BACKGROUND Gut microbiota and its metabolites may be involved in the pathogenesis of inflammatory bowel disease.Several clinical studies have recently shown that patients with ulcerative colitis(UC)have altered profil...BACKGROUND Gut microbiota and its metabolites may be involved in the pathogenesis of inflammatory bowel disease.Several clinical studies have recently shown that patients with ulcerative colitis(UC)have altered profiles of fecal bile acids(BAs).It was observed that BA receptors Takeda G-protein-coupled receptor 5(TGR5)and vitamin D receptor(VDR)participate in intestinal inflammatory responses by regulating NF-ĸB signaling.We hypothesized that altered profiles of fecal BAs might be correlated with gut microbiota and inflammatory responses in patients with UC.AIM To investigate the changes in fecal BAs and analyze the relationship of BAs with gut microbiota and inflammation in patients with UC.METHODS The present study used 16S rDNA sequencing technology to detect the differences in the intestinal flora between UC patients and healthy controls(HCs).Fecal BAs were measured by targeted metabolomics approaches.Mucosal TGR5 and VDR expression was analyzed using immunohistochemistry,and serum inflammatory cytokine levels were detected by ELISA.RESULTS Thirty-two UC patients and twenty-three HCs were enrolled in this study.It was found that the diversity of gut microbiota in UC patients was reduced compared with that in HCs.Firmicutes,Clostridium IV,Butyricicoccus,Clostridium XlVa,Faecalibacterium,and Roseburia were significantly decreased in patients with UC(P=3.75E-05,P=8.28E-07,P=0.0002,P=0.003,P=0.0003,and P=0.0004,respectively).Proteobacteria,Escherichia,Enterococcus,Klebsiella,and Streptococcus were significantly enriched in the UC group(P=2.99E-09,P=3.63E-05,P=8.59E-05,P=0.003,and P=0.016,respectively).The concentrations of fecal secondary BAs,such as lithocholic acid,deoxycholic acid,glycodeoxycholic acid,glycolithocholic acid,and taurolithocholate,in UC patients were significantly lower than those in HCs(P=8.1E-08,P=1.2E-07,P=3.5E-04,P=1.9E-03,and P=1.8E-02,respectively)and were positively correlated with Butyricicoccus,Roseburia,Clostridium IV,Faecalibacterium,and Clostridium XlVb(P<0.01).The concentrations of展开更多
Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR3...Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR39 attenuates neuropathic pain remains unclear.In this study,we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats.Intrathecal injection of TC-G 1008,a specific agonist of GPR39,significantly alleviated mechanical allodynia in the rats with spared nerve injury,improved spinal cord mitochondrial biogenesis,and alleviated neuroinflammation.These changes were abolished by GPR39 small interfering RNA(siRNA),Ex-527(SIRT1 inhibitor),and PGC-1αsiRNA.Taken together,these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1αpathway in rats with spared nerve injury.展开更多
The coronavirus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has been significantly alleviated.However,long-term health effects and prevention strategy remain un...The coronavirus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has been significantly alleviated.However,long-term health effects and prevention strategy remain unresolved.Thus,it is essential to explore the pathophysiological mechanisms and intervention for SARS-CoV-2 infection.Emerging research indicates a link between COVID-19 and bile acids,traditionally known for facilitating dietary fat absorption.The bile acid ursodeoxycholic acid potentially protects against SARS-CoV-2 infection by inhibiting the farnesoid X receptor,a bile acid nuclear receptor.The activation of G-protein-coupled bile acid receptor,another membrane receptor for bile acids,has also been found to regulate the expression of angiotensin-converting enzyme 2,the receptor through which the virus enters human cells.Here,we review the latest basic and clinical evidence linking bile acids to SARS-CoV-2,and reveal their complicated pathophysiological mechanisms.展开更多
Stroma surrounding the tumor cells plays crucial roles for tumor progression.However,little is known about the factors that maintain the symbiosis between stroma and tumor cells.In this study,we found that the transcr...Stroma surrounding the tumor cells plays crucial roles for tumor progression.However,little is known about the factors that maintain the symbiosis between stroma and tumor cells.In this study,we found that the transcriptional regulator-signal transducer and activator of transcription 3(Stat3)was frequently activated in cancer-associated fibroblasts(CAFs),which was a potent facilitator of tumor malignancy,and formed forward feedback loop with platelet-activating factor receptor(PAFR)both in CAFs and tumor cells.Importantly,PAFR/Stat3 axis connected intercellular signaling crosstalk between CAFs and cancer cells and drove mutual transcriptional programming of these two types of cells.Two central Stat3-related cytokine signaling molecules-interleukin 6(IL-6)and IL-11 played the critical role in the process of PAFR/Stat3 axis-mediated communication between tumor and CAFs.Pharmacological inhibition of PAFR and Stat3 activities effectively reduced tumor progression using CAFs/tumor co-culture xenograft model.Our study reveals that PAFR/Stat3 axis enhances the interaction between tumor and its associated stroma and suggests that targeting this axis can be an effective therapeutic strategy against tumor malignancy.展开更多
Coronary heart disease(CHD) continues to be the greatest mortality risk factor in the developed world. Estrogens are recognized to have great therapeutic potential to treat CHD and other cardiovascular diseases; howev...Coronary heart disease(CHD) continues to be the greatest mortality risk factor in the developed world. Estrogens are recognized to have great therapeutic potential to treat CHD and other cardiovascular diseases; however,a significant array of potentially debilitating side effects continues to limit their use. Moreover,recent clinical trials have indicated that long-term postmenopausal estrogen therapy may actually be detrimental to cardiovascular health. An exciting new development is the finding that the more recently discovered G-protein-coupled estrogen receptor(GPER) is expressed in coronary arteries-both in coronary endothelium and in smooth muscle within the vascular wall. Accumulating evidence indicates that GPER activation dilates coronary arteries and can also inhibit the prolif-eration and migration of coronary smooth muscle cells. Thus,selective GPER activation has the potential to increase coronary blood flow and possibly limit the debilitating consequences of coronary atherosclerotic disease. This review will highlight what is currently known regarding the impact of GPER activation on coronary arteries and the potential signaling mechanisms stimulated by GPER agonists in these vessels. A thorough understanding of GPER function in coronary arteries may promote the development of new therapies that would help alleviate CHD,while limiting the potentially dangerous side effects of estrogen therapy.展开更多
G-protein-coupled receptor kinases (GRKs) interact with the agonist-activated form of G-protein-coupled receptor (GPCR) to affect receptor phosphorylation and to initiate profound impairment of receptor signaling, or ...G-protein-coupled receptor kinases (GRKs) interact with the agonist-activated form of G-protein-coupled receptor (GPCR) to affect receptor phosphorylation and to initiate profound impairment of receptor signaling, or desensitization. GPCR forms the largest family of cell surface receptors, and defects in GRK function have the potential consequence to affect GPCR-stimulated biological responses in many pathological situations.展开更多
Chronic inflammatory pain resulting from arthritis, nerve injury and tumor growth is a serious public health issue. One of the major challenges in chronic inflammatory pain research is to develop new pharmacologic tre...Chronic inflammatory pain resulting from arthritis, nerve injury and tumor growth is a serious public health issue. One of the major challenges in chronic inflammatory pain research is to develop new pharmacologic treatments with long-term efficacy and few side effects. The mediators released from inflamed sites induce complex changes in peripheral and central processing by directly acting on transducer receptors located on primary sensory neurons to transmit pain signals or indirectly modulating pain signals by activating receptors coupled with G-proteins and second messengers. High local proton concentration(acidosis) is thought to be a decisive factor in inflammatory pain and other mediators such as prostaglandin, bradykinin, and serotonin enhance proton-induced pain. Proton-sensing ion channels [transient receptor potential V1(TRPV1) and the acid-sensing ion channel(ASIC) family] are major receptors for direct excitation of nociceptive sensory neurons in response to acidosis or inflammation.G-protein-coupled receptors activated by prostaglandin, bradykinin, serotonin, and proton modulate functions of TRPV1, ASICs or other ion channels, thus leading to inflammation- or acidosis-linked hyperalgesia. Although detailed mechanisms remain unsolved, clearly different types of pain or hyperalgesia could be due to complex interactions between a distinct subset of inflammatory mediator receptors expressed in a subset of nociceptors. This review describes new directions for the development of novel therapeutic treatments in pain.展开更多
G-protein-coupled receptors(GPCRs)mediate a wide range of cellular responses to various ligands or stimuli,and are the most important drug targets associated with human diseases.While major advances in GPCR structural...G-protein-coupled receptors(GPCRs)mediate a wide range of cellular responses to various ligands or stimuli,and are the most important drug targets associated with human diseases.While major advances in GPCR structural biology have greatly deepened our understanding of its activation mechanism,the highly complex changes in the structural dynamics of GPCRs during activation remain underdetermined and their links to physiological functions largely unknown.Solution nuclear magnetic resonance(NMR)spectroscopy is an essential technique that allows the characterization of protein structural dynamics at atomic level,and has been applied in the studies of GPCR structural-function relationship in the past decade.Herein,we summarize a few specific studies in which solution NMR methods were employed and provided novel insights into questions difficult to be addressed by other methods.展开更多
基金Supported by National Key Technology Support Program during“12th Five-Year Plan”Period of China,No.2014BAI08B00National Key Research and Development Plan for Precision Medicine Research,No.2017YFC0910002and Leapforward Development Program for Beijing Biopharmaceutical Industry(G20),No.Z171100001717008.
文摘BACKGROUND Gut microbiota and its metabolites may be involved in the pathogenesis of inflammatory bowel disease.Several clinical studies have recently shown that patients with ulcerative colitis(UC)have altered profiles of fecal bile acids(BAs).It was observed that BA receptors Takeda G-protein-coupled receptor 5(TGR5)and vitamin D receptor(VDR)participate in intestinal inflammatory responses by regulating NF-ĸB signaling.We hypothesized that altered profiles of fecal BAs might be correlated with gut microbiota and inflammatory responses in patients with UC.AIM To investigate the changes in fecal BAs and analyze the relationship of BAs with gut microbiota and inflammation in patients with UC.METHODS The present study used 16S rDNA sequencing technology to detect the differences in the intestinal flora between UC patients and healthy controls(HCs).Fecal BAs were measured by targeted metabolomics approaches.Mucosal TGR5 and VDR expression was analyzed using immunohistochemistry,and serum inflammatory cytokine levels were detected by ELISA.RESULTS Thirty-two UC patients and twenty-three HCs were enrolled in this study.It was found that the diversity of gut microbiota in UC patients was reduced compared with that in HCs.Firmicutes,Clostridium IV,Butyricicoccus,Clostridium XlVa,Faecalibacterium,and Roseburia were significantly decreased in patients with UC(P=3.75E-05,P=8.28E-07,P=0.0002,P=0.003,P=0.0003,and P=0.0004,respectively).Proteobacteria,Escherichia,Enterococcus,Klebsiella,and Streptococcus were significantly enriched in the UC group(P=2.99E-09,P=3.63E-05,P=8.59E-05,P=0.003,and P=0.016,respectively).The concentrations of fecal secondary BAs,such as lithocholic acid,deoxycholic acid,glycodeoxycholic acid,glycolithocholic acid,and taurolithocholate,in UC patients were significantly lower than those in HCs(P=8.1E-08,P=1.2E-07,P=3.5E-04,P=1.9E-03,and P=1.8E-02,respectively)and were positively correlated with Butyricicoccus,Roseburia,Clostridium IV,Faecalibacterium,and Clostridium XlVb(P<0.01).The concentrations of
基金supported by the National Notural Science Foundation of China,Nos.82071556 and 82271291 (both to WM)
文摘Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR39 attenuates neuropathic pain remains unclear.In this study,we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats.Intrathecal injection of TC-G 1008,a specific agonist of GPR39,significantly alleviated mechanical allodynia in the rats with spared nerve injury,improved spinal cord mitochondrial biogenesis,and alleviated neuroinflammation.These changes were abolished by GPR39 small interfering RNA(siRNA),Ex-527(SIRT1 inhibitor),and PGC-1αsiRNA.Taken together,these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1αpathway in rats with spared nerve injury.
基金This study was supported by National Natural Science Foundation of China(NSFC Grant Nos.U21A20336,81820108031,and 91939301)National Key Research and Development Program of China(Grant No.2022YFC3602400)+1 种基金Beijing Municipal Natural Science Foundation(Grant No.7222218,China)Medical research management/basic and clinical research unit of metabolic cardiovascular diseases,Chinese Academy of Medical Sciences(Grant No.2021RU003,China).
文摘The coronavirus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has been significantly alleviated.However,long-term health effects and prevention strategy remain unresolved.Thus,it is essential to explore the pathophysiological mechanisms and intervention for SARS-CoV-2 infection.Emerging research indicates a link between COVID-19 and bile acids,traditionally known for facilitating dietary fat absorption.The bile acid ursodeoxycholic acid potentially protects against SARS-CoV-2 infection by inhibiting the farnesoid X receptor,a bile acid nuclear receptor.The activation of G-protein-coupled bile acid receptor,another membrane receptor for bile acids,has also been found to regulate the expression of angiotensin-converting enzyme 2,the receptor through which the virus enters human cells.Here,we review the latest basic and clinical evidence linking bile acids to SARS-CoV-2,and reveal their complicated pathophysiological mechanisms.
基金supported by National Natural Science Foundation of China(Nos.81988101,81830086,and 81972243,China)CAMS Innovation Fund for Medical Sciences(No.2019-I2M-5081,China)Guangdong Basic and Applied Basic Research Foundation(No.2019B030302012,China)。
文摘Stroma surrounding the tumor cells plays crucial roles for tumor progression.However,little is known about the factors that maintain the symbiosis between stroma and tumor cells.In this study,we found that the transcriptional regulator-signal transducer and activator of transcription 3(Stat3)was frequently activated in cancer-associated fibroblasts(CAFs),which was a potent facilitator of tumor malignancy,and formed forward feedback loop with platelet-activating factor receptor(PAFR)both in CAFs and tumor cells.Importantly,PAFR/Stat3 axis connected intercellular signaling crosstalk between CAFs and cancer cells and drove mutual transcriptional programming of these two types of cells.Two central Stat3-related cytokine signaling molecules-interleukin 6(IL-6)and IL-11 played the critical role in the process of PAFR/Stat3 axis-mediated communication between tumor and CAFs.Pharmacological inhibition of PAFR and Stat3 activities effectively reduced tumor progression using CAFs/tumor co-culture xenograft model.Our study reveals that PAFR/Stat3 axis enhances the interaction between tumor and its associated stroma and suggests that targeting this axis can be an effective therapeutic strategy against tumor malignancy.
基金Supported by The American Heart Association,Texas Affiliate,No.7370061the Center for Chronic Disorders of Aging,PCOM
文摘Coronary heart disease(CHD) continues to be the greatest mortality risk factor in the developed world. Estrogens are recognized to have great therapeutic potential to treat CHD and other cardiovascular diseases; however,a significant array of potentially debilitating side effects continues to limit their use. Moreover,recent clinical trials have indicated that long-term postmenopausal estrogen therapy may actually be detrimental to cardiovascular health. An exciting new development is the finding that the more recently discovered G-protein-coupled estrogen receptor(GPER) is expressed in coronary arteries-both in coronary endothelium and in smooth muscle within the vascular wall. Accumulating evidence indicates that GPER activation dilates coronary arteries and can also inhibit the prolif-eration and migration of coronary smooth muscle cells. Thus,selective GPER activation has the potential to increase coronary blood flow and possibly limit the debilitating consequences of coronary atherosclerotic disease. This review will highlight what is currently known regarding the impact of GPER activation on coronary arteries and the potential signaling mechanisms stimulated by GPER agonists in these vessels. A thorough understanding of GPER function in coronary arteries may promote the development of new therapies that would help alleviate CHD,while limiting the potentially dangerous side effects of estrogen therapy.
基金Supported by the National Natural Science Foundation of China, No. 30300465 Scientific Research Fund of Medical College of Chinese People’s Armed Police Forces, No. WY2002-19
文摘G-protein-coupled receptor kinases (GRKs) interact with the agonist-activated form of G-protein-coupled receptor (GPCR) to affect receptor phosphorylation and to initiate profound impairment of receptor signaling, or desensitization. GPCR forms the largest family of cell surface receptors, and defects in GRK function have the potential consequence to affect GPCR-stimulated biological responses in many pathological situations.
基金Supported by(In part)Intramural Funding from Academia Sinicaby grants from the National Science Council,Taiwan(NSC 102-2325-B-001-042 to Chen CCNSC 101-2321-B-008-001 to Sun WH)
文摘Chronic inflammatory pain resulting from arthritis, nerve injury and tumor growth is a serious public health issue. One of the major challenges in chronic inflammatory pain research is to develop new pharmacologic treatments with long-term efficacy and few side effects. The mediators released from inflamed sites induce complex changes in peripheral and central processing by directly acting on transducer receptors located on primary sensory neurons to transmit pain signals or indirectly modulating pain signals by activating receptors coupled with G-proteins and second messengers. High local proton concentration(acidosis) is thought to be a decisive factor in inflammatory pain and other mediators such as prostaglandin, bradykinin, and serotonin enhance proton-induced pain. Proton-sensing ion channels [transient receptor potential V1(TRPV1) and the acid-sensing ion channel(ASIC) family] are major receptors for direct excitation of nociceptive sensory neurons in response to acidosis or inflammation.G-protein-coupled receptors activated by prostaglandin, bradykinin, serotonin, and proton modulate functions of TRPV1, ASICs or other ion channels, thus leading to inflammation- or acidosis-linked hyperalgesia. Although detailed mechanisms remain unsolved, clearly different types of pain or hyperalgesia could be due to complex interactions between a distinct subset of inflammatory mediator receptors expressed in a subset of nociceptors. This review describes new directions for the development of novel therapeutic treatments in pain.
文摘G-protein-coupled receptors(GPCRs)mediate a wide range of cellular responses to various ligands or stimuli,and are the most important drug targets associated with human diseases.While major advances in GPCR structural biology have greatly deepened our understanding of its activation mechanism,the highly complex changes in the structural dynamics of GPCRs during activation remain underdetermined and their links to physiological functions largely unknown.Solution nuclear magnetic resonance(NMR)spectroscopy is an essential technique that allows the characterization of protein structural dynamics at atomic level,and has been applied in the studies of GPCR structural-function relationship in the past decade.Herein,we summarize a few specific studies in which solution NMR methods were employed and provided novel insights into questions difficult to be addressed by other methods.
