibody,obtained a better clinical benefit in patients compared with the controlled.In phase II trials,combination treatment of epirubicin,oxaliplatin and capecitabine(EOX)+zolbetuximab achieved the optimal effects of overall survival which extended to 13.2 months with tolerable safety events,indicating its greater potential playing the second promising target in gastric cancer.This review will reveal the definitive clinical benefit CLDN18.2-targeting therapies have achieved and update the highlighting development(like chimeric antigen receptor T-cell immunotherapy)to CLDN18.2 positive patients.We then focus on 10 questions arisen from recent progress and anticipate to provide a future perspective for novel cancer treatment.展开更多
AIM:To investigate the effect of emodin on pancreatic claudin-5 and occludin expression,and pancreatic paracellular permeability in acute pancreatitis(AP).METHODS:Experimental pancreatitis was induced by retrograde in...AIM:To investigate the effect of emodin on pancreatic claudin-5 and occludin expression,and pancreatic paracellular permeability in acute pancreatitis(AP).METHODS:Experimental pancreatitis was induced by retrograde injection of 5% sodium taurocholate into the biliopancreatic duct.Emodin was injected via the external jugular vein 0 or 6 h after induction of AP.Rats from sham operation and AP groups were injected with normal saline at the same time.Samples of pancreas were obtained 6 or 12 h after drug administration.Pancreatic morphology was examined with hematoxylin and eosin staining.Pancreatic edema was estimated by measuring tissue water content.Tumor necrosis factor(TNF)-α and interleukin(IL)-6 level were measured by enzyme-linked immunosorbent assay.Pancreatic paracellular permeability was assessed by tissue dye extravasation.Expression of pancreatic claudin-5 and occludin was examined by immunohistology,quantitative real-time reverse transcriptase polymerase chain reaction and western blotting.RESULTS:Pancreatic TNF-α and IL-6 levels,wet/dry ratio,dye extravasation,and histological score were significantly elevated at 3,6 and 12 h following sodium taurocholate infusion;treatment with emodin prevented these changes at all time points.Immunostaining of claudin-5 and occludin was detected in rat pancreas,which was distributed in pancreatic acinar cells,ductal cells and vascular endothelial cells,respectively.Sodium taurocholate infusion significantly decreased pancreatic claudin-5 and occludin mRNA and protein levels at 3,6 and 12 h,and that could be promoted by intravenous administration of emodin at all time points.CONCLUSION:These results demonstrate that emodin could promote pancreatic claudin-5 and occludin expression,and reduce pancreatic paracellular permeability.展开更多
The membrane protein claudin-3(CLDN3) is critical for the formation and maintenance of tight junction and its high expression has been implicated in dictating malignant progression in various cancers. However, the pos...The membrane protein claudin-3(CLDN3) is critical for the formation and maintenance of tight junction and its high expression has been implicated in dictating malignant progression in various cancers. However, the post-translational modification of CLDN3 and its biological function remains poorly understood. Here, we report that CLDN3 is positively correlated with ovarian cancer progression both in vitro and in vivo. Of interest, CLDN3 undergoes S-palmitoylation on three juxtamembrane cysteine residues, which contribute to the accurate plasma membrane localization and protein stability of CLDN3. Moreover, the deprivation of S-palmitoylation in CLDN3 significantly abolishes its tumorigenic promotion effect in ovarian cancer cells. By utilizing the co-immunoprecipitation assay, we further identify ZDHHC12 as a CLDN3-targating palmitoyltransferase from 23 ZDHHC family proteins.Furthermore, the knockdown of ZDHHC12 also significantly inhibits CLDN3 accurate membrane localization, protein stability and ovarian cancer cells tumorigenesis. Thus, our work reveals S-palmitoylation as a novel regulatory mechanism that modulates CLDN3 function, which implies that targeting ZDHHC12-mediated CLDN3 S-palmitoylation might be a potential strategy for ovarian cancer therapy.展开更多
Claudin 14 has been shown to promote nerve repair and regeneration in the early stages of Wallerian degeneration （0-4 days） in rats with sciatic nerve injury, but the mechanism underlying this process remains poorly...Claudin 14 has been shown to promote nerve repair and regeneration in the early stages of Wallerian degeneration （0-4 days） in rats with sciatic nerve injury, but the mechanism underlying this process remains poorly understood. This study reported the effects of claudin 14 on nerve degeneration and regeneration during early Wallerian degeneration. Claudin 14 expression was up-regulated in sciatic nerve 4 days after Wallerian degeneration. The altered expression of claudin 14 in Schwann cells resulted in expression changes of cytokines in vitro. Expression of claudin 14 affected c-Jun, but not Akt anal ERK1/2 patl^ways, l^urther studies reve^ed that enhanced expression of claudin 14 could promote Schwann cell proliferation and migration. Silencing of claudin 14 expression resulted in Schwann cell apoptosis and reduction in Schwann cell proliferation. Our data revealed the role of claudin 14 in early Wallerian degeneration, which may provide new insights into the molecular mechanisms of Wallerian degeneration.展开更多
基金Supported by The Association for International Cancer Research(AICRto Dr.Al-Hassi HO)+6 种基金ScotlandFunded by the AICRgrant No.120234a BBSRC Strategic Research Grant(to English N and Knight SCWMNIP33458)the St Mark’s Hospital FoundationUnited Kingdom
文摘Inflammatory bowel diseases are characterised by inflammation that compromises the integrity of the epithelial barrier. The intestinal epithelium is not only a static barrier but has evolved complex mechanisms to control and regulate bacterial interactions with the mucosal surface. Apical tight junction proteins are critical in the maintenance of epithelial barrier function and control of paracellular permeability. The characterisation of alterations in tight junction proteins as key players in epithelial barrier function in inflammatory bowel diseases is rapidly enhancing our understanding of critical mechanisms in disease pathogenesis as well as novel therapeutic opportunities. Here we give an overview of recent literature focusing on the role of tight junction proteins, in particular claudins, in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer.
基金Supported by National Natural Science Foundation of China, No. 30500688
文摘AIM: To investigate the effect of emodin on expression of claudin4, claudin5 and occludin, as well as the alveolar epithelial barrier in rats with pancreatitis induced by sodium taurocholate. METHODS: Experimental pancreatitis was induced by retrograde injection of 5% sodium taurocholate into the biliopancreatic duct. Emodin was injected via the external jugular vein 3 h after induction of acute pancreatitis. Rats from sham operation group and acute pancreatitis group were injected with normal saline (an equivalent volume as emodin) at the same time point. Samples of lung and serum were obtained 6 h after drug administration. Pulmonary morphology was examined with HE staining. Pulmonary edema was estimated by measuring water content in lung tissue samples. Tumor necrosis factorα (TNFα) and interleukin6 (IL6) level were measured by enzymelinked immunospecific assay. Serum amylase and pulmonary myeloperoxidase (MPO) activity were detected by spectrophotometry. Alveolar epithelial barrier was assessed by pulmonary dye extravasation. Expression of claudin4, claudin5 and occludin in lung tissue samples was examined by immunohistology, quantitative realtime reverse transcription polymerase chain reaction and Western blotting analysis, respectively.RESULTS: Pancreatitis-associated lung injury was char-acterized by pulmonary edema, leukocyte infiltration, alveolar collapse, and elevated serum amylase level. The pulmonary damage, pulmonary pathological scores, serum amylase and MPO activity, TNF-α and IL-6 levels, and wet/dry ratio were decreased in rats after treatment with emodin. Immunostaining of claudin-4, claudin-5 and occludin was detected in lung tissue samples from rats in sham operation group, which was distributed in alveolar epithelium, vascular endothelium, and bron-chial epithelium, respectively. The mRNA and protein expression levels of claudin-4, claudin-5 and occludin in lung tissue samples were markedly decreased, the expression level of claudin-4, claudin-5 and occluding was increased, and the pulmon
基金supported by the National Key Research and Development Program of China(No.2017YFC1308900)。
文摘Claudin 18.2(CLDN18.2)is a tight-junction protein.CLDN18.2-targeting strategy has cut a striking figure in CLDN18.2 positive patients with advanced gastric cancer.Zolbetuximab,the CLDN18.2 antibody,obtained a better clinical benefit in patients compared with the controlled.In phase II trials,combination treatment of epirubicin,oxaliplatin and capecitabine(EOX)+zolbetuximab achieved the optimal effects of overall survival which extended to 13.2 months with tolerable safety events,indicating its greater potential playing the second promising target in gastric cancer.This review will reveal the definitive clinical benefit CLDN18.2-targeting therapies have achieved and update the highlighting development(like chimeric antigen receptor T-cell immunotherapy)to CLDN18.2 positive patients.We then focus on 10 questions arisen from recent progress and anticipate to provide a future perspective for novel cancer treatment.
基金Supported by National Natural Science Foundation of China,No.30500688
文摘AIM:To investigate the effect of emodin on pancreatic claudin-5 and occludin expression,and pancreatic paracellular permeability in acute pancreatitis(AP).METHODS:Experimental pancreatitis was induced by retrograde injection of 5% sodium taurocholate into the biliopancreatic duct.Emodin was injected via the external jugular vein 0 or 6 h after induction of AP.Rats from sham operation and AP groups were injected with normal saline at the same time.Samples of pancreas were obtained 6 or 12 h after drug administration.Pancreatic morphology was examined with hematoxylin and eosin staining.Pancreatic edema was estimated by measuring tissue water content.Tumor necrosis factor(TNF)-α and interleukin(IL)-6 level were measured by enzyme-linked immunosorbent assay.Pancreatic paracellular permeability was assessed by tissue dye extravasation.Expression of pancreatic claudin-5 and occludin was examined by immunohistology,quantitative real-time reverse transcriptase polymerase chain reaction and western blotting.RESULTS:Pancreatic TNF-α and IL-6 levels,wet/dry ratio,dye extravasation,and histological score were significantly elevated at 3,6 and 12 h following sodium taurocholate infusion;treatment with emodin prevented these changes at all time points.Immunostaining of claudin-5 and occludin was detected in rat pancreas,which was distributed in pancreatic acinar cells,ductal cells and vascular endothelial cells,respectively.Sodium taurocholate infusion significantly decreased pancreatic claudin-5 and occludin mRNA and protein levels at 3,6 and 12 h,and that could be promoted by intravenous administration of emodin at all time points.CONCLUSION:These results demonstrate that emodin could promote pancreatic claudin-5 and occludin expression,and reduce pancreatic paracellular permeability.
基金supported by grants from the National Natural Science Foundation of China(No.91753114 to Hong JiangNo.81872885 to Ji Cao)+1 种基金Zhejiang Provincial Natural Science Foundation(No.Y18H310005 to Ji Cao,China)the Talent Project of Zhejiang Association for Science and Technology(No.2018YCGC002 to Ji Cao,China)
文摘The membrane protein claudin-3(CLDN3) is critical for the formation and maintenance of tight junction and its high expression has been implicated in dictating malignant progression in various cancers. However, the post-translational modification of CLDN3 and its biological function remains poorly understood. Here, we report that CLDN3 is positively correlated with ovarian cancer progression both in vitro and in vivo. Of interest, CLDN3 undergoes S-palmitoylation on three juxtamembrane cysteine residues, which contribute to the accurate plasma membrane localization and protein stability of CLDN3. Moreover, the deprivation of S-palmitoylation in CLDN3 significantly abolishes its tumorigenic promotion effect in ovarian cancer cells. By utilizing the co-immunoprecipitation assay, we further identify ZDHHC12 as a CLDN3-targating palmitoyltransferase from 23 ZDHHC family proteins.Furthermore, the knockdown of ZDHHC12 also significantly inhibits CLDN3 accurate membrane localization, protein stability and ovarian cancer cells tumorigenesis. Thus, our work reveals S-palmitoylation as a novel regulatory mechanism that modulates CLDN3 function, which implies that targeting ZDHHC12-mediated CLDN3 S-palmitoylation might be a potential strategy for ovarian cancer therapy.
基金supported by grants from the National Natural Science Foundation of China,Grant No.81370982,31170946Key Program,Grant No.81130080+1 种基金the Scientific Research Foundation for Returned Scholars,Ministry of Education of Chinathe Priority Academic Program Development of Jiangsu Higher Education Institutions
文摘Claudin 14 has been shown to promote nerve repair and regeneration in the early stages of Wallerian degeneration （0-4 days） in rats with sciatic nerve injury, but the mechanism underlying this process remains poorly understood. This study reported the effects of claudin 14 on nerve degeneration and regeneration during early Wallerian degeneration. Claudin 14 expression was up-regulated in sciatic nerve 4 days after Wallerian degeneration. The altered expression of claudin 14 in Schwann cells resulted in expression changes of cytokines in vitro. Expression of claudin 14 affected c-Jun, but not Akt anal ERK1/2 patl^ways, l^urther studies reve^ed that enhanced expression of claudin 14 could promote Schwann cell proliferation and migration. Silencing of claudin 14 expression resulted in Schwann cell apoptosis and reduction in Schwann cell proliferation. Our data revealed the role of claudin 14 in early Wallerian degeneration, which may provide new insights into the molecular mechanisms of Wallerian degeneration.
