Objective Inflammation and fibrosis are key features of diabetic nephropathy(DN).Triptolide(TP)exhibits anti-inflammatory and anti-fibrotic properties,though its mechanisms of action in DN remain unclear.CREKA(Cys-Arg...Objective Inflammation and fibrosis are key features of diabetic nephropathy(DN).Triptolide(TP)exhibits anti-inflammatory and anti-fibrotic properties,though its mechanisms of action in DN remain unclear.CREKA(Cys-Arg-Glu-Lys-Ala)is a pentapeptide that specifically binds to fibronectin(FN),and the CREKA-modified liposome(CREKA-Lip)represents a novel FN-targeted drug delivery system.This study aimed to investigate the role of TP in diabetic db/db mice and determine whether encapsulation within CREKA-Lip enhances therapeutic efficacy while reducing the multi-organ toxicity of TP.Methods Eight-week-old diabetic db/db mice received tail vein injections twice weekly with vehicle,free TP,or CREKA-Lip/TP for 10 weeks.Urine and serum parameters were measured,and kidney,heart,liver,and testis tissues were collected for pathological evaluation.Protein-protein interaction networks were constructed using Cytoscape and its plug-ins to identify core targets and elucidate the therapeutic mechanism of TP against DN.Inflammatory,fibrotic,apoptotic,and lipid metabolism markers were evaluated in the kidneys of diabetic mice with DN and in high glucose-treated mouse mesangial cells and podocytes using qPCR,Western blot,immunohistochemistry,and immunofluorescence assays.Results TP administration reduced fasting blood glucose levels and glomerular mesangial expansion in diabetic mice.TP significantly suppressed renal inflammation,fibrosis,and apoptosis while enhancing lipid metabolism.Integration of network pharmacology,molecular docking,and transcriptomics revealed that TP ameliorated DN by inhibiting the JAK2-STAT1 signaling pathway.In vitro,TP inhibited high glucose-induced phosphorylation of JAK2 and STAT1,reduced collagen production in mesangial cells,decreased apoptosis,and improved lipid metabolism in podocytes.Moreover,CREKA-Lip/TP exhibited superior efficacy compared with free TP,with a more sustained reduction in urine albumin-to-creatinine ratio and greater inhibition of mesangial expansion.Notably,CREKA-Lip/TP treatment did not induce systemic toxicity.Conclusion TP improves renal inflammation,fibrosis,apoptosis,and lipid homeostasis,thereby ameliorating DN by inhibiting JAK2-STAT1 activation.Targeted delivery of TP via FN-binding CREKA-Lip enhances therapeutic efficacy while minimizing multi-organ toxicity.展开更多
Background:Intrahepatic cholangiocarcinoma(ICC)is the second most frequent primary liver cancer.The involvement of Y-box binding protein 1(YBX1)in tumor advancement is well-documented.However,its function in ICC is no...Background:Intrahepatic cholangiocarcinoma(ICC)is the second most frequent primary liver cancer.The involvement of Y-box binding protein 1(YBX1)in tumor advancement is well-documented.However,its function in ICC is not fully understood.This study aimed to explore the function and regulatory mechanism of YBX1 in ICC and provide evidence for YBX1 as a potential new approach for immunotherapy in ICC.Methods:Tissue immunohistochemistry,TCGA,and GEO databases were used to analyze the expression of YBX1 in ICC.The expression of YBX1 was silenced and overexpressed in cell lines.Both in vitro and in vivo assays were conducted to examine the antitumor T-cell responses.Actinomycin D,RNA immunoprecipitation,and methylated RNA immunoprecipitation assays were used to identify mechanism of YBX1 on downstream genes.Immunofluorescence assay was used to validate the association between YBX1 and relevant genes in clinical specimens of ICC.Results:The research findings indicated that ICC exhibited high levels of YBX1 expression,which was strongly associated with unfavorable outcomes.YBX1 promoted tumor progression by suppressing antitumor T-cell responses.YBX1 enhanced signal transducer and activator of transcription 1(STAT1)translation by serving as a 5-methylated cytosine(m5C)reader and activating the STAT1/PD-L1 pathway.Mouse experiments and clinical samples of ICC confirmed the strong correlation between the levels of YBX1,STAT1,and PD-L1 expression.Conclusions:YBX1 regulates STAT1 stability in an m5C dependent manner and maintains PD-L1 expression in ICC.展开更多
信号转导与转录激活因子(signal transducer and activator of transcription,STAT)是一类参与细胞信号转导的转录因子家族。STAT1是STATs蛋白质家族中重要成员之一,它主要通过酪氨酸激酶信号转导与转录激活因子(Janus associated kinas...信号转导与转录激活因子(signal transducer and activator of transcription,STAT)是一类参与细胞信号转导的转录因子家族。STAT1是STATs蛋白质家族中重要成员之一,它主要通过酪氨酸激酶信号转导与转录激活因子(Janus associated kinase-STAT,JAK-STAT)信号通路在细胞的生长、分化、增殖及凋亡等过程中发挥重要调控作用。STAT1被普遍认为是一种肿瘤抑制因子,具有抑制细胞生长及促进凋亡的作用。该文就STAT1与肿瘤的关系研究进行综述并展望肿瘤治疗的前景。展开更多
文摘Objective Inflammation and fibrosis are key features of diabetic nephropathy(DN).Triptolide(TP)exhibits anti-inflammatory and anti-fibrotic properties,though its mechanisms of action in DN remain unclear.CREKA(Cys-Arg-Glu-Lys-Ala)is a pentapeptide that specifically binds to fibronectin(FN),and the CREKA-modified liposome(CREKA-Lip)represents a novel FN-targeted drug delivery system.This study aimed to investigate the role of TP in diabetic db/db mice and determine whether encapsulation within CREKA-Lip enhances therapeutic efficacy while reducing the multi-organ toxicity of TP.Methods Eight-week-old diabetic db/db mice received tail vein injections twice weekly with vehicle,free TP,or CREKA-Lip/TP for 10 weeks.Urine and serum parameters were measured,and kidney,heart,liver,and testis tissues were collected for pathological evaluation.Protein-protein interaction networks were constructed using Cytoscape and its plug-ins to identify core targets and elucidate the therapeutic mechanism of TP against DN.Inflammatory,fibrotic,apoptotic,and lipid metabolism markers were evaluated in the kidneys of diabetic mice with DN and in high glucose-treated mouse mesangial cells and podocytes using qPCR,Western blot,immunohistochemistry,and immunofluorescence assays.Results TP administration reduced fasting blood glucose levels and glomerular mesangial expansion in diabetic mice.TP significantly suppressed renal inflammation,fibrosis,and apoptosis while enhancing lipid metabolism.Integration of network pharmacology,molecular docking,and transcriptomics revealed that TP ameliorated DN by inhibiting the JAK2-STAT1 signaling pathway.In vitro,TP inhibited high glucose-induced phosphorylation of JAK2 and STAT1,reduced collagen production in mesangial cells,decreased apoptosis,and improved lipid metabolism in podocytes.Moreover,CREKA-Lip/TP exhibited superior efficacy compared with free TP,with a more sustained reduction in urine albumin-to-creatinine ratio and greater inhibition of mesangial expansion.Notably,CREKA-Lip/TP treatment did not induce systemic toxicity.Conclusion TP improves renal inflammation,fibrosis,apoptosis,and lipid homeostasis,thereby ameliorating DN by inhibiting JAK2-STAT1 activation.Targeted delivery of TP via FN-binding CREKA-Lip enhances therapeutic efficacy while minimizing multi-organ toxicity.
基金supported by a grant from the National Natural Science Foundation of China(No.82070643)。
文摘Background:Intrahepatic cholangiocarcinoma(ICC)is the second most frequent primary liver cancer.The involvement of Y-box binding protein 1(YBX1)in tumor advancement is well-documented.However,its function in ICC is not fully understood.This study aimed to explore the function and regulatory mechanism of YBX1 in ICC and provide evidence for YBX1 as a potential new approach for immunotherapy in ICC.Methods:Tissue immunohistochemistry,TCGA,and GEO databases were used to analyze the expression of YBX1 in ICC.The expression of YBX1 was silenced and overexpressed in cell lines.Both in vitro and in vivo assays were conducted to examine the antitumor T-cell responses.Actinomycin D,RNA immunoprecipitation,and methylated RNA immunoprecipitation assays were used to identify mechanism of YBX1 on downstream genes.Immunofluorescence assay was used to validate the association between YBX1 and relevant genes in clinical specimens of ICC.Results:The research findings indicated that ICC exhibited high levels of YBX1 expression,which was strongly associated with unfavorable outcomes.YBX1 promoted tumor progression by suppressing antitumor T-cell responses.YBX1 enhanced signal transducer and activator of transcription 1(STAT1)translation by serving as a 5-methylated cytosine(m5C)reader and activating the STAT1/PD-L1 pathway.Mouse experiments and clinical samples of ICC confirmed the strong correlation between the levels of YBX1,STAT1,and PD-L1 expression.Conclusions:YBX1 regulates STAT1 stability in an m5C dependent manner and maintains PD-L1 expression in ICC.
文摘信号转导与转录激活因子(signal transducer and activator of transcription,STAT)是一类参与细胞信号转导的转录因子家族。STAT1是STATs蛋白质家族中重要成员之一,它主要通过酪氨酸激酶信号转导与转录激活因子(Janus associated kinase-STAT,JAK-STAT)信号通路在细胞的生长、分化、增殖及凋亡等过程中发挥重要调控作用。STAT1被普遍认为是一种肿瘤抑制因子,具有抑制细胞生长及促进凋亡的作用。该文就STAT1与肿瘤的关系研究进行综述并展望肿瘤治疗的前景。
