Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although th...Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing prote展开更多
Nonalcoholic fatty liver disease(NAFLD)has emerged as a common public health problem in recent decades.However,the underlying mechanisms leading to the development of NAFLD are not fully understood.The endoplasmic ret...Nonalcoholic fatty liver disease(NAFLD)has emerged as a common public health problem in recent decades.However,the underlying mechanisms leading to the development of NAFLD are not fully understood.The endoplasmic reticulum(ER)stress response has recently been proposed to play a crucial role in both the development of steatosis and progression to nonalcoholic steatohepatitis.ER stress is activated to regulate protein synthesis and restore homeostatic equilibrium when the cell is stressed due to the accumulation of unfolded or misfolded proteins.However,delayed or insufficient responses to ER stress may turn physiological mechanisms into pathological consequences,including fat accumulation,insulin resistance,inflammation,and apoptosis,all of which play important roles in the pathogenesis of NAFLD.Therefore,understanding the role of ER stress in the pathogenesis of NAFLD has become a topic of intense investigation.This review highlights the recent findings linking ER stress signaling pathways to the pathogenesis of NAFLD.展开更多
Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as ...Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as regulation of cell cycle progression, division, development and differentiation, apoptosis, cell trafficking, and modulation of the immune and inflammatory responses. The central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, an adenosine triphosphate-dependent, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process. Aberration of this system leads to the dysregulation of cellular homeostasis and the development of multiple diseases. In this review, we described the basic biochemistry and molecular biology of the ubiquitin-proteasome system, and its complex role in the development of inflammatory and autoimmune diseases. In addition, therapies and potential therapeutic targets related to the ubiquitin-proteasome system are discussed as well.展开更多
Background:The 2019 novel coronavirus has caused the outbreak of the acute respiratory disease in Wuhan,Hubei Province of China since December 2019.This study was performed to analyze the clinical characteristics of p...Background:The 2019 novel coronavirus has caused the outbreak of the acute respiratory disease in Wuhan,Hubei Province of China since December 2019.This study was performed to analyze the clinical characteristics of patients who succumbed to and who recovered from 2019 novel coronavirus disease(COVID-19).Methods:Clinical data were collected from two tertiary hospitals in Wuhan.A retrospective investigation was conducted to analyze the clinical characteristics of fatal cases of COVID-19(death group)and we compare them with recovered patients(recovered group).Continuous variables were analyzed using the Mann-WhitneyU test.Categorical variables were analyzed byχ2 test or Fisher exact test as appropriate.Results:Our study enrolled 109 COVID-19 patients who died during hospitalization and 116 recovered patients.The median age of the death group was older than the recovered group(69[62,74]vs.40[33,57]years,Z=9.738,P<0.001).More patients in the death group had underlying diseases(72.5%vs.41.4%,χ2=22.105,P<0.001).Patients in the death group had a significantly longer time of illness onset to hospitalization(10.0[6.5,12.0]vs.7.0[5.0,10.0]days,Z=3.216,P=0.001).On admission,the proportions of patients with symptoms of dyspnea(70.6%vs.19.0%,χ2=60.905,P<0.001)and expectoration(32.1%vs.12.1%,χ2=13.250,P<0.001)were significantly higher in the death group.The blood oxygen saturation was significantly lower in the death group(85[77,91]%vs.97[95,98]%,Z=10.625,P<0.001).The white blood cell(WBC)in death group was significantly higher on admission(7.23[4.87,11.17]vs.4.52[3.62,5.88]×109/L,Z=7.618,P<0.001).Patients in the death group exhibited significantly lower lymphocyte count(0.63[0.40,0.79]vs.1.00[0.72,1.27]×109/L,Z=8.037,P<0.001)and lymphocyte percentage(7.10[4.45,12.73]%vs.23.50[15.27,31.25]%,Z=10.315,P<0.001)on admission,and the lymphocyte percentage continued to decrease during hospitalization(7.10[4.45,12.73]%vs.2.91[1.79,6.13]%,Z=5.242,P<0.001).Alanine transaminase(22.00[15.00,34.00]vs.18.70[13.00,30.38]U/L,Z=2.592,P=0展开更多
Gradual degeneration and loss of dopaminergic neurons in the substantia nigra,pars compacta and subsequent reduction of dopamine levels in striatum are associated with motor deficits that characterize Parkinson’s dis...Gradual degeneration and loss of dopaminergic neurons in the substantia nigra,pars compacta and subsequent reduction of dopamine levels in striatum are associated with motor deficits that characterize Parkinson’s disease(PD).In addition,half of the PD patients also exhibit frontostriatal-mediated executive dysfunction,including deficits in attention,short-term working memory,speed of mental processing,and impulsivity.The most commonly used treatments for PD are only partially or transiently effective and are available or applicable to a minority of patients.Because,these therapies neither restore the lost or degenerated dopaminergic neurons,nor prevent or delay the disease progression,the need for more effective therapeutics is critical.In this review,we provide a comprehensive overview of the current understanding of the molecular signaling pathways involved in PD,particularly within the context of how genetic and environmental factors contribute to the initiation and progression of this disease.The involvement of molecular chaperones,autophagy-lysosomal pathways,and proteasome systems in PD are also highlighted.In addition,emerging therapies,including pharmacological manipulations,surgical procedures,stem cell transplantation,gene therapy,as well as complementary,supportive and rehabilitation therapies to prevent or delay the progression of this complex disease are reviewed.展开更多
Objective：To review recent research advances on tau,a major player in Alzheimer＇s disease （AD） pathogenesis,a biomarker for AD onset,and potential target for AD therapy.Data Sources：This review was based on a com...Objective：To review recent research advances on tau,a major player in Alzheimer＇s disease （AD） pathogenesis,a biomarker for AD onset,and potential target for AD therapy.Data Sources：This review was based on a comprehensive search using online literature databases,including PubMed,Web of Science,and Google Scholar.Study Selection：Literature search was based on the following keywords：Alzheimer＇s disease,tau protein,biomarker,cerebrospinal fluid （CSF）,therapeutics,plasma,imaging,propagation,spreading,seeding,prion,conformational templating,and posttranslational modification.Relevant articles were carefully reviewed,with no exclusions applied to study design and publication type.Results：Amyloid plaques enriched with extracellular amyloid beta （Aβ） and intracellular neurofibrillary tangles comprised of hyperphosphorylated tau proteins are the two main pathological hallmarks ofAD.Although the Aβ hypothesis has dominated AD research for many years,clinical Aβ-targeting strategies have consistently failed to effectively treat AD or prevent AD onset.The research focus in AD has recently shifted to the role oftau in AD.In addition to phosphorylation,tau is acetylated and proteolytically cleaved,which also contribute to its physiological and pathological functions.Emerging evidence characterizing pathological tau propagation and spreading provides new avenues for research into the molecular and cellular mechanisms underlying AD pathogenesis.Techniques to detect tau at minute levels in CSF and blood have been developed,and improved tracers have facilitated tau imaging in the brain.These advances have potential to accurately determine tau levels at early diagnostic stages in AD.Given that tau is a potential therapeutic target,anti-tau immunotherapy may potentially be a viable treatment strategy in AD intervention.Conclusion：Detecting changes in tau and targeting tau pathology represent a promising lead in the diagnosis and treatment of AD.展开更多
BACKGROUND： Coagulopathy and its association with disease severity in hyperlipidemia （HL）- and non-hyperlipidemia （NHL）-induced acute pancreatitis （AP） are not dear. The present study was to evaluate the relati...BACKGROUND： Coagulopathy and its association with disease severity in hyperlipidemia （HL）- and non-hyperlipidemia （NHL）-induced acute pancreatitis （AP） are not dear. The present study was to evaluate the relationship between coagulation homeostasis and AP.展开更多
AIM: To determine the overall prevalence of H pylori and CagA positive H pylori infection and the prevalence of other bacterial and viral causes of chronic infection in patients with coronary heart disease (CHD), and ...AIM: To determine the overall prevalence of H pylori and CagA positive H pylori infection and the prevalence of other bacterial and viral causes of chronic infection in patients with coronary heart disease (CHD), and the potential role of anti-heat-shock protein 60 (Hsp60) anti- body response to these proteins in increasing the risk of CHD development. METHODS: Eighty patients with CHD and 160 controls were employed. We also compared the levels of anti- heat-shock protein 60 (Hsp60) antibodies in the two groups. The H pylori infection and the CagA status were determined serologically, using commercially available enzyme-linked immunosorbent assays (ELISA), and a Western blotting method developed in our laboratory. Systemic antibodies to Hsp60 were determined by a sandwich ELISA, using a polyclonal antibody to Hsp60 to sensitise polystyrene plates and a commercially available human Hsp60 as an antigen. RESULTS: The overall prevalence of H pylori infec- tion was 78.7% (n = 63) in patients and 76.2% (n = 122) in controls (P = 0.07). Patients infected by CagA- positive (CagA+) H pylori strains were 71.4% (n = 45) vs 52.4% of infected controls (P = 0.030, OR = 2.27). Sys-temic levels of IgG to Hsp60 were increased in H pylori- negative patients compared with uninfected controls (P < 0.001) and CagA-positive infected patients compared with CagA-positive infected controls (P = 0.007). CONCLUSION: CagA positive H pylori infection may concur to the development of CHD; high levels of anti- Hsp60 antibodies may constitute a marker and/or a con- comitant pathogenic factor of the disease.展开更多
文摘Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing prote
基金Supported by National Key Basic Research Development Program,No.2012CB524905National Science and Technology Support Plan Project,No.2012BAI06B04+4 种基金National Natural Science Foundation of China,No.30900677,No.81070315,No.81070366,No.81100278,No.81170378,No.81230012 and No.81270487Zhejiang Provincial Natural Science Foundation of China,No.Y2090463 and No.Y2110026International Science and Technology Cooperation Projects of Zhejiang Province,No.2013C24010Science Foundation of Health Bureau of Zhejiang Province,No.2009A070 and No.2012RCA026Specialized Research Fund for the Doctoral Program of Higher Education,No.20090101120110
文摘Nonalcoholic fatty liver disease(NAFLD)has emerged as a common public health problem in recent decades.However,the underlying mechanisms leading to the development of NAFLD are not fully understood.The endoplasmic reticulum(ER)stress response has recently been proposed to play a crucial role in both the development of steatosis and progression to nonalcoholic steatohepatitis.ER stress is activated to regulate protein synthesis and restore homeostatic equilibrium when the cell is stressed due to the accumulation of unfolded or misfolded proteins.However,delayed or insufficient responses to ER stress may turn physiological mechanisms into pathological consequences,including fat accumulation,insulin resistance,inflammation,and apoptosis,all of which play important roles in the pathogenesis of NAFLD.Therefore,understanding the role of ER stress in the pathogenesis of NAFLD has become a topic of intense investigation.This review highlights the recent findings linking ER stress signaling pathways to the pathogenesis of NAFLD.
文摘Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as regulation of cell cycle progression, division, development and differentiation, apoptosis, cell trafficking, and modulation of the immune and inflammatory responses. The central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, an adenosine triphosphate-dependent, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process. Aberration of this system leads to the dysregulation of cellular homeostasis and the development of multiple diseases. In this review, we described the basic biochemistry and molecular biology of the ubiquitin-proteasome system, and its complex role in the development of inflammatory and autoimmune diseases. In addition, therapies and potential therapeutic targets related to the ubiquitin-proteasome system are discussed as well.
文摘Background:The 2019 novel coronavirus has caused the outbreak of the acute respiratory disease in Wuhan,Hubei Province of China since December 2019.This study was performed to analyze the clinical characteristics of patients who succumbed to and who recovered from 2019 novel coronavirus disease(COVID-19).Methods:Clinical data were collected from two tertiary hospitals in Wuhan.A retrospective investigation was conducted to analyze the clinical characteristics of fatal cases of COVID-19(death group)and we compare them with recovered patients(recovered group).Continuous variables were analyzed using the Mann-WhitneyU test.Categorical variables were analyzed byχ2 test or Fisher exact test as appropriate.Results:Our study enrolled 109 COVID-19 patients who died during hospitalization and 116 recovered patients.The median age of the death group was older than the recovered group(69[62,74]vs.40[33,57]years,Z=9.738,P<0.001).More patients in the death group had underlying diseases(72.5%vs.41.4%,χ2=22.105,P<0.001).Patients in the death group had a significantly longer time of illness onset to hospitalization(10.0[6.5,12.0]vs.7.0[5.0,10.0]days,Z=3.216,P=0.001).On admission,the proportions of patients with symptoms of dyspnea(70.6%vs.19.0%,χ2=60.905,P<0.001)and expectoration(32.1%vs.12.1%,χ2=13.250,P<0.001)were significantly higher in the death group.The blood oxygen saturation was significantly lower in the death group(85[77,91]%vs.97[95,98]%,Z=10.625,P<0.001).The white blood cell(WBC)in death group was significantly higher on admission(7.23[4.87,11.17]vs.4.52[3.62,5.88]×109/L,Z=7.618,P<0.001).Patients in the death group exhibited significantly lower lymphocyte count(0.63[0.40,0.79]vs.1.00[0.72,1.27]×109/L,Z=8.037,P<0.001)and lymphocyte percentage(7.10[4.45,12.73]%vs.23.50[15.27,31.25]%,Z=10.315,P<0.001)on admission,and the lymphocyte percentage continued to decrease during hospitalization(7.10[4.45,12.73]%vs.2.91[1.79,6.13]%,Z=5.242,P<0.001).Alanine transaminase(22.00[15.00,34.00]vs.18.70[13.00,30.38]U/L,Z=2.592,P=0
文摘Gradual degeneration and loss of dopaminergic neurons in the substantia nigra,pars compacta and subsequent reduction of dopamine levels in striatum are associated with motor deficits that characterize Parkinson’s disease(PD).In addition,half of the PD patients also exhibit frontostriatal-mediated executive dysfunction,including deficits in attention,short-term working memory,speed of mental processing,and impulsivity.The most commonly used treatments for PD are only partially or transiently effective and are available or applicable to a minority of patients.Because,these therapies neither restore the lost or degenerated dopaminergic neurons,nor prevent or delay the disease progression,the need for more effective therapeutics is critical.In this review,we provide a comprehensive overview of the current understanding of the molecular signaling pathways involved in PD,particularly within the context of how genetic and environmental factors contribute to the initiation and progression of this disease.The involvement of molecular chaperones,autophagy-lysosomal pathways,and proteasome systems in PD are also highlighted.In addition,emerging therapies,including pharmacological manipulations,surgical procedures,stem cell transplantation,gene therapy,as well as complementary,supportive and rehabilitation therapies to prevent or delay the progression of this complex disease are reviewed.
基金This work was supported by grants from the National Natural Science Foundation of China （No. 81671352, 91232709）, the National Key Project of Research and Development Plan （No. 2016YFC1306404）, the National Institute of Health （No. R21 AG048519, R01 AG021173, R01 AG038710, R01 AG044420, R01 NS046673, RF1 AG056130, and RF1 AG056114）, the Tanz Family Fund as well as scholarship from China Scholarship Council （No. 201608350068）.
文摘Objective：To review recent research advances on tau,a major player in Alzheimer＇s disease （AD） pathogenesis,a biomarker for AD onset,and potential target for AD therapy.Data Sources：This review was based on a comprehensive search using online literature databases,including PubMed,Web of Science,and Google Scholar.Study Selection：Literature search was based on the following keywords：Alzheimer＇s disease,tau protein,biomarker,cerebrospinal fluid （CSF）,therapeutics,plasma,imaging,propagation,spreading,seeding,prion,conformational templating,and posttranslational modification.Relevant articles were carefully reviewed,with no exclusions applied to study design and publication type.Results：Amyloid plaques enriched with extracellular amyloid beta （Aβ） and intracellular neurofibrillary tangles comprised of hyperphosphorylated tau proteins are the two main pathological hallmarks ofAD.Although the Aβ hypothesis has dominated AD research for many years,clinical Aβ-targeting strategies have consistently failed to effectively treat AD or prevent AD onset.The research focus in AD has recently shifted to the role oftau in AD.In addition to phosphorylation,tau is acetylated and proteolytically cleaved,which also contribute to its physiological and pathological functions.Emerging evidence characterizing pathological tau propagation and spreading provides new avenues for research into the molecular and cellular mechanisms underlying AD pathogenesis.Techniques to detect tau at minute levels in CSF and blood have been developed,and improved tracers have facilitated tau imaging in the brain.These advances have potential to accurately determine tau levels at early diagnostic stages in AD.Given that tau is a potential therapeutic target,anti-tau immunotherapy may potentially be a viable treatment strategy in AD intervention.Conclusion：Detecting changes in tau and targeting tau pathology represent a promising lead in the diagnosis and treatment of AD.
文摘BACKGROUND： Coagulopathy and its association with disease severity in hyperlipidemia （HL）- and non-hyperlipidemia （NHL）-induced acute pancreatitis （AP） are not dear. The present study was to evaluate the relationship between coagulation homeostasis and AP.
基金Supported by a grant from the University of Siena, PAR 2004 "H pylori infection, hosts’ aplotypes of inflammatory cytokines and the risk of ischemic heart disease"
文摘AIM: To determine the overall prevalence of H pylori and CagA positive H pylori infection and the prevalence of other bacterial and viral causes of chronic infection in patients with coronary heart disease (CHD), and the potential role of anti-heat-shock protein 60 (Hsp60) anti- body response to these proteins in increasing the risk of CHD development. METHODS: Eighty patients with CHD and 160 controls were employed. We also compared the levels of anti- heat-shock protein 60 (Hsp60) antibodies in the two groups. The H pylori infection and the CagA status were determined serologically, using commercially available enzyme-linked immunosorbent assays (ELISA), and a Western blotting method developed in our laboratory. Systemic antibodies to Hsp60 were determined by a sandwich ELISA, using a polyclonal antibody to Hsp60 to sensitise polystyrene plates and a commercially available human Hsp60 as an antigen. RESULTS: The overall prevalence of H pylori infec- tion was 78.7% (n = 63) in patients and 76.2% (n = 122) in controls (P = 0.07). Patients infected by CagA- positive (CagA+) H pylori strains were 71.4% (n = 45) vs 52.4% of infected controls (P = 0.030, OR = 2.27). Sys-temic levels of IgG to Hsp60 were increased in H pylori- negative patients compared with uninfected controls (P < 0.001) and CagA-positive infected patients compared with CagA-positive infected controls (P = 0.007). CONCLUSION: CagA positive H pylori infection may concur to the development of CHD; high levels of anti- Hsp60 antibodies may constitute a marker and/or a con- comitant pathogenic factor of the disease.
