BACKGROUND External factors in ulcerative colitis(UC)exacerbate colonic epithelial permea-bility and inflammatory responses.Keratin 1(KRT1)is crucial in regulating these alterations,but its specific role in the progre...BACKGROUND External factors in ulcerative colitis(UC)exacerbate colonic epithelial permea-bility and inflammatory responses.Keratin 1(KRT1)is crucial in regulating these alterations,but its specific role in the progression of UC remains to be fully eluci-dated.AIM To explore the role and mechanisms of KRT1 in the regulation of colonic epithelial permeability and inflammation in UC.METHODS A KRT1 antibody concentration gradient test,along with a dextran sulfate sodium(DSS)-induced animal model,was implemented to investigate the role of KRT1 in modulating the activation of the kallikrein kinin system(KKS)and the cleavage of bradykinin(BK)/high molecular weight kininogen(HK)in UC.RESULTS Treatment with KRT1 antibody in Caco-2 cells suppressed cell proliferation,induced apoptosis,reduced HK expression,and increased BK expression.It further downregulated intestinal barrier proteins,including occludin,zonula occludens-1,and claudin,and negatively impacted the coagulation factor XII.These changes led to enhanced activation of BK and HK cleavage,thereby intensifying KKS-mediated inflammation in UC.In the DSS-induced mouse model,administration of KRT1 antibody mitigated colonic injury,increased colon length,alleviated weight loss,and suppressed inflammatory cytokines such as interleukin(IL)-1,IL-6,tumor necrosis factor-α.It also facilitated repair of the intestinal barrier,reducing DSS-induced injury.CONCLUSION KRT1 inhibits BK expression,suppresses inflammatory cytokines,and enhances markers of intestinal barrier function,thus ameliorating colonic damage and maintaining barrier integrity.KRT1 is a viable therapeutic target for UC.展开更多
The kallikrein-kinin system(KKS) is an intricate endogenous pathway involved in several physiological and pathological cascades in the brain. Due to the pathological effects of kinins in blood vessels and tissues, the...The kallikrein-kinin system(KKS) is an intricate endogenous pathway involved in several physiological and pathological cascades in the brain. Due to the pathological effects of kinins in blood vessels and tissues, their formation and degradation are tightly controlled. Their components have been related to several central nervous system diseases such as stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy and others. Bradykinin and its receptors(B1R and B2R) may have a role in the pathophysiology of certain central nervous system diseases. It has been suggested that kinin B1R is up-regulated in pathological conditions and has a neurodegenerative pattern, while kinin B2R is constitutive and can act as a neuroprotective factor in many neurological conditions. The renin angiotensin system(RAS) is an important blood pressure regulator and controls both sodium and water intake. AngⅡ is a potent vasoconstrictor molecule and angiotensin converting enzyme is the major enzyme responsible for its release. AngⅡ acts mainly on the AT1 receptor, with involvement in several systemic and neurological disorders. Brain RAS has been associated with physiological pathways, but is also associated with brain disorders. This review describes topics relating to the involvement of both systems in several forms of brain dysfunction and indicates components of the KKS and RAS that have been used as targets in several pharmacological approaches.展开更多
The tissue kallikrein-kinin system exerts a wide spectrum of biological activities in the cardiovascular, renal and central nervous systems. Tissue kallikrein-kinin modulates the proliferation, viability, mobility and...The tissue kallikrein-kinin system exerts a wide spectrum of biological activities in the cardiovascular, renal and central nervous systems. Tissue kallikrein-kinin modulates the proliferation, viability, mobility and functional activity of certain stem cell populations, namely mesenchymal stem cells(MSCs), endothelial progenitor cells(EPCs), mononuclear cell subsets and neural stem cells. Stimulation of these stem cells by tissue kallikrein-kinin may lead to protection against renal, cardiovascular and neural damage by inhibiting apoptosis, inflammation, fibrosis and oxidative stress and promoting neovascularization. Moreover, MSCs and EPCs genetically modified with tissue kallikrein are resistant to hypoxia- and oxidative stress-induced apoptosis, and offer enhanced protective actions in animal models of heart and kidney injury and hindlimb ischemia. In addition, activation of the plasma kallikrein-kinin system promotes EPC recruitment to the inflamed synovium of arthritic rats. Conversely, cleaved high molecular weight kininogen, a product of plasma kallikrein, reduces the viability and vasculogenic activity of EPCs. Therefore, kallikrein-kinin provides a new approach in enhancing the efficacy of stem cell therapy for human diseases.展开更多
AIM： To investigate a potential protective role of the kinin B2 receptor in a glycerol-induced rhabdomyolysis mouse model. METHODS： We separated 28 C57Bl/6 male mice into 4 groups： untreated WT animals, untreated B...AIM： To investigate a potential protective role of the kinin B2 receptor in a glycerol-induced rhabdomyolysis mouse model. METHODS： We separated 28 C57Bl/6 male mice into 4 groups： untreated WT animals, untreated B2 knockout mice, glycerol-treated WT and glycerol-treated B2 knockout mice. Glycerol-treated animals received one intramuscular injections of glycerol solution （50% v/v, 7 mL/kg）. After 48 h, urine and blood samples were collected to measure creatinine and urea levels. Addi-tionally, kidney samples were extracted for histological evaluation, and the mRNA expression levels of kinin B1 and B2 receptors and infammatory mediators were measured by real-time polymerase chain reaction. RESULTS： Serum creatinine and urea levels showed differences between untreated wild-type and glycerol-treated wild-type mice （0.66 ± 0.04 vs 2.61 ± 0.53 mg/dL, P 〈 0.01; and 33.51 ± 2.08 vs 330.2 ± 77.7 mg/dL, P 〈 0.005）, and between untreated B2 knock-out mice and glycerol-treated knockout mice （0.56 ± 0.03 vs 2.23 ± 0.87 mg/dL, P 〈 0.05; and 42.49 ± 3.2 vs 327.2 ± 58.4 mg/dL, P 〈 0.01）, but there was no difference between the glycerol-treated wild-type and glycerol-treated knockout mice. Glycerol was able to in-duce a striking increase in kinin B2 receptor expression （〉 30 times, 31.34 ± 8.9） in kidney. Animals injected with glycerol had a higher degree of tubular injury than untreated animals. Wild-type and knockout mice treat-ed with glycerol intramuscularly present kidney injury, with impairment in renal function. However, B2 knock-out mice treated with glycerol did not show a different phenotype regarding kidney injury markers, when com-pared to the wild-type glycerol-treated group. CONCLUSION： We conclude that the kinin B2 receptordoes not have a protective role in renal injury.展开更多
Background:The neovascular aged-related macular degeneration(AMD)is the leading cause of legal blindness in the elderly.It is presently treated by anti-VEGF intravitreal injection in order to stop the neovascularizati...Background:The neovascular aged-related macular degeneration(AMD)is the leading cause of legal blindness in the elderly.It is presently treated by anti-VEGF intravitreal injection in order to stop the neovascularization.In seeking of more efficient treatments to prevent retinal damage,it has been proposed that the kinin-kallikrein system(KKS),a key player in inflammation,could be involved in AMD etiology.However,the role of kinin receptors and their interaction with VEGF in AMD is poorly understood.Methods:In order to address this question,choroidal neovascularization(CNV)was induced in the left eye of Long-Evans rat.After laser induction,anti-VEGF or IgG control were injected into the vitreal cavity.Gene expression was measured by qRT-PCR,retinal adherent leukocytes were labelled with FITC-Concanavalin A lectin,vascular leakage by the method of Evans blue and cellular localisation by immunohistochemistry.Results:The number of labelled adherent leucocytes was significantly increased in laser-induced CNV compared to the control eye.This was significantly reversed by one single injection of anti-VEGF.Extravasation of Evans blue dye was significantly increased in laser-induced CNV eyes compared to control eyes and partially reversed by one single injection of anti-VEGF or by R954 treatment.The mRNA expression of inflammatory mediators was significantly increased in the retina of CNV rats.Immunodetection of B1R was significantly increased in CNV eyes.B1R immunolabeling was detected on endothelial and ganglion cells.Conclusions:This study is the first to highlight an effect of the kinin/kallikrein system in a model of CNV that could be reduced by both anti-VEGF therapy and topically administered B1R antagonist R-954.展开更多
基金Supported by the National Natural Science Foundation of China,No.82160113the“Xingdian Talents”Support Project of Yunnan Province,No.RLMY20220007+1 种基金the Yunnan Province Clinical Research Center for Digestive Diseases,No.202102AA100062the Applied Basic Research Projects of Yunnan Province,No.2019FE001-039.
文摘BACKGROUND External factors in ulcerative colitis(UC)exacerbate colonic epithelial permea-bility and inflammatory responses.Keratin 1(KRT1)is crucial in regulating these alterations,but its specific role in the progression of UC remains to be fully eluci-dated.AIM To explore the role and mechanisms of KRT1 in the regulation of colonic epithelial permeability and inflammation in UC.METHODS A KRT1 antibody concentration gradient test,along with a dextran sulfate sodium(DSS)-induced animal model,was implemented to investigate the role of KRT1 in modulating the activation of the kallikrein kinin system(KKS)and the cleavage of bradykinin(BK)/high molecular weight kininogen(HK)in UC.RESULTS Treatment with KRT1 antibody in Caco-2 cells suppressed cell proliferation,induced apoptosis,reduced HK expression,and increased BK expression.It further downregulated intestinal barrier proteins,including occludin,zonula occludens-1,and claudin,and negatively impacted the coagulation factor XII.These changes led to enhanced activation of BK and HK cleavage,thereby intensifying KKS-mediated inflammation in UC.In the DSS-induced mouse model,administration of KRT1 antibody mitigated colonic injury,increased colon length,alleviated weight loss,and suppressed inflammatory cytokines such as interleukin(IL)-1,IL-6,tumor necrosis factor-α.It also facilitated repair of the intestinal barrier,reducing DSS-induced injury.CONCLUSION KRT1 inhibits BK expression,suppresses inflammatory cytokines,and enhances markers of intestinal barrier function,thus ameliorating colonic damage and maintaining barrier integrity.KRT1 is a viable therapeutic target for UC.
基金Supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq),Funda o de AmparoàPesquisa do Estado de S o Paulo(FAPESP)and Instituto Nacional de Neurociência Translacional(INNT),Programa de Núcleos de Excelência(PRONEX)(Brazil)
文摘The kallikrein-kinin system(KKS) is an intricate endogenous pathway involved in several physiological and pathological cascades in the brain. Due to the pathological effects of kinins in blood vessels and tissues, their formation and degradation are tightly controlled. Their components have been related to several central nervous system diseases such as stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy and others. Bradykinin and its receptors(B1R and B2R) may have a role in the pathophysiology of certain central nervous system diseases. It has been suggested that kinin B1R is up-regulated in pathological conditions and has a neurodegenerative pattern, while kinin B2R is constitutive and can act as a neuroprotective factor in many neurological conditions. The renin angiotensin system(RAS) is an important blood pressure regulator and controls both sodium and water intake. AngⅡ is a potent vasoconstrictor molecule and angiotensin converting enzyme is the major enzyme responsible for its release. AngⅡ acts mainly on the AT1 receptor, with involvement in several systemic and neurological disorders. Brain RAS has been associated with physiological pathways, but is also associated with brain disorders. This review describes topics relating to the involvement of both systems in several forms of brain dysfunction and indicates components of the KKS and RAS that have been used as targets in several pharmacological approaches.
基金Supported by National Institutes of Health,No.HL118516,HL29397 and HL44083
文摘The tissue kallikrein-kinin system exerts a wide spectrum of biological activities in the cardiovascular, renal and central nervous systems. Tissue kallikrein-kinin modulates the proliferation, viability, mobility and functional activity of certain stem cell populations, namely mesenchymal stem cells(MSCs), endothelial progenitor cells(EPCs), mononuclear cell subsets and neural stem cells. Stimulation of these stem cells by tissue kallikrein-kinin may lead to protection against renal, cardiovascular and neural damage by inhibiting apoptosis, inflammation, fibrosis and oxidative stress and promoting neovascularization. Moreover, MSCs and EPCs genetically modified with tissue kallikrein are resistant to hypoxia- and oxidative stress-induced apoptosis, and offer enhanced protective actions in animal models of heart and kidney injury and hindlimb ischemia. In addition, activation of the plasma kallikrein-kinin system promotes EPC recruitment to the inflamed synovium of arthritic rats. Conversely, cleaved high molecular weight kininogen, a product of plasma kallikrein, reduces the viability and vasculogenic activity of EPCs. Therefore, kallikrein-kinin provides a new approach in enhancing the efficacy of stem cell therapy for human diseases.
基金Supported by The National Council of Scientific and Technological Development-CNPq,No.135020/2011-5
文摘AIM： To investigate a potential protective role of the kinin B2 receptor in a glycerol-induced rhabdomyolysis mouse model. METHODS： We separated 28 C57Bl/6 male mice into 4 groups： untreated WT animals, untreated B2 knockout mice, glycerol-treated WT and glycerol-treated B2 knockout mice. Glycerol-treated animals received one intramuscular injections of glycerol solution （50% v/v, 7 mL/kg）. After 48 h, urine and blood samples were collected to measure creatinine and urea levels. Addi-tionally, kidney samples were extracted for histological evaluation, and the mRNA expression levels of kinin B1 and B2 receptors and infammatory mediators were measured by real-time polymerase chain reaction. RESULTS： Serum creatinine and urea levels showed differences between untreated wild-type and glycerol-treated wild-type mice （0.66 ± 0.04 vs 2.61 ± 0.53 mg/dL, P 〈 0.01; and 33.51 ± 2.08 vs 330.2 ± 77.7 mg/dL, P 〈 0.005）, and between untreated B2 knock-out mice and glycerol-treated knockout mice （0.56 ± 0.03 vs 2.23 ± 0.87 mg/dL, P 〈 0.05; and 42.49 ± 3.2 vs 327.2 ± 58.4 mg/dL, P 〈 0.01）, but there was no difference between the glycerol-treated wild-type and glycerol-treated knockout mice. Glycerol was able to in-duce a striking increase in kinin B2 receptor expression （〉 30 times, 31.34 ± 8.9） in kidney. Animals injected with glycerol had a higher degree of tubular injury than untreated animals. Wild-type and knockout mice treat-ed with glycerol intramuscularly present kidney injury, with impairment in renal function. However, B2 knock-out mice treated with glycerol did not show a different phenotype regarding kidney injury markers, when com-pared to the wild-type glycerol-treated group. CONCLUSION： We conclude that the kinin B2 receptordoes not have a protective role in renal injury.
文摘Background:The neovascular aged-related macular degeneration(AMD)is the leading cause of legal blindness in the elderly.It is presently treated by anti-VEGF intravitreal injection in order to stop the neovascularization.In seeking of more efficient treatments to prevent retinal damage,it has been proposed that the kinin-kallikrein system(KKS),a key player in inflammation,could be involved in AMD etiology.However,the role of kinin receptors and their interaction with VEGF in AMD is poorly understood.Methods:In order to address this question,choroidal neovascularization(CNV)was induced in the left eye of Long-Evans rat.After laser induction,anti-VEGF or IgG control were injected into the vitreal cavity.Gene expression was measured by qRT-PCR,retinal adherent leukocytes were labelled with FITC-Concanavalin A lectin,vascular leakage by the method of Evans blue and cellular localisation by immunohistochemistry.Results:The number of labelled adherent leucocytes was significantly increased in laser-induced CNV compared to the control eye.This was significantly reversed by one single injection of anti-VEGF.Extravasation of Evans blue dye was significantly increased in laser-induced CNV eyes compared to control eyes and partially reversed by one single injection of anti-VEGF or by R954 treatment.The mRNA expression of inflammatory mediators was significantly increased in the retina of CNV rats.Immunodetection of B1R was significantly increased in CNV eyes.B1R immunolabeling was detected on endothelial and ganglion cells.Conclusions:This study is the first to highlight an effect of the kinin/kallikrein system in a model of CNV that could be reduced by both anti-VEGF therapy and topically administered B1R antagonist R-954.
