Physarum polycephalum L., a naturally synchronized myxomycophyta, was demonstrated to contain a cyclin B1-like protein by Western blot and immunoelectron microscopy. The content and subcellular location of the protein...Physarum polycephalum L., a naturally synchronized myxomycophyta, was demonstrated to contain a cyclin B1-like protein by Western blot and immunoelectron microscopy. The content and subcellular location of the protein varied during the cell cycle. The cyclin B1-like protein was first detected in the plasmodia of S phase while it did not appear in the nuclei until late G2 phase. The content of the protein in both the plasmodia and nuclei rose gradually onwards, peaked at metaphase and disappeared abruptly at ana-telophase. The protein was found to be distributed in both the cytoplasm and nuclei in late G2 phase and metaphase. In nuclei, the protein was mainly located in the chromosomal and nucleolar areas. The results suggest that the cyclin B1-like protein of P. polycephalum begins to be synthesized at S phase, enters the nuclei at late G2 phase, accumulates in both cytoplasm and nuclei onwards and breaks down at ana-telophase. The results also suggest that the cyclin B1-like protein acts as a cytoplasmic-nuclear protein during certain phases of the cell cycle.展开更多
Background:Serum chitinase-3-like protein 1(CHI3L1)is a potential biomarker for fibrosis assessment.We aimed to evaluate serum CHI3L1 as a noninvasive diagnostic marker for chronic hepatitis B virusrelated fibrosis.Me...Background:Serum chitinase-3-like protein 1(CHI3L1)is a potential biomarker for fibrosis assessment.We aimed to evaluate serum CHI3L1 as a noninvasive diagnostic marker for chronic hepatitis B virusrelated fibrosis.Methods:Serum CHI3L1 levels were measured by ELISA in 134 chronic hepatitis B(CHB)patients.Significant fibrosis was defined as a liver stiffness>9.7 kPa.The performance of CHI3L1 was assessed and compared to that of other noninvasive tests by receiver operating characteristic(ROC)analysis.Results:Serum CHI3L1 levels were significantly higher in CHB patients with significant hepatic fibrosis(≥F2)than in those without significant hepatic fibrosis(<F2)(56.5 ng/mL vs.81.9 ng/mL,P<0.001).In CHB patients,the specificity and sensitivity of CHI3L1 for predicting significant fibrosis were 75.6%and 59.1%,respectively,with a cut-off of 76.0 ng/mL and an area under the ROC curve of 0.728(95%CI:0.637–0.820).Conclusions:Serum CHI3L1 levels could be an effective new serological biomarker for the diagnosis of liver fibrosis.Moreover,CHI3L1 is feasible in monitoring disease progression.展开更多
Atherosclerosis is the major complication of diabetes and has become a major issue in the provision of medical care.In particular the economic burden is growing at an alarming rate in parallel with the increasing worl...Atherosclerosis is the major complication of diabetes and has become a major issue in the provision of medical care.In particular the economic burden is growing at an alarming rate in parallel with the increasing worldwide prevalence of diabetes.The major disturbance of lipid metabolism in diabetes relates to the effect of insulin on fat metabolism.Raised triglycerides being the hallmark of uncontrolled diabetes,i.e.,in the presence of hyperglycaemia.The explosion of type 2 diabetes has generated increasing interest on the aetiology ofatherosclerosis in diabetic patients.The importance of the atherogenic properties of triglyceride rich lipoproteins has only recently been recognised by the majority of diabetologists and cardiologists even though experimental evidence has been strong for many years.In the post-prandial phase 50% of triglyceride rich lipoproteins come from chylomicrons produced in the intestine.Recent evidence has secured the chylomicron as a major player in the atherogenic process.In diabetes chylomicron production is increased through disturbance in cholesterol absorption,in particular Neimann Pick C1-like1 activity is increased as is intestinal synthesis of cholesterol through 3-hydroxy-3-methyl glutaryl co enzyme A reductase.ATP binding cassette proteins G5 and G8 which regulate cholesterol in the intestine is reduced leading to chylomicronaemia.The chylomicron particle itself is atherogenic but the increase in the triglyceride-rich lipoproteins lead to an atherogenic low density lipoprotein and low high density lipoprotein.The various steps in the absorption process and the disturbance in chylomicron synthesis are discussed.展开更多
AIM:To evaluate the potential of two trabecular meshwork(TM)-specific promoters,Chitinase 3-like 1(Ch3L1)and matrix gla protein(MGP),for improving specificity and safety in glaucoma gene therapy based on self-compleme...AIM:To evaluate the potential of two trabecular meshwork(TM)-specific promoters,Chitinase 3-like 1(Ch3L1)and matrix gla protein(MGP),for improving specificity and safety in glaucoma gene therapy based on self-complementary AAV2(scAAV2)vector technologies.METHODS:An scAAV2 vector with C3 transferase(C3)as the reporter gene(scAAV2-C3)was selected.The scAAV2-C3 vectors were driven by Ch3L1(scAAV2-Ch3L1-C3),MGP(scAAV2-MGP-C3),enhanced MGP(scAAV2-eMGP-C3)and cytomegalovirus(scAAV2-CMV-C3),respectively.The cultured primary human TM cells were treated with each vector at different multiplicities of infections.Changes in cell morphology were observed by phase contrast microscopy.Actin stress fibers and Rho GTPases/Rho-associated protein kinase pathway-related molecules were assessed by immunofluorescence staining,real-time quantitative polymerase chain reaction and Western blot.Each vector was injected intracamerally into the one eye of each rat at low and high doses respectively.In vivo green fluorescence was visualized by a Micron III Retinal Imaging Microscope.Intraocular pressure(IOP)was monitored using a rebound tonometer.Ocular responses were evaluated by slit-lamp microscopy.Ocular histopathology analysis was examined by hematoxylin and eosin staining.RESULTS:In TM cell culture studies,the vectormediated C3 expression induced morphologic changes,disruption of actin cytoskeleton and reduction of fibronectin expression in TM cells by inhibiting the Rho GTPases/Rhoassociated protein kinase signaling pathway.At the same dose,these changes were significant in TM cells treated with scAAV2-CMV-C3 or scAAV2-Ch3L1-C3,but not in cells treated with scAAV2-eMGP-C3 or scAAV2-MGP-C3.At lowinjected dose,the IOP was significantly decreased in the scAAV2-Ch3L1-C3-injected eyes but not in scAAV2-MGPC3-injected and scAAV2-eMGP-C3-injected eyes.At highinjected dose,significant IOP reduction was observed in the scAAV2-eMGP-C3-injected eyes but not in scAAV2-MGP-C3-injected eyes.Similar to scAAV2-CMV-C3,scAAV2-Ch3L1-C3 vector showed efficient transduction both in the TM and corneal endothelium.In anterior segment tissues of scAAV2-eMGP-C3-injected eyes,no obvious morphological changes were found except for the TM.Inflammation was absent.CONCLUSION:In scAAV2-transduced TM cells,the promoter-driven efficiency of Ch3L1 is close to that of cytomegalovirus,but obviously higher than that of MGP.In the anterior chamber of rat eye,the transgene expression pattern of scAAV2 vector is presumably affected by MGP promoter,but not by Ch3L1 promoter.These findings would provide a useful reference for improvement of specificity and safety in glaucoma gene therapy using scAAV2 vector.展开更多
Background:Visinin-like protein-1(VILIP-1)and chitinase-3-like protein 1(CHI3L1 or YKL-40)in cerebrospinal fluid(CSF)are newly discovered markers indicating neuronal damage and microglial activation,respectively.Phosp...Background:Visinin-like protein-1(VILIP-1)and chitinase-3-like protein 1(CHI3L1 or YKL-40)in cerebrospinal fluid(CSF)are newly discovered markers indicating neuronal damage and microglial activation,respectively.Phosphorylated tau(p-tau)reflects the neuropathology of Alzheimer’s disease(AD)and is useful as diagnostic markers for AD.However,it is unknown whether these biomarkers have similar or complementary information in AD.Methods:We stratified 121 participants from the Alzheimer’s Disease Neuroimaging Initiative(ADNI)database into cognitively normal(CN),stable mild cognitive impairment(sMCI),progressive MCI(pMCI),and dementia due to AD.Analysis of covariance(ANOVA)and chi-square analyses,Spearman correlation,and logistic regression models were performed to test the demographic,associations between biomarkers,and diagnostic accuracies,respectively.Linear mixed-effects models were used to evaluate the effects of CSF amyloid-β(Aβ)on above biomarkers within diagnostic groups,the combination of diagnostic group and Aβstatus as predictor,and CSF biomarkers as predictors of AD features,including cognition measured by Mini–Mental State Examination(MMSE)and brain structure and white matter hyperintensity(WMH)measured by magnetic resonance imaging(MRI).Results:P-tau,VILIP-1,and YKL-40 were all predictors of AD diagnosis,but combinations of biomarkers did not improve the diagnostic accuracy(AUC 0.924 for p-tau,VILIP-1,and YKL-40)compared to p-tau(AUC 0.922).P-tau and VILIP-1 were highly correlated(r=0.639,p<0.001)and strongly associated with Aβpathology across clinical stages of AD,while YKL-40 was correlated with Aβpathology in CN and AD groups.VILIP-1 was associated with acceleration of cognitive decline,hippocampal atrophy,and expansion of ventricles in longitudinal analyses.YKL-40 was associated with hippocampal atrophy at baseline and follow-up,while p-tau was only associated with worsening WMH at baseline.Conclusions:CSF levels of p-tau,VILIP-1,and YKL-40 may have utility for discriminating between cognitively normal subjects and patients with AD.Increased levels of both VILIP-1 and YKL-40 may be associated with disease degeneration.These CSF biomarkers should be considered for future assessment in the characterization of the natural history of AD.展开更多
As abscisic acid(ABA)receptor,the pyrabactin resistance 1-like(PYR/PYL)protein(named PYL for simplicity)plays an important part to unveil the signal transduction of ABA and its regulatory mechanisms.Glycyrrhiza uralen...As abscisic acid(ABA)receptor,the pyrabactin resistance 1-like(PYR/PYL)protein(named PYL for simplicity)plays an important part to unveil the signal transduction of ABA and its regulatory mechanisms.Glycyrrhiza uralensis,a drought-tolerant medicinal plant,is a good model for the mechanism analysis of ABA response and active compound biosynthesis.However,knowledge about PYL family in G.uralensis remains largely unknown.Here,10 PYLs were identified in G.uralensis genome.Characterization analysis indicated that PYLs in G.uralensis(Gu PYLs)are relatively conserved.Phylogenetic analysis showed that Gu PYL1-3 belongs to subfamily I,Gu PYL4-6 and Gu PYL10 belong to subfamily II and Gu PYL7-9 belongs to subfamily III.In addition,transcriptome data presented various expression levels of Gu PYLs under different exogenous ABA stresses.The expression pattern of Gu PYLs was verified by Quantitative real-time polymerase chain reaction(q RT-PCR).The study proved that Gu PYL4,Gu PYL5,Gu PYL8 and Gu PYL9 genes are significantly up-regulated by ABA stress and the response process is dynamic.This study paves the way for elucidating the regulation mechanism of ABA signal to secondary metabolites and improving the cultivation and quality of G.uralensis using agricultural strategies.展开更多
AIM:To investigate the interaction of interleukin-23 receptor(IL23R)(rs1004819 and rs2201841),autophagy-related 16-like 1(ATG16L1)(rs2241880), caspase recruitment domain-containing protein 15 (CARD15)genes,and IBD5 lo...AIM:To investigate the interaction of interleukin-23 receptor(IL23R)(rs1004819 and rs2201841),autophagy-related 16-like 1(ATG16L1)(rs2241880), caspase recruitment domain-containing protein 15 (CARD15)genes,and IBD5 locus in Crohn's disease(CD) patients. METHODS:A total of 315 unrelated subjects with CD and 314 healthy controls were genotyped.Interactions and specific genotype combinations of a total of eight variants were tested.The variants of IBD5locus(IGR2198a_1 rs11739135 and IGR2096a_1 rs12521868),CARD15(R702W rs2066845 and L1007fs rs2066847),ATG16L1(rs2241880)and IL23R (rs1004819,rs2201841)genes were genotyped by PCR-RFLP,the G908R(rs2066844)in CARD15 was determined by direct sequencing. RESULTS:The association of ATG16L1 T300A with CD was confirmed[P=0.004,odds ratio(OR)=1.69, 95%CI:1.19-2.41],and both IL23R variants were found to represent significant risk for the disease(P= 0.008,OR=2.05,95%CI:1.20-3.50 for rs1004819 AA;P<0.001,OR=2.97,95%CI:1.65-5.33 for rs2201841 CC).Logistic regression analysis of pairwise interaction of the inflammatory bowel disease (IBD)loci indicated that IL23R,ATG16L1,CARD15 and IBD5(IGR2198a_1)contribute independently to disease risk.We also analysed the specific combina- tions by pair of individual ATG16L1,IL23R rs1004819, rs2201841,IGR2198a_1,IGR2096a_1 and CARD15 genotypes for disease risk influence.In almost all cases,the combined risk of susceptibility pairs was higher in patients carrying two different risk-associated gene variants together than individuals with just one polymorphism.The highest OR was found for IL23R rs2201841 homozygous genotype with combination of positive CARD15 status(P<0.001,OR=9.15,95% CI:2.05-40.74). CONCLUSION:The present study suggests a cumulative effect of individual IBD susceptibility loci.展开更多
The treatment of hepatocellular carcinoma(HCC)has been dominated by multikinase inhibitors for more than a decade.However,drug resistance can severely restrict the efficacy of these drugs.Using CRISPR/CAS9 genome libr...The treatment of hepatocellular carcinoma(HCC)has been dominated by multikinase inhibitors for more than a decade.However,drug resistance can severely restrict the efficacy of these drugs.Using CRISPR/CAS9 genome library screening,we evaluated Kelch-like ECH-associated protein 1(KEAP1)as a key regulator of sorafenib’s susceptibility in HCC.We also investigated whether KEAP1’s knockdown can stabilize nuclear factor(erythroid-derived 2)-like 2(NRF2)protein levels that led to sorafenib’s resistance,including an NRF2 inhibitor that can synergize with sorafenib to abolish HCC’s growth in vitro and in vivo.Furthermore,we clarified that fibroblast growth factor 21(FGF21)is an important downstream regulator of NRF2 in HCC.Intriguingly,we observed that FGF21 bound to NRF2 through the C-terminus of FGF21,thereby stabilizing NRF2 by reducing its ubiquitination and generating a positive feedback loop in sorafenib-resistant HCC.These findings,therefore,propose that targeting FGF21 is a promising strategy to combat HCC sorafenib’s resistance.展开更多
Cerebral ischemia is a neurological disorder associated with complex pathological mechanisms,including autophagic degradation of neuronal mitochondria,or termed mitophagy,following ischemic events.Despite being well-d...Cerebral ischemia is a neurological disorder associated with complex pathological mechanisms,including autophagic degradation of neuronal mitochondria,or termed mitophagy,following ischemic events.Despite being well-documented,the cellular and molecular mechanisms under-lying the regulation of neuronal mitophagy remain unknown.So far,the evidence suggests neuronal autophagy and mitophagy are separately regulated in ischemic neurons,the latter being more likely activated by reperfusional injury.Specifically,given the polarized morphology of neurons,mitophagy is regulated by different neuronal compartments,with axonal mitochondria being degraded by autophagy in the cell body following ischemia-reperfusion insult.A variety of molecules have been associated with neuronal adaptation to ischemia,including PTEN-induced kinase 1,Parkin,BCL2 and adenovirus E1B 19-kDa-interacting protein 3(Bnip3),Bnip3-like(Bnip3l)and FUN14 domain-containing 1.Moreover,it is still controversial whether mitophagy protects against or instead aggravates ischemic brain injury.Here,we review recent studies on this topic and provide an updated overview of the role and regulation of mitophagy during ischemic events.展开更多
Background： Acute coronary syndrome （ACS） is closely related to unstable plaques and secondary thrombosis. The inflammatory cells in plaques and their inflammatory products may be the cause for plaque instability a...Background： Acute coronary syndrome （ACS） is closely related to unstable plaques and secondary thrombosis. The inflammatory cells in plaques and their inflammatory products may be the cause for plaque instability and ruptures. The study aimed to disclose the changes of inflammatory factors including serum intracellular adhesion molecule-1（ICAM-1 ）, chitinase-3-like protein I （YKL-40）, and lipoprotein-associated phospholipase A2 （Lp-PLA2） in patients with ACS and its clinical significance. Methods： A total of 120 patients with coronary heart disease （CHD） were categorized into 2 groups： 69 with ACS and 51 with stable angina pectoris （SAP）： 20 patients with chest pain and normal angiography served as a control group. The 120 patients with CHD were categorized into single-vessel disease group, double-vessel disease group, and three-vessel disease group based on the number of coronary artery stenosis. The severity of coronary artery stenosis was quantified based on coronary angiography using Gensini score. They were further divided into mild CHD group with its Gensini score 〈26 （n = 36）, moderate CHD group with its Gensini score being 26-54 （n = 48） and severe CHD group with its Gensini score 〉54 （n = 36）. Serum levels of ICAM-1, YKL-40, and Lp-PLA2 of different groups were determined by enzyme-linked immunosorbent assay. Correlation between ICAM-1, YKL-40, Lp-PLA2, and Gensini score was analyzed. Results： The levels of serum inflammatory factors ICAM-1, YKL-40, and Lp-PLA2 were significantly higher in the ACS group than those in control group and SAP group （all P 〈 0.05）： and compared with control group, no significant difference was observed in terms of the serum ICAM-1, YKL-40, and Lp-PLA2 levels in the SAP group （P 〉 0.05）.The levels of serum ICAM-1, YKL-40, and Lp-PLA2 were not significantly different among control group, single-vessel disease group, double-vessel disease group, and three-vessel disease group （all P 〉 0.05）. The levels of serum ICAM-1, YKL-40, and Lp-PLA2 were not significantly different among control group, mild CHD group （Gensini score 〈26）, moderate CHD group （Gensini score 26-54）, and severe CHD group （Gensini score 〉54） （all P 〉 0.05）. Nonparametric Spearman correlation analysis showed that the levels of serum ICAM-1, YKL-40, and Lp-PLA2 were not correlated with the Gensini score in CHD patients （r=0.093, r=-0.149, and r= -0.085, all P 〉 0.05; respectively）. Conclusions： The serum levels of ICAM-1, YKL-40, and Lp-PLA2 were correlated with different clinical types of CHD, but not well correlated the severity and extent of artery stenosis, suggesting that ICAM-1, YKL-40, and Lp-PLA2 rnight be involved in occurrence of instability of atherosclerotic plaque, and might reflect the severity of CHD mostly through reflecting the plaque stability.展开更多
Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the P...Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the Parkin gene,which itself belongs to an E3 ubiquitin ligase.Since the discovery of the Parkin gene in the late 1990s,researchers in many countries have begun extensive research on this gene and found that in addition to AR-JP,the Parkin gene is associated with many diseases,including type 2 diabetes,leprosy,Alzheimer’s,autism,and cancer.Recent studies have found that the loss or dysfunction of Parkin has a certain relationship with tumorigenesis.In general,the Parkin gene,a well-established tumor suppressor,is deficient and mutated in a variety of malignancies.Parkin overexpres-sion inhibits tumor cell growth and promotes apoptosis.However,the functions of Parkin in tumorigenesis and its regulatory mechanisms are still not fully understood.This article describes the structure,functions,and post-transla-tional modifications of Parkin,and summarizes the recent advances in the tumor suppressive function of Parkin and its underlying mechanisms.展开更多
Objective： To investigate the relationship between inflammatory factors and two Chinese medicine（CM） syndrome types of qi stagnation and blood stasis（QSBS） and qi deficiency and blood stasis（QDBS） in patients w...Objective： To investigate the relationship between inflammatory factors and two Chinese medicine（CM） syndrome types of qi stagnation and blood stasis（QSBS） and qi deficiency and blood stasis（QDBS） in patients with acute coronary syndrome（ACS）. Methods： Sixty subjects with ACS, whose pathogenesis changes belongs to qi disturbance blood stasis syndrome, were divided into 2 groups： 30 in the QSBS group and 30 in the QDBS group. The comparative analysis on them was carried out through comparing general information, coronary angiography and inflammatory factors including intracellular adhesion molecule-1（ICAM-1）, chitinase-3-like protein 1（YKL-40） and lipoprotein-associated phospholipase A2（Lp-PLA2）. Results： Compared with the QSBS group, Lp-PLA2 and YKL-40 levels in the QDBS group showed no-significant difference（P〉0.05）; ICAM-1 was significantly higher in the QDBS group than in the QSBS group in the pathological processes of qi disturbance and blood stasis syndrome of ACS（P〈0.05）. Conclusion： Inflammatory factor ICAM-1 may be an objective basis for syndrome typing of QSBS and QDBS, which provides a research direction for standardization research of CM syndrome types.展开更多
Endoplasmic reticulum(ER)stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion.The unfolded protein response(UPR),comprising of inositol-requiring enzyme 1...Endoplasmic reticulum(ER)stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion.The unfolded protein response(UPR),comprising of inositol-requiring enzyme 1 a(IRE1 a),double-stranded RNA-dependent protein kinase(PKR)-like ER kinase(PERK)and activating transcription factor 6(ATF6)signaling pathways,is a protective cellular response activated by ER stress.However,UPR activation can also induce cell death upon persistent ER stress.The liver is susceptible to ER stress given its synthetic and other biological functions.Numerous studies from human liver samples and animal disease models have indicated a crucial role of ER stress and the UPR signaling pathways in the pathogenesis of liver diseases,including non-alcoholic fatty liver disease(NAFLD),alcoholic liver disease(ALD),alpha-1 antitrypsin(AAT)deficiency(AATD),cholestatic liver disease,drug-induced liver injury,ischemia/reperfusion(I/R)injury,viral hepatitis and hepatocel-lular carcinoma(HCC).Extensive investigations have demonstrated the potential underlying mechanisms of the induction of ER stress and the contribution of the UPR pathways during the development of the diseases.Moreover,ER stress and the UPR proteins and genes have become emerging therapeutic targets to treat liver diseases.展开更多
文摘Physarum polycephalum L., a naturally synchronized myxomycophyta, was demonstrated to contain a cyclin B1-like protein by Western blot and immunoelectron microscopy. The content and subcellular location of the protein varied during the cell cycle. The cyclin B1-like protein was first detected in the plasmodia of S phase while it did not appear in the nuclei until late G2 phase. The content of the protein in both the plasmodia and nuclei rose gradually onwards, peaked at metaphase and disappeared abruptly at ana-telophase. The protein was found to be distributed in both the cytoplasm and nuclei in late G2 phase and metaphase. In nuclei, the protein was mainly located in the chromosomal and nucleolar areas. The results suggest that the cyclin B1-like protein of P. polycephalum begins to be synthesized at S phase, enters the nuclei at late G2 phase, accumulates in both cytoplasm and nuclei onwards and breaks down at ana-telophase. The results also suggest that the cyclin B1-like protein acts as a cytoplasmic-nuclear protein during certain phases of the cell cycle.
基金the Research Ethics Committee of The First Affiliated Hospital of Zhejiang University School of Medicine(No.2018-918).
文摘Background:Serum chitinase-3-like protein 1(CHI3L1)is a potential biomarker for fibrosis assessment.We aimed to evaluate serum CHI3L1 as a noninvasive diagnostic marker for chronic hepatitis B virusrelated fibrosis.Methods:Serum CHI3L1 levels were measured by ELISA in 134 chronic hepatitis B(CHB)patients.Significant fibrosis was defined as a liver stiffness>9.7 kPa.The performance of CHI3L1 was assessed and compared to that of other noninvasive tests by receiver operating characteristic(ROC)analysis.Results:Serum CHI3L1 levels were significantly higher in CHB patients with significant hepatic fibrosis(≥F2)than in those without significant hepatic fibrosis(<F2)(56.5 ng/mL vs.81.9 ng/mL,P<0.001).In CHB patients,the specificity and sensitivity of CHI3L1 for predicting significant fibrosis were 75.6%and 59.1%,respectively,with a cut-off of 76.0 ng/mL and an area under the ROC curve of 0.728(95%CI:0.637–0.820).Conclusions:Serum CHI3L1 levels could be an effective new serological biomarker for the diagnosis of liver fibrosis.Moreover,CHI3L1 is feasible in monitoring disease progression.
文摘Atherosclerosis is the major complication of diabetes and has become a major issue in the provision of medical care.In particular the economic burden is growing at an alarming rate in parallel with the increasing worldwide prevalence of diabetes.The major disturbance of lipid metabolism in diabetes relates to the effect of insulin on fat metabolism.Raised triglycerides being the hallmark of uncontrolled diabetes,i.e.,in the presence of hyperglycaemia.The explosion of type 2 diabetes has generated increasing interest on the aetiology ofatherosclerosis in diabetic patients.The importance of the atherogenic properties of triglyceride rich lipoproteins has only recently been recognised by the majority of diabetologists and cardiologists even though experimental evidence has been strong for many years.In the post-prandial phase 50% of triglyceride rich lipoproteins come from chylomicrons produced in the intestine.Recent evidence has secured the chylomicron as a major player in the atherogenic process.In diabetes chylomicron production is increased through disturbance in cholesterol absorption,in particular Neimann Pick C1-like1 activity is increased as is intestinal synthesis of cholesterol through 3-hydroxy-3-methyl glutaryl co enzyme A reductase.ATP binding cassette proteins G5 and G8 which regulate cholesterol in the intestine is reduced leading to chylomicronaemia.The chylomicron particle itself is atherogenic but the increase in the triglyceride-rich lipoproteins lead to an atherogenic low density lipoprotein and low high density lipoprotein.The various steps in the absorption process and the disturbance in chylomicron synthesis are discussed.
基金Supported by the National Natural Science Foundation of China(No.81900829,No.82070963)the Xiamen Medical and Health Guiding Project Fund Project(No.3502Z20214ZD1214)+1 种基金the Guangdong Basic and Applied Basic Research Foundation(No.2019A1515011234)the Science and Technology Innovation Committee of Shenzhen(No.JCYJ20210324125614039)。
文摘AIM:To evaluate the potential of two trabecular meshwork(TM)-specific promoters,Chitinase 3-like 1(Ch3L1)and matrix gla protein(MGP),for improving specificity and safety in glaucoma gene therapy based on self-complementary AAV2(scAAV2)vector technologies.METHODS:An scAAV2 vector with C3 transferase(C3)as the reporter gene(scAAV2-C3)was selected.The scAAV2-C3 vectors were driven by Ch3L1(scAAV2-Ch3L1-C3),MGP(scAAV2-MGP-C3),enhanced MGP(scAAV2-eMGP-C3)and cytomegalovirus(scAAV2-CMV-C3),respectively.The cultured primary human TM cells were treated with each vector at different multiplicities of infections.Changes in cell morphology were observed by phase contrast microscopy.Actin stress fibers and Rho GTPases/Rho-associated protein kinase pathway-related molecules were assessed by immunofluorescence staining,real-time quantitative polymerase chain reaction and Western blot.Each vector was injected intracamerally into the one eye of each rat at low and high doses respectively.In vivo green fluorescence was visualized by a Micron III Retinal Imaging Microscope.Intraocular pressure(IOP)was monitored using a rebound tonometer.Ocular responses were evaluated by slit-lamp microscopy.Ocular histopathology analysis was examined by hematoxylin and eosin staining.RESULTS:In TM cell culture studies,the vectormediated C3 expression induced morphologic changes,disruption of actin cytoskeleton and reduction of fibronectin expression in TM cells by inhibiting the Rho GTPases/Rhoassociated protein kinase signaling pathway.At the same dose,these changes were significant in TM cells treated with scAAV2-CMV-C3 or scAAV2-Ch3L1-C3,but not in cells treated with scAAV2-eMGP-C3 or scAAV2-MGP-C3.At lowinjected dose,the IOP was significantly decreased in the scAAV2-Ch3L1-C3-injected eyes but not in scAAV2-MGPC3-injected and scAAV2-eMGP-C3-injected eyes.At highinjected dose,significant IOP reduction was observed in the scAAV2-eMGP-C3-injected eyes but not in scAAV2-MGP-C3-injected eyes.Similar to scAAV2-CMV-C3,scAAV2-Ch3L1-C3 vector showed efficient transduction both in the TM and corneal endothelium.In anterior segment tissues of scAAV2-eMGP-C3-injected eyes,no obvious morphological changes were found except for the TM.Inflammation was absent.CONCLUSION:In scAAV2-transduced TM cells,the promoter-driven efficiency of Ch3L1 is close to that of cytomegalovirus,but obviously higher than that of MGP.In the anterior chamber of rat eye,the transgene expression pattern of scAAV2 vector is presumably affected by MGP promoter,but not by Ch3L1 promoter.These findings would provide a useful reference for improvement of specificity and safety in glaucoma gene therapy using scAAV2 vector.
基金Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative(ADNI)(National Institutes of Health Grant U01 AG024904)DOD ADNI(Department of Defense award number W81XWH-12-2-0012)+4 种基金This work was supported by the Weston Brain Institute,Canadian Institutes of Health Research(CIHR)(MOP-11-51-31,PR-N)the Alzheimer’s Association(NIRG-12-92090,NIRP-12-259245,PR-N)Fonds de Recherche du Québec-Santé(FRQSChercheur Boursier,PR-N)Clinical key specialist fund,the Department of Neurology,the First Affiliated Hospital of Chongqing Medical University(scholarship,HZ).
文摘Background:Visinin-like protein-1(VILIP-1)and chitinase-3-like protein 1(CHI3L1 or YKL-40)in cerebrospinal fluid(CSF)are newly discovered markers indicating neuronal damage and microglial activation,respectively.Phosphorylated tau(p-tau)reflects the neuropathology of Alzheimer’s disease(AD)and is useful as diagnostic markers for AD.However,it is unknown whether these biomarkers have similar or complementary information in AD.Methods:We stratified 121 participants from the Alzheimer’s Disease Neuroimaging Initiative(ADNI)database into cognitively normal(CN),stable mild cognitive impairment(sMCI),progressive MCI(pMCI),and dementia due to AD.Analysis of covariance(ANOVA)and chi-square analyses,Spearman correlation,and logistic regression models were performed to test the demographic,associations between biomarkers,and diagnostic accuracies,respectively.Linear mixed-effects models were used to evaluate the effects of CSF amyloid-β(Aβ)on above biomarkers within diagnostic groups,the combination of diagnostic group and Aβstatus as predictor,and CSF biomarkers as predictors of AD features,including cognition measured by Mini–Mental State Examination(MMSE)and brain structure and white matter hyperintensity(WMH)measured by magnetic resonance imaging(MRI).Results:P-tau,VILIP-1,and YKL-40 were all predictors of AD diagnosis,but combinations of biomarkers did not improve the diagnostic accuracy(AUC 0.924 for p-tau,VILIP-1,and YKL-40)compared to p-tau(AUC 0.922).P-tau and VILIP-1 were highly correlated(r=0.639,p<0.001)and strongly associated with Aβpathology across clinical stages of AD,while YKL-40 was correlated with Aβpathology in CN and AD groups.VILIP-1 was associated with acceleration of cognitive decline,hippocampal atrophy,and expansion of ventricles in longitudinal analyses.YKL-40 was associated with hippocampal atrophy at baseline and follow-up,while p-tau was only associated with worsening WMH at baseline.Conclusions:CSF levels of p-tau,VILIP-1,and YKL-40 may have utility for discriminating between cognitively normal subjects and patients with AD.Increased levels of both VILIP-1 and YKL-40 may be associated with disease degeneration.These CSF biomarkers should be considered for future assessment in the characterization of the natural history of AD.
基金supported by the National Science and Technology Major Project for“Significant New Drugs Development”(No.2019ZX09201005-006-003)the ChinesAcademy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS)(No.2016-I2M-3-016)。
文摘As abscisic acid(ABA)receptor,the pyrabactin resistance 1-like(PYR/PYL)protein(named PYL for simplicity)plays an important part to unveil the signal transduction of ABA and its regulatory mechanisms.Glycyrrhiza uralensis,a drought-tolerant medicinal plant,is a good model for the mechanism analysis of ABA response and active compound biosynthesis.However,knowledge about PYL family in G.uralensis remains largely unknown.Here,10 PYLs were identified in G.uralensis genome.Characterization analysis indicated that PYLs in G.uralensis(Gu PYLs)are relatively conserved.Phylogenetic analysis showed that Gu PYL1-3 belongs to subfamily I,Gu PYL4-6 and Gu PYL10 belong to subfamily II and Gu PYL7-9 belongs to subfamily III.In addition,transcriptome data presented various expression levels of Gu PYLs under different exogenous ABA stresses.The expression pattern of Gu PYLs was verified by Quantitative real-time polymerase chain reaction(q RT-PCR).The study proved that Gu PYL4,Gu PYL5,Gu PYL8 and Gu PYL9 genes are significantly up-regulated by ABA stress and the response process is dynamic.This study paves the way for elucidating the regulation mechanism of ABA signal to secondary metabolites and improving the cultivation and quality of G.uralensis using agricultural strategies.
基金Supported by Grant of Hungarian Scientific Research Foundation,No.OTKA T 73430
文摘AIM:To investigate the interaction of interleukin-23 receptor(IL23R)(rs1004819 and rs2201841),autophagy-related 16-like 1(ATG16L1)(rs2241880), caspase recruitment domain-containing protein 15 (CARD15)genes,and IBD5 locus in Crohn's disease(CD) patients. METHODS:A total of 315 unrelated subjects with CD and 314 healthy controls were genotyped.Interactions and specific genotype combinations of a total of eight variants were tested.The variants of IBD5locus(IGR2198a_1 rs11739135 and IGR2096a_1 rs12521868),CARD15(R702W rs2066845 and L1007fs rs2066847),ATG16L1(rs2241880)and IL23R (rs1004819,rs2201841)genes were genotyped by PCR-RFLP,the G908R(rs2066844)in CARD15 was determined by direct sequencing. RESULTS:The association of ATG16L1 T300A with CD was confirmed[P=0.004,odds ratio(OR)=1.69, 95%CI:1.19-2.41],and both IL23R variants were found to represent significant risk for the disease(P= 0.008,OR=2.05,95%CI:1.20-3.50 for rs1004819 AA;P<0.001,OR=2.97,95%CI:1.65-5.33 for rs2201841 CC).Logistic regression analysis of pairwise interaction of the inflammatory bowel disease (IBD)loci indicated that IL23R,ATG16L1,CARD15 and IBD5(IGR2198a_1)contribute independently to disease risk.We also analysed the specific combina- tions by pair of individual ATG16L1,IL23R rs1004819, rs2201841,IGR2198a_1,IGR2096a_1 and CARD15 genotypes for disease risk influence.In almost all cases,the combined risk of susceptibility pairs was higher in patients carrying two different risk-associated gene variants together than individuals with just one polymorphism.The highest OR was found for IL23R rs2201841 homozygous genotype with combination of positive CARD15 status(P<0.001,OR=9.15,95% CI:2.05-40.74). CONCLUSION:The present study suggests a cumulative effect of individual IBD susceptibility loci.
基金supported by the National Natural Science Foundation of China(81702981,81827804,81902367,81772546and LQ18H160010)Zhejiang Provincial Natural Science Foundation of China(LY20H160021 and Y15H160052)+1 种基金China Postdoctoral Science Foundation(2020T130584 and 2020M671755)Health Innovation Talent Support Project of Zhejiang Medical and Health Science and Technology Plan(2021447581)。
文摘The treatment of hepatocellular carcinoma(HCC)has been dominated by multikinase inhibitors for more than a decade.However,drug resistance can severely restrict the efficacy of these drugs.Using CRISPR/CAS9 genome library screening,we evaluated Kelch-like ECH-associated protein 1(KEAP1)as a key regulator of sorafenib’s susceptibility in HCC.We also investigated whether KEAP1’s knockdown can stabilize nuclear factor(erythroid-derived 2)-like 2(NRF2)protein levels that led to sorafenib’s resistance,including an NRF2 inhibitor that can synergize with sorafenib to abolish HCC’s growth in vitro and in vivo.Furthermore,we clarified that fibroblast growth factor 21(FGF21)is an important downstream regulator of NRF2 in HCC.Intriguingly,we observed that FGF21 bound to NRF2 through the C-terminus of FGF21,thereby stabilizing NRF2 by reducing its ubiquitination and generating a positive feedback loop in sorafenib-resistant HCC.These findings,therefore,propose that targeting FGF21 is a promising strategy to combat HCC sorafenib’s resistance.
基金funded by National Natural Science Foundation of China(81973402)Natural Science Foundation of Zhejiang Province(LYY22H310009)+1 种基金Hospital Pharmacy Scientific Research Funding Project of Zhejiang Pharmaceutical Association(2020ZYY10)Clinical research fund project of Zhejiang Medical Association(2020ZYC-A07).
文摘Cerebral ischemia is a neurological disorder associated with complex pathological mechanisms,including autophagic degradation of neuronal mitochondria,or termed mitophagy,following ischemic events.Despite being well-documented,the cellular and molecular mechanisms under-lying the regulation of neuronal mitophagy remain unknown.So far,the evidence suggests neuronal autophagy and mitophagy are separately regulated in ischemic neurons,the latter being more likely activated by reperfusional injury.Specifically,given the polarized morphology of neurons,mitophagy is regulated by different neuronal compartments,with axonal mitochondria being degraded by autophagy in the cell body following ischemia-reperfusion insult.A variety of molecules have been associated with neuronal adaptation to ischemia,including PTEN-induced kinase 1,Parkin,BCL2 and adenovirus E1B 19-kDa-interacting protein 3(Bnip3),Bnip3-like(Bnip3l)and FUN14 domain-containing 1.Moreover,it is still controversial whether mitophagy protects against or instead aggravates ischemic brain injury.Here,we review recent studies on this topic and provide an updated overview of the role and regulation of mitophagy during ischemic events.
文摘【目的】明确Src与胶原同源插头蛋白(Src homology and collagen homology,Shc)调控曲格列酮(troglitazone,TZ)引起的猪血管内皮(porcine aortic endothelial,PAE)细胞自噬的机制。【方法】我们先利用激光共聚焦显微镜、蛋白免疫杂交检测了TZ引起的PAE细胞自噬;然后通过siRNA干扰敲降Shc,转染wtShc、3mShc等质粒的方法确定了p52Shc参与自噬的调控;最后通过siRNA干扰敲降Ulk1得到最终结论。【结果】通过研究发现,敲降Shc,会增加细胞的自噬;而过量表达p52Shc抑制了TZ引起的细胞自噬;p52Shc抑制自噬与其自身的酪氨酸磷酸化位点Tyr239、Tyr240和Tyr317相关;同时发现,p52Shc能抑制自噬调节分子磷酸腺苷激活的蛋白激酶(AMP-activated protein kinase,AMPK)及其下游底物Unc51样激酶1(UNC-51-like kinase-1,Ulk1)的活性。【结论】Shc通过调控AMPK与Ulk1的磷酸化调节TZ引起的细胞自噬。
文摘Background： Acute coronary syndrome （ACS） is closely related to unstable plaques and secondary thrombosis. The inflammatory cells in plaques and their inflammatory products may be the cause for plaque instability and ruptures. The study aimed to disclose the changes of inflammatory factors including serum intracellular adhesion molecule-1（ICAM-1 ）, chitinase-3-like protein I （YKL-40）, and lipoprotein-associated phospholipase A2 （Lp-PLA2） in patients with ACS and its clinical significance. Methods： A total of 120 patients with coronary heart disease （CHD） were categorized into 2 groups： 69 with ACS and 51 with stable angina pectoris （SAP）： 20 patients with chest pain and normal angiography served as a control group. The 120 patients with CHD were categorized into single-vessel disease group, double-vessel disease group, and three-vessel disease group based on the number of coronary artery stenosis. The severity of coronary artery stenosis was quantified based on coronary angiography using Gensini score. They were further divided into mild CHD group with its Gensini score 〈26 （n = 36）, moderate CHD group with its Gensini score being 26-54 （n = 48） and severe CHD group with its Gensini score 〉54 （n = 36）. Serum levels of ICAM-1, YKL-40, and Lp-PLA2 of different groups were determined by enzyme-linked immunosorbent assay. Correlation between ICAM-1, YKL-40, Lp-PLA2, and Gensini score was analyzed. Results： The levels of serum inflammatory factors ICAM-1, YKL-40, and Lp-PLA2 were significantly higher in the ACS group than those in control group and SAP group （all P 〈 0.05）： and compared with control group, no significant difference was observed in terms of the serum ICAM-1, YKL-40, and Lp-PLA2 levels in the SAP group （P 〉 0.05）.The levels of serum ICAM-1, YKL-40, and Lp-PLA2 were not significantly different among control group, single-vessel disease group, double-vessel disease group, and three-vessel disease group （all P 〉 0.05）. The levels of serum ICAM-1, YKL-40, and Lp-PLA2 were not significantly different among control group, mild CHD group （Gensini score 〈26）, moderate CHD group （Gensini score 26-54）, and severe CHD group （Gensini score 〉54） （all P 〉 0.05）. Nonparametric Spearman correlation analysis showed that the levels of serum ICAM-1, YKL-40, and Lp-PLA2 were not correlated with the Gensini score in CHD patients （r=0.093, r=-0.149, and r= -0.085, all P 〉 0.05; respectively）. Conclusions： The serum levels of ICAM-1, YKL-40, and Lp-PLA2 were correlated with different clinical types of CHD, but not well correlated the severity and extent of artery stenosis, suggesting that ICAM-1, YKL-40, and Lp-PLA2 rnight be involved in occurrence of instability of atherosclerotic plaque, and might reflect the severity of CHD mostly through reflecting the plaque stability.
基金This work was supported by the National Natural Science Foundation of China(81622005)Beijing Natural Science Foundation(7172213).
文摘Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the Parkin gene,which itself belongs to an E3 ubiquitin ligase.Since the discovery of the Parkin gene in the late 1990s,researchers in many countries have begun extensive research on this gene and found that in addition to AR-JP,the Parkin gene is associated with many diseases,including type 2 diabetes,leprosy,Alzheimer’s,autism,and cancer.Recent studies have found that the loss or dysfunction of Parkin has a certain relationship with tumorigenesis.In general,the Parkin gene,a well-established tumor suppressor,is deficient and mutated in a variety of malignancies.Parkin overexpres-sion inhibits tumor cell growth and promotes apoptosis.However,the functions of Parkin in tumorigenesis and its regulatory mechanisms are still not fully understood.This article describes the structure,functions,and post-transla-tional modifications of Parkin,and summarizes the recent advances in the tumor suppressive function of Parkin and its underlying mechanisms.
基金Supported by National Basic Research Program of China(973 program,No.2015CB554404)
文摘Objective： To investigate the relationship between inflammatory factors and two Chinese medicine（CM） syndrome types of qi stagnation and blood stasis（QSBS） and qi deficiency and blood stasis（QDBS） in patients with acute coronary syndrome（ACS）. Methods： Sixty subjects with ACS, whose pathogenesis changes belongs to qi disturbance blood stasis syndrome, were divided into 2 groups： 30 in the QSBS group and 30 in the QDBS group. The comparative analysis on them was carried out through comparing general information, coronary angiography and inflammatory factors including intracellular adhesion molecule-1（ICAM-1）, chitinase-3-like protein 1（YKL-40） and lipoprotein-associated phospholipase A2（Lp-PLA2）. Results： Compared with the QSBS group, Lp-PLA2 and YKL-40 levels in the QDBS group showed no-significant difference（P〉0.05）; ICAM-1 was significantly higher in the QDBS group than in the QSBS group in the pathological processes of qi disturbance and blood stasis syndrome of ACS（P〈0.05）. Conclusion： Inflammatory factor ICAM-1 may be an objective basis for syndrome typing of QSBS and QDBS, which provides a research direction for standardization research of CM syndrome types.
基金This work was supported by USA National Institute of Diabetes and Digestive and Kidney Diseases(NIDDK)R01 DK093807.
文摘Endoplasmic reticulum(ER)stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion.The unfolded protein response(UPR),comprising of inositol-requiring enzyme 1 a(IRE1 a),double-stranded RNA-dependent protein kinase(PKR)-like ER kinase(PERK)and activating transcription factor 6(ATF6)signaling pathways,is a protective cellular response activated by ER stress.However,UPR activation can also induce cell death upon persistent ER stress.The liver is susceptible to ER stress given its synthetic and other biological functions.Numerous studies from human liver samples and animal disease models have indicated a crucial role of ER stress and the UPR signaling pathways in the pathogenesis of liver diseases,including non-alcoholic fatty liver disease(NAFLD),alcoholic liver disease(ALD),alpha-1 antitrypsin(AAT)deficiency(AATD),cholestatic liver disease,drug-induced liver injury,ischemia/reperfusion(I/R)injury,viral hepatitis and hepatocel-lular carcinoma(HCC).Extensive investigations have demonstrated the potential underlying mechanisms of the induction of ER stress and the contribution of the UPR pathways during the development of the diseases.Moreover,ER stress and the UPR proteins and genes have become emerging therapeutic targets to treat liver diseases.
