BACKGROUND Gastric cancer(GC)is a common malignant tumor with high incidence and mortality rates globally,especially in East Asian countries.Helicobacter pylori(H.pylori)infection is a significant and independent risk...BACKGROUND Gastric cancer(GC)is a common malignant tumor with high incidence and mortality rates globally,especially in East Asian countries.Helicobacter pylori(H.pylori)infection is a significant and independent risk factor for GC.However,its underlying mechanism of action is not fully understood.Dickkopf-related protein(DKK)1 is a Wnt signaling antagonist,and cytoskeleton-associated protein(CKAP)4 is a newly identified DKK1 receptor.Recent studies found that the binding of DKK1 to CAKP4 mediated the procancer signaling of DKK1 independent of Wnt signaling.We hypothesize that H.pylori-induced activation of DKK1/CKAP4 signaling contributes to the initiation and progression of GC.AIM To investigate the interaction of H.pylori infection,DKK1 and CAKP4 in GC,as well as the underlying molecular mechanisms.METHODS RNA sequencing was used to identify differentially expressed genes(DEGs)between H.pylori-infected and uninfected primary GC cells.Gain-and loss-offunction experiments were performed to verify the H.pylori-induced upregulation of activator protein-1(AP-1)in GC cells.A dual-luciferase reporter assay and co-immunoprecipitation were used to determine the binding of AP-1 to the DKK1 promoter and DKK1 to CKAP4.Western blotting and immunohistochemistry detected the expression of DKK1,CKAP4,and phosphatidylinositol 3-kinase(PI3K)pathway-related proteins in GC cells and tissues.Functional experiments and tumorigenicity in nude mice detected malignant behavior of GC cells in vitro and in vivo.RESULTS We identified 32 DEGs between primary GC cells with and without H.pylori infection,including JUN,fos-like antigen-1(FOSL1),and DKK1,and confirmed that the three proteins and CKAP4 were highly expressed in H.pylori-infected GC cells,H.pylori-infected gerbil gastric tissues,and human GC tissues.JUN and FOSL1 form AP-1 to transcriptionally activate DKK1 expression by binding to the DKK1 promoter.Activated DKK1 bound to CKAP4,but not the most common Wnt coreceptor low-density lipoprotein receptor-related protein 5/6,to promote GC cell growth,colony formation,migration,invasion,and xenograft tumor growth in nude mice.All these effects were driven by activation of the PI3K/AKT/mammalian target of rapamycin(mTOR)pathway.Targeting the PI3K signaling pathway by LY294002 inhibited DKK1-mediated CKAP4/PI3K signaling activity and the malignant behavior of GC cells.CONCLUSION H.pylori induces JUN and FOSL1 expression to form AP-1,which transcriptionally activates DKK1.Binding of DKK1 to KAKP4 contributes to gastric tumorigenesis via the PI3K/AKT/mTOR pathway.展开更多
for about 20%of all clinically confirmed pregnancy.It is the main cause of early abortion.Vaginal bleeding is the main clinical manifestation,which seriously affects the mental health and quality of life of pregnant w...for about 20%of all clinically confirmed pregnancy.It is the main cause of early abortion.Vaginal bleeding is the main clinical manifestation,which seriously affects the mental health and quality of life of pregnant women.Currently,there is effective treatment for this condition.A recent meta-analysis showed that Shoutai Pill(ST Pill),a traditional Chinese medicine(TCM)formula,can effectively decrease the rate of threatened abortion.However,high heterogeneity was found among the studies included in the meta-analysis,this conclusion on the efficacy of TCM is not definitive.Although several have been conducted,some of them do not describe randomization and blinding methods.To address these problems,this article proposes an improved clinical treatment scheme based on ST Pill,which is to be tested through a well-designed randomized controlled trial,for the treatment of threatened abortion.Methods:This is a double-blinded,randomized,placebo-controlled trial to be conducted in a public Three-A hospital in China's Mainland.A total of 200 people will be enrolled.Using computer-generated random numbers,the participants will be randomly divided into two groups at a ratio of 1:1(treatment group(treated with ST Pill group)and placebo group).Both groups will receive medication to the end of the 20th gestational week or 1 week after vaginal bleeding stops,depending on which is longer.Participants in the treatment group will be treated with ST Pill(20 pills/time,once a day),and those in the placebo group will receive a placebo drug which is similar in appearance and smell with ST Pill.The main observation index is the live birth rate.Discussion:Although the efficacy of ST Pill in threatened abortion is well-known,no study has tested its efficacy through a double-blinded,randomized trials.Therefore,there is an urgent need for a standardized randomized double-blinded controlled trial to evaluate the clinical efficacy of ST Pill.ST Pill is likely to be a convenient and effective TCM pill for the prevention of threatened abortion.展开更多
基金the National Natural Science Foundation of China,No.32160166,No.31760328,and No.31960028Natural Science Foundation of Guizhou Province,No.ZC[2020]4Y026,No.JC[2020]1Z010,No.JC[2020]1Y333,and No.ZK[2022]041Scientific Research Project of Guizhou Medical University,No.20NSP068.
文摘BACKGROUND Gastric cancer(GC)is a common malignant tumor with high incidence and mortality rates globally,especially in East Asian countries.Helicobacter pylori(H.pylori)infection is a significant and independent risk factor for GC.However,its underlying mechanism of action is not fully understood.Dickkopf-related protein(DKK)1 is a Wnt signaling antagonist,and cytoskeleton-associated protein(CKAP)4 is a newly identified DKK1 receptor.Recent studies found that the binding of DKK1 to CAKP4 mediated the procancer signaling of DKK1 independent of Wnt signaling.We hypothesize that H.pylori-induced activation of DKK1/CKAP4 signaling contributes to the initiation and progression of GC.AIM To investigate the interaction of H.pylori infection,DKK1 and CAKP4 in GC,as well as the underlying molecular mechanisms.METHODS RNA sequencing was used to identify differentially expressed genes(DEGs)between H.pylori-infected and uninfected primary GC cells.Gain-and loss-offunction experiments were performed to verify the H.pylori-induced upregulation of activator protein-1(AP-1)in GC cells.A dual-luciferase reporter assay and co-immunoprecipitation were used to determine the binding of AP-1 to the DKK1 promoter and DKK1 to CKAP4.Western blotting and immunohistochemistry detected the expression of DKK1,CKAP4,and phosphatidylinositol 3-kinase(PI3K)pathway-related proteins in GC cells and tissues.Functional experiments and tumorigenicity in nude mice detected malignant behavior of GC cells in vitro and in vivo.RESULTS We identified 32 DEGs between primary GC cells with and without H.pylori infection,including JUN,fos-like antigen-1(FOSL1),and DKK1,and confirmed that the three proteins and CKAP4 were highly expressed in H.pylori-infected GC cells,H.pylori-infected gerbil gastric tissues,and human GC tissues.JUN and FOSL1 form AP-1 to transcriptionally activate DKK1 expression by binding to the DKK1 promoter.Activated DKK1 bound to CKAP4,but not the most common Wnt coreceptor low-density lipoprotein receptor-related protein 5/6,to promote GC cell growth,colony formation,migration,invasion,and xenograft tumor growth in nude mice.All these effects were driven by activation of the PI3K/AKT/mammalian target of rapamycin(mTOR)pathway.Targeting the PI3K signaling pathway by LY294002 inhibited DKK1-mediated CKAP4/PI3K signaling activity and the malignant behavior of GC cells.CONCLUSION H.pylori induces JUN and FOSL1 expression to form AP-1,which transcriptionally activates DKK1.Binding of DKK1 to KAKP4 contributes to gastric tumorigenesis via the PI3K/AKT/mTOR pathway.
文摘for about 20%of all clinically confirmed pregnancy.It is the main cause of early abortion.Vaginal bleeding is the main clinical manifestation,which seriously affects the mental health and quality of life of pregnant women.Currently,there is effective treatment for this condition.A recent meta-analysis showed that Shoutai Pill(ST Pill),a traditional Chinese medicine(TCM)formula,can effectively decrease the rate of threatened abortion.However,high heterogeneity was found among the studies included in the meta-analysis,this conclusion on the efficacy of TCM is not definitive.Although several have been conducted,some of them do not describe randomization and blinding methods.To address these problems,this article proposes an improved clinical treatment scheme based on ST Pill,which is to be tested through a well-designed randomized controlled trial,for the treatment of threatened abortion.Methods:This is a double-blinded,randomized,placebo-controlled trial to be conducted in a public Three-A hospital in China's Mainland.A total of 200 people will be enrolled.Using computer-generated random numbers,the participants will be randomly divided into two groups at a ratio of 1:1(treatment group(treated with ST Pill group)and placebo group).Both groups will receive medication to the end of the 20th gestational week or 1 week after vaginal bleeding stops,depending on which is longer.Participants in the treatment group will be treated with ST Pill(20 pills/time,once a day),and those in the placebo group will receive a placebo drug which is similar in appearance and smell with ST Pill.The main observation index is the live birth rate.Discussion:Although the efficacy of ST Pill in threatened abortion is well-known,no study has tested its efficacy through a double-blinded,randomized trials.Therefore,there is an urgent need for a standardized randomized double-blinded controlled trial to evaluate the clinical efficacy of ST Pill.ST Pill is likely to be a convenient and effective TCM pill for the prevention of threatened abortion.
