The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle.The covalent M^(pro)inhibitor nirmatrelvir(in combination with ...The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle.The covalent M^(pro)inhibitor nirmatrelvir(in combination with ritonavir,a pharmacokinetic enhancer)and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use.Effective antiviral drugs are needed to fight the pandemic,while non-covalent M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable druggability.Numerous non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)inhibitors,followed by a general overview and critical analysis of the available information.Prospective viewpoints and insights into current strategies for the development of non-covalent M^(pro)inhibitors are also discussed.展开更多
Acute kidney injury(AKI)is a serious clinical complication with high morbidity and mortality rates.Despite substantial progress in understanding the mechanism of AKI,no effective therapy is available for treatment or ...Acute kidney injury(AKI)is a serious clinical complication with high morbidity and mortality rates.Despite substantial progress in understanding the mechanism of AKI,no effective therapy is available for treatment or prevention.We previously found that G protein-coupled receptor(GPCR)family member free fatty acid receptor 4(FFAR4)agonist TUG891 alleviated kidney dysfunction and tubular injury in AKI mice.However,the versatile role of FFAR4 in kidney has not been well characterized.In the study,the expression of FFAR4 was abnormally decreased in tubular epithelial cells(TECs)of cisplatin,cecal ligation/perforation and ischemia/reperfusion injury-induced AKI mice,respectively.Systemic and conditional TEC-specific knockout of FFAR4 aggravated renal function and pathological damage,whereas FFAR4 activation by TUG-891 alleviated the severity of disease in cisplatin-induced AKI mice.Notably,FFAR4,as a key determinant,was firstly explored to regulate cellular senescence both in injured kidneys of AKI mice and TECs,which was indicated by senescence-associatedβ-galactosidase(SA-β-gal)activity,marker protein p53,p21,Lamin B1,phospho-histone H2A.X,phospho-Rb expression,and secretory phenotype IL-6 level.Mechanistically,pharmacological activation and overexpression of FFAR4 reversed the decrease of aging-related SirT3 protein,where FFAR4 regulated SirT3 expression to exhibit anti-senescent effect via Gq subunit-mediated CaMKKβ/AMPK signaling in cisplatin-induced mice and TECs.These findings highlight the original role of tubular FFAR4 in cellular senescence via AMPK/SirT3 signaling and identify FFAR4 as a potential drug target against AKI.展开更多
During the chemotherapy of tumors,the cytotoxic effect of drugs is vital to kill tumor cells,and the delivery of a chemotherapeutic agent is of great importance for optimal therapeutic effects.The high in vivo clearan...During the chemotherapy of tumors,the cytotoxic effect of drugs is vital to kill tumor cells,and the delivery of a chemotherapeutic agent is of great importance for optimal therapeutic effects.The high in vivo clearance rate and low delivery efficiency of conventional chemotherapeutic agents affect the therapeutic effect.In recent years,the responsive drug delivery nanosystem has received increasing concern owing to its excellent biocompatibility,stable delivery performance,and controlled drug release strategies.To lucidly explain the cytocidal and immunotherapeutic effects of such responsive nanosystems in breast cancer,this review discusses the various stimuli and responses of drug-loaded liposomal nanosystems.The light/magnetic response of drug-loaded bionic membranes nanosystems and the heat/magnetic response of drug-loaded iron oxide nanosystems are also elaborated.Their cancer cell-killing efficacy and antitumor immunotherapeutic effects are also scrutinized.展开更多
Artificial intelligent aided design and manufacturing have been recognized as one kind of robust data-driven and data-intensive technologies in the integrated computational material engi-neering(ICME)era.Motivated by ...Artificial intelligent aided design and manufacturing have been recognized as one kind of robust data-driven and data-intensive technologies in the integrated computational material engi-neering(ICME)era.Motivated by the dramatical developments of the services of China Railway High-speed series for more than a decade,it is essential to reveal the foundations of lifecycle man-agement of those trains under environmental conditions.Here,the smart design and manufacturing of welded Q350 steel frames of CR200J series are introduced,presenting the capability and opportu-nity of ICME in weight reduction and lifecycle management at a cost-effective approach.In order to address the required fatigue life time enduring more than 9×10^(6)km,the response of optimized frames to the static and the dynamic loads are comprehensively investigated.It is highlighted that the maximum residual stress of the optimized welded frame is reduced to 69 MPa from 477 MPa of previous existing one.Based on the measured stress and acceleration from the railways,the fatigue life of modified frame under various loading modes could fulfil the requirements of the lifecycle man-agement.Moreover,our recent developed intelligent quality control strategy of welding process mediated by machine learning is also introduced,envisioning its application in the intelligent weld-ing.展开更多
目的探讨影响肝移植术后早期二次气管插管生存率的危险因素,为提高患者生存率提供实践经验和理论依据。方法回顾性分析2005年1月—2012年12月在武警总医院实施原位肝移植治疗并于术后早期接受二次气管插管患者的病例资料,统计术后3个月...目的探讨影响肝移植术后早期二次气管插管生存率的危险因素,为提高患者生存率提供实践经验和理论依据。方法回顾性分析2005年1月—2012年12月在武警总医院实施原位肝移植治疗并于术后早期接受二次气管插管患者的病例资料,统计术后3个月内患者生存情况,按照术后3个月时的生存情况分为生存组和死亡组。比较两组患者术前、术中及供肝等重要参数情况,将生存率作为因变量,对纳入的变量先后进行单因素和多因素回归分析,筛选出对生存率有显著影响的自变量。结果本组55例二次插管患者术后3个月时生存率为30.9%(17/55)。死亡组术前终末期肝病模型(model for end stage liver disease,MELD)评分(U=52.00,P <0.001)、国际标准化比值(U=167.50,P <0.001)、血清总胆红素值(U=191.00,P=0.016)、肺部感染合并症发生率(χ~2=5.30,P=0.001)及腹水合并症发生率(χ~2=5.33, P=0.001)均显著高于生存组。年龄、术前血肌酐水平、门静脉血栓发生率、胸水发生率、肝移植手术时长和无肝期时长、术中出血量和输血量、供肝热缺血时间和冷缺血时间等在两组间均无统计学差异。回归分析结果显示肺部感染合并症与MELD评分(OR=6.157,P=0.042;OR=1.312,P <0.001)是影响二次插管生存率的独立危险因素。结论对于肝移植受者,术前MELD评分及肺部感染合并症是影响术后早期二次气管插管生存率的独立危险因素。术前积极控制肺部感染并努力降低MELD评分有助于提高生存率。展开更多
基金We gratefully acknowledge financial support from Major Basic Research Project of Shandong Provincial Natural Science Foundation(ZR2021ZD17,China)Science Foundation for Outstanding Young Scholars of Shandong Province(ZR2020JQ31,China)+4 种基金Foreign Cultural and Educational Experts Project(GXL20200015001,China)Guangdong Basic and Applied Basic Research Foundation(2021A1515110740,China)China Postdoctoral Science Foundation(2021M702003)This work was supported in part by the Ministry of Science and Innovation of Spain through grant PID2019-104176RBI00/AEI/10.13039/501100011033 awarded to Luis Menéndez-AriasAn institutional grant of the Fundación Ramón Areces(Madrid,Spain)to the CBMSO is also acknowledged.Luis Menéndez-Arias is member of the Global Virus Network.
文摘The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle.The covalent M^(pro)inhibitor nirmatrelvir(in combination with ritonavir,a pharmacokinetic enhancer)and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use.Effective antiviral drugs are needed to fight the pandemic,while non-covalent M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable druggability.Numerous non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)inhibitors,followed by a general overview and critical analysis of the available information.Prospective viewpoints and insights into current strategies for the development of non-covalent M^(pro)inhibitors are also discussed.
基金National Key R&D Program of China(2020YFC2005000)Science/Technology Project of Sichuan province(2020YFQ0055,2021YFQ0027)+1 种基金1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University(ZYGD18027)The schematic illustration was designed by Figdraw.
文摘Acute kidney injury(AKI)is a serious clinical complication with high morbidity and mortality rates.Despite substantial progress in understanding the mechanism of AKI,no effective therapy is available for treatment or prevention.We previously found that G protein-coupled receptor(GPCR)family member free fatty acid receptor 4(FFAR4)agonist TUG891 alleviated kidney dysfunction and tubular injury in AKI mice.However,the versatile role of FFAR4 in kidney has not been well characterized.In the study,the expression of FFAR4 was abnormally decreased in tubular epithelial cells(TECs)of cisplatin,cecal ligation/perforation and ischemia/reperfusion injury-induced AKI mice,respectively.Systemic and conditional TEC-specific knockout of FFAR4 aggravated renal function and pathological damage,whereas FFAR4 activation by TUG-891 alleviated the severity of disease in cisplatin-induced AKI mice.Notably,FFAR4,as a key determinant,was firstly explored to regulate cellular senescence both in injured kidneys of AKI mice and TECs,which was indicated by senescence-associatedβ-galactosidase(SA-β-gal)activity,marker protein p53,p21,Lamin B1,phospho-histone H2A.X,phospho-Rb expression,and secretory phenotype IL-6 level.Mechanistically,pharmacological activation and overexpression of FFAR4 reversed the decrease of aging-related SirT3 protein,where FFAR4 regulated SirT3 expression to exhibit anti-senescent effect via Gq subunit-mediated CaMKKβ/AMPK signaling in cisplatin-induced mice and TECs.These findings highlight the original role of tubular FFAR4 in cellular senescence via AMPK/SirT3 signaling and identify FFAR4 as a potential drug target against AKI.
基金funded by the Basic Scientific Research Funds of Department of Education of Zhejiang Province(KYQN202103 and KYZD202103)A Project Supported by Scientific Research Fund of Zhejiang Provincial Education Department(Y202249203)+4 种基金General Program of the National Natural Science Foundation of China(61976075 to XX)the Key Research and Development Program of Zhejiang Province(2019C03002 to XX)National Innovation and Entrepreneurship Training Program for College Students(202213023011)Innovation and Entrepreneurship Training Program for College Students of Zhejiang Province(S202213023052)Zhejiang Provincial Natural Science Foundation of China under Grant No.LTGY23H180019.
文摘During the chemotherapy of tumors,the cytotoxic effect of drugs is vital to kill tumor cells,and the delivery of a chemotherapeutic agent is of great importance for optimal therapeutic effects.The high in vivo clearance rate and low delivery efficiency of conventional chemotherapeutic agents affect the therapeutic effect.In recent years,the responsive drug delivery nanosystem has received increasing concern owing to its excellent biocompatibility,stable delivery performance,and controlled drug release strategies.To lucidly explain the cytocidal and immunotherapeutic effects of such responsive nanosystems in breast cancer,this review discusses the various stimuli and responses of drug-loaded liposomal nanosystems.The light/magnetic response of drug-loaded bionic membranes nanosystems and the heat/magnetic response of drug-loaded iron oxide nanosystems are also elaborated.Their cancer cell-killing efficacy and antitumor immunotherapeutic effects are also scrutinized.
基金supported by the National Basic Scientific Research Project of China (No.JCKY2020607B003)CRRC (No.202CDA001)
文摘Artificial intelligent aided design and manufacturing have been recognized as one kind of robust data-driven and data-intensive technologies in the integrated computational material engi-neering(ICME)era.Motivated by the dramatical developments of the services of China Railway High-speed series for more than a decade,it is essential to reveal the foundations of lifecycle man-agement of those trains under environmental conditions.Here,the smart design and manufacturing of welded Q350 steel frames of CR200J series are introduced,presenting the capability and opportu-nity of ICME in weight reduction and lifecycle management at a cost-effective approach.In order to address the required fatigue life time enduring more than 9×10^(6)km,the response of optimized frames to the static and the dynamic loads are comprehensively investigated.It is highlighted that the maximum residual stress of the optimized welded frame is reduced to 69 MPa from 477 MPa of previous existing one.Based on the measured stress and acceleration from the railways,the fatigue life of modified frame under various loading modes could fulfil the requirements of the lifecycle man-agement.Moreover,our recent developed intelligent quality control strategy of welding process mediated by machine learning is also introduced,envisioning its application in the intelligent weld-ing.
文摘目的探讨影响肝移植术后早期二次气管插管生存率的危险因素,为提高患者生存率提供实践经验和理论依据。方法回顾性分析2005年1月—2012年12月在武警总医院实施原位肝移植治疗并于术后早期接受二次气管插管患者的病例资料,统计术后3个月内患者生存情况,按照术后3个月时的生存情况分为生存组和死亡组。比较两组患者术前、术中及供肝等重要参数情况,将生存率作为因变量,对纳入的变量先后进行单因素和多因素回归分析,筛选出对生存率有显著影响的自变量。结果本组55例二次插管患者术后3个月时生存率为30.9%(17/55)。死亡组术前终末期肝病模型(model for end stage liver disease,MELD)评分(U=52.00,P <0.001)、国际标准化比值(U=167.50,P <0.001)、血清总胆红素值(U=191.00,P=0.016)、肺部感染合并症发生率(χ~2=5.30,P=0.001)及腹水合并症发生率(χ~2=5.33, P=0.001)均显著高于生存组。年龄、术前血肌酐水平、门静脉血栓发生率、胸水发生率、肝移植手术时长和无肝期时长、术中出血量和输血量、供肝热缺血时间和冷缺血时间等在两组间均无统计学差异。回归分析结果显示肺部感染合并症与MELD评分(OR=6.157,P=0.042;OR=1.312,P <0.001)是影响二次插管生存率的独立危险因素。结论对于肝移植受者,术前MELD评分及肺部感染合并症是影响术后早期二次气管插管生存率的独立危险因素。术前积极控制肺部感染并努力降低MELD评分有助于提高生存率。
