Inflammatory bowel disease(IBD)is a complex disease with multiple pathogenic factors.Although the pathogenesis of IBD is still unclear,a current hypothesis suggests that genetic susceptibility,environmental factors,a ...Inflammatory bowel disease(IBD)is a complex disease with multiple pathogenic factors.Although the pathogenesis of IBD is still unclear,a current hypothesis suggests that genetic susceptibility,environmental factors,a dysfunctional immune system,the microbiome,and the interactions of these factors substantially contribute to the occurrence and development of IBD.Although existing and emerging drugs have been proven to be effective in treating IBD,none can cure IBD permanently.G protein-coupled receptors(GPCRs)are critical signaling molecules implicated in the immune response,cell proliferation,inflammation regulation and intestinal barrier maintenance.Breakthroughs in the understanding of the structures and functions of GPCRs have provided a driving force for exploring the roles of GPCRs in the pathogenesis of diseases,thereby leading to the development of GPCR-targeted medication.To date,a number of GPCRs have been shown to be associated with IBD,significantly advancing the drug discovery process for IBD.The associations between GPCRs and disease activity,disease severity,and disease phenotypes have also paved new avenues for the precise management of patients with IBD.In this review,we mainly focus on the roles of the most studied proton-sensing GPCRs,cannabinoid receptors,and estrogen-related GPCRs in the pathogenesis of IBD and their potential clinical values in IBD and some other diseases.展开更多
Anti-microbial peptides are essential for the intestinal innate immunity that protects the intestinal epithelia from attacks by foreign pathogens. Human β-defensin (HBD) is one of the pivotal anti-microbial peptides ...Anti-microbial peptides are essential for the intestinal innate immunity that protects the intestinal epithelia from attacks by foreign pathogens. Human β-defensin (HBD) is one of the pivotal anti-microbial peptides that are expressed in the colonic epithelia. This study investigated the effect and the signaling mechanism of inducible β-defensin HBD2 by an essential amino acid, isoleucine (Ile) in colonic epithelial cells. Here we examined the expression level of HBD2 on induction of Ile in epithelial cells, and checked this pathway. HBD2 mRNA was induced by co-incubation with IL-1α and Ile in Caco2 cells, but not by Ile alone. An inhibitor of either ERK or Gi, a subunit of G-proteins, reduced the induction of HBD2 mRNA by Ile. The treatment with Ile also increased the intracellular calcium ion concentration, thus suggesting that the GPCR and ERK signaling pathway mediate the effects of Ile. These results indicate that an essential amino acid, Ile, enhances the expression of an inducible β-defensin, namely HBD2, by IL-1α through the activation of GPCRs and ERK signaling pathway. The administration of Ile may therefore represent a possible option to safely treat intestinal inflammation.展开更多
Estrogens play important roles in the development and progression of multiple tumor types.Accumulating evidence points to the significance of estrogen action not only in tumors of hormonally regulated tissues such as ...Estrogens play important roles in the development and progression of multiple tumor types.Accumulating evidence points to the significance of estrogen action not only in tumors of hormonally regulated tissues such as the breast,endometrium and ovary,but also in the development of colorectal cancer(CRC).The effects of estrogens in physiological and pathophysiological conditions are mediated by the nuclear estrogen receptorsαandβ,as well as the membranebound G protein-coupled estrogen receptor(GPER).The roles of GPER in CRC development and progression,however,remain poorly understood.Studies on the functions of GPER in the colon have shown that this estrogen receptor regulates colonic motility as well as immune responses in CRC-associated diseases,such as Crohn’s disease and ulcerative colitis.GPER is also involved in cell cycle regulation,endoplasmic reticulum stress,proliferation,apoptosis,vascularization,cell migration,and the regulation of fatty acid and estrogen metabolism in CRC cells.Thus,multiple lines of evidence suggest that GPER may play an important role in colorectal carcinogenesis.In this review,we present the current state of knowledge regarding the contribution of GPER to colon function and CRC.展开更多
Kaposi sarcoma-associated herpesvirus(KSHV) is necessary but not sufficient to cause Kaposi sarcoma(KS).Coinfection with human immunodeficiency virus type 1(HIV-1), in the absence of antiretroviral suppressive therapy...Kaposi sarcoma-associated herpesvirus(KSHV) is necessary but not sufficient to cause Kaposi sarcoma(KS).Coinfection with human immunodeficiency virus type 1(HIV-1), in the absence of antiretroviral suppressive therapy, drastically increases the risk of KS.Previously, we identified that HIV-1 transactivative transcription protein(Tat) was an important cofactor that activated lytic cycle replication of KSHV.Here, we further investigated the potential of Tat to influence tumorigenesis induced by KSHV Kaposin A, a product of KSHV that was encoded by the open reading frame K12(a KSHV-transforming gene).By using colony formation in soft agar, H-3-TdR incorporation, cell cycle, and microarray gene expression analyses, we demonstrated that Tat enhanced proliferation as well as mitogen-activated protein kinase, signal transducer and activator of transcription 3, and phosphatidylinositol 3-kinase/protein kinase B signaling induced by Kaposin A in NIH3T3 cells.Animal experiments further demonstrated that Tat accelerated tumorigenesis by Kaposin A in athymic nu/nu mice.Cells obtained from primary tumors of nude mice succeeded inducing tumors in immunocompetent mice.These data suggest that Tat can accelerate tumorigenesis induced by Kaposin A.Our data present the first line of evidence that Tat may participate in KS pathogenesis by collaborating with Kaposin A in acquired immunodeficiency syndrome(AIDS)-related KS(AIDS-KS) patients.Our data also suggest that the model for Kaposin and Tat-mediated oncogenesis will contribute to our understanding of the pathogenesis of AIDS-KS at the molecular level and may even be important in exploring a novel therapeutic method for AIDS-KS.展开更多
基金National Natural Science Foundation of China,No.81570502the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University,No.ZYJC18037.
文摘Inflammatory bowel disease(IBD)is a complex disease with multiple pathogenic factors.Although the pathogenesis of IBD is still unclear,a current hypothesis suggests that genetic susceptibility,environmental factors,a dysfunctional immune system,the microbiome,and the interactions of these factors substantially contribute to the occurrence and development of IBD.Although existing and emerging drugs have been proven to be effective in treating IBD,none can cure IBD permanently.G protein-coupled receptors(GPCRs)are critical signaling molecules implicated in the immune response,cell proliferation,inflammation regulation and intestinal barrier maintenance.Breakthroughs in the understanding of the structures and functions of GPCRs have provided a driving force for exploring the roles of GPCRs in the pathogenesis of diseases,thereby leading to the development of GPCR-targeted medication.To date,a number of GPCRs have been shown to be associated with IBD,significantly advancing the drug discovery process for IBD.The associations between GPCRs and disease activity,disease severity,and disease phenotypes have also paved new avenues for the precise management of patients with IBD.In this review,we mainly focus on the roles of the most studied proton-sensing GPCRs,cannabinoid receptors,and estrogen-related GPCRs in the pathogenesis of IBD and their potential clinical values in IBD and some other diseases.
文摘Anti-microbial peptides are essential for the intestinal innate immunity that protects the intestinal epithelia from attacks by foreign pathogens. Human β-defensin (HBD) is one of the pivotal anti-microbial peptides that are expressed in the colonic epithelia. This study investigated the effect and the signaling mechanism of inducible β-defensin HBD2 by an essential amino acid, isoleucine (Ile) in colonic epithelial cells. Here we examined the expression level of HBD2 on induction of Ile in epithelial cells, and checked this pathway. HBD2 mRNA was induced by co-incubation with IL-1α and Ile in Caco2 cells, but not by Ile alone. An inhibitor of either ERK or Gi, a subunit of G-proteins, reduced the induction of HBD2 mRNA by Ile. The treatment with Ile also increased the intracellular calcium ion concentration, thus suggesting that the GPCR and ERK signaling pathway mediate the effects of Ile. These results indicate that an essential amino acid, Ile, enhances the expression of an inducible β-defensin, namely HBD2, by IL-1α through the activation of GPCRs and ERK signaling pathway. The administration of Ile may therefore represent a possible option to safely treat intestinal inflammation.
基金Supported by grants from the National Science Centre,Poland(2017/24/T/NZ5/00045 and2015/17/N/NZ5/00336 to Damian Jacenik)the U.S.National Institutes of Health(NIH R01CA163890 and CA194496 to Eric R.Prossnitz+3 种基金 R01 CA207051 to Ellen J.Beswick)the UNM Comprehensive Cancer Center(P30 CA118100)the Autophagy,Inflammation and Metabolism Center of Biomedical Research Excellence(P20 GM121176)Dialysis Clinic,Inc.(to Eric R.Prossnitz)
文摘Estrogens play important roles in the development and progression of multiple tumor types.Accumulating evidence points to the significance of estrogen action not only in tumors of hormonally regulated tissues such as the breast,endometrium and ovary,but also in the development of colorectal cancer(CRC).The effects of estrogens in physiological and pathophysiological conditions are mediated by the nuclear estrogen receptorsαandβ,as well as the membranebound G protein-coupled estrogen receptor(GPER).The roles of GPER in CRC development and progression,however,remain poorly understood.Studies on the functions of GPER in the colon have shown that this estrogen receptor regulates colonic motility as well as immune responses in CRC-associated diseases,such as Crohn’s disease and ulcerative colitis.GPER is also involved in cell cycle regulation,endoplasmic reticulum stress,proliferation,apoptosis,vascularization,cell migration,and the regulation of fatty acid and estrogen metabolism in CRC cells.Thus,multiple lines of evidence suggest that GPER may play an important role in colorectal carcinogenesis.In this review,we present the current state of knowledge regarding the contribution of GPER to colon function and CRC.
文摘Kaposi sarcoma-associated herpesvirus(KSHV) is necessary but not sufficient to cause Kaposi sarcoma(KS).Coinfection with human immunodeficiency virus type 1(HIV-1), in the absence of antiretroviral suppressive therapy, drastically increases the risk of KS.Previously, we identified that HIV-1 transactivative transcription protein(Tat) was an important cofactor that activated lytic cycle replication of KSHV.Here, we further investigated the potential of Tat to influence tumorigenesis induced by KSHV Kaposin A, a product of KSHV that was encoded by the open reading frame K12(a KSHV-transforming gene).By using colony formation in soft agar, H-3-TdR incorporation, cell cycle, and microarray gene expression analyses, we demonstrated that Tat enhanced proliferation as well as mitogen-activated protein kinase, signal transducer and activator of transcription 3, and phosphatidylinositol 3-kinase/protein kinase B signaling induced by Kaposin A in NIH3T3 cells.Animal experiments further demonstrated that Tat accelerated tumorigenesis by Kaposin A in athymic nu/nu mice.Cells obtained from primary tumors of nude mice succeeded inducing tumors in immunocompetent mice.These data suggest that Tat can accelerate tumorigenesis induced by Kaposin A.Our data present the first line of evidence that Tat may participate in KS pathogenesis by collaborating with Kaposin A in acquired immunodeficiency syndrome(AIDS)-related KS(AIDS-KS) patients.Our data also suggest that the model for Kaposin and Tat-mediated oncogenesis will contribute to our understanding of the pathogenesis of AIDS-KS at the molecular level and may even be important in exploring a novel therapeutic method for AIDS-KS.
