BACKGROUND Hepatocellular carcinoma(HCC)is a common malignancy worldwide,and the mortality rate continues to rise each year.SMARCA4 expression has been associated with poor prognosis in various types of cancer;however...BACKGROUND Hepatocellular carcinoma(HCC)is a common malignancy worldwide,and the mortality rate continues to rise each year.SMARCA4 expression has been associated with poor prognosis in various types of cancer;however,the specific mechanism of action of SMARCA4 in HCC needs to be fully elucidated.AIM To explore the specific mechanism of action of SMARCA4 in HCC.METHODS Herein,the expression level of SMARCA4 as well as its association with HCC prognosis were evaluated using transcriptome profiling and clinical data of 18 different types of cancer collected from The Cancer Genome Atlas database.Furthermore,SMARCA4-high and-low groups were identified.Thereafter,gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify the function of SMARCA4,followed by construction of a SMARCA4-specific competing endogenous RNA(ceRNA)network using starBase database.The role of SMARCA4 in immunotherapy and its association with immune cells were assessed using correlation analysis.RESULTS It was observed that SMARCA4 was overexpressed and negatively correlated with prognosis in HCC.Further,SMARCA4 expression was positively associated with tumor mutational burden,microsatellite stability,and immunotherapy efficacy.The SNHG3/THUMP3-AS1-miR-139-5p-SMARCA4 ceRNA network was established and could be assumed to serve as a stimulatory mechanism in HCC.CONCLUSION The findings of this study demonstrated that SMARCA4 plays a significant role in progression and immune infiltration in HCC.Moreover,a ceRNA network was detected,which was found to be correlated with poor prognosis in HCC.The findings of this study could contribute towards the identification of predictive markers for immunotherapy and a novel mechanism of action for HCC treatment.展开更多
Objective In this study, the pharmacological kinetics of Buthus martensi Karsch （BmK） AS, a specific modulator of voltage-gated sodium channel site 4, was investigated on Nav1.3 expressed in Xenopus oocytes. Methods...Objective In this study, the pharmacological kinetics of Buthus martensi Karsch （BmK） AS, a specific modulator of voltage-gated sodium channel site 4, was investigated on Nav1.3 expressed in Xenopus oocytes. Methods Two-electrode voltage clamp was used to record the whole-cell sodium current. Results The peak currents of Nav1.3 were depressed by BmK AS over a wide range of concentrations （10, 100, and 500 nmol/L）. Most remarkably, BmK AS at 100 nmol/L hyperpolarized the voltage-dependence and increased the voltage-sensitivity of steady-state activation/inactivation. In addition, BmK AS was capable of hyperpolarizing not only the fast inactivation but also the slow inactivation, with a greater preference for the latter. Moreover, BmK AS accelerated the time constant and increased the ratio of recovery in Nav1.3 at all concentrations. Conclusion This study provides direct evidence that BmK AS facilitates steady-state activation and inhibits slow inactivation by stabilizing both the closed and open states of the Nav1.3 channel, which might result from an integrative binding to two receptor sites on the voltage-gated sodium channels. These results may shed light on therapeutics against Nav1.3-targeted pathology.展开更多
Despite the advent of biological products, such as anti-tumor necrosis factor-α monoclonal antibodies (infliximab and adalimumab), for treatment of moderate to severe cases of inflammatory bowel disease (I...Despite the advent of biological products, such as anti-tumor necrosis factor-α monoclonal antibodies (infliximab and adalimumab), for treatment of moderate to severe cases of inflammatory bowel disease (IBD), most patients depend upon aminosalicylates as the conventional treatment option. In recent years, the increased knowledge of complex pathophysiological processes underlying IBD has resulted in development of a number of newer pharmaceutical agents like low-molecular-weight heparin, omega-3 fatty acids, probiotics and innovative formulations such as high-dose, once-daily multi-matrix mesalamine, which are designed to minimize the inflammatory process through inhibition of different targets. Optimization of delivery of existing drugs to the colon using the prodrug approach is another attractive alternative that has been utilized and commercialized for 5-aminosalicylic acid (ASA) in the form of sulfasalazine, balsalazide, olsalazine and ipsalazine, but rarely for its positional isomer 4-ASA - a well-established antitubercular drug that is twice as potent as 5-ASA against IBD, and more specifically, ulcerative colitis. The present review focuses on the complete profile of 4-ASA and its advantages over 5-ASA and colon-targeting prodrugs reported so far for the management of IBD. The review also emphasizes the need for reappraisal of this promising but unexplored entity as a potential treatment option for IBD.展开更多
Dimethylations of histone H3 lysine 9 and lysine 27 are important epigenetic marks associated with transcription repression. Here, we identified KIAA1718 （KDM7A） as a novel histone demethylase specific for these two...Dimethylations of histone H3 lysine 9 and lysine 27 are important epigenetic marks associated with transcription repression. Here, we identified KIAA1718 （KDM7A） as a novel histone demethylase specific for these two repressing marks. Using mouse embryonic stem cells, we demonstrated that KIAA1718 expression increased at the early phase of neural differentiation. Knockdown of the gene blocked neural differentiation and the effect was rescued by the wild-type human gene, and not by a catalytically inactive mutant. In addition, overexpression of KIAA1718 accelerated neural differentiation. We provide the evidence that the pro-neural differentiation effect of KDM7A is mediated through direct transcriptional activation of FGF4, a signal molecule implicated in neural differentiation. Thus, our study identified a dual-specificity histone demethylase that regulates neural differentiation through FGF4.展开更多
An approach was proposed to specify the C4ISR capability of domain-specific modeling language.To confine the domain modeling within a standard architecture framework,formally a C4ISR capability meta-ontology was defin...An approach was proposed to specify the C4ISR capability of domain-specific modeling language.To confine the domain modeling within a standard architecture framework,formally a C4ISR capability meta-ontology was defined according to the meta-model of DoD Architecture Framework.The meta-ontology is used for extending UML Profile so that the domain experts can model the C4ISR domains using the C4ISR capability meta-concepts to define a domain-specific modeling language.The domain models can be then checked to guarantee the consistency and completeness through converting the UML models into the Description Logic ontology and making use of inference engine Pellet to verify the ontology.展开更多
In plants,heteromorphic self-incompatibility(HetSI)is a strategy for avoiding self-pollination and promoting outcrossing,and during this process,numerous protein-protein interaction events occur between the pistil and...In plants,heteromorphic self-incompatibility(HetSI)is a strategy for avoiding self-pollination and promoting outcrossing,and during this process,numerous protein-protein interaction events occur between the pistil and pollen.Previous studies in Primula and Fagopyrum that focused on HetSI systems have provided interesting insights;however,the molecular mechanism underlying HetSI remains largely unknown.In this study,we profiled the proteome of Plumbago auriculata stigmas before and after self-incompatible(SI)and self-compatible(SC)pollination.Comparative analyses were conducted by 4D-DIA(Four-dimensional data independent acquisition),a promising technology that increases the sensitivity and reduces the spectral complexity of proteomic analysis by adding a fourth dimension,ion mobility.The results revealed 33387 peptides and 5311 proteins in all samples.The pathways in which the differentially expressed proteins(DEPs)identified in the P×P(Pin style self-pollinated with pin pollen)vs.PS(Pin style)and T×T(Thrum style self-pollinated with thrum pollen)vs.TS(Thrum style)comparisons were significantly enriched were biosynthesis of secondary metabolites and pentose and glucuronate interconversions.In the P×T(Pin style cross-pollinated with thrum pollen)vs.PS and T×P(Thrum style cross-pollinated with pin pollen)vs.TS comparison,the top three pathways were biosynthesis of secondary metabolites,pentose and glucuronate interconversions,and phenylpropanoid biosynthesis.The phenylpropanoid biosynthesis,cutin,suberine and wax biosynthesis,and flavonoid biosynthesis pathways were enriched in the P×T vs.P×P comparison,and starch and sucrose metabolism,glycerophospholipid metabolism,and alpha-linolenic acid metabolism were abundant in the T×T vs.T×P comparison.The enriched pathways between PS and TS were the biosynthesis of secondary metabolites,phenylpropanoid biosynthesis,and pentose and glucuronate interconversion.Self-incompatibility protein S1(SI S1),Mitogen-activated protein kinase 3/4(MPK3/4),Mitogen-activated protein kinase kinase 2/3(M2K2/3),Exocyst complex component EXO70A1(E70A1)and Thioredoxin H1/2(TRXH1/2)were found to be HetSI-related candidates,and O-fucosyltransferase 23(OFT23),3-ketoacyl-CoA synthase 6(KCS6),Receptor-like protein kinase FERONIA(FERON),Fimbrin-5(FIMB5),Pollen-specific leucine-rich repeat extensin-like protein 4(PLRX4),Transcription initiation factor IIB-2(TF2B2)and Pectinesterase 1(AL11A),etc.,were identified as other regulatory transducers.These findings combined with our morphological and reactive oxygen species(ROS)intensity analyses indicate that P.auriculata has typical dry-stigmas and that the HetSI mechanism might differ between the pin and thrum.SI S1 might be the key factor in HetSI,and ROS are overexpressed during SC pollination to rapidly activate the mitogen-activated protein kinase(MAPK)-mediated phosphorylation of E70A1 to maintain stigma receptivity in plants with HetSI.展开更多
Accurately assessing and tracking the progression of liver-specific injury remains a major challenge in the field of biomarker research.Here,we took a retrospective validation approach built on the mutuality between s...Accurately assessing and tracking the progression of liver-specific injury remains a major challenge in the field of biomarker research.Here,we took a retrospective validation approach built on the mutuality between serum and tissue biomarkers to characterize the liver-specific damage of bile duct cells caused by a-naphthyl isothiocyanate(ANIT).We found that carboxylesterase 1(CES1),as an intrahepatic marker,and dipeptidyl peptidase 4(DPP-IV),as an extrahepatic marker,can reflect the different pathophysiologies of liver injury.Levels of CES1 and DPP-IV can be used to identify liver damage itself and the inflammatory state,respectively.While the levels of the conventional serological biomarkers alkaline phosphatase(ALP),alanine aminotransferase(ALT),and aspartate aminotransferase(AST)were all concomitantly elevated in serum and tissues after ANIT-induced injury,the levels of bile acids decreased in bile,increased in serum,and ascended in intrahepatic tissue.Although the level of γ-glutamyl transpeptidase(γ-GT)changed in an opposite direction,the duration was much shorter than that of CES1 and was quickly restored to normal levels.Therefore,among the abovementioned biomarkers,only CES1 made it possible to specifically determine whether the liver cells were destroyed or damaged without interference from inflammation.CES1 also enabled accurate assessment of the anti-cholestasis effects of ursodeoxycholic acid(UDCA;single component)and Qing Fei Pai Du Decoction(QFPDD;multicomponent).We found that both QFPDD and UDCA attenuated ANIT-induced liver damage.UDCA was more potent in promoting bile excretion but showed relatively weaker anti-injury and antiinflammatory effects than QFPDD,whereas QFPDD was more effective in blocking liver inflammation and repairing liver damage.Our data highlights the potential of the combined use of CES1(as an intrahepatic marker of liver damage)and DPP-IV(as an extrahepatic marker of inflammation)for the accurate evaluation and tracking of liver-specific injury—an application that allows for the differentiation of liver damage and inflammatory liver injury.展开更多
Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidati...Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.展开更多
Multiple sclerosis(MS)is the most common chronic disease of the central nervous system(CNS)in young adults and represents the first cause of severe handicap,originally non-traumatic(Oh et al.,2018).MS is chara cterize...Multiple sclerosis(MS)is the most common chronic disease of the central nervous system(CNS)in young adults and represents the first cause of severe handicap,originally non-traumatic(Oh et al.,2018).MS is chara cterized by the infiltration of auto reactive lymphocytes specific to myelin through the blood-brain barrier,which results in the appearance of inflammatory demyelinating lesions caused by the death of the central nervous system myelinating cells,oligodendrocytes(Oh et al.,2018).There is a prevalence sexual with a ratio of three times more affected women than men.展开更多
T cell activation following alloantigen recognition plays a critical role in the development of the rejection in all solid organ, tissue and cell transplantation. A recombinant molecule, cytotoxic T lymphocyte antigen...T cell activation following alloantigen recognition plays a critical role in the development of the rejection in all solid organ, tissue and cell transplantation. A recombinant molecule, cytotoxic T lymphocyte antigen 4 antibody （CTLA-4Ig）, is known to induce to T-cell into ＂anergy＂ by blocking the costimulatory B7-CD28 interaction. Either systemic or localized administration of CTLA-Ig has been shown to prolong allograft survival and induce donor-specific tolerance in some transplant models. In this study, we characterized the expression and immunosuppressive effectiveness of adenoviral-mediated CTLA-4Ig gene transfer. We demonstrated transduction of the allografts with AdCTLA-4Ig resulted in localized expression, permanent graft survival and stable donor-specific tolerance. In addition, by performing simultaneous dual-organ through a local expression of CTLA-4Ig via adenoviral-mediated transplantation, we targeted on immunosuppression gene transfer into pancreatic allografts.展开更多
文摘BACKGROUND Hepatocellular carcinoma(HCC)is a common malignancy worldwide,and the mortality rate continues to rise each year.SMARCA4 expression has been associated with poor prognosis in various types of cancer;however,the specific mechanism of action of SMARCA4 in HCC needs to be fully elucidated.AIM To explore the specific mechanism of action of SMARCA4 in HCC.METHODS Herein,the expression level of SMARCA4 as well as its association with HCC prognosis were evaluated using transcriptome profiling and clinical data of 18 different types of cancer collected from The Cancer Genome Atlas database.Furthermore,SMARCA4-high and-low groups were identified.Thereafter,gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify the function of SMARCA4,followed by construction of a SMARCA4-specific competing endogenous RNA(ceRNA)network using starBase database.The role of SMARCA4 in immunotherapy and its association with immune cells were assessed using correlation analysis.RESULTS It was observed that SMARCA4 was overexpressed and negatively correlated with prognosis in HCC.Further,SMARCA4 expression was positively associated with tumor mutational burden,microsatellite stability,and immunotherapy efficacy.The SNHG3/THUMP3-AS1-miR-139-5p-SMARCA4 ceRNA network was established and could be assumed to serve as a stimulatory mechanism in HCC.CONCLUSION The findings of this study demonstrated that SMARCA4 plays a significant role in progression and immune infiltration in HCC.Moreover,a ceRNA network was detected,which was found to be correlated with poor prognosis in HCC.The findings of this study could contribute towards the identification of predictive markers for immunotherapy and a novel mechanism of action for HCC treatment.
基金supported by grants from the National Basic Research Development Program of China (2010CB529806)the National Natural Science Foundation of China (31171064)+1 种基金the Key Research Program of Science and Technology Commissions of Shanghai Municipality (11JC1404300)the Leading Academic Discipline Project of Shanghai Municipal Education Commission (J50108)
文摘Objective In this study, the pharmacological kinetics of Buthus martensi Karsch （BmK） AS, a specific modulator of voltage-gated sodium channel site 4, was investigated on Nav1.3 expressed in Xenopus oocytes. Methods Two-electrode voltage clamp was used to record the whole-cell sodium current. Results The peak currents of Nav1.3 were depressed by BmK AS over a wide range of concentrations （10, 100, and 500 nmol/L）. Most remarkably, BmK AS at 100 nmol/L hyperpolarized the voltage-dependence and increased the voltage-sensitivity of steady-state activation/inactivation. In addition, BmK AS was capable of hyperpolarizing not only the fast inactivation but also the slow inactivation, with a greater preference for the latter. Moreover, BmK AS accelerated the time constant and increased the ratio of recovery in Nav1.3 at all concentrations. Conclusion This study provides direct evidence that BmK AS facilitates steady-state activation and inhibits slow inactivation by stabilizing both the closed and open states of the Nav1.3 channel, which might result from an integrative binding to two receptor sites on the voltage-gated sodium channels. These results may shed light on therapeutics against Nav1.3-targeted pathology.
文摘Despite the advent of biological products, such as anti-tumor necrosis factor-α monoclonal antibodies (infliximab and adalimumab), for treatment of moderate to severe cases of inflammatory bowel disease (IBD), most patients depend upon aminosalicylates as the conventional treatment option. In recent years, the increased knowledge of complex pathophysiological processes underlying IBD has resulted in development of a number of newer pharmaceutical agents like low-molecular-weight heparin, omega-3 fatty acids, probiotics and innovative formulations such as high-dose, once-daily multi-matrix mesalamine, which are designed to minimize the inflammatory process through inhibition of different targets. Optimization of delivery of existing drugs to the colon using the prodrug approach is another attractive alternative that has been utilized and commercialized for 5-aminosalicylic acid (ASA) in the form of sulfasalazine, balsalazide, olsalazine and ipsalazine, but rarely for its positional isomer 4-ASA - a well-established antitubercular drug that is twice as potent as 5-ASA against IBD, and more specifically, ulcerative colitis. The present review focuses on the complete profile of 4-ASA and its advantages over 5-ASA and colon-targeting prodrugs reported so far for the management of IBD. The review also emphasizes the need for reappraisal of this promising but unexplored entity as a potential treatment option for IBD.
基金Supplementary information is linked to the online version of the paper on the Cell Research website.Acknowledgments We thank Anning Lin （The University of Chicago） for the critical reading of the paper, members in the Chen lab for technical help, the cell biology and molecular biology core facilities for confocal study and Q-PCR, and Shanghai Biochip Co Ltd. for microarray analysis. The H3K27me2 antibody was kindly provided by Li Tang （Fudan University） and Thomas Jenuwein （Research Institute of Molecular Pathology, The Vienna Biocenter）. This work was supported by the National Basic Research Program of China （2007CB957900, 2006CB943902, 2007CB947101, 2008KR0695, 2009CB941100, 2005CB522704）, the Chinese Academy of Sciences （KSCX2-YW-R-04）, the National Natural Science Foundation of China （90919026, 30870538,30623003, 30721065, 30830034, 90919046）, the Shanghai Pujiang Program （0757S11361）, the Shanghai Key Project of Basic Science Research （06DJ14001, 06DZ22032, 08DJ1400501）, and the Council of Shanghai Municipal Government for Science and Technology （088014199）.
文摘Dimethylations of histone H3 lysine 9 and lysine 27 are important epigenetic marks associated with transcription repression. Here, we identified KIAA1718 （KDM7A） as a novel histone demethylase specific for these two repressing marks. Using mouse embryonic stem cells, we demonstrated that KIAA1718 expression increased at the early phase of neural differentiation. Knockdown of the gene blocked neural differentiation and the effect was rescued by the wild-type human gene, and not by a catalytically inactive mutant. In addition, overexpression of KIAA1718 accelerated neural differentiation. We provide the evidence that the pro-neural differentiation effect of KDM7A is mediated through direct transcriptional activation of FGF4, a signal molecule implicated in neural differentiation. Thus, our study identified a dual-specificity histone demethylase that regulates neural differentiation through FGF4.
基金Project(2007AA01Z126) supported by the National High Technology Research and Development Program of ChinaProject(51306010202) supported by the National Defense Advance Research Program of China
文摘An approach was proposed to specify the C4ISR capability of domain-specific modeling language.To confine the domain modeling within a standard architecture framework,formally a C4ISR capability meta-ontology was defined according to the meta-model of DoD Architecture Framework.The meta-ontology is used for extending UML Profile so that the domain experts can model the C4ISR domains using the C4ISR capability meta-concepts to define a domain-specific modeling language.The domain models can be then checked to guarantee the consistency and completeness through converting the UML models into the Description Logic ontology and making use of inference engine Pellet to verify the ontology.
基金Scientific Research Foundation of Science&Technology Department of Sichuan Province(2021YJ0497).
文摘In plants,heteromorphic self-incompatibility(HetSI)is a strategy for avoiding self-pollination and promoting outcrossing,and during this process,numerous protein-protein interaction events occur between the pistil and pollen.Previous studies in Primula and Fagopyrum that focused on HetSI systems have provided interesting insights;however,the molecular mechanism underlying HetSI remains largely unknown.In this study,we profiled the proteome of Plumbago auriculata stigmas before and after self-incompatible(SI)and self-compatible(SC)pollination.Comparative analyses were conducted by 4D-DIA(Four-dimensional data independent acquisition),a promising technology that increases the sensitivity and reduces the spectral complexity of proteomic analysis by adding a fourth dimension,ion mobility.The results revealed 33387 peptides and 5311 proteins in all samples.The pathways in which the differentially expressed proteins(DEPs)identified in the P×P(Pin style self-pollinated with pin pollen)vs.PS(Pin style)and T×T(Thrum style self-pollinated with thrum pollen)vs.TS(Thrum style)comparisons were significantly enriched were biosynthesis of secondary metabolites and pentose and glucuronate interconversions.In the P×T(Pin style cross-pollinated with thrum pollen)vs.PS and T×P(Thrum style cross-pollinated with pin pollen)vs.TS comparison,the top three pathways were biosynthesis of secondary metabolites,pentose and glucuronate interconversions,and phenylpropanoid biosynthesis.The phenylpropanoid biosynthesis,cutin,suberine and wax biosynthesis,and flavonoid biosynthesis pathways were enriched in the P×T vs.P×P comparison,and starch and sucrose metabolism,glycerophospholipid metabolism,and alpha-linolenic acid metabolism were abundant in the T×T vs.T×P comparison.The enriched pathways between PS and TS were the biosynthesis of secondary metabolites,phenylpropanoid biosynthesis,and pentose and glucuronate interconversion.Self-incompatibility protein S1(SI S1),Mitogen-activated protein kinase 3/4(MPK3/4),Mitogen-activated protein kinase kinase 2/3(M2K2/3),Exocyst complex component EXO70A1(E70A1)and Thioredoxin H1/2(TRXH1/2)were found to be HetSI-related candidates,and O-fucosyltransferase 23(OFT23),3-ketoacyl-CoA synthase 6(KCS6),Receptor-like protein kinase FERONIA(FERON),Fimbrin-5(FIMB5),Pollen-specific leucine-rich repeat extensin-like protein 4(PLRX4),Transcription initiation factor IIB-2(TF2B2)and Pectinesterase 1(AL11A),etc.,were identified as other regulatory transducers.These findings combined with our morphological and reactive oxygen species(ROS)intensity analyses indicate that P.auriculata has typical dry-stigmas and that the HetSI mechanism might differ between the pin and thrum.SI S1 might be the key factor in HetSI,and ROS are overexpressed during SC pollination to rapidly activate the mitogen-activated protein kinase(MAPK)-mediated phosphorylation of E70A1 to maintain stigma receptivity in plants with HetSI.
基金This article is supported by the National Key Research and Development Program of China(2017YFC1702000,2020YFC0845400,and 2021YFE0200900)National Natural Science Foundation of China(81773810,81922070,and 81973393).The authors would like to thank Peter for his help in publishing the article,and the support provided by Zhaoyan(Suzhou)New Drug Research Center Co,.Ltd.
文摘Accurately assessing and tracking the progression of liver-specific injury remains a major challenge in the field of biomarker research.Here,we took a retrospective validation approach built on the mutuality between serum and tissue biomarkers to characterize the liver-specific damage of bile duct cells caused by a-naphthyl isothiocyanate(ANIT).We found that carboxylesterase 1(CES1),as an intrahepatic marker,and dipeptidyl peptidase 4(DPP-IV),as an extrahepatic marker,can reflect the different pathophysiologies of liver injury.Levels of CES1 and DPP-IV can be used to identify liver damage itself and the inflammatory state,respectively.While the levels of the conventional serological biomarkers alkaline phosphatase(ALP),alanine aminotransferase(ALT),and aspartate aminotransferase(AST)were all concomitantly elevated in serum and tissues after ANIT-induced injury,the levels of bile acids decreased in bile,increased in serum,and ascended in intrahepatic tissue.Although the level of γ-glutamyl transpeptidase(γ-GT)changed in an opposite direction,the duration was much shorter than that of CES1 and was quickly restored to normal levels.Therefore,among the abovementioned biomarkers,only CES1 made it possible to specifically determine whether the liver cells were destroyed or damaged without interference from inflammation.CES1 also enabled accurate assessment of the anti-cholestasis effects of ursodeoxycholic acid(UDCA;single component)and Qing Fei Pai Du Decoction(QFPDD;multicomponent).We found that both QFPDD and UDCA attenuated ANIT-induced liver damage.UDCA was more potent in promoting bile excretion but showed relatively weaker anti-injury and antiinflammatory effects than QFPDD,whereas QFPDD was more effective in blocking liver inflammation and repairing liver damage.Our data highlights the potential of the combined use of CES1(as an intrahepatic marker of liver damage)and DPP-IV(as an extrahepatic marker of inflammation)for the accurate evaluation and tracking of liver-specific injury—an application that allows for the differentiation of liver damage and inflammatory liver injury.
基金supported by the National Natural Science Foundation of China,Nos.82271444(to JP),82271268(to BZ),and 82001346(to YL)the National Key Research and Development Program of China,No.2022YFE0210100(to BZ)。
文摘Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.
基金supported by a grant from the French Multiple Sclerosis Society(ARSEP,Grant Number:R20163LL)(to AMG)。
文摘Multiple sclerosis(MS)is the most common chronic disease of the central nervous system(CNS)in young adults and represents the first cause of severe handicap,originally non-traumatic(Oh et al.,2018).MS is chara cterized by the infiltration of auto reactive lymphocytes specific to myelin through the blood-brain barrier,which results in the appearance of inflammatory demyelinating lesions caused by the death of the central nervous system myelinating cells,oligodendrocytes(Oh et al.,2018).There is a prevalence sexual with a ratio of three times more affected women than men.
文摘T cell activation following alloantigen recognition plays a critical role in the development of the rejection in all solid organ, tissue and cell transplantation. A recombinant molecule, cytotoxic T lymphocyte antigen 4 antibody （CTLA-4Ig）, is known to induce to T-cell into ＂anergy＂ by blocking the costimulatory B7-CD28 interaction. Either systemic or localized administration of CTLA-Ig has been shown to prolong allograft survival and induce donor-specific tolerance in some transplant models. In this study, we characterized the expression and immunosuppressive effectiveness of adenoviral-mediated CTLA-4Ig gene transfer. We demonstrated transduction of the allografts with AdCTLA-4Ig resulted in localized expression, permanent graft survival and stable donor-specific tolerance. In addition, by performing simultaneous dual-organ through a local expression of CTLA-4Ig via adenoviral-mediated transplantation, we targeted on immunosuppression gene transfer into pancreatic allografts.
