Severe fever with thrombocytopenia syndrome(SFTS)is an emerging hemorrhagic fever disease caused by SFTSV,a newly discovered phlebovirus that is named after the disease.Currently,no effective vaccines or drugs are ava...Severe fever with thrombocytopenia syndrome(SFTS)is an emerging hemorrhagic fever disease caused by SFTSV,a newly discovered phlebovirus that is named after the disease.Currently,no effective vaccines or drugs are available for use against SFTSV infection,as our understanding of the viral pathogenesis is limited.Bortezomib(PS-341),a dipeptideboronic acid analog,is the first clinically approved proteasome inhibitor for use in humans.In this study,the antiviral efficacy of PS-341 against SFTSV infection was tested in human embryonic kidney HEK293T(293T)cells.We employed four different assays to analyze the antiviral ability of PS-341 and determined that PS-341 inhibited the proliferation of SFTSV in 293T cells under various treatment conditions.Although PS-341 did not affect the virus absorption,PS-341 treatment within a non-toxic concentration range resulted in a significant reduction of progeny viral titers in infected cells.Dual-luciferase reporter assays and Western blot analysis revealed that PS-341 could reverse the SFTSV-encoded nonstructural protein(NS)mediated degradation of retinoic acid-inducible gene-1(RIG-I),thereby antagonizing the inhibitory effect of NSs on interferons and blocking virus replication.In addition,we observed that inhibition of apoptosis promotes virus replication.These results indicate that targeting of cellular interferon pathways and apoptosis during acute infection might serve as the bases of future therapeutics for the treatment of SFTSV infections.展开更多
脑胶质瘤是成人中枢神经系统中最常见的恶性肿瘤之一,尤其是恶性程度高的胶质母细胞瘤,其预后极差,传统的手术、放疗和化疗等治疗方式效果有限。蛋白酶体抑制剂作为一种新兴的抗肿瘤治疗方式,通过抑制细胞蛋白降解的通路,干扰细胞内蛋...脑胶质瘤是成人中枢神经系统中最常见的恶性肿瘤之一,尤其是恶性程度高的胶质母细胞瘤,其预后极差,传统的手术、放疗和化疗等治疗方式效果有限。蛋白酶体抑制剂作为一种新兴的抗肿瘤治疗方式,通过抑制细胞蛋白降解的通路,干扰细胞内蛋白质稳态,进而诱导肿瘤细胞死亡。本文综述了蛋白酶体抑制剂在脑胶质瘤治疗中的作用机制、临床前和临床研究进展,并探讨了其应用前景和面临的挑战。Gliomas are one of the most common malignant tumors in the adult central nervous system, especially highly malignant glioblastomas, which have a very poor prognosis. Traditional treatments such as surgery, radiotherapy, and chemotherapy have limited effectiveness. Proteasome inhibitors, as an emerging anti-tumor therapy, interfere with intracellular protein homeostasis by inhibiting the pathway of cellular protein degradation, thereby inducing tumor cell death. This article reviews the mechanism of action, preclinical and clinical research progress of proteasome inhibitors in the treatment of glioblastoma, and explores their application prospects and challenges.展开更多
基金supported by the National Science Foundation of China (31270201)the National Key Research and Development Program of China (2017YFA0205102)+1 种基金the Seed Foundation of Tianjin University (2014XRX-0026)the National Science Foundation of Tianjin (No.16JCQNJC09800)
文摘Severe fever with thrombocytopenia syndrome(SFTS)is an emerging hemorrhagic fever disease caused by SFTSV,a newly discovered phlebovirus that is named after the disease.Currently,no effective vaccines or drugs are available for use against SFTSV infection,as our understanding of the viral pathogenesis is limited.Bortezomib(PS-341),a dipeptideboronic acid analog,is the first clinically approved proteasome inhibitor for use in humans.In this study,the antiviral efficacy of PS-341 against SFTSV infection was tested in human embryonic kidney HEK293T(293T)cells.We employed four different assays to analyze the antiviral ability of PS-341 and determined that PS-341 inhibited the proliferation of SFTSV in 293T cells under various treatment conditions.Although PS-341 did not affect the virus absorption,PS-341 treatment within a non-toxic concentration range resulted in a significant reduction of progeny viral titers in infected cells.Dual-luciferase reporter assays and Western blot analysis revealed that PS-341 could reverse the SFTSV-encoded nonstructural protein(NS)mediated degradation of retinoic acid-inducible gene-1(RIG-I),thereby antagonizing the inhibitory effect of NSs on interferons and blocking virus replication.In addition,we observed that inhibition of apoptosis promotes virus replication.These results indicate that targeting of cellular interferon pathways and apoptosis during acute infection might serve as the bases of future therapeutics for the treatment of SFTSV infections.
文摘脑胶质瘤是成人中枢神经系统中最常见的恶性肿瘤之一,尤其是恶性程度高的胶质母细胞瘤,其预后极差,传统的手术、放疗和化疗等治疗方式效果有限。蛋白酶体抑制剂作为一种新兴的抗肿瘤治疗方式,通过抑制细胞蛋白降解的通路,干扰细胞内蛋白质稳态,进而诱导肿瘤细胞死亡。本文综述了蛋白酶体抑制剂在脑胶质瘤治疗中的作用机制、临床前和临床研究进展,并探讨了其应用前景和面临的挑战。Gliomas are one of the most common malignant tumors in the adult central nervous system, especially highly malignant glioblastomas, which have a very poor prognosis. Traditional treatments such as surgery, radiotherapy, and chemotherapy have limited effectiveness. Proteasome inhibitors, as an emerging anti-tumor therapy, interfere with intracellular protein homeostasis by inhibiting the pathway of cellular protein degradation, thereby inducing tumor cell death. This article reviews the mechanism of action, preclinical and clinical research progress of proteasome inhibitors in the treatment of glioblastoma, and explores their application prospects and challenges.
