Background:Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases globally.Hepatic stellate cells(HSCs)are the major effector cells of liver fibrosis.HSCs contain abundant lipid drople...Background:Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases globally.Hepatic stellate cells(HSCs)are the major effector cells of liver fibrosis.HSCs contain abundant lipid droplets(LDs)in their cytoplasm during quiescence.Perilipin 5(PLIN 5)is a LD surface-associated protein that plays a crucial role in lipid homeostasis.However,little is known about the role of PLIN 5 in HSC activation.Methods:PLIN 5 was overexpressed in HSCs of Sprague–Dawley rats by lentivirus transfection.At the same time,PLIN 5 gene knockout mice were constructed and fed with a high-fat diet(HFD)for 20 weeks to study the role of PLIN 5 in NAFLD.The corresponding reagent kits were used to measure TG,GSH,Caspase 3 activity,ATP level,and mitochondrial DNA copy number.Metabolomic analysis of mice liver tissue metabolism was performed based on UPLC-MS/MS.AMPK,mitochondrial function,cell proliferation,and apoptosis-related genes and proteins were detected by western blotting and qPCR.Results:Overexpression of PLIN 5 in activated HSCs led to a decrease in ATP levels in mitochondria,inhibition of cell proliferation,and a significant increase in cell apoptosis through AMPK activation.In addition,compared with the HFD-fed C57BL/6J mice,PLIN 5 knockout mice fed with HFD showed reduced liver fat deposition,decreased LD abundance and size,and reduced liver fibrosis.Conclusion:These findings highlight the unique regulatory role of PLIN 5 in HSCs and the role of PLIN 5 in the fibrosis process of NAFLD.展开更多
Histone lysine specific demethylase 1(LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. ...Histone lysine specific demethylase 1(LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. Herein, we report the discovery of the hit compound 8 a(IC50=3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15 u(IC50=49 nmol/L, and Ki= 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3 K4 me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency ofcompound 15 u. Compound 15 u also showed strong antiproliferative activity against four leukemia cell lines(OCL-AML3, K562, THP-1 and U937) as well as the lymphoma cell line Raji with the IC50 values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, 15 u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15 u induced expression of CD86 and CD11 b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation.The findings further indicate that targeting LSD1 is a promising strategy for AML treatment, the triazolefused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1 A inhibitors.展开更多
Targeting immune checkpoints such as programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for treating melanoma,gastric cancer(GC)and bladder cancer with clinical benefit.Neverth...Targeting immune checkpoints such as programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for treating melanoma,gastric cancer(GC)and bladder cancer with clinical benefit.Nevertheless,many patients failed to respond to anti-PD-1/PD-L1 treatment,so it is necessary to seek an alternative strategy for traditional PD-1/PD-L1 targeting immunotherapy.Here with the data from The Cancer Genome Atlas(TCGA)and our in-house tissue library,PD-L1 expression was found to be positively correlated with the expression of ubiquitin-specific processing protease 7(USP7)in GC.Furthermore,USP7 directly interacted with PD-L1 in order to stabilize it,Gastric cancer;Immunosuppression;Cancer biologywhile abrogation of USP7 attenuated PD-L1/PD-1 interaction and sensitized cancer cells to T cell killing in vitro and in vivo.Besides,USP7 inhibitor suppressed GC cells proliferation by stabilizing P53 in vitro and in vivo.Collectively,our findings indicate that in addition to inhibiting cancer cells proliferation,USP7 inhibitor can also downregulate PD-L1 expression to enhance anti-tumor immune response simultaneously.Hence,these data posit USP7 inhibitor as an anti-proliferation agent as well as a novel therapeutic agent in PD-L1/PD-1 blockade strategy that can promote the immune response of the tumor.展开更多
Novel biologics that redirect cytotoxic T lymphocytes (CTLs) to kill tumor cells bearing a tumor associated antigen hold great promise in the clinic. However, the ability to safely and potently target CD3 on CTL tow...Novel biologics that redirect cytotoxic T lymphocytes (CTLs) to kill tumor cells bearing a tumor associated antigen hold great promise in the clinic. However, the ability to safely and potently target CD3 on CTL toward tumor associated antigens (TAA) expressed on tumor cells remains a challenge of both technology and biol- ogy. Herein we describe the use of a Half DVD-Ig format that can redirect CTL to kill tumor cells. Notably, Half DVD-Ig molecules that are monovalent for each speci- ficity demonstrated reduced non-specific CTL activation and conditional CTL activation upon binding to TAA compared to intact tetravalent DVD-Ig molecules that are bivalent for each specificity, while maintaining good drug like properties and appropriate PK properties.展开更多
Acquired resistance to chemotherapy is a major limitation in clinical treatment for breast cancer.Accumulating evidence from in vitro,in vivo and clinical studies suggest that acquired chemoresistance is progressive,m...Acquired resistance to chemotherapy is a major limitation in clinical treatment for breast cancer.Accumulating evidence from in vitro,in vivo and clinical studies suggest that acquired chemoresistance is progressive,multifactorial and involve genetic and epigenetic aberrations.Among various mechanisms that contribute to chemoresistance,cellular reprogramming has extensively been implicated in breast cancer resistance lately.Cellular reprogramming events such as acquisition of epithelial to mesenchymal transition(EMT)and cancer stemness(CSCs)not only provide cancer cells with reversible phenotypic plasticity and survival advantage against cytotoxicity but also leads to aggressiveness,metastasis,clinical resistance,tumor recurrence and poor survival.The transient and reversible nature of cellular reprogramming processes and their controlled interaction with epigenetic regulatory complexes strongly support the involvement of dynamic epigenetic regulatory network in governing the cellular reprogramming and associated acquired chemoresistance.Further,epigenetic modulations are also gaining interest as promising interventions addressing the cancer cell reprogramming machinery to overcome acquired chemoresistance.This review discusses the previous reports and our recent findings that lead to current understanding of epigenetic dysregulation dictating the cellular reprogramming processes such as acquisition of EMT and CSCs phenotype and how they co-ordinate to establish acquired drug resistance in breast cancer.展开更多
A novel and efficient[3+2]annulation of 2-substituted aziridines and N-tosyl cyanamides via a dominoregioselective ring-opening/5-exo-dig cyclization procedure has been developed,allowing the directpreparation of N_(2...A novel and efficient[3+2]annulation of 2-substituted aziridines and N-tosyl cyanamides via a dominoregioselective ring-opening/5-exo-dig cyclization procedure has been developed,allowing the directpreparation of N_(2)-unprotected five-membered cyclic guanidines in good to excellent yields under mildconditions without metals and strong bases.Moreover,the highly biologically interesting urea analoguescould also be conveniently obtained via hydrolysis of the produced guanidines.展开更多
基金Discipline Key Special ProjectGrant/Award Number:XKZDQY202001+7 种基金Henan Provincial Key R&D and Promotion Special ProjectGrant/Award Number:212102310033Henan Provincial Medical Science and Technology Tackling ProgramGrant/Award Number:LHGJ20220557Key R&D Program of ChinaGrant/Award Number:2020YFC2006100,2020YFC2009000 and 2020YFC2009006National Natural Science Foundation of ChinaGrant/Award Number:31471330 and 81870408。
文摘Background:Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases globally.Hepatic stellate cells(HSCs)are the major effector cells of liver fibrosis.HSCs contain abundant lipid droplets(LDs)in their cytoplasm during quiescence.Perilipin 5(PLIN 5)is a LD surface-associated protein that plays a crucial role in lipid homeostasis.However,little is known about the role of PLIN 5 in HSC activation.Methods:PLIN 5 was overexpressed in HSCs of Sprague–Dawley rats by lentivirus transfection.At the same time,PLIN 5 gene knockout mice were constructed and fed with a high-fat diet(HFD)for 20 weeks to study the role of PLIN 5 in NAFLD.The corresponding reagent kits were used to measure TG,GSH,Caspase 3 activity,ATP level,and mitochondrial DNA copy number.Metabolomic analysis of mice liver tissue metabolism was performed based on UPLC-MS/MS.AMPK,mitochondrial function,cell proliferation,and apoptosis-related genes and proteins were detected by western blotting and qPCR.Results:Overexpression of PLIN 5 in activated HSCs led to a decrease in ATP levels in mitochondria,inhibition of cell proliferation,and a significant increase in cell apoptosis through AMPK activation.In addition,compared with the HFD-fed C57BL/6J mice,PLIN 5 knockout mice fed with HFD showed reduced liver fat deposition,decreased LD abundance and size,and reduced liver fibrosis.Conclusion:These findings highlight the unique regulatory role of PLIN 5 in HSCs and the role of PLIN 5 in the fibrosis process of NAFLD.
基金supported by the National Key Research Program of Proteins(Nos.2016YFA0501800 and 2017YFD0501401,China)the National Natural Science Foundation of China(Nos.81703326,81773562,81430085 and 21403200,China)+5 种基金the Open Fund of State Key Laboratory of Pharmaceutical Biotechnology,Nan-jing University,China(No.KF-GN-201902,China)Outstanding Young Talent Research Fund of Zhengzhou University(No.1521331002,China)Scientific Program of Henan Province(Nos.182102310123 and 161100310100,China)China Postdoctoral Science Foundation(No.2018M630840,China)Key Research Program of Higher Education of Henan Province(Nos.15A350018 and 18B350009,China)the Starting Grant of Zhengzhou University(No.32210533,China)
文摘Histone lysine specific demethylase 1(LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. Herein, we report the discovery of the hit compound 8 a(IC50=3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15 u(IC50=49 nmol/L, and Ki= 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3 K4 me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency ofcompound 15 u. Compound 15 u also showed strong antiproliferative activity against four leukemia cell lines(OCL-AML3, K562, THP-1 and U937) as well as the lymphoma cell line Raji with the IC50 values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, 15 u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15 u induced expression of CD86 and CD11 b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation.The findings further indicate that targeting LSD1 is a promising strategy for AML treatment, the triazolefused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1 A inhibitors.
基金supported by National Natural Science Foundation of China(Project No.81602961 for Yichao ZhengNos.81430085,81773562,and 82020108030 for Hongmin Liu)+2 种基金National Key Research Program of Proteins(Nos.2016YFA0501800 and 2018YFE0195100 for Hongmin Liu,China)Key Research Program of Henan Province(No.161100310100,for Hongmin Liu,China)Science and Technology Innovation Talents of Henan Provincial Education Department(19IRTSTHN001,China)。
文摘Targeting immune checkpoints such as programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for treating melanoma,gastric cancer(GC)and bladder cancer with clinical benefit.Nevertheless,many patients failed to respond to anti-PD-1/PD-L1 treatment,so it is necessary to seek an alternative strategy for traditional PD-1/PD-L1 targeting immunotherapy.Here with the data from The Cancer Genome Atlas(TCGA)and our in-house tissue library,PD-L1 expression was found to be positively correlated with the expression of ubiquitin-specific processing protease 7(USP7)in GC.Furthermore,USP7 directly interacted with PD-L1 in order to stabilize it,Gastric cancer;Immunosuppression;Cancer biologywhile abrogation of USP7 attenuated PD-L1/PD-1 interaction and sensitized cancer cells to T cell killing in vitro and in vivo.Besides,USP7 inhibitor suppressed GC cells proliferation by stabilizing P53 in vitro and in vivo.Collectively,our findings indicate that in addition to inhibiting cancer cells proliferation,USP7 inhibitor can also downregulate PD-L1 expression to enhance anti-tumor immune response simultaneously.Hence,these data posit USP7 inhibitor as an anti-proliferation agent as well as a novel therapeutic agent in PD-L1/PD-1 blockade strategy that can promote the immune response of the tumor.
文摘Novel biologics that redirect cytotoxic T lymphocytes (CTLs) to kill tumor cells bearing a tumor associated antigen hold great promise in the clinic. However, the ability to safely and potently target CD3 on CTL toward tumor associated antigens (TAA) expressed on tumor cells remains a challenge of both technology and biol- ogy. Herein we describe the use of a Half DVD-Ig format that can redirect CTL to kill tumor cells. Notably, Half DVD-Ig molecules that are monovalent for each speci- ficity demonstrated reduced non-specific CTL activation and conditional CTL activation upon binding to TAA compared to intact tetravalent DVD-Ig molecules that are bivalent for each specificity, while maintaining good drug like properties and appropriate PK properties.
文摘Acquired resistance to chemotherapy is a major limitation in clinical treatment for breast cancer.Accumulating evidence from in vitro,in vivo and clinical studies suggest that acquired chemoresistance is progressive,multifactorial and involve genetic and epigenetic aberrations.Among various mechanisms that contribute to chemoresistance,cellular reprogramming has extensively been implicated in breast cancer resistance lately.Cellular reprogramming events such as acquisition of epithelial to mesenchymal transition(EMT)and cancer stemness(CSCs)not only provide cancer cells with reversible phenotypic plasticity and survival advantage against cytotoxicity but also leads to aggressiveness,metastasis,clinical resistance,tumor recurrence and poor survival.The transient and reversible nature of cellular reprogramming processes and their controlled interaction with epigenetic regulatory complexes strongly support the involvement of dynamic epigenetic regulatory network in governing the cellular reprogramming and associated acquired chemoresistance.Further,epigenetic modulations are also gaining interest as promising interventions addressing the cancer cell reprogramming machinery to overcome acquired chemoresistance.This review discusses the previous reports and our recent findings that lead to current understanding of epigenetic dysregulation dictating the cellular reprogramming processes such as acquisition of EMT and CSCs phenotype and how they co-ordinate to establish acquired drug resistance in breast cancer.
基金support from the Natural Science Foundation of Henan Province(grant no.212300410152)the Key Scientific and Technological Project of Henan Province(grant no.212102110439)+1 种基金Henan University of Animal Husbandry and Economy(grant no.2019HNUAHEDF011 and XKYCXJJ2020006)the Key Scientific Research Project for Colleges and Universities of Henan Province(grant no.22B150005)。
文摘A novel and efficient[3+2]annulation of 2-substituted aziridines and N-tosyl cyanamides via a dominoregioselective ring-opening/5-exo-dig cyclization procedure has been developed,allowing the directpreparation of N_(2)-unprotected five-membered cyclic guanidines in good to excellent yields under mildconditions without metals and strong bases.Moreover,the highly biologically interesting urea analoguescould also be conveniently obtained via hydrolysis of the produced guanidines.