Neutrophils are major innate immune effector cells for host defense and have been a topic of active research for their participation in the pathogenesis of autoimmune inflammatory diseases including rheumatoid arthrit...Neutrophils are major innate immune effector cells for host defense and have been a topic of active research for their participation in the pathogenesis of autoimmune inflammatory diseases including rheumatoid arthritis(RA)due to recently discovered neutrophil extracellular trap(NET) formation. NET formation and other mechanisms leading to the release of neutrophil nuclear and cytoplasmic contents are implicated as a source of citrullinated antigens in RA. Further investigations are required to delineate what factors diverge neutrophils from host defense to autoimmune response in RA.展开更多
Medical futility has been proposed for many years to define the procedure that simply prolongs the suffering of patients but heals nothing[1].To deal with the decision procedure for treatment,two ideas arise:patients...Medical futility has been proposed for many years to define the procedure that simply prolongs the suffering of patients but heals nothing[1].To deal with the decision procedure for treatment,two ideas arise:patients’autonomy and doctors’authority.Widely recognized in 1960s,patients’autonomy respected patients’willingness over treatment,requiring specific consent for treatment and right to choose during medical procedure.Another idea for futility is doctors’authority,explained from the paternalistic perspective as well[2].Modern medicine,which is based on展开更多
One definition of futility is any treatment that merely preserves permanent unconsciousness or fails to end total dependence of a patient on intensive medical care^([1]).However,no agreement has ever been reached on w...One definition of futility is any treatment that merely preserves permanent unconsciousness or fails to end total dependence of a patient on intensive medical care^([1]).However,no agreement has ever been reached on what the exact definition of futility is,as it is not only based on temporary values but also evolves into different subtypes,making it harder to define.The difficulty in dealing with futility problem is how doctors evaluate the futile situation,which is further complicated by lack of stan-展开更多
The proteolysis targeting chimeras(PROTACs)technology has been rapidly developed since its birth in 2001,attracting rapidly growing attention of scientific institutes and pharmaceutical companies.At present,a variety ...The proteolysis targeting chimeras(PROTACs)technology has been rapidly developed since its birth in 2001,attracting rapidly growing attention of scientific institutes and pharmaceutical companies.At present,a variety of small molecule PROTACs have entered the clinical trial.However,as small molecule PROTACs flourish,non-small molecule PROTACs(NSM-PROTACs)such as peptide PROTACs,nucleic acid PROTACs and antibody PROTACs have also advanced considerably over recent years,exhibiting the unique characters beyond the small molecule PROTACs.Here,we briefly introduce the types of NSM-PROTACs,describe the advantages of NSM-PROTACs,and summarize the development of NSM-PROTACs so far in detail.We hope this article could not only provide useful insights into NSM-PROTACs,but also expand the research interest of NSM-PROTACs.展开更多
Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level,which acts as an orientation to develop drugs with new mechanisms.The molecular chaperones exert signi...Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level,which acts as an orientation to develop drugs with new mechanisms.The molecular chaperones exert significant biological functions on modulation of protein fate decision and protein homeostasis under constantly changing environmental conditions through extensive protein-protein interactions(PPIs)with their client proteins.With the help of molecular chaperone machinery the processes of protein folding,trafficking,quality control and degradation of client proteins could be arranged properly.The core members of molecular chaperones,including heat shock proteins(HSPs)family and their co-chaperones,are emerging as potential drug targets since they are involved in numerous disease conditions.Development of small molecule modulators targeting not only chaperones themselves but also the PPIs among chaperones,co-chaperones and clients is attracting more and more attention.These modulators are widely used as chemical tools to study chaperone networks as well as potential drug candidates for a broader set of diseases.Here,we reviewed the key checkpoints of molecular chaperone machinery HSPs as well as their co-chaperones to discuss the small molecules targeting on them for modulation of protein fate decision.展开更多
基金supported by Rheumatology Research Foundation Innovative and Pilot grants and VA Merit Review grant(BX002858).
文摘Neutrophils are major innate immune effector cells for host defense and have been a topic of active research for their participation in the pathogenesis of autoimmune inflammatory diseases including rheumatoid arthritis(RA)due to recently discovered neutrophil extracellular trap(NET) formation. NET formation and other mechanisms leading to the release of neutrophil nuclear and cytoplasmic contents are implicated as a source of citrullinated antigens in RA. Further investigations are required to delineate what factors diverge neutrophils from host defense to autoimmune response in RA.
文摘Medical futility has been proposed for many years to define the procedure that simply prolongs the suffering of patients but heals nothing[1].To deal with the decision procedure for treatment,two ideas arise:patients’autonomy and doctors’authority.Widely recognized in 1960s,patients’autonomy respected patients’willingness over treatment,requiring specific consent for treatment and right to choose during medical procedure.Another idea for futility is doctors’authority,explained from the paternalistic perspective as well[2].Modern medicine,which is based on
文摘One definition of futility is any treatment that merely preserves permanent unconsciousness or fails to end total dependence of a patient on intensive medical care^([1]).However,no agreement has ever been reached on what the exact definition of futility is,as it is not only based on temporary values but also evolves into different subtypes,making it harder to define.The difficulty in dealing with futility problem is how doctors evaluate the futile situation,which is further complicated by lack of stan-
基金supported by Projects 81773581,82173680 and 81930100 of the National Natural Science Foundation of Chinathe Priority Academic Program Development of Jiangsu Higher Education Institutions,CPU2018GY02 of Double First Class Innovation Team of China Pharmaceutical University+2 种基金the Project Program of State Key Laboratory of Natural Medicines,China Pharmaceutical University(No.SKLNMZZ202003)the“Qing Lan”Project of Jiangsu Provincethe Young Elite Scientists Sponsorship Program by CAST(No.YESS20180146,China)。
文摘The proteolysis targeting chimeras(PROTACs)technology has been rapidly developed since its birth in 2001,attracting rapidly growing attention of scientific institutes and pharmaceutical companies.At present,a variety of small molecule PROTACs have entered the clinical trial.However,as small molecule PROTACs flourish,non-small molecule PROTACs(NSM-PROTACs)such as peptide PROTACs,nucleic acid PROTACs and antibody PROTACs have also advanced considerably over recent years,exhibiting the unique characters beyond the small molecule PROTACs.Here,we briefly introduce the types of NSM-PROTACs,describe the advantages of NSM-PROTACs,and summarize the development of NSM-PROTACs so far in detail.We hope this article could not only provide useful insights into NSM-PROTACs,but also expand the research interest of NSM-PROTACs.
基金the financial support by National Natural Science Foundation of China(81773639,81773581,81872737 and 81930100)the Natural Science Foundation of Jiangsu Province(BK20190559,BK20160746 China)+6 种基金National Science&Technology Major Project‘Key New Drug Creation and Manufacturing Program’(Nos.2018ZX09711002 and 2017ZX09302003,China)the Priority Academic Program Development of Jiangsu Higher Education Institutionsthe Fundamental Research Funds for the Central Universities of China Pharmaceutical University(2632018ZD15,China)the Double First Class Innovation Team of China Pharmaceutical University(CPU2018GY02,China)Program for Outstanding Scientific and Technological Innovation Team of Jiangsu Higher Educationthe Young Elite Scientists Sponsorship Program by CASTthe Jiangsu Qing Lan Project
文摘Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level,which acts as an orientation to develop drugs with new mechanisms.The molecular chaperones exert significant biological functions on modulation of protein fate decision and protein homeostasis under constantly changing environmental conditions through extensive protein-protein interactions(PPIs)with their client proteins.With the help of molecular chaperone machinery the processes of protein folding,trafficking,quality control and degradation of client proteins could be arranged properly.The core members of molecular chaperones,including heat shock proteins(HSPs)family and their co-chaperones,are emerging as potential drug targets since they are involved in numerous disease conditions.Development of small molecule modulators targeting not only chaperones themselves but also the PPIs among chaperones,co-chaperones and clients is attracting more and more attention.These modulators are widely used as chemical tools to study chaperone networks as well as potential drug candidates for a broader set of diseases.Here,we reviewed the key checkpoints of molecular chaperone machinery HSPs as well as their co-chaperones to discuss the small molecules targeting on them for modulation of protein fate decision.
