This paper deals with the parallel information-based complexity of numerical integration on Sobolev class. We obtain tight bounds on the complexity, considered as a function of two variables simultaneously:the number ...This paper deals with the parallel information-based complexity of numerical integration on Sobolev class. We obtain tight bounds on the complexity, considered as a function of two variables simultaneously:the number of processors, the rquired precision. This result seems to be new even in serial case.展开更多
Olfactory ensheathing glia promote axonal regeneration in the mammalian central nervous system,including retinal ganglion cell axonal growth through the injured optic nerve.Still,it is unknown whether olfactory enshea...Olfactory ensheathing glia promote axonal regeneration in the mammalian central nervous system,including retinal ganglion cell axonal growth through the injured optic nerve.Still,it is unknown whether olfactory ensheathing glia also have neuroprotective properties.Olfactory ensheathing glia express brain-derived neurotrophic factor,one of the best neuroprotectants for axotomized retinal ganglion cells.Therefore,we aimed to investigate the neuroprotective capacity of olfactory ensheating glia after optic nerve crush.Olfactory ensheathing glia cells from an established rat immortalized clonal cell line,TEG3,were intravitreally injected in intact and axotomized retinas in syngeneic and allogeneic mode with or without microglial inhibition or immunosuppressive treatments.Anatomical and gene expression analyses were performed.Olfactory bulb-derived primary olfactory ensheathing glia and TEG3 express major histocompatibility complex classⅡmolecules.Allogeneically and syngenically transplanted TEG3 cells survived in the vitreous for up to 21 days,forming an epimembrane.In axotomized retinas,only the allogeneic TEG3 transplant rescued retinal ganglion cells at 7 days but not at 21 days.In these retinas,microglial anatomical activation was higher than after optic nerve crush alone.In intact retinas,both transplants activated microglial cells and caused retinal ganglion cell death at 21 days,a loss that was higher after allotransplantation,triggered by pyroptosis and partially rescued by microglial inhibition or immunosuppression.However,neuroprotection of axotomized retinal ganglion cells did not improve with these treatments.The different neuroprotective properties,different toxic effects,and different responses to microglial inhibitory treatments of olfactory ensheathing glia in the retina depending on the type of transplant highlight the importance of thorough preclinical studies to explore these variables.展开更多
The expression of major histocompatibility complex class I(MHC-I),a key antigen-presenting protein,can be induced in dopaminergic neurons in the substantia nigra,thus indicating its possible involvement in the occurre...The expression of major histocompatibility complex class I(MHC-I),a key antigen-presenting protein,can be induced in dopaminergic neurons in the substantia nigra,thus indicating its possible involvement in the occurrence and development of Parkinson’s disease.However,it remains unclear whether oxidative stress induces Parkinson’s disease through the MHC-I pathway.In the present study,polymerase chain reaction and western blot assays were used to determine the expression of MHC-I in 1-methyl-4-phenylpyridinium(MPP+)-treated SH-SY5Y cells and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s disease mouse model.The findings revealed that MHC-I was expressed in both models.To detect whether the expression of MHC-I was able to trigger the infiltration of cytotoxic T cells,immunofluorescence staining was used to detect cytotoxic cluster of differentiation 8(CD8)+T cell infiltration in the substantia nigra of MPTP-treated mice.The results indicated that the presentation of MHC-I in dopaminergic neurons was indeed accompanied by an increase in the number of CD8+T cells.Moreover,in MPTP-induced Parkinson’s disease model mice,the genetic knockdown of endogenous MHC-I,which was caused by injecting specific adenovirus into the substantia nigra,led to a significant reduction in CD8+T cell infiltration and alleviated dopaminergic neuronal death.To further investigate the molecular mechanisms of oxidative stress-induced MHC-I presentation,the expression of PTEN-induced kinase 1(PINK1)was silenced in MPP+-treated SH-SY5Y cells using specific small interfering RNA(siRNA),and there was more presentation of MHC-I in these cells compared with control siRNA-treated cells.Taken together,MPP+-/MPTP-induced oxidative stress can trigger MHC-I presentation and autoimmune activation,thus rendering dopaminergic neurons susceptible to immune cells and degeneration.This may be one of the mechanisms of oxidative stress-induced Parkinson’s disease,and implies the potential neuroprotective role of PINK1 in oxidative stress-induced MHC-I presentation.All animal experiments were approved by the Southern Medical University Ethics Committee(No.81802040,approved on February 25,2018).展开更多
Alcoholic patients have a high incidence of hepatitis C virus （HCV） infection. Alcohol consumption enhances the severity of the HCV disease course and worsens the outcome of chronic hepatitis C. The accumulation of ...Alcoholic patients have a high incidence of hepatitis C virus （HCV） infection. Alcohol consumption enhances the severity of the HCV disease course and worsens the outcome of chronic hepatitis C. The accumulation of virally infected cells in the liver is related to the HCV- induced inability of the immune system to recognize infected cells and to develop the immune responses. This review covers the effects of HCV proteins and ethanol on major histocompatibility complex （MHC） class Ⅰ- and class Ⅱ-restricted antigen presentation. Here, we discuss the liver which functions as an immune privilege organ; factors, which affect cleavage and loading of antigenic peptides onto MHC class I and class ~I in hepatocytes and dendritic cells, and the modulating effects of ethanol and HCV on antigen presentation by liver cells. Altered antigen presentation in the liver limits the ability ＇of the immune system to clear HCV and infected cells and contributes to disease progression. HCV by itself affects dendritic cell function, switching their cytokine profile to the suppressive phenotype of interleukin-10 （IL-10） and transforming growth factor beta （TGFβ） predominance, preventing cell maturation and allostimulation capacity. The synergistic action of ethanol with HCV results in the suppression of MHC class Ⅱ-restricted antigen presentation. In addition, ethanol metabolism and HCV proteins reduce proteasome function and interferon signaling, thereby suppressing the generation of peptides for MHC class I -restricted antigen presentation. Collectively, ethanol exposure further impairs antigen presentation in HCV-infected liver cells, which may provide a partial explanation for exacerbations and the poor outcome of HCV infection in alcoholics.展开更多
Objective:To collect the main components and targets of Jiang-zhi-dai-pao-cha(JZDPC)and investigate the mechanism of JZDPC for the treatment of hyperlipidemia by network pharmacology.Methods:The components and targets...Objective:To collect the main components and targets of Jiang-zhi-dai-pao-cha(JZDPC)and investigate the mechanism of JZDPC for the treatment of hyperlipidemia by network pharmacology.Methods:The components and targets of JZDPC were searched from ETCM databases,the targets related to hyperlipidemia were searched from DisGeNET and GeneCards databases,and then the intersection targets and corresponding key components were obtained.Cytoscape 3.8.2 software was used to construct and analyze networks,and then Metascape online database was applied for gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of genes and genomes(KEGG)pathway enrichment analysis of core putative targets.Results:There were 99 overlapping targets between JZDPC and hyperlipidemia,among which NR3C1,ESR1,NR1I2,NFKB1,ESR2,ALOX5,PTGS1,PPARA,RXRA,LPL,PLA2G1B,PYGM,CYP2C9 were the core putative targets,and many members of nuclear receptor 1(NR1)subfamily were included.The core components of JZDPC,such as Ursolic Acid,β-Sitosterol,Resveratrol,Arirubic Acid,Alisol A,Oleanolic Acid,Rhein,Chrysophanol and Emodin,can regulate blood lipid by regulating a series of signaling pathways including the above core potential targets,such as non-alcoholic fatty liver disease(NAFLD)signaling pathway,pathways in cancer,arachidonic acid(AA)metabolism signaling pathway and peroxisome proliferator activated receptor(PPAR)signaling pathway,Starch and sucrose metabolism signaling pathway,etc.They play many roles in the treatment of hyperlipidemia by participating in lipid synthesis and metabolism,anti inflammation,anti oxidative stress,regulating hormone levels and carbohydrate metabolism.Conclusion:Network pharmacology provides a theoretical basis for investigating the mechanism of action of JZDPC,and the NAFLD signaling pathway is one of the most valuable pathways.展开更多
Background Humoral immunity is an important factor for long-term survival of renal allograft. Here we performed a four-year follow-up to explore the clinical significance of monitoring anti-human leukocyte antigens （...Background Humoral immunity is an important factor for long-term survival of renal allograft. Here we performed a four-year follow-up to explore the clinical significance of monitoring anti-human leukocyte antigens （HLA） and anti-major histocompatibility complex class I-related chain A （MICA） antibody expression after kidney transplantation. Methods We obtained serial serum samples from 84 kidney transplant patients over a four-year period. All patients were followed up at least 6 months after transplantation and had at least two follow-up points. Anti-HLA and anti-MICA antibody titres and serum creatinine （SCr） levels were evaluated at each follow-up. Patients were divided into 4 groups： HLA（＋） MICA（-）, HLA（-）MICA（＋）, HLA（＋）MICA（＋） and HLA（-）MICA（-）. The impact of post-transplant antibody level on kidney allograft function was evaluated. Results Antibodies were detected in 38.1% （32/84） of the renal allograft recipients. HLA, MICA and HLA＋MICA expression was observed in 18.89%, 14.44% and 5.93% of the recipients respectively. The most frequent anti-HLA and anti-MICA specific antibodies identified were All, A24, A29, A32, A33, A80; B7, B13, B37; DR17, DR12, DR18, DR52, DR53, DR1, DR4, DR9, DR51; DQ7, DQ4, DQ8, DQ2, DQ9, DQ5, DQ6 and MICA02, MICA18, MICA19, MICA07, MICA27. As the time after transplantation elapsed, more recipients developed de novo antibody expression. Total 11.91% （10/84） of the recipients had de novo antibody expression during the follow up. The average level of SCr and the percentage of recipients with abnormal allograft function were significantly higher in recipients with anti-HLA and/or anti- MICA antibody expression than those without. The appearance of anti-HLA and anti-MICA antibody expression always preceded the increase in SCr value. Conclusions Anti-HLA and anti-MICA antibody expression has predictive value for early and late allograft dysfunction. The presence of donor specific antibody is detrimental to graft function and graft survival.展开更多
Background Sensitized recipients have a high risk of immunological graft loss due to hyperacute rejection and/or accelerated acute rejection. The presence of major histocompatibility complex class I-related chain A （...Background Sensitized recipients have a high risk of immunological graft loss due to hyperacute rejection and/or accelerated acute rejection. The presence of major histocompatibility complex class I-related chain A （MICA） antibodies has also been described associated with an increased rate of kidney-allograft rejection. The aim of this study was to describe the expression of MICA antibodies in sensitized recipients of renal transplantation and evaluate its influence on the kidney transplantation recipients.Methods A total of 29 sensitized recipients were included in this study. All patients received the MICA antibodies detection before and after protein A immunoadsorption. Panel reactive antibody （PRA）, HLA-matches, acute rejection and postoperative one to four-week serum creatinine level were also collected and analyzed, respectively. No prisoners were used in this study.Results Eight patients （27.6%） in all 29 sensitized recipients expressed the MICA antibodies but did not show higher acute rejection rate than the non-expressed patients （3/8, 37.5% vs. 8/21, 38.1%; P=1.000）. Recipients with PRA 〉40% showed higher expression levels of MICA antibodies than the recipients with PRA 〈40% （7/16, 43.8% vs. 1/13, 8.3%; P=0.044）. HLA mismatch did not have any effect on the expression of MICA antibodies （P=1.000）. MICA antibodies positive group had higher serum creatinine level than the control in postoperative one week （（135.4±21.4） μmol/L vs. （108.6±31.6） μmol/L, P=0.036）, but no significant difference in postoperative four weeks （（89.0±17.1） μmol/L vs. （77.1±15.9） μmol/L, P=0.089）. MICA antibodies decreased significantly after protein A immunoadsorption.Conclusions MICA antibodies increase in the sensitized recipients, which have significant effects on the function of aliograft in early postoperative period. Protein A immunoadsorption can decrease MICA antibodies effectively in sensitized recipients.展开更多
Objective To review the role of polymorphism of major histocompatibility complex class I-related chain A （MICA） gene and antibodies against MICA antigens in transplant immunology. Data sources The data used in this ...Objective To review the role of polymorphism of major histocompatibility complex class I-related chain A （MICA） gene and antibodies against MICA antigens in transplant immunology. Data sources The data used in this review were mainly from our own results and from the relevant English language literatures published from 1999 to 2010. Some data presented in this review are in press.Study selection Articles regarding MICA gene discovery and pioneering finding of antibodies against MICA antigen and allograft rejection were selected. This review chronicles the development of our understanding of the role that MICA antigens and antibodies may play in organ transplantation.Results Polymorphic glycoprotein MICA antigens were detected on freshly isolated human umbilical cord endothelial cells, but not on peripheral lymphocytes. Antibodies were found and typing of recipients and donors by sequencing the MICA alleles has established that de novo antibodies produced in kidney transplant recipients are directed at mismatched MICA epitopes and are associated with acute rejection and chronic transplant failure. The specificity of antibodies against the epitopes of MICA antigens were well characterized by donor MICA typing, single antigen array testing with antibody absorption and elution. Acute graft-versus-host disease was observed in stem-cell recipients who were mismatched for MICA.Conclusions Immunization against mismatched MICA epitopes encountered in donor organs after transplantation may result in antibodies against MICA alleles. Testing for MICA donor-specific antibodies （DSA） which are associated with early failure of kidney transplants may be helpful for identifying some of the targets of antibodies against antigens other than the human leukocyte antigen （HLA） and for improving transplantation outcome.展开更多
Objective： This review focuses on the current knowledge on the implication and significance of beta 2 microglobulin （β2M）, a conservative immune molecule in vertebrate.Data Sources： The data used in this review w...Objective： This review focuses on the current knowledge on the implication and significance of beta 2 microglobulin （β2M）, a conservative immune molecule in vertebrate.Data Sources： The data used in this review were obtained from PubMed up to October 2015.Terms of β2M, immune response, and infection were used in the search.Study Selections： Articles related to β2M were retrieved and reviewed.Articles focusing on the characteristic and function of β2M were selected.The exclusion criteria of articles were that the studies on β2M-related molecules.Results： β2M is critical for the immune surveillance and modulation in vertebrate animals.The dysregulation of β2M is associated with multiple diseases, including endogenous and infectious diseases.β2M could directly participate in the development of cancer cells, and the level of β2M is deemed as a prognostic marker for several malignancies.It also involves in forming major histocompatibility complex （MHC class Ⅰ or MHC Ⅰ） or like heterodimers, covering from antigen presentation to immune homeostasis.Conclusions： Based on the characteristic of β2M, it or its signaling pathway has been targeted as biomedical or therapeutic tools.Moreover, β2M is highly conserved among different species, and overall structures are virtually identical, implying the versatility of β2M on applications.展开更多
Background：Amyloid-β deposition and accumulation of autophagic vacuoles are pathologic features of Alzheimer＇s disease （AD）.Dysregulation of the endosomal-autophagic-lysosomal （EAL） pathway,which impairs amyloi...Background：Amyloid-β deposition and accumulation of autophagic vacuoles are pathologic features of Alzheimer＇s disease （AD）.Dysregulation of the endosomal-autophagic-lysosomal （EAL） pathway,which impairs amyloid precursor protein processing,is one of the earliest changes in AD.However,the precise role of EAL pathway in neurodegeneration remains unclear.This study aimed to investigate the role of EAL pathway in AD and further study the mechanism of EAL dysfunction.Methods：We used 3-,7-,and 12-month-old APPswe/PSEN1dE9 （APP/PS1） mice to model different stages of AD with age-and gender-matched wild-type littermates as controls （4-7 mice per group） and detected the changes of EAL markers,endosomal organizers Rab5 and Rab7,autophagosome marker LC3B,and lysosomal proteins Lamp 1/2 in cortex and hippocampus by immunohistochemistry and Western blotting analysis.To further explore the mechanism of EAL dysregulation in AD,components of the class Ⅲ phosphatidylinositol 3-kinase （PI3KC3） complex,activators ofRab7 （Beclin1 and UVRAG）,and the negative regulator of Rab7 （Rubicon） were also measured in this two brain regions.Results：In 7-month-old APP/PS1 brain that amyloid beta initiated to accumulate intracellularly,EAL pathway,and related PI3KC3 members,UVRAG and Beclin1 were upregulated both in cortex and hippocampus （all P 〈 0.05）.By the age of 12 months old,when abundant amyloid plaques formed,EAL markers,UVRAG,and Beclin 1 were also upregulated in the cortex （all P 〈 0.05）.However,Rab7 was decreased significantly （P =0.0447）,accompanied by a reduction of its activating PI3KC complex component Beclin1 （P =0.0215） and enhancement of its inhibiting component Rubicon （P =0.0055） in the hippocampus.Conclusions：Our study implies that EAL pathway,represented as Rab7 and its PI3KC3 regulators＇ expressions,showed temporal and spatial variation in brains at different stages of AD.It provides new insights into the role of EAL pathway in pathogenesis and indicates potential therapeutic targets in neurodegenerative diseases.展开更多
基金this work was supported by china State Major Key Project for Basic Researchers
文摘This paper deals with the parallel information-based complexity of numerical integration on Sobolev class. We obtain tight bounds on the complexity, considered as a function of two variables simultaneously:the number of processors, the rquired precision. This result seems to be new even in serial case.
基金supported by the Spanish Ministry of Economy and Competitiveness,No.PID2019-106498GB-I00(to MVS)the Instituto de Salud CarlosⅢ,Fondo Europeo de Desarrollo Regional“Una manera de hacer Europa”,No.PI19/00071(to MAB)+1 种基金Ministerio de Ciencia e Innovación Project,No.SAF2017-82736-C2-1-R(to MTMF)in Universidad Autónoma de MadridFundación Universidad Francisco de Vitoria(to JS)。
文摘Olfactory ensheathing glia promote axonal regeneration in the mammalian central nervous system,including retinal ganglion cell axonal growth through the injured optic nerve.Still,it is unknown whether olfactory ensheathing glia also have neuroprotective properties.Olfactory ensheathing glia express brain-derived neurotrophic factor,one of the best neuroprotectants for axotomized retinal ganglion cells.Therefore,we aimed to investigate the neuroprotective capacity of olfactory ensheating glia after optic nerve crush.Olfactory ensheathing glia cells from an established rat immortalized clonal cell line,TEG3,were intravitreally injected in intact and axotomized retinas in syngeneic and allogeneic mode with or without microglial inhibition or immunosuppressive treatments.Anatomical and gene expression analyses were performed.Olfactory bulb-derived primary olfactory ensheathing glia and TEG3 express major histocompatibility complex classⅡmolecules.Allogeneically and syngenically transplanted TEG3 cells survived in the vitreous for up to 21 days,forming an epimembrane.In axotomized retinas,only the allogeneic TEG3 transplant rescued retinal ganglion cells at 7 days but not at 21 days.In these retinas,microglial anatomical activation was higher than after optic nerve crush alone.In intact retinas,both transplants activated microglial cells and caused retinal ganglion cell death at 21 days,a loss that was higher after allotransplantation,triggered by pyroptosis and partially rescued by microglial inhibition or immunosuppression.However,neuroprotection of axotomized retinal ganglion cells did not improve with these treatments.The different neuroprotective properties,different toxic effects,and different responses to microglial inhibitory treatments of olfactory ensheathing glia in the retina depending on the type of transplant highlight the importance of thorough preclinical studies to explore these variables.
基金This work was supported by the National Natural Science Foundation of China,Nos.81671240(to SZZ),81560220(to GHL)the Youth Science Foundation of Jiangxi Province of China,No.20151BAB215014(to GHL)Health and Family Planning Commission of Jiangxi Province of China,No.20195109(to GHL)。
文摘The expression of major histocompatibility complex class I(MHC-I),a key antigen-presenting protein,can be induced in dopaminergic neurons in the substantia nigra,thus indicating its possible involvement in the occurrence and development of Parkinson’s disease.However,it remains unclear whether oxidative stress induces Parkinson’s disease through the MHC-I pathway.In the present study,polymerase chain reaction and western blot assays were used to determine the expression of MHC-I in 1-methyl-4-phenylpyridinium(MPP+)-treated SH-SY5Y cells and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s disease mouse model.The findings revealed that MHC-I was expressed in both models.To detect whether the expression of MHC-I was able to trigger the infiltration of cytotoxic T cells,immunofluorescence staining was used to detect cytotoxic cluster of differentiation 8(CD8)+T cell infiltration in the substantia nigra of MPTP-treated mice.The results indicated that the presentation of MHC-I in dopaminergic neurons was indeed accompanied by an increase in the number of CD8+T cells.Moreover,in MPTP-induced Parkinson’s disease model mice,the genetic knockdown of endogenous MHC-I,which was caused by injecting specific adenovirus into the substantia nigra,led to a significant reduction in CD8+T cell infiltration and alleviated dopaminergic neuronal death.To further investigate the molecular mechanisms of oxidative stress-induced MHC-I presentation,the expression of PTEN-induced kinase 1(PINK1)was silenced in MPP+-treated SH-SY5Y cells using specific small interfering RNA(siRNA),and there was more presentation of MHC-I in these cells compared with control siRNA-treated cells.Taken together,MPP+-/MPTP-induced oxidative stress can trigger MHC-I presentation and autoimmune activation,thus rendering dopaminergic neurons susceptible to immune cells and degeneration.This may be one of the mechanisms of oxidative stress-induced Parkinson’s disease,and implies the potential neuroprotective role of PINK1 in oxidative stress-induced MHC-I presentation.All animal experiments were approved by the Southern Medical University Ethics Committee(No.81802040,approved on February 25,2018).
基金Supported by Development funds from Section of Gastroenterology/Hepatology, Internal Medicine, University of Nebraska Medical Center
文摘Alcoholic patients have a high incidence of hepatitis C virus （HCV） infection. Alcohol consumption enhances the severity of the HCV disease course and worsens the outcome of chronic hepatitis C. The accumulation of virally infected cells in the liver is related to the HCV- induced inability of the immune system to recognize infected cells and to develop the immune responses. This review covers the effects of HCV proteins and ethanol on major histocompatibility complex （MHC） class Ⅰ- and class Ⅱ-restricted antigen presentation. Here, we discuss the liver which functions as an immune privilege organ; factors, which affect cleavage and loading of antigenic peptides onto MHC class I and class ~I in hepatocytes and dendritic cells, and the modulating effects of ethanol and HCV on antigen presentation by liver cells. Altered antigen presentation in the liver limits the ability ＇of the immune system to clear HCV and infected cells and contributes to disease progression. HCV by itself affects dendritic cell function, switching their cytokine profile to the suppressive phenotype of interleukin-10 （IL-10） and transforming growth factor beta （TGFβ） predominance, preventing cell maturation and allostimulation capacity. The synergistic action of ethanol with HCV results in the suppression of MHC class Ⅱ-restricted antigen presentation. In addition, ethanol metabolism and HCV proteins reduce proteasome function and interferon signaling, thereby suppressing the generation of peptides for MHC class I -restricted antigen presentation. Collectively, ethanol exposure further impairs antigen presentation in HCV-infected liver cells, which may provide a partial explanation for exacerbations and the poor outcome of HCV infection in alcoholics.
基金2019 national talent project of TCM characteristic technology inheritance(No.T20194828003)Medical science and technology development plan project of Yancheng City(No.YK2020039).
文摘Objective:To collect the main components and targets of Jiang-zhi-dai-pao-cha(JZDPC)and investigate the mechanism of JZDPC for the treatment of hyperlipidemia by network pharmacology.Methods:The components and targets of JZDPC were searched from ETCM databases,the targets related to hyperlipidemia were searched from DisGeNET and GeneCards databases,and then the intersection targets and corresponding key components were obtained.Cytoscape 3.8.2 software was used to construct and analyze networks,and then Metascape online database was applied for gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of genes and genomes(KEGG)pathway enrichment analysis of core putative targets.Results:There were 99 overlapping targets between JZDPC and hyperlipidemia,among which NR3C1,ESR1,NR1I2,NFKB1,ESR2,ALOX5,PTGS1,PPARA,RXRA,LPL,PLA2G1B,PYGM,CYP2C9 were the core putative targets,and many members of nuclear receptor 1(NR1)subfamily were included.The core components of JZDPC,such as Ursolic Acid,β-Sitosterol,Resveratrol,Arirubic Acid,Alisol A,Oleanolic Acid,Rhein,Chrysophanol and Emodin,can regulate blood lipid by regulating a series of signaling pathways including the above core potential targets,such as non-alcoholic fatty liver disease(NAFLD)signaling pathway,pathways in cancer,arachidonic acid(AA)metabolism signaling pathway and peroxisome proliferator activated receptor(PPAR)signaling pathway,Starch and sucrose metabolism signaling pathway,etc.They play many roles in the treatment of hyperlipidemia by participating in lipid synthesis and metabolism,anti inflammation,anti oxidative stress,regulating hormone levels and carbohydrate metabolism.Conclusion:Network pharmacology provides a theoretical basis for investigating the mechanism of action of JZDPC,and the NAFLD signaling pathway is one of the most valuable pathways.
基金the grants from the the National Science Foundation of China，the Key Discipline of Medicine of Jiangsu Province，the Outstanding Medical Academic Leader Program of Jiangsu Province，the Science Foundation of Jiangsu Province，the Key Laboratory Foundation of Suzhou
文摘Background Humoral immunity is an important factor for long-term survival of renal allograft. Here we performed a four-year follow-up to explore the clinical significance of monitoring anti-human leukocyte antigens （HLA） and anti-major histocompatibility complex class I-related chain A （MICA） antibody expression after kidney transplantation. Methods We obtained serial serum samples from 84 kidney transplant patients over a four-year period. All patients were followed up at least 6 months after transplantation and had at least two follow-up points. Anti-HLA and anti-MICA antibody titres and serum creatinine （SCr） levels were evaluated at each follow-up. Patients were divided into 4 groups： HLA（＋） MICA（-）, HLA（-）MICA（＋）, HLA（＋）MICA（＋） and HLA（-）MICA（-）. The impact of post-transplant antibody level on kidney allograft function was evaluated. Results Antibodies were detected in 38.1% （32/84） of the renal allograft recipients. HLA, MICA and HLA＋MICA expression was observed in 18.89%, 14.44% and 5.93% of the recipients respectively. The most frequent anti-HLA and anti-MICA specific antibodies identified were All, A24, A29, A32, A33, A80; B7, B13, B37; DR17, DR12, DR18, DR52, DR53, DR1, DR4, DR9, DR51; DQ7, DQ4, DQ8, DQ2, DQ9, DQ5, DQ6 and MICA02, MICA18, MICA19, MICA07, MICA27. As the time after transplantation elapsed, more recipients developed de novo antibody expression. Total 11.91% （10/84） of the recipients had de novo antibody expression during the follow up. The average level of SCr and the percentage of recipients with abnormal allograft function were significantly higher in recipients with anti-HLA and/or anti- MICA antibody expression than those without. The appearance of anti-HLA and anti-MICA antibody expression always preceded the increase in SCr value. Conclusions Anti-HLA and anti-MICA antibody expression has predictive value for early and late allograft dysfunction. The presence of donor specific antibody is detrimental to graft function and graft survival.
文摘Background Sensitized recipients have a high risk of immunological graft loss due to hyperacute rejection and/or accelerated acute rejection. The presence of major histocompatibility complex class I-related chain A （MICA） antibodies has also been described associated with an increased rate of kidney-allograft rejection. The aim of this study was to describe the expression of MICA antibodies in sensitized recipients of renal transplantation and evaluate its influence on the kidney transplantation recipients.Methods A total of 29 sensitized recipients were included in this study. All patients received the MICA antibodies detection before and after protein A immunoadsorption. Panel reactive antibody （PRA）, HLA-matches, acute rejection and postoperative one to four-week serum creatinine level were also collected and analyzed, respectively. No prisoners were used in this study.Results Eight patients （27.6%） in all 29 sensitized recipients expressed the MICA antibodies but did not show higher acute rejection rate than the non-expressed patients （3/8, 37.5% vs. 8/21, 38.1%; P=1.000）. Recipients with PRA 〉40% showed higher expression levels of MICA antibodies than the recipients with PRA 〈40% （7/16, 43.8% vs. 1/13, 8.3%; P=0.044）. HLA mismatch did not have any effect on the expression of MICA antibodies （P=1.000）. MICA antibodies positive group had higher serum creatinine level than the control in postoperative one week （（135.4±21.4） μmol/L vs. （108.6±31.6） μmol/L, P=0.036）, but no significant difference in postoperative four weeks （（89.0±17.1） μmol/L vs. （77.1±15.9） μmol/L, P=0.089）. MICA antibodies decreased significantly after protein A immunoadsorption.Conclusions MICA antibodies increase in the sensitized recipients, which have significant effects on the function of aliograft in early postoperative period. Protein A immunoadsorption can decrease MICA antibodies effectively in sensitized recipients.
文摘Objective To review the role of polymorphism of major histocompatibility complex class I-related chain A （MICA） gene and antibodies against MICA antigens in transplant immunology. Data sources The data used in this review were mainly from our own results and from the relevant English language literatures published from 1999 to 2010. Some data presented in this review are in press.Study selection Articles regarding MICA gene discovery and pioneering finding of antibodies against MICA antigen and allograft rejection were selected. This review chronicles the development of our understanding of the role that MICA antigens and antibodies may play in organ transplantation.Results Polymorphic glycoprotein MICA antigens were detected on freshly isolated human umbilical cord endothelial cells, but not on peripheral lymphocytes. Antibodies were found and typing of recipients and donors by sequencing the MICA alleles has established that de novo antibodies produced in kidney transplant recipients are directed at mismatched MICA epitopes and are associated with acute rejection and chronic transplant failure. The specificity of antibodies against the epitopes of MICA antigens were well characterized by donor MICA typing, single antigen array testing with antibody absorption and elution. Acute graft-versus-host disease was observed in stem-cell recipients who were mismatched for MICA.Conclusions Immunization against mismatched MICA epitopes encountered in donor organs after transplantation may result in antibodies against MICA alleles. Testing for MICA donor-specific antibodies （DSA） which are associated with early failure of kidney transplants may be helpful for identifying some of the targets of antibodies against antigens other than the human leukocyte antigen （HLA） and for improving transplantation outcome.
基金This study was funded by the grant from the National Nature Science Foundation of China
文摘Objective： This review focuses on the current knowledge on the implication and significance of beta 2 microglobulin （β2M）, a conservative immune molecule in vertebrate.Data Sources： The data used in this review were obtained from PubMed up to October 2015.Terms of β2M, immune response, and infection were used in the search.Study Selections： Articles related to β2M were retrieved and reviewed.Articles focusing on the characteristic and function of β2M were selected.The exclusion criteria of articles were that the studies on β2M-related molecules.Results： β2M is critical for the immune surveillance and modulation in vertebrate animals.The dysregulation of β2M is associated with multiple diseases, including endogenous and infectious diseases.β2M could directly participate in the development of cancer cells, and the level of β2M is deemed as a prognostic marker for several malignancies.It also involves in forming major histocompatibility complex （MHC class Ⅰ or MHC Ⅰ） or like heterodimers, covering from antigen presentation to immune homeostasis.Conclusions： Based on the characteristic of β2M, it or its signaling pathway has been targeted as biomedical or therapeutic tools.Moreover, β2M is highly conserved among different species, and overall structures are virtually identical, implying the versatility of β2M on applications.
基金This work was supported by a grant of National Natural Science Foundation of China （No. 81271406）.
文摘Background：Amyloid-β deposition and accumulation of autophagic vacuoles are pathologic features of Alzheimer＇s disease （AD）.Dysregulation of the endosomal-autophagic-lysosomal （EAL） pathway,which impairs amyloid precursor protein processing,is one of the earliest changes in AD.However,the precise role of EAL pathway in neurodegeneration remains unclear.This study aimed to investigate the role of EAL pathway in AD and further study the mechanism of EAL dysfunction.Methods：We used 3-,7-,and 12-month-old APPswe/PSEN1dE9 （APP/PS1） mice to model different stages of AD with age-and gender-matched wild-type littermates as controls （4-7 mice per group） and detected the changes of EAL markers,endosomal organizers Rab5 and Rab7,autophagosome marker LC3B,and lysosomal proteins Lamp 1/2 in cortex and hippocampus by immunohistochemistry and Western blotting analysis.To further explore the mechanism of EAL dysregulation in AD,components of the class Ⅲ phosphatidylinositol 3-kinase （PI3KC3） complex,activators ofRab7 （Beclin1 and UVRAG）,and the negative regulator of Rab7 （Rubicon） were also measured in this two brain regions.Results：In 7-month-old APP/PS1 brain that amyloid beta initiated to accumulate intracellularly,EAL pathway,and related PI3KC3 members,UVRAG and Beclin1 were upregulated both in cortex and hippocampus （all P 〈 0.05）.By the age of 12 months old,when abundant amyloid plaques formed,EAL markers,UVRAG,and Beclin 1 were also upregulated in the cortex （all P 〈 0.05）.However,Rab7 was decreased significantly （P =0.0447）,accompanied by a reduction of its activating PI3KC complex component Beclin1 （P =0.0215） and enhancement of its inhibiting component Rubicon （P =0.0055） in the hippocampus.Conclusions：Our study implies that EAL pathway,represented as Rab7 and its PI3KC3 regulators＇ expressions,showed temporal and spatial variation in brains at different stages of AD.It provides new insights into the role of EAL pathway in pathogenesis and indicates potential therapeutic targets in neurodegenerative diseases.
