目的:探讨聚(ADP-核糖)聚合酶家族成员3[Poly(ADP-Ribose)Polymerase Family Member 3,PARP3]在脂多糖(Lipopolysaccharide,LPS)诱导的小胶质细胞BV2炎症及凋亡中的作用机制,为视神经损伤的临床治疗提供潜在靶点。方法:通过LPS刺激BV2...目的:探讨聚(ADP-核糖)聚合酶家族成员3[Poly(ADP-Ribose)Polymerase Family Member 3,PARP3]在脂多糖(Lipopolysaccharide,LPS)诱导的小胶质细胞BV2炎症及凋亡中的作用机制,为视神经损伤的临床治疗提供潜在靶点。方法:通过LPS刺激BV2小胶质细胞,构建体外炎症损伤模型,随后利用实时荧光定量聚合酶链反应技术、蛋白质印迹及流式细胞术等技术手段,检测PARP3的蛋白及mRNA表达水平、炎症因子的分泌以及细胞凋亡的情况。结果:LPS处理后,BV2细胞中PARP3表达水平显著上调,炎症因子分泌增加,细胞活性氧增多,细胞凋亡率增加,而抑制PARP3能显著减少这些效应。结论:PARP3在LPS诱导的BV2细胞炎症及凋亡中起关键作用,为视神经损伤治疗提供了新的潜在靶点。展开更多
Objective:Ovarian cancer(OC)ranks among the leading causes of mortality among the female cancers worldwide.Numerous studies have explored the development and progression of OC at multiple genetic regulatory levels.How...Objective:Ovarian cancer(OC)ranks among the leading causes of mortality among the female cancers worldwide.Numerous studies have explored the development and progression of OC at multiple genetic regulatory levels.However,relatively few studies have explored the impact of post-translational modifications(PTM)on OC progression,which is essential for uncovering new therapeutic targets.This study aimed to systematically identify the key PTM types involved in OCprogression,and to explore and evaluate their translational potential as therapeutic targets.Methods:First,we utilized multiple general PTM antibodies to compare gross PTM levels between normal ovarian and OC tissues from clinical females.After identifying lactylation as the PTM with the most significant differences,we selected representative samples for label-free mass spectrometry to identify specific lactylation sites.Next,we transfected A2780(OC)cells with either wild-type(WT)or mutant(K192A[Q])poly(ADP-ribose)polymerase 1(PARP1)conjugated to enhanced green fluorescent protein(EGFP)with a StrepⅡpeptide tag and assessed various cellular indexes related to cell proliferation(clonogenicity assay),migration(scratch wound healing assay),and reactive oxygen species levels.Results:Pan-lactylation was significantly upregulated in clinical OC samples,with PARP1 lactylation at K192 being one of the most common modifications.The growth and migration of A2780 cells were markedly suppressed by overexpressing PARP1-WT but not mutant PARP1.Overexpressing PARP1 significantly downregulated the phosphorylation of extracellular signal-regulated kinases 1/2(ERK1/2).Conclusion:This study uncovered a novel PTM of PARP1 in OC,lactylation,and demonstrated that lactylation at K192 is crucial in regulating OC cell growth and migration via the ERK1/2 pathway.Further investigations are required to elucidate the broader functional implications of PARP1 lactylation and its therapeutic potential.展开更多
卵巢癌是妇科疾病中预后最差的恶性肿瘤,由于早期症状不典型、缺乏特异性,所以早期诊断困难。初始治疗后复发率高,5年总生存率仅为40%,晚期卵巢癌的治疗成为临床工作中的难题。近年来,PARP抑制剂的应用,极大地改善了卵巢癌患者的生存期...卵巢癌是妇科疾病中预后最差的恶性肿瘤,由于早期症状不典型、缺乏特异性,所以早期诊断困难。初始治疗后复发率高,5年总生存率仅为40%,晚期卵巢癌的治疗成为临床工作中的难题。近年来,PARP抑制剂的应用,极大地改善了卵巢癌患者的生存期时间。PARP抑制剂作为一种新型的靶向治疗药物,在卵巢癌的维持治疗中取得了显著进展。本文对PARP抑制剂在卵巢癌维持治疗中的作用机制、临床研究、安全性等方面的研究进展进行综述,旨在为卵巢癌的临床治疗提供参考。Ovarian cancer is a malignant tumor with the worst prognosis in gynecological diseases, and early diagnosis is difficult because of the untypical early symptoms and lack of specificity. The recurrence rate after initial treatment is high, the 5-year overall survival rate is only 40%, and the treatment of advanced ovarian cancer has become a difficult problem in clinical work. In recent years, the application of PARP inhibitors has greatly improved the survival time of ovarian cancer patients. As a new type of targeted therapy, PARP inhibitors have made remarkable progress in the maintenance therapy of ovarian cancer. In this paper, the research progress of the mechanism of action, clinical research and safety of PARP inhibitors in the maintenance treatment of ovarian cancer is reviewed, aiming to provide a reference for the clinical treatment of ovarian cancer.展开更多
Pamiparib is a potent and selective oral poly(adenosine diphosphate(ADP)-ribose)-polymerase(PARP)1/2inhibitor(PARPi).Pamiparib has good bioavailability and shows greater cytotoxic potency and similar DNA-trapping capa...Pamiparib is a potent and selective oral poly(adenosine diphosphate(ADP)-ribose)-polymerase(PARP)1/2inhibitor(PARPi).Pamiparib has good bioavailability and shows greater cytotoxic potency and similar DNA-trapping capacity compared to olaparib.It is not affected by adenosine triphosphate(ATP)-binding cassette transporters.展开更多
文摘目的:探讨聚(ADP-核糖)聚合酶家族成员3[Poly(ADP-Ribose)Polymerase Family Member 3,PARP3]在脂多糖(Lipopolysaccharide,LPS)诱导的小胶质细胞BV2炎症及凋亡中的作用机制,为视神经损伤的临床治疗提供潜在靶点。方法:通过LPS刺激BV2小胶质细胞,构建体外炎症损伤模型,随后利用实时荧光定量聚合酶链反应技术、蛋白质印迹及流式细胞术等技术手段,检测PARP3的蛋白及mRNA表达水平、炎症因子的分泌以及细胞凋亡的情况。结果:LPS处理后,BV2细胞中PARP3表达水平显著上调,炎症因子分泌增加,细胞活性氧增多,细胞凋亡率增加,而抑制PARP3能显著减少这些效应。结论:PARP3在LPS诱导的BV2细胞炎症及凋亡中起关键作用,为视神经损伤治疗提供了新的潜在靶点。
文摘Objective:Ovarian cancer(OC)ranks among the leading causes of mortality among the female cancers worldwide.Numerous studies have explored the development and progression of OC at multiple genetic regulatory levels.However,relatively few studies have explored the impact of post-translational modifications(PTM)on OC progression,which is essential for uncovering new therapeutic targets.This study aimed to systematically identify the key PTM types involved in OCprogression,and to explore and evaluate their translational potential as therapeutic targets.Methods:First,we utilized multiple general PTM antibodies to compare gross PTM levels between normal ovarian and OC tissues from clinical females.After identifying lactylation as the PTM with the most significant differences,we selected representative samples for label-free mass spectrometry to identify specific lactylation sites.Next,we transfected A2780(OC)cells with either wild-type(WT)or mutant(K192A[Q])poly(ADP-ribose)polymerase 1(PARP1)conjugated to enhanced green fluorescent protein(EGFP)with a StrepⅡpeptide tag and assessed various cellular indexes related to cell proliferation(clonogenicity assay),migration(scratch wound healing assay),and reactive oxygen species levels.Results:Pan-lactylation was significantly upregulated in clinical OC samples,with PARP1 lactylation at K192 being one of the most common modifications.The growth and migration of A2780 cells were markedly suppressed by overexpressing PARP1-WT but not mutant PARP1.Overexpressing PARP1 significantly downregulated the phosphorylation of extracellular signal-regulated kinases 1/2(ERK1/2).Conclusion:This study uncovered a novel PTM of PARP1 in OC,lactylation,and demonstrated that lactylation at K192 is crucial in regulating OC cell growth and migration via the ERK1/2 pathway.Further investigations are required to elucidate the broader functional implications of PARP1 lactylation and its therapeutic potential.
文摘卵巢癌是妇科疾病中预后最差的恶性肿瘤,由于早期症状不典型、缺乏特异性,所以早期诊断困难。初始治疗后复发率高,5年总生存率仅为40%,晚期卵巢癌的治疗成为临床工作中的难题。近年来,PARP抑制剂的应用,极大地改善了卵巢癌患者的生存期时间。PARP抑制剂作为一种新型的靶向治疗药物,在卵巢癌的维持治疗中取得了显著进展。本文对PARP抑制剂在卵巢癌维持治疗中的作用机制、临床研究、安全性等方面的研究进展进行综述,旨在为卵巢癌的临床治疗提供参考。Ovarian cancer is a malignant tumor with the worst prognosis in gynecological diseases, and early diagnosis is difficult because of the untypical early symptoms and lack of specificity. The recurrence rate after initial treatment is high, the 5-year overall survival rate is only 40%, and the treatment of advanced ovarian cancer has become a difficult problem in clinical work. In recent years, the application of PARP inhibitors has greatly improved the survival time of ovarian cancer patients. As a new type of targeted therapy, PARP inhibitors have made remarkable progress in the maintenance therapy of ovarian cancer. In this paper, the research progress of the mechanism of action, clinical research and safety of PARP inhibitors in the maintenance treatment of ovarian cancer is reviewed, aiming to provide a reference for the clinical treatment of ovarian cancer.
基金supported in part by funding from BeiGene,Ltd.,USA(Grant No.:KPR081)with additional support from the Alessandra Bono Foundation,Italy.
文摘Pamiparib is a potent and selective oral poly(adenosine diphosphate(ADP)-ribose)-polymerase(PARP)1/2inhibitor(PARPi).Pamiparib has good bioavailability and shows greater cytotoxic potency and similar DNA-trapping capacity compared to olaparib.It is not affected by adenosine triphosphate(ATP)-binding cassette transporters.
