AIM: To observe the attenuation of ethanol extract of Herba Scutellaria barbata (SE) against diabetic retinopathy (DR) and its engaged mechanism. METHODS: C57BL/6J mice were intraperitoneally injected with stre...AIM: To observe the attenuation of ethanol extract of Herba Scutellaria barbata (SE) against diabetic retinopathy (DR) and its engaged mechanism. METHODS: C57BL/6J mice were intraperitoneally injected with streptozotocin (STZ, 55 mg/kg) for 5 consecutive days to induce diabetes, The diabetic mice were orally given with SE (100, 200 mg/kg) for lmo at lmo after STZ injection. Blood-retinal barrier (BRB) breakdown was detected by using Evans blue permeation assay. Real-time polymerase chain reaction (RT-PCR), Western blot and immunofiuorescence staining were used to detect mRNA and protein expression. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum contents of tumor necrosis factor-e (TNF-a) and interleukin (IL)-II. RESULTS: SE (100, 200 mg/kg) reversed the breakdown of BRB in STZ-induced diabetic mice. The decreased expression of retinal claudin-1 and claudin-19, which are both tight junction (T J) proteins, was reversed by SE. SE decreased the increased serum contents and retinal mRNA expression of TNF-a and IL-113. SE also decreased the increased retinal expression of intercellular cell adhesion molecule-1 (ICAM-1). SE reduced the increased phosphorylation of nuclear factor kappa B (NFKB) p65 and its subsequent nuclear translocation in retinas from STZ- induced diabetic mice. Results of Western blot and retinal immunofluorescence staining of ionized calcium-binding adapter molecule 1 (Ibal) demonstrated that SE abrogated the activation of microglia cells in STZ-induced diabetic mice. CONCLUSION: SE attenuates the development of DR by inhibiting retinal inflammation and restoring the decreased expression of TJ proteins including claudin-1 and claudin-19.展开更多
AIM:To determine the molecular mechanisms of Shugan decoction(SGD) in the regulation of colonic motility and visceral hyperalgesia(VHL) in irritable bowel syndrome(IBS).METHODS:The chemical compounds contained in SGD ...AIM:To determine the molecular mechanisms of Shugan decoction(SGD) in the regulation of colonic motility and visceral hyperalgesia(VHL) in irritable bowel syndrome(IBS).METHODS:The chemical compounds contained in SGD were measured by high-performance liquid chromatography.A rat model of IBS was induced by chronic water avoidance stress(WAS).The number of fecal pellets was counted after WAS and the pain pressure threshold was measured by colorectal distension.Morphological changes in colonic mucosa were detected by hematoxylin-eosin staining.The contents of tumor necrosis factor(TNF)-αin colonic tissue and calcitonin-gene-related peptide(CGRP)in serum were measured by ELISA.The protein expression of serotonin[5-hydroxytryptamide(5-HT)],serotonin transporter(SERT),chromogranin A(Cg A)and CGRP incolon tissue was measured by immunohistochemistry.RESULTS:SGD inhibited colonic motility dysfunction and VHL in rats with IBS.Blockers of transient receptor potential(TRP)vanilloid 1(TRPV1)(Ruthenium Red)and TRP ankyrin-1(TRPA1)(HC-030031)and activator of protease-activated receptor(PAR)4 increased the pain pressure threshold,whereas activators of PAR2and TRPV4 decreased the pain pressure threshold in rats with IBS.The effect of SGD on pain pressure threshold in these rats was abolished by activators of TRPV1(capsaicin),TRPV4(RN1747),TRPA1(Polygodial)and PAR2(AC55541).In addition,CGRP levels in serum and colonic tissue were both increased in these rats.TNF-αlevel in colonic tissue was also significantly upregulated.However,the levels of 5-HT,SERT and Cg A in colonic tissue were decreased.All these pathological changes in rats with IBS were attenuated by SGD.CONCLUSION:SGD alleviated VHL and attenuated colon motility in IBS,partly by regulating TRPV1,TRPV4,TRPA1,PAR2,5-HT,Cg A and SERT,and reducing CGRP and TNF-αlevel.展开更多
The inducible co-activator PGC-1α plays a crucial role in adaptive thermogenesis and increases energy expenditure in brown adipose tissue(BAT). Meanwhile, chronic inflammation caused by infiltrated-macrophage in the ...The inducible co-activator PGC-1α plays a crucial role in adaptive thermogenesis and increases energy expenditure in brown adipose tissue(BAT). Meanwhile, chronic inflammation caused by infiltrated-macrophage in the white adipose tissue(WAT) is a target for the treatment of obesity. Bofutsushosan(BF), a traditional Chinese medicine composed of 17 crude drugs, has been widely used to treat obesity in China, Japan, and other Asia countries. However, the mechanism underlying anti-obesity remains to be elucidated. In the present study, we demonstrated that BF oral administration reduced the body weight of obese mice induced by high-fat diet(HFD) and alleviated the level of biochemical markers(P < 0.05), including blood glucose(Glu), total cholesterol(TC), triglyceride(TG), low density lipoprotein(LDL-C) and insulin. Our further results also indicated that oral BF administration increased the expression of PGC-1α and UCP1 in BAT. Moreover, BF also reduced the expression of inflammatory cytokines in WAT, such as tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6). These findings suggested that the mechanism of BF against obesity was at least partially through increasing gene expression of PGC-1α and UCP1 for energy consumption in BAT and inhibiting inflammation in WAT.展开更多
Bile acids(BAs) are not only digestive surfactants but also important cell signaling molecules,which stimulate several signaling pathways to regulate some important biological processes. The bileacid-activated nuclear...Bile acids(BAs) are not only digestive surfactants but also important cell signaling molecules,which stimulate several signaling pathways to regulate some important biological processes. The bileacid-activated nuclear receptor, farnesoid X receptor(FXR), plays a pivotal role in regulating bile acid,lipid and glucose homeostasis as well as in regulating the inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles ofFXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases.展开更多
Obesity and its associated complications are highly related to a current public health crisis around the world.A growing body of evidence has indicated that G-protein coupled bile acid(BA) receptor TGR5(also known as ...Obesity and its associated complications are highly related to a current public health crisis around the world.A growing body of evidence has indicated that G-protein coupled bile acid(BA) receptor TGR5(also known as Gpbar-1) is a potential drug target to treat obesity and associated metabolic disorders.We have identified notoginsenoside Ftl(Ftl) from Panax notoginseng as an agonist of TGR5 in vitro.However,the pharmacological effects of Ftl on diet-induced obese(DIO) mice and the underlying mechanisms are still elusive.Here we show that Ftl(100 mg/100 diet) increased adipose lipolysis,promoted fat browning in inguinal adipose tissue and induced glucagon-like peptide-1(GLP-1) secretion in the ileum of wild type but not Tgr5^(-/-) obese mice.In addition,Ftl elevated serum free and taurineconjugated bile acids(BAs) by antagonizing Fxr transcriptional activities in the ileum to activate Tgr5 in the adipose tissues.The metabolic benefits of Ftl were abolished in Cyp27 al^(-/-) mice which have much lower BA levels.These results identify Ftl as a single compound with opposite activities on two key BA receptors to alleviate high fat diet-induced obesity and insulin resistance in mice.展开更多
Objective: To evaluate the effects of the ethanol extract isolated from Weiqi Decoction (胃祺饮, WQD-EE) on AGS cell proliferation and apoptosis. Methods: By using high-performance liquid chromatography with ultra...Objective: To evaluate the effects of the ethanol extract isolated from Weiqi Decoction (胃祺饮, WQD-EE) on AGS cell proliferation and apoptosis. Methods: By using high-performance liquid chromatography with ultraviolet detectors (HPLC-UV) assay and MTT method, the main compounds in WQD-EE and cell viability were detected. And cell cycle distributions were determined by flow cytometry with propidium iodine (PI) staining while apoptosis was detected by flow cytometry with annexin V/PI double staining. Finally, caspase-3 activities were measured by colorimetric method and protein expression was determined by Western blotting. Results: HPLC analysis showed that naringin (35.92 μg/mg), nobiletin (21.98 μ g/mg), neohesperidin (17.98μg/mg) and tangeretin (0.756μ g/mg) may be the main compounds in WQD-EE. WQD-EE not only inhibited AGS and MCF 7 cell proliferation in a dose-dependent manner, but also blocked cell cycle progression at G2/M stage as well as inducing cell apoptosis at concentrations triggering significant inhibition of proliferation and cell cycle arrest in AGS cells. While at 0.5 mg/mL, WQD-EE significantly increased caspase-3 activity by 2.75 and 7.47 times at 24 h and 48 h, respectively. Moreover, WQD-EE in one hand reduced protein expressions of p53 and cyclin B1, and in other hand enhanced protein expressions of cytochrome c and Bax. Protein levels of Bcl-2, Fas L and Fas were not significantly affected by WQD-EE. Conclusions: WQD-EE inhibits AGS cell proliferation through G2/M arrest due to down-regulation of cyclin B1 protein expression, and promotes apoptosis by caspase-3 and mitochondria-dependent pathways, but not by p53-dependent pathway.展开更多
The epidemic of obesity and its co-mortalities has reached an alarming level worldwide.Currently,metabolic surgeries,especially the Roux-en-Y gastric bypass and vertical sleeve gastrectomy,are the most effective and s...The epidemic of obesity and its co-mortalities has reached an alarming level worldwide.Currently,metabolic surgeries,especially the Roux-en-Y gastric bypass and vertical sleeve gastrectomy,are the most effective and sustainable treatments for obesity,type 2 diabetes,non-alcoholic steatohepatitis,as well as other metabolic diseases.However,the invasive nature of the surgeries limits their broad ap-plications to the general public.Therefore,developing alternative non-invasive approaches to mimic metabolic surgery is an important direction of the field.Recent studies have identified several potential metabolic surgery-induced downstream endocrine mediators,among which bile acids are key candidate signaling molecules.Bile acids are profoundly altered by metabolic surgery,which contributes to the metabolic effects of the surgery.In this review,we focus on the most recent studies on the roles of bile acids and bile acid receptors farnesoid X receptor and Takeda G protein-coupled receptor 5 in mediating the metabolic effects of metabolic surgery.We conclude that targeting bile acid pathways may be a promising pharmacological approach to mimic the beneficial effects of metabolic surgery.展开更多
基金Supported by the National Natural Science Foundation of China(No.81173517No.81322053)
文摘AIM: To observe the attenuation of ethanol extract of Herba Scutellaria barbata (SE) against diabetic retinopathy (DR) and its engaged mechanism. METHODS: C57BL/6J mice were intraperitoneally injected with streptozotocin (STZ, 55 mg/kg) for 5 consecutive days to induce diabetes, The diabetic mice were orally given with SE (100, 200 mg/kg) for lmo at lmo after STZ injection. Blood-retinal barrier (BRB) breakdown was detected by using Evans blue permeation assay. Real-time polymerase chain reaction (RT-PCR), Western blot and immunofiuorescence staining were used to detect mRNA and protein expression. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum contents of tumor necrosis factor-e (TNF-a) and interleukin (IL)-II. RESULTS: SE (100, 200 mg/kg) reversed the breakdown of BRB in STZ-induced diabetic mice. The decreased expression of retinal claudin-1 and claudin-19, which are both tight junction (T J) proteins, was reversed by SE. SE decreased the increased serum contents and retinal mRNA expression of TNF-a and IL-113. SE also decreased the increased retinal expression of intercellular cell adhesion molecule-1 (ICAM-1). SE reduced the increased phosphorylation of nuclear factor kappa B (NFKB) p65 and its subsequent nuclear translocation in retinas from STZ- induced diabetic mice. Results of Western blot and retinal immunofluorescence staining of ionized calcium-binding adapter molecule 1 (Ibal) demonstrated that SE abrogated the activation of microglia cells in STZ-induced diabetic mice. CONCLUSION: SE attenuates the development of DR by inhibiting retinal inflammation and restoring the decreased expression of TJ proteins including claudin-1 and claudin-19.
基金Supported by Innovation Program of the Shanghai Municipal Education Commission,No.12YZ065National Natural Science Foundation of China,No.81072786,No.81473630 and No.81202665+2 种基金Longhua Medical Project,No.D-09High level Project of the University of Educational Commission of Shanghai,China,No.2008GSP19Shanghai Leading Academic Discipline Project,No.J50305
文摘AIM:To determine the molecular mechanisms of Shugan decoction(SGD) in the regulation of colonic motility and visceral hyperalgesia(VHL) in irritable bowel syndrome(IBS).METHODS:The chemical compounds contained in SGD were measured by high-performance liquid chromatography.A rat model of IBS was induced by chronic water avoidance stress(WAS).The number of fecal pellets was counted after WAS and the pain pressure threshold was measured by colorectal distension.Morphological changes in colonic mucosa were detected by hematoxylin-eosin staining.The contents of tumor necrosis factor(TNF)-αin colonic tissue and calcitonin-gene-related peptide(CGRP)in serum were measured by ELISA.The protein expression of serotonin[5-hydroxytryptamide(5-HT)],serotonin transporter(SERT),chromogranin A(Cg A)and CGRP incolon tissue was measured by immunohistochemistry.RESULTS:SGD inhibited colonic motility dysfunction and VHL in rats with IBS.Blockers of transient receptor potential(TRP)vanilloid 1(TRPV1)(Ruthenium Red)and TRP ankyrin-1(TRPA1)(HC-030031)and activator of protease-activated receptor(PAR)4 increased the pain pressure threshold,whereas activators of PAR2and TRPV4 decreased the pain pressure threshold in rats with IBS.The effect of SGD on pain pressure threshold in these rats was abolished by activators of TRPV1(capsaicin),TRPV4(RN1747),TRPA1(Polygodial)and PAR2(AC55541).In addition,CGRP levels in serum and colonic tissue were both increased in these rats.TNF-αlevel in colonic tissue was also significantly upregulated.However,the levels of 5-HT,SERT and Cg A in colonic tissue were decreased.All these pathological changes in rats with IBS were attenuated by SGD.CONCLUSION:SGD alleviated VHL and attenuated colon motility in IBS,partly by regulating TRPV1,TRPV4,TRPA1,PAR2,5-HT,Cg A and SERT,and reducing CGRP and TNF-αlevel.
基金supported by Opening Project of Shanghai Key Laboratory of Complex Prescription(Shanghai University of Traditional Chinese Medicine)(11DZ2272300)Huahai Pharmaceutical Graduate Student Innovation Fund(HH13B011)+1 种基金National Natural Science Foundation of China(No.81573484)Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)
文摘The inducible co-activator PGC-1α plays a crucial role in adaptive thermogenesis and increases energy expenditure in brown adipose tissue(BAT). Meanwhile, chronic inflammation caused by infiltrated-macrophage in the white adipose tissue(WAT) is a target for the treatment of obesity. Bofutsushosan(BF), a traditional Chinese medicine composed of 17 crude drugs, has been widely used to treat obesity in China, Japan, and other Asia countries. However, the mechanism underlying anti-obesity remains to be elucidated. In the present study, we demonstrated that BF oral administration reduced the body weight of obese mice induced by high-fat diet(HFD) and alleviated the level of biochemical markers(P < 0.05), including blood glucose(Glu), total cholesterol(TC), triglyceride(TG), low density lipoprotein(LDL-C) and insulin. Our further results also indicated that oral BF administration increased the expression of PGC-1α and UCP1 in BAT. Moreover, BF also reduced the expression of inflammatory cytokines in WAT, such as tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6). These findings suggested that the mechanism of BF against obesity was at least partially through increasing gene expression of PGC-1α and UCP1 for energy consumption in BAT and inhibiting inflammation in WAT.
基金supported by National Cancer Institute of United States (No.1R01-CA139158,to Wendong Huang)National Natural Science Foundation of China (Nos.81303186 and ZYX-NSFC-016)China Postdoctoral Science Foundation (No.2013M531202)
文摘Bile acids(BAs) are not only digestive surfactants but also important cell signaling molecules,which stimulate several signaling pathways to regulate some important biological processes. The bileacid-activated nuclear receptor, farnesoid X receptor(FXR), plays a pivotal role in regulating bile acid,lipid and glucose homeostasis as well as in regulating the inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles ofFXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases.
基金Project supported by the "Shu Guang" Project from Shanghai Municipal Education Commission and Shanghai Education Development Foundation(No.13SG43)the National Natural Science Foundation of China(No.81322053)the Program for New Century Excellent Talents in University(No.NCET-11-1054),China
基金financially sponsored by Shanghai Pujiang Program(17PJ1408800,China)the Natural Science Foundations of China to Lili Ding(81773961)+6 种基金Zhengtao Wang(81920108033)Yingbo Yang(81703682)financially supported by the National S&T Major Special Projects of China(No.2017ZX09309006)to Li YangInterdisciplinary Program of Shanghai Jiao Tong University to Qiaoling Yang(YG2019QNA03,China)partially supported by R01DK124627George Schaeffer fundJohn Hench fund(USA)to Wendong Huang。
文摘Obesity and its associated complications are highly related to a current public health crisis around the world.A growing body of evidence has indicated that G-protein coupled bile acid(BA) receptor TGR5(also known as Gpbar-1) is a potential drug target to treat obesity and associated metabolic disorders.We have identified notoginsenoside Ftl(Ftl) from Panax notoginseng as an agonist of TGR5 in vitro.However,the pharmacological effects of Ftl on diet-induced obese(DIO) mice and the underlying mechanisms are still elusive.Here we show that Ftl(100 mg/100 diet) increased adipose lipolysis,promoted fat browning in inguinal adipose tissue and induced glucagon-like peptide-1(GLP-1) secretion in the ileum of wild type but not Tgr5^(-/-) obese mice.In addition,Ftl elevated serum free and taurineconjugated bile acids(BAs) by antagonizing Fxr transcriptional activities in the ileum to activate Tgr5 in the adipose tissues.The metabolic benefits of Ftl were abolished in Cyp27 al^(-/-) mice which have much lower BA levels.These results identify Ftl as a single compound with opposite activities on two key BA receptors to alleviate high fat diet-induced obesity and insulin resistance in mice.
基金Project supported by the Program for New Century Excellent Talents in University(No.NCET-11-1054)the National Natural Science Foundation of China(No.81322053)the Program for Changjiang Scholars and Innovative Research Team in University(No.PCSIRTIRT1071),China
基金Project supported by the National Natural Science Foundation of China(No.81322053)the Program for New Century Excellent Talents in University(No.NCET-11-1054)+1 种基金the"Shu Guang"Project of Shanghai Municipal Education Commission and Shanghai Education Development Foundation(No.13SG43)the State Major Science and Technology Special Projects during the 12th Five-Year Plan(No.2012ZX09505001-002),China
基金Supported by High Level Project of University of Educational Commission of Shanghai,Shanghai,China(No.2008GSP19)Shanghai Municipal Natural Science Foundation,Shanghai China(09ZR1431800)+1 种基金Opening Project of Shanghai Key Laboratory of Complex Prescription,Shanghai,China(No.11DZ2272300)Educational Commission of Shanghai,Shanghai,China(No.09JW21 and No.2012JW19)
文摘Objective: To evaluate the effects of the ethanol extract isolated from Weiqi Decoction (胃祺饮, WQD-EE) on AGS cell proliferation and apoptosis. Methods: By using high-performance liquid chromatography with ultraviolet detectors (HPLC-UV) assay and MTT method, the main compounds in WQD-EE and cell viability were detected. And cell cycle distributions were determined by flow cytometry with propidium iodine (PI) staining while apoptosis was detected by flow cytometry with annexin V/PI double staining. Finally, caspase-3 activities were measured by colorimetric method and protein expression was determined by Western blotting. Results: HPLC analysis showed that naringin (35.92 μg/mg), nobiletin (21.98 μ g/mg), neohesperidin (17.98μg/mg) and tangeretin (0.756μ g/mg) may be the main compounds in WQD-EE. WQD-EE not only inhibited AGS and MCF 7 cell proliferation in a dose-dependent manner, but also blocked cell cycle progression at G2/M stage as well as inducing cell apoptosis at concentrations triggering significant inhibition of proliferation and cell cycle arrest in AGS cells. While at 0.5 mg/mL, WQD-EE significantly increased caspase-3 activity by 2.75 and 7.47 times at 24 h and 48 h, respectively. Moreover, WQD-EE in one hand reduced protein expressions of p53 and cyclin B1, and in other hand enhanced protein expressions of cytochrome c and Bax. Protein levels of Bcl-2, Fas L and Fas were not significantly affected by WQD-EE. Conclusions: WQD-EE inhibits AGS cell proliferation through G2/M arrest due to down-regulation of cyclin B1 protein expression, and promotes apoptosis by caspase-3 and mitochondria-dependent pathways, but not by p53-dependent pathway.
基金This work was supported by the National Natural Science Foundation of China(81773961)to L.Ding,along with grants from John Hench foundation,George Schaeffer foundation and National Institute of Diabetes and Digestive and Kidney Diseases(R01DK124627)to W.Huang.
文摘The epidemic of obesity and its co-mortalities has reached an alarming level worldwide.Currently,metabolic surgeries,especially the Roux-en-Y gastric bypass and vertical sleeve gastrectomy,are the most effective and sustainable treatments for obesity,type 2 diabetes,non-alcoholic steatohepatitis,as well as other metabolic diseases.However,the invasive nature of the surgeries limits their broad ap-plications to the general public.Therefore,developing alternative non-invasive approaches to mimic metabolic surgery is an important direction of the field.Recent studies have identified several potential metabolic surgery-induced downstream endocrine mediators,among which bile acids are key candidate signaling molecules.Bile acids are profoundly altered by metabolic surgery,which contributes to the metabolic effects of the surgery.In this review,we focus on the most recent studies on the roles of bile acids and bile acid receptors farnesoid X receptor and Takeda G protein-coupled receptor 5 in mediating the metabolic effects of metabolic surgery.We conclude that targeting bile acid pathways may be a promising pharmacological approach to mimic the beneficial effects of metabolic surgery.