BACKGROUND Thrombocytopenia 2,an autosomal dominant inherited disease characterized by moderate thrombocytopenia,predisposition to myeloid malignancies and normal platelet size and function,can be caused by 5’-untran...BACKGROUND Thrombocytopenia 2,an autosomal dominant inherited disease characterized by moderate thrombocytopenia,predisposition to myeloid malignancies and normal platelet size and function,can be caused by 5’-untranslated region(UTR)point mutations in ankyrin repeat domain containing 26(ANKRD26).Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1)have been identified as negative regulators of ANKRD26.However,the positive regulators of ANKRD26 are still unknown.AIM To prove the positive regulatory effect of GATA binding protein 2(GATA2)on ANKRD26 transcription.METHODS Human induced pluripotent stem cells derived from bone marrow(hiPSC-BM)INTRODUCTION Ankyrin repeat domain containing protein 26(ANKRD26)acts as a regulator of adipogenesis and is involved in the regulation of feeding behavior[1-3].The ANKRD26 gene is located on chromosome 10 and shares regions of homology with the primate-specific gene family POTE.According to the Human Protein Atlas database,the ANKRD26 protein is localized to the Golgi apparatus and vesicles,and its expression can be detected in nearly all human tissues[4].Moreover,UniProt annotation revealed that ANKRD26 is localized in the centrosome and contains coiled-coil domains formed by spectrin helices and ankyrin repeats[5,6].The most common disease related to ANKRD26 is thrombocytopenia 2(THC2),which is a rare autosomal dominant inherited disease characterized by lifelong mild-to-moderate thrombocytopenia and mild bleeding[7-9].Caused by the variants in the 5’-untranslated region(UTR)of ANKRD26,THC2 is defined by a decrease in the number of platelets in circulating blood and results in increased bleeding and decreased clotting ability[8,10].Due to the point mutations that occur in the 5’-UTR of ANKRD26,its negative transcription factors(TFs),Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1),lose their repression effect[11].The persistent expression of ANKRD26 increases the activity of the mitogen activated protein kinase and extracellular signal regulated kinase 1/2 signaling pathways,which are potentially involved in the regulation of thrombopoietin-dependent signaling and further impair proplatelet formation by megakaryocytes(MKs)[11].However,the positive regulators of ANKRD26,which might be associated with THC2 pathology,are still unknown.展开更多
This editorial summarizes the latest literature on the roles of neuronal PAS domain protein 2 and KN motif/ankyrin repeat domain 1 in type 2 diabetes(T2D).We highlight their involvement inβ-cell dysfunction,explore t...This editorial summarizes the latest literature on the roles of neuronal PAS domain protein 2 and KN motif/ankyrin repeat domain 1 in type 2 diabetes(T2D).We highlight their involvement inβ-cell dysfunction,explore their potential as therapeutic targets,and discuss the implications for new treatment strategies.We offer valuable insights into relevant gene regulation and cellular mechanisms relevant for the targeted management of T2D.展开更多
AIM To investigate the anti-fibrotic effects of the traditional oriental herbal medicine Daikenchuto(DKT) associated with transient receptor potential ankyrin 1(TRPA1) channels in intestinal myofibroblasts. METHODS In...AIM To investigate the anti-fibrotic effects of the traditional oriental herbal medicine Daikenchuto(DKT) associated with transient receptor potential ankyrin 1(TRPA1) channels in intestinal myofibroblasts. METHODS Inflammatory and fibrotic changes were detected in a2,4,6-trinitrobenzenesulfonic acid(TNBS) chronic colitis model of wild-type and TRPA1-knockout(TRPA1-KO) mice via pathological staining and immunoblotting analysis.Ca^(2+) imaging experiments examined the effects of DKT and its components/ingredients on intestinal myofibroblast(In Myo Fib) cell TRPA1 channel function.Profibrotic factors and transforming growth factor (TGF) -β1-associated signaling were tested in an In Myo Fib cell line by q PCR and immunoblotting experiments.Samples from non-stenotic and stenotic regions of the intestines of patients with Crohn’s disease (CD) were used for pathological analysis. RESULTS Chronic treatment with TNBS caused more severe inflammation and fibrotic changes in TRPA1-KO than in wild-type mice.A one-week enema administration of DKT reduced fibrotic lesions in wild-type but not in TRPA1-KO mice.The active ingredients of DKT,i.e.,hydroxyα-sanshool and 6-shogaol,induced Ca^(2+) influxes in In Myo Fib,and this was antagonized by co-treatment with a selective TRPA1 channel blocker,HC-030031.DKT counteracted TGF-β1-induced expression of TypeⅠcollagen andα-smooth muscle actin (α-SMA) ,which were accompanied by a reduction in the phosphorylation of Smad-2 and p38-mitogen-activated protein kinase (p38-MAPK) and the expression of myocardin.Importantly,24-h incubation with a DKT active component Japanese Pepper increased the m RNA and protein expression levels of TRPA1 in In Myo Fibs,which in turn negatively regulated collagen synthesis.In the stenotic regions of the intestines of CD patients,TRPA1 expression was significantly enhanced.CONCLUSION The effects of DKT on the expression and activation of the TRPA1 channel could be advantageous for suppressing intestinal fibrosis,and benefit inflammatory bowel disease treatment.展开更多
BACKGROUND Hereditary spherocytosis(HS)is a common type of hemolytic anemia caused by a red cell membrane disorder.HS type 1(HS1)is mostly caused by mutations in ankyrin(ANK1).Newborns with HS1 usually only exhibit an...BACKGROUND Hereditary spherocytosis(HS)is a common type of hemolytic anemia caused by a red cell membrane disorder.HS type 1(HS1)is mostly caused by mutations in ankyrin(ANK1).Newborns with HS1 usually only exhibit anemia and mild jaundice.We herein report a case of HS1 and discuss its clinical characteristics.CASE SUMMARY A 2-d-old male full-term newborn was admitted to our hospital with severe,intractable neonatal jaundice.Laboratory investigations showed hemolytic anemia and hyperbilirubinemia and excluded immune-mediated hemolysis.The patient underwent two exchange transfusions and one plasmapheresis resulting in significantly reduced serum bilirubin.Hematologic analyses and genomic DNA sequencing studies were performed.The trio clinical exome sequencing revealed a de novo null heterozygous mutation in the patient's ANK1 gene:c.841C>T(p.Arg281Ter).This mutation results in the premature termination of the ANK1 protein.CONCLUSION Our case demonstrates that genetic analysis can be an essential method for diagnosing HS when a newborn has severe hyperbilirubinemia.展开更多
Background: Transient receptor potential ankyrin (TRPA) 1 is known as a peripheral initiator of acute inflammation and hyperalgesia. However, its role in the facilitation of innate immune responses followed by resolut...Background: Transient receptor potential ankyrin (TRPA) 1 is known as a peripheral initiator of acute inflammation and hyperalgesia. However, its role in the facilitation of innate immune responses followed by resolution of the inflammation triggered by a surgical incision has not been fully investigated. Therefore, we evaluated the mechanism by which TRPA1 regulates the inflammatory responses mainly facilitated by neutrophils and macrophages in the early course of wound repair after an incision. Methods: Plantar incision was performed in wild-type and TRPA1-/- mice. The infiltration of polymorphonuclear neutrophils, macrophage phenotype, and induction of inflammatory mediators were assessed for 7 days postoperatively. Results: TRPA1-/-?mice exhibited decreased infiltration of polymorphonuclear neutrophilscompared with wild-type mice on day 1. Consistently, the influx of F4/80+ iNOS+ proinflammatory M1 macrophages to incised sites was markedly decreased on day 2. Similarly, F4/80+ CD206+M2 macrophages, which regulate the resolution of inflammation and promote wound healing in the later phase of acute inflammation, were significantly decreased in TRPA1-/- compared with those in wild-type mice on day 7. In addition, the induction of heme oxygenase-1, which promotes wound healing by switching phenotype of macrophages, was decreased in the early phase of acute inflammation, whereas the expression of proinflammatory mediators such as tumor necrosis factor and cyclooxygenase-2, and 15-lipoxygenase, which are involved in the resolution of inflammation was increased in the late phase in TRPA1-/- mice. Conclusions: Early innate immune responses including neutrophil infiltration and macrophage polarization at incised sites were inhibited in TRPA1-/- mice, associated with increased pro-inflammatory mediators in later phase. Peripheral TRPA1 may facilitate the acute inflammatory process, leading to the promotion of macrophage-mediated resolution of inflammation and wound repair after a surgical incision.展开更多
OBJECTIVE:To investigate the efficacy of Zhenxin Anshen formula(镇心安神方,ZXAS)on atopic dermatitis(AD)by transient receptor potential vanilloid 1(TRPV1)and transient receptor potential ankyrin 1(TRPA1)signalling pat...OBJECTIVE:To investigate the efficacy of Zhenxin Anshen formula(镇心安神方,ZXAS)on atopic dermatitis(AD)by transient receptor potential vanilloid 1(TRPV1)and transient receptor potential ankyrin 1(TRPA1)signalling pathway in mice and in vitro.METHODS:AD-like lesions were induced by 1-chloro-2,4-dinitrobenzene(DNCB)to the shaved dorsal skin of BALB/c mice.BALB/c mice were divided into five groups:normal control,model control,cetirizine,low-,medium-,and high-dose of ZXAS.After ZXAS in-tervention,the skin lesions and blood samples were collected for hematoxylin and eosin-stained and measuring the concentrations of inflammatory cytokines.Immunoglobulin E(IgE),interleukin(IL)-4,IL-5,IL-13,and thymic stromal lymphopoietin(TSLP)were de-tected by Enzyme-linked immunosorbent assay(ELISA).The spinal cords were collected for measuring the expression of gastrin-releasing peptide receptor(GRPR),TRPV1,and TRPA1 by using immunohistochemistry,western blotting,and quantitative real-time polymerase chain reaction(qR T-PCR)analyses.In addition,3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide(MTT)assay,flow cytometry,ELISA,and Western blotting were conducted for analysis of primary dorsal root ganglia(DRG)neurons in vitro.RESULTS:ZXAS treatment improved DNCB-induced AD-like lesions through reducing dermatitis score,number of scratching and epidermal thickness,accompanied by the de-creased IgE and Th2 inflammatory cytokines.ZXAS also supressed the mRNA and protein expression of GRPR,TRPV1,and TRPA1 in the spinal cord.The medicated sera of ZXAS decreased capsaicin-induced Ca^(2+)influx and downregulated the expression of TRPV1,TRPA1,and phospholipase C in DRG neurons.CONCLUSIONS:The therapeutic effect of ZXAS on AD may be related to the regulation of TRPV1 and TRPA1 and inhibition of Ca^(2+)signals in neurons.展开更多
基金Supported by General Program of National Natural Science Foundation of China,No.81770197Scientific and Technological Research Major Program of Chongqing Municipal Education Commission,No.KJZD-M202312802+1 种基金Chongqing Natural Science Foundation of China,No.CSTB2022NSCQ-MSX0190,No.CSTB2022NSCQ-MSX0176,and No.cstc2020jcyj-msxmX0051Xinqiao Young Postdoc Talent Incubation Program,No.2022YQB098.
文摘BACKGROUND Thrombocytopenia 2,an autosomal dominant inherited disease characterized by moderate thrombocytopenia,predisposition to myeloid malignancies and normal platelet size and function,can be caused by 5’-untranslated region(UTR)point mutations in ankyrin repeat domain containing 26(ANKRD26).Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1)have been identified as negative regulators of ANKRD26.However,the positive regulators of ANKRD26 are still unknown.AIM To prove the positive regulatory effect of GATA binding protein 2(GATA2)on ANKRD26 transcription.METHODS Human induced pluripotent stem cells derived from bone marrow(hiPSC-BM)INTRODUCTION Ankyrin repeat domain containing protein 26(ANKRD26)acts as a regulator of adipogenesis and is involved in the regulation of feeding behavior[1-3].The ANKRD26 gene is located on chromosome 10 and shares regions of homology with the primate-specific gene family POTE.According to the Human Protein Atlas database,the ANKRD26 protein is localized to the Golgi apparatus and vesicles,and its expression can be detected in nearly all human tissues[4].Moreover,UniProt annotation revealed that ANKRD26 is localized in the centrosome and contains coiled-coil domains formed by spectrin helices and ankyrin repeats[5,6].The most common disease related to ANKRD26 is thrombocytopenia 2(THC2),which is a rare autosomal dominant inherited disease characterized by lifelong mild-to-moderate thrombocytopenia and mild bleeding[7-9].Caused by the variants in the 5’-untranslated region(UTR)of ANKRD26,THC2 is defined by a decrease in the number of platelets in circulating blood and results in increased bleeding and decreased clotting ability[8,10].Due to the point mutations that occur in the 5’-UTR of ANKRD26,its negative transcription factors(TFs),Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1),lose their repression effect[11].The persistent expression of ANKRD26 increases the activity of the mitogen activated protein kinase and extracellular signal regulated kinase 1/2 signaling pathways,which are potentially involved in the regulation of thrombopoietin-dependent signaling and further impair proplatelet formation by megakaryocytes(MKs)[11].However,the positive regulators of ANKRD26,which might be associated with THC2 pathology,are still unknown.
文摘This editorial summarizes the latest literature on the roles of neuronal PAS domain protein 2 and KN motif/ankyrin repeat domain 1 in type 2 diabetes(T2D).We highlight their involvement inβ-cell dysfunction,explore their potential as therapeutic targets,and discuss the implications for new treatment strategies.We offer valuable insights into relevant gene regulation and cellular mechanisms relevant for the targeted management of T2D.
基金MEXT,KAKENHI,No.15K08978,No.22790677 and No.25860571a MEXT-Supported Program supporting research activities of female researchers+1 种基金the Clinical Research Foundationthe Central Research Institute of Fukuoka University,No.151045 and No.147104
文摘AIM To investigate the anti-fibrotic effects of the traditional oriental herbal medicine Daikenchuto(DKT) associated with transient receptor potential ankyrin 1(TRPA1) channels in intestinal myofibroblasts. METHODS Inflammatory and fibrotic changes were detected in a2,4,6-trinitrobenzenesulfonic acid(TNBS) chronic colitis model of wild-type and TRPA1-knockout(TRPA1-KO) mice via pathological staining and immunoblotting analysis.Ca^(2+) imaging experiments examined the effects of DKT and its components/ingredients on intestinal myofibroblast(In Myo Fib) cell TRPA1 channel function.Profibrotic factors and transforming growth factor (TGF) -β1-associated signaling were tested in an In Myo Fib cell line by q PCR and immunoblotting experiments.Samples from non-stenotic and stenotic regions of the intestines of patients with Crohn’s disease (CD) were used for pathological analysis. RESULTS Chronic treatment with TNBS caused more severe inflammation and fibrotic changes in TRPA1-KO than in wild-type mice.A one-week enema administration of DKT reduced fibrotic lesions in wild-type but not in TRPA1-KO mice.The active ingredients of DKT,i.e.,hydroxyα-sanshool and 6-shogaol,induced Ca^(2+) influxes in In Myo Fib,and this was antagonized by co-treatment with a selective TRPA1 channel blocker,HC-030031.DKT counteracted TGF-β1-induced expression of TypeⅠcollagen andα-smooth muscle actin (α-SMA) ,which were accompanied by a reduction in the phosphorylation of Smad-2 and p38-mitogen-activated protein kinase (p38-MAPK) and the expression of myocardin.Importantly,24-h incubation with a DKT active component Japanese Pepper increased the m RNA and protein expression levels of TRPA1 in In Myo Fibs,which in turn negatively regulated collagen synthesis.In the stenotic regions of the intestines of CD patients,TRPA1 expression was significantly enhanced.CONCLUSION The effects of DKT on the expression and activation of the TRPA1 channel could be advantageous for suppressing intestinal fibrosis,and benefit inflammatory bowel disease treatment.
文摘BACKGROUND Hereditary spherocytosis(HS)is a common type of hemolytic anemia caused by a red cell membrane disorder.HS type 1(HS1)is mostly caused by mutations in ankyrin(ANK1).Newborns with HS1 usually only exhibit anemia and mild jaundice.We herein report a case of HS1 and discuss its clinical characteristics.CASE SUMMARY A 2-d-old male full-term newborn was admitted to our hospital with severe,intractable neonatal jaundice.Laboratory investigations showed hemolytic anemia and hyperbilirubinemia and excluded immune-mediated hemolysis.The patient underwent two exchange transfusions and one plasmapheresis resulting in significantly reduced serum bilirubin.Hematologic analyses and genomic DNA sequencing studies were performed.The trio clinical exome sequencing revealed a de novo null heterozygous mutation in the patient's ANK1 gene:c.841C>T(p.Arg281Ter).This mutation results in the premature termination of the ANK1 protein.CONCLUSION Our case demonstrates that genetic analysis can be an essential method for diagnosing HS when a newborn has severe hyperbilirubinemia.
文摘Background: Transient receptor potential ankyrin (TRPA) 1 is known as a peripheral initiator of acute inflammation and hyperalgesia. However, its role in the facilitation of innate immune responses followed by resolution of the inflammation triggered by a surgical incision has not been fully investigated. Therefore, we evaluated the mechanism by which TRPA1 regulates the inflammatory responses mainly facilitated by neutrophils and macrophages in the early course of wound repair after an incision. Methods: Plantar incision was performed in wild-type and TRPA1-/- mice. The infiltration of polymorphonuclear neutrophils, macrophage phenotype, and induction of inflammatory mediators were assessed for 7 days postoperatively. Results: TRPA1-/-?mice exhibited decreased infiltration of polymorphonuclear neutrophilscompared with wild-type mice on day 1. Consistently, the influx of F4/80+ iNOS+ proinflammatory M1 macrophages to incised sites was markedly decreased on day 2. Similarly, F4/80+ CD206+M2 macrophages, which regulate the resolution of inflammation and promote wound healing in the later phase of acute inflammation, were significantly decreased in TRPA1-/- compared with those in wild-type mice on day 7. In addition, the induction of heme oxygenase-1, which promotes wound healing by switching phenotype of macrophages, was decreased in the early phase of acute inflammation, whereas the expression of proinflammatory mediators such as tumor necrosis factor and cyclooxygenase-2, and 15-lipoxygenase, which are involved in the resolution of inflammation was increased in the late phase in TRPA1-/- mice. Conclusions: Early innate immune responses including neutrophil infiltration and macrophage polarization at incised sites were inhibited in TRPA1-/- mice, associated with increased pro-inflammatory mediators in later phase. Peripheral TRPA1 may facilitate the acute inflammatory process, leading to the promotion of macrophage-mediated resolution of inflammation and wound repair after a surgical incision.
基金the National Natural Science Foundation of China:Study on the Mechanism of Zhenxin Anshen Formula Regulating GRPR/MrgprA3/TRPs Signaling Pathway for Atop-ic Dermatitis based on the Theory of All Kinds of Diseases with PainItching+7 种基金and Sores are Exclusively Related to the HeartNo.81704087the Regulation of Zhenxin Anshen Formula on Neuroimmune Function in Atopic Dermatitis from STIM1-ORAI1 Mediated Store Oper-ated Calcium EntryNo.82274537Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences:Based on PAR2/TRPV1 Pathway to Regulate Nerve-Epidermal Pruritus Information Transmission to Explore the Mechanism of Longmu Decoction on“Stress-Type Atopic Dermatitis”MiceNo.CI2021A02315Belt and Road Initiative Cooperation Project of Traditional Chinese Medicine of the Chinese Academy of Traditional Chinese Medicine:Evaluation of the Effect of Chinese Medicine on Allergic Diseases and Material Basis ResearchNo.GH201910。
文摘OBJECTIVE:To investigate the efficacy of Zhenxin Anshen formula(镇心安神方,ZXAS)on atopic dermatitis(AD)by transient receptor potential vanilloid 1(TRPV1)and transient receptor potential ankyrin 1(TRPA1)signalling pathway in mice and in vitro.METHODS:AD-like lesions were induced by 1-chloro-2,4-dinitrobenzene(DNCB)to the shaved dorsal skin of BALB/c mice.BALB/c mice were divided into five groups:normal control,model control,cetirizine,low-,medium-,and high-dose of ZXAS.After ZXAS in-tervention,the skin lesions and blood samples were collected for hematoxylin and eosin-stained and measuring the concentrations of inflammatory cytokines.Immunoglobulin E(IgE),interleukin(IL)-4,IL-5,IL-13,and thymic stromal lymphopoietin(TSLP)were de-tected by Enzyme-linked immunosorbent assay(ELISA).The spinal cords were collected for measuring the expression of gastrin-releasing peptide receptor(GRPR),TRPV1,and TRPA1 by using immunohistochemistry,western blotting,and quantitative real-time polymerase chain reaction(qR T-PCR)analyses.In addition,3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide(MTT)assay,flow cytometry,ELISA,and Western blotting were conducted for analysis of primary dorsal root ganglia(DRG)neurons in vitro.RESULTS:ZXAS treatment improved DNCB-induced AD-like lesions through reducing dermatitis score,number of scratching and epidermal thickness,accompanied by the de-creased IgE and Th2 inflammatory cytokines.ZXAS also supressed the mRNA and protein expression of GRPR,TRPV1,and TRPA1 in the spinal cord.The medicated sera of ZXAS decreased capsaicin-induced Ca^(2+)influx and downregulated the expression of TRPV1,TRPA1,and phospholipase C in DRG neurons.CONCLUSIONS:The therapeutic effect of ZXAS on AD may be related to the regulation of TRPV1 and TRPA1 and inhibition of Ca^(2+)signals in neurons.
