HIV- 1 RT is an important target for the treatment of AIDS. There are two major classes of antiviral agents that inhibit HIV- 1 RT have been identified, nucleoside RT inhibitors （NRTIs） and non-nucleoside RT inhibit...HIV- 1 RT is an important target for the treatment of AIDS. There are two major classes of antiviral agents that inhibit HIV- 1 RT have been identified, nucleoside RT inhibitors （NRTIs） and non-nucleoside RT inhibitors （NNRTIs）. In this report, a noval class of non-nucleoside compound with potential RT inhibitory activity were found from the traditional Chinese medicines database （TCMD） using a combination of virtual screening, docking, molecular dynamic simulations, where results were ranked by scoring function of the docking tool. The result indicates that M4753 （a compound derived from TCMD） has not only the lowest bonding energy but also the best match in geometric conformation with the forthcoming NNRTIs. Accordingly M4753 might possibly become a promising lead compound of NNRTIs for AIDS therapy.展开更多
Vascular calcification(VC)is a critical vascular pathological event,contributing to the rise in both the prevalence and fatality of cardiovascular diseases.However,the lack of effective therapeutic strategies for VC i...Vascular calcification(VC)is a critical vascular pathological event,contributing to the rise in both the prevalence and fatality of cardiovascular diseases.However,the lack of effective therapeutic strategies for VC is attributed primarily to the incomplete understanding of its underlying molecular mechanisms.In this study,we discovered that long interspersed nuclear element 1(LINE1)was significantly upregulated in the calcified arteries of both human individuals and mouse models.Mechanistically,silencing LINE1 expression or inhibiting its activity with adding nucleoside reverse transcriptase inhibitors(NRTIs,a class of validated LINE1 inhibitors)effectively prevented the osteogenic reprogramming of vascular smooth muscle cells(VSMCs).Moreover,NRTIs treatment substantially mitigated VC in chronic kidney disease(CKD)-induced and vitamin D3-overloaded VC mouse models.RNA sequencing analysis revealed that LINE1 depletion(via small interfering RNA)or NRTIs intervention downregulated the cGAS-STING signaling pathway and its associated inflammatory genes in VSMCs.Functional validation revealed that stimulation of the cGAS-STING pathway exacerbated VC,whereas its pharmacological inhibition alleviated VC.Notably,we identified LINE1-derived cDNA as a direct activator of the cGAS-STING pathway,demonstrating that LINE1 inhibition suppresses VC by blocking cGAS-STING activation and subsequent inflammatory responses.Clinically,a cross-sectional study involving 1,785 participants revealed that patients receiving NRTIs therapy presented a significantly lower incidence of VC and reduced calcification scores.Multivariate logistic regression analysis further confirmed that NRTIs use is an independent protective factor against VC incidence and progression.Collectively,these findings establish LINE1 as promising therapeutic targets for VC and highlight NRTIs as potential candidates for developing novel strategies against VC.展开更多
Background Liver injury is one of the most important adverse effects of antiretroviral therapy, leading to therapy changing or discontinuation. Data on liver injury in human immunodeficiency virus-1-infected patients ...Background Liver injury is one of the most important adverse effects of antiretroviral therapy, leading to therapy changing or discontinuation. Data on liver injury in human immunodeficiency virus-1-infected patients receiving antiretroviral therapy are limited in China. The purpose of this study was to investigate the features of liver injury in human immunodeficiency virus type 1-infected patients receiving non-nucleosides reverse transcriptase inhibitors-based antiretroviral therapy in China.Methods Seventy-five patients on antiretroviral therapy containing non-nucleosides reverse transcriptase inhibitors were retrospectively studied. The patients were divided into 2 groups： group 1 （with liver injury, n=45） and group 2（without liver injury, n=30）. The features of liver injury were analyzed. The sex, age, baseline CD4 counts, hepatitis B virus （HBV） and/or hepatitis C virus （HCV） co-infection, hepatotoxic drug use and nevirapine or efavirenz use were compared between two groups.Results Forty-five patients （60.0%）, 31 （68.9%） males and 14 （31.1%） females, aged 12 to 52 years （averaged （3g±9）years）, experienced at least one episode of liver injury. Forty （53.3%） patients were co-infected with HBV and/or HCV, 42 （56%） patients had concomitant use of antituberculosis drugs or cotrimoxazole, 46 （61.3%） and 29 （38.7%） patients received regimen containing nevirapine and efavirenz, respectively. Grade 1 liver injuries were observed in 26 （57.8%）patients, grade 2 in 16 （35.6%）, grade 3 in 2 （4.0%） and grade 4 in 1 （2.2%）. Three （6.7%） patients discontinued highly active antiretroviral therapy （HAART） due to liver injury. In group 1, there were 29 （64.4%） patients co-infected with HBV and/or HCV, 32 （71.1%） patients received regimen containing nevirapine, and 30 （66.7%） patients had concomitant use of anti-tuberculosis drugs or cotrimoxazole, respectively, significantly higher than those in group 2 （11 （36.7%）, 14 （46.7%）and 12 （40%）, respectively; P=0.018, 0.033, 0.023, respectively）. The sex, age, baseline CD4 counts and disease stage were not factors associated with liver injury.Conclusions Liver injury associated with HAART containing non-nucleosides reverse transcriptase inhibitors was mild to moderate and those who were co-infected with HBV and/or HCV, had concomitant use of antituberculosis drugs or cotrimoxazole and received a regimen containing nevirapine were prone to liver injury while receiving HAART.展开更多
目的:建立容量滴定法测定去羟肌苷的含量。方法:采用非水溶液滴定法,以冰醋酸-醋酐混合溶液(4∶1)为滴定介质,电位滴定指示终点,每次加液体积为0.05 m L,等当点突跃幅度EPC设定为30,进行含量测定,并对分析方法进行验证,具体阐述了容量...目的:建立容量滴定法测定去羟肌苷的含量。方法:采用非水溶液滴定法,以冰醋酸-醋酐混合溶液(4∶1)为滴定介质,电位滴定指示终点,每次加液体积为0.05 m L,等当点突跃幅度EPC设定为30,进行含量测定,并对分析方法进行验证,具体阐述了容量滴定法的方法验证过程和验证结果的认可标准。结果:去羟肌苷测定的成比例系统误差、额外系统误差及精密度均符合规范要求。结论:本法经方法学验证,可用于去羟肌苷原料的含量测定。展开更多
基金supported by the grants from Chinese National Science Foundation(No.30472166)the Tianjin Commission of Sciences and Technology under the Contract(No.06YFGZSH07000)
文摘HIV- 1 RT is an important target for the treatment of AIDS. There are two major classes of antiviral agents that inhibit HIV- 1 RT have been identified, nucleoside RT inhibitors （NRTIs） and non-nucleoside RT inhibitors （NNRTIs）. In this report, a noval class of non-nucleoside compound with potential RT inhibitory activity were found from the traditional Chinese medicines database （TCMD） using a combination of virtual screening, docking, molecular dynamic simulations, where results were ranked by scoring function of the docking tool. The result indicates that M4753 （a compound derived from TCMD） has not only the lowest bonding energy but also the best match in geometric conformation with the forthcoming NNRTIs. Accordingly M4753 might possibly become a promising lead compound of NNRTIs for AIDS therapy.
基金funded by various organizations,including Shenzhen Science and Technology Program(ZDSYS20220606100801004,KCXFZ20211020163801002,SGDX20230116092459009,JCYJ20220530144417039,JCYJ20230807110913027)Shenzhen Medical Research Fund(B2302020)+7 种基金National Natural Science Foundation of China(nos.82330021,82270771,82204384,82473913)Shenzhen Key Medical Discipline Construction Fund(SZXK002)Futian District Public Health Scientific Research Project of Shenzhen(FTWS2022001,FTWS2022025)Chinese Association of Integrative Medicine-Shanghai Hutchison Pharmaceuticals Fund(HMPE202202)China Heart House-Chinese Cardiovascular Association HX Fund(2022-CCA-HX090)RGC General Research Fund(T12-101/23-N)startup funds from the City University of Hong Kong(no.9380154)TBSC Project Fund,and Futian Research Project 9609327.
文摘Vascular calcification(VC)is a critical vascular pathological event,contributing to the rise in both the prevalence and fatality of cardiovascular diseases.However,the lack of effective therapeutic strategies for VC is attributed primarily to the incomplete understanding of its underlying molecular mechanisms.In this study,we discovered that long interspersed nuclear element 1(LINE1)was significantly upregulated in the calcified arteries of both human individuals and mouse models.Mechanistically,silencing LINE1 expression or inhibiting its activity with adding nucleoside reverse transcriptase inhibitors(NRTIs,a class of validated LINE1 inhibitors)effectively prevented the osteogenic reprogramming of vascular smooth muscle cells(VSMCs).Moreover,NRTIs treatment substantially mitigated VC in chronic kidney disease(CKD)-induced and vitamin D3-overloaded VC mouse models.RNA sequencing analysis revealed that LINE1 depletion(via small interfering RNA)or NRTIs intervention downregulated the cGAS-STING signaling pathway and its associated inflammatory genes in VSMCs.Functional validation revealed that stimulation of the cGAS-STING pathway exacerbated VC,whereas its pharmacological inhibition alleviated VC.Notably,we identified LINE1-derived cDNA as a direct activator of the cGAS-STING pathway,demonstrating that LINE1 inhibition suppresses VC by blocking cGAS-STING activation and subsequent inflammatory responses.Clinically,a cross-sectional study involving 1,785 participants revealed that patients receiving NRTIs therapy presented a significantly lower incidence of VC and reduced calcification scores.Multivariate logistic regression analysis further confirmed that NRTIs use is an independent protective factor against VC incidence and progression.Collectively,these findings establish LINE1 as promising therapeutic targets for VC and highlight NRTIs as potential candidates for developing novel strategies against VC.
文摘Background Liver injury is one of the most important adverse effects of antiretroviral therapy, leading to therapy changing or discontinuation. Data on liver injury in human immunodeficiency virus-1-infected patients receiving antiretroviral therapy are limited in China. The purpose of this study was to investigate the features of liver injury in human immunodeficiency virus type 1-infected patients receiving non-nucleosides reverse transcriptase inhibitors-based antiretroviral therapy in China.Methods Seventy-five patients on antiretroviral therapy containing non-nucleosides reverse transcriptase inhibitors were retrospectively studied. The patients were divided into 2 groups： group 1 （with liver injury, n=45） and group 2（without liver injury, n=30）. The features of liver injury were analyzed. The sex, age, baseline CD4 counts, hepatitis B virus （HBV） and/or hepatitis C virus （HCV） co-infection, hepatotoxic drug use and nevirapine or efavirenz use were compared between two groups.Results Forty-five patients （60.0%）, 31 （68.9%） males and 14 （31.1%） females, aged 12 to 52 years （averaged （3g±9）years）, experienced at least one episode of liver injury. Forty （53.3%） patients were co-infected with HBV and/or HCV, 42 （56%） patients had concomitant use of antituberculosis drugs or cotrimoxazole, 46 （61.3%） and 29 （38.7%） patients received regimen containing nevirapine and efavirenz, respectively. Grade 1 liver injuries were observed in 26 （57.8%）patients, grade 2 in 16 （35.6%）, grade 3 in 2 （4.0%） and grade 4 in 1 （2.2%）. Three （6.7%） patients discontinued highly active antiretroviral therapy （HAART） due to liver injury. In group 1, there were 29 （64.4%） patients co-infected with HBV and/or HCV, 32 （71.1%） patients received regimen containing nevirapine, and 30 （66.7%） patients had concomitant use of anti-tuberculosis drugs or cotrimoxazole, respectively, significantly higher than those in group 2 （11 （36.7%）, 14 （46.7%）and 12 （40%）, respectively; P=0.018, 0.033, 0.023, respectively）. The sex, age, baseline CD4 counts and disease stage were not factors associated with liver injury.Conclusions Liver injury associated with HAART containing non-nucleosides reverse transcriptase inhibitors was mild to moderate and those who were co-infected with HBV and/or HCV, had concomitant use of antituberculosis drugs or cotrimoxazole and received a regimen containing nevirapine were prone to liver injury while receiving HAART.
文摘目的:建立容量滴定法测定去羟肌苷的含量。方法:采用非水溶液滴定法,以冰醋酸-醋酐混合溶液(4∶1)为滴定介质,电位滴定指示终点,每次加液体积为0.05 m L,等当点突跃幅度EPC设定为30,进行含量测定,并对分析方法进行验证,具体阐述了容量滴定法的方法验证过程和验证结果的认可标准。结果:去羟肌苷测定的成比例系统误差、额外系统误差及精密度均符合规范要求。结论:本法经方法学验证,可用于去羟肌苷原料的含量测定。
