AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyse...AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in th...BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in the tumor microenvir-onment.Inflammation regulates the expression of programmed death ligand-1(PD-L1)in the immunosuppressive tumor microenvironment and affects im-munotherapy efficacy.Interleukin-17A(IL-17A)is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors.We hypothesized that IL-17A participates in tumor progression by affe-cting the level of immune checkpoint molecules in HCC.The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR,western blotting,and flow cytometry.Mechanistic studies were conducted with gene knockout models and pathway inhibitors.The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells.The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro,and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.RESULTS IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner,whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A.IL-17A enhanced the survival of HCC cells in the coculture system.IL-17A increased the viability,G2/M ratio,and migration of HCC cells and decreased the apoptotic index.Cyclin D1,VEGF,MMP9,and Bcl-1 expression increased after IL-17A treatment,whereas BAX expression decreased.The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8+T lymphocyte infiltration in an HCC mouse model.CONCLUSION IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapenta-plegic 2 signaling pathway in HCC cells.Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.展开更多
目的:探究血清自噬相关基因7(Autophagy Related 7,ATG7),白细胞介素17(Interleukin 17,IL-17)和一氧化氮(Nitric Oxide,NO)水平与急诊肺炎伴呼吸衰竭患者病情及转归关系。方法:研究纳入2022年3月至2024年10月期间本院收治的62例急诊肺...目的:探究血清自噬相关基因7(Autophagy Related 7,ATG7),白细胞介素17(Interleukin 17,IL-17)和一氧化氮(Nitric Oxide,NO)水平与急诊肺炎伴呼吸衰竭患者病情及转归关系。方法:研究纳入2022年3月至2024年10月期间本院收治的62例急诊肺炎伴呼吸衰竭患者(观察组)、同期59例单纯急诊肺炎患者(对照组)和65例健康体检的健康者(健康组)。比较三组血清ATG7、IL-17、NO水平。根据疾病严重程度将观察组分为轻度组33例,重度组29例。根据患者的转归情况将观察组分为转归良好组51例,转归不良组11例。检测对比不同严重程度及不同转归患者的血清ATG7、IL-17、NO水平。采用Pearson分析血清ATG7、IL-17、NO与疾病严重程度及转归的相关性。结果:与对照组、健康组相比,观察组血清ATG7、IL-17水平显著升高,NO水平显著降低(P<0.05);与健康组相比,对照组的血清ATG7、IL-17水平升高,NO水平降低(P<0.05)。重度组血清ATG7、IL-17水平高于轻度组,NO水平低于轻度组(P<0.05)。转归不良组的血清ATG7、IL-17水平高于转归良好组,NO水平低于转归良好组(P<0.05)。Pearson相关性分析显示,血清ATG7、IL-17水平与急诊肺炎伴呼吸衰竭的严重程度及不良转归呈正相关,血清NO水平与疾病严重程度及不良转归呈负相关(P<0.05)。结论:血清ATG7、IL-17和NO与急诊肺炎伴呼吸衰竭患者病情及转归密切相关。展开更多
The aim of this study is to observe the therapeutic effect of Inonotus Obliquus Polysaccharide(IOP)on chronic nonbacterial prostatitis(CNP)and its effect on the helper T cells(Th17)and regulatory T cells(Treg)immune i...The aim of this study is to observe the therapeutic effect of Inonotus Obliquus Polysaccharide(IOP)on chronic nonbacterial prostatitis(CNP)and its effect on the helper T cells(Th17)and regulatory T cells(Treg)immune imbalance.The CNP rat models established by injecting Xiaozhiling injection were randomly divided into the model group,cernilton(40 mg/kg,i.g.)group and low-dose(35 mg/kg,i.g.),medium-dose(70 mg/kg,i.g.)and high-dose(140 mg/kg,i.g.)groups,with the same volume of saline injected into the same site as the control group.The prostate’s wet weight and body mass served as the basis for calculating the prostate index.The serum level of prostate-specific antigen(PSA)was detected by ELISA and the histopathology of prostate tissue was detected by HE staining.The protein expression of Foxp3,ROR-γt and STAT3 in rat prostatic tissue was determined by Western blot.The levels of Th17 and Treg cells infiltrated into the spleen were measured by flow cytometry.The results showed that treatment with IOP significantly reduced the levels of prostate index and serum PSA,and attenuated the pathological injury of the prostate tissue induced by CNP.With respect to samples induced by CNP alone,IOP treatment repressed the increased mRNA levels of IL-6,IL-17,IL-21,IL-23,ROR-γt and STAT3 in prostate tissue,while increasing the mRNA levels of IL-10,TGF-βand Foxp3 in prostate tissue.Meanwhile,IOP treatment attenuated the upregulation of the protein expression levels of ROR-γt and STAT3 in prostate tissue.Additionally,the protein expression of Foxp3 in prostate tissue was increased in the IOP-treated group.Flow cytometry analysis further demonstrated that IOP treatment regulated the balance between Th17 and Treg cells in the spleen in rat with CNP.Our study is the first to elucidate that IOP has significant therapeutic effects on CNP through regulation of Th17/Treg balance.Collectively,the study provides evidence for the potential of IOP to treat CNP.展开更多
文摘AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.
基金Supported by the Natural Science Foundation of Gansu Province,No.21JR7RA373 and No.24JRRA295.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in the tumor microenvir-onment.Inflammation regulates the expression of programmed death ligand-1(PD-L1)in the immunosuppressive tumor microenvironment and affects im-munotherapy efficacy.Interleukin-17A(IL-17A)is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors.We hypothesized that IL-17A participates in tumor progression by affe-cting the level of immune checkpoint molecules in HCC.The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR,western blotting,and flow cytometry.Mechanistic studies were conducted with gene knockout models and pathway inhibitors.The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells.The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro,and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.RESULTS IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner,whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A.IL-17A enhanced the survival of HCC cells in the coculture system.IL-17A increased the viability,G2/M ratio,and migration of HCC cells and decreased the apoptotic index.Cyclin D1,VEGF,MMP9,and Bcl-1 expression increased after IL-17A treatment,whereas BAX expression decreased.The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8+T lymphocyte infiltration in an HCC mouse model.CONCLUSION IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapenta-plegic 2 signaling pathway in HCC cells.Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.
文摘目的:探究血清自噬相关基因7(Autophagy Related 7,ATG7),白细胞介素17(Interleukin 17,IL-17)和一氧化氮(Nitric Oxide,NO)水平与急诊肺炎伴呼吸衰竭患者病情及转归关系。方法:研究纳入2022年3月至2024年10月期间本院收治的62例急诊肺炎伴呼吸衰竭患者(观察组)、同期59例单纯急诊肺炎患者(对照组)和65例健康体检的健康者(健康组)。比较三组血清ATG7、IL-17、NO水平。根据疾病严重程度将观察组分为轻度组33例,重度组29例。根据患者的转归情况将观察组分为转归良好组51例,转归不良组11例。检测对比不同严重程度及不同转归患者的血清ATG7、IL-17、NO水平。采用Pearson分析血清ATG7、IL-17、NO与疾病严重程度及转归的相关性。结果:与对照组、健康组相比,观察组血清ATG7、IL-17水平显著升高,NO水平显著降低(P<0.05);与健康组相比,对照组的血清ATG7、IL-17水平升高,NO水平降低(P<0.05)。重度组血清ATG7、IL-17水平高于轻度组,NO水平低于轻度组(P<0.05)。转归不良组的血清ATG7、IL-17水平高于转归良好组,NO水平低于转归良好组(P<0.05)。Pearson相关性分析显示,血清ATG7、IL-17水平与急诊肺炎伴呼吸衰竭的严重程度及不良转归呈正相关,血清NO水平与疾病严重程度及不良转归呈负相关(P<0.05)。结论:血清ATG7、IL-17和NO与急诊肺炎伴呼吸衰竭患者病情及转归密切相关。
基金Shanxi Province Traditional Chinese Medicine Administration Research Project(Grant No.2022ZYYC094)Science and technology innovation project of universities in Shanxi Province(Grant No.2022L342)+1 种基金Shanxi Leader Team of Medical Science&Technology Innovations(Grant No.2020TD02)Discipline Construction Project of Chinese Medicine Chemistry(Grant No.2024XKJS-25).
文摘The aim of this study is to observe the therapeutic effect of Inonotus Obliquus Polysaccharide(IOP)on chronic nonbacterial prostatitis(CNP)and its effect on the helper T cells(Th17)and regulatory T cells(Treg)immune imbalance.The CNP rat models established by injecting Xiaozhiling injection were randomly divided into the model group,cernilton(40 mg/kg,i.g.)group and low-dose(35 mg/kg,i.g.),medium-dose(70 mg/kg,i.g.)and high-dose(140 mg/kg,i.g.)groups,with the same volume of saline injected into the same site as the control group.The prostate’s wet weight and body mass served as the basis for calculating the prostate index.The serum level of prostate-specific antigen(PSA)was detected by ELISA and the histopathology of prostate tissue was detected by HE staining.The protein expression of Foxp3,ROR-γt and STAT3 in rat prostatic tissue was determined by Western blot.The levels of Th17 and Treg cells infiltrated into the spleen were measured by flow cytometry.The results showed that treatment with IOP significantly reduced the levels of prostate index and serum PSA,and attenuated the pathological injury of the prostate tissue induced by CNP.With respect to samples induced by CNP alone,IOP treatment repressed the increased mRNA levels of IL-6,IL-17,IL-21,IL-23,ROR-γt and STAT3 in prostate tissue,while increasing the mRNA levels of IL-10,TGF-βand Foxp3 in prostate tissue.Meanwhile,IOP treatment attenuated the upregulation of the protein expression levels of ROR-γt and STAT3 in prostate tissue.Additionally,the protein expression of Foxp3 in prostate tissue was increased in the IOP-treated group.Flow cytometry analysis further demonstrated that IOP treatment regulated the balance between Th17 and Treg cells in the spleen in rat with CNP.Our study is the first to elucidate that IOP has significant therapeutic effects on CNP through regulation of Th17/Treg balance.Collectively,the study provides evidence for the potential of IOP to treat CNP.
