Peripheral artery disease(PAD)is a common condition characterized by atherosclerosis in the peripheral arteries,associated with concomitant coronary and cerebrovascular diseases.Proprotein convertase subtilisin/kexin ...Peripheral artery disease(PAD)is a common condition characterized by atherosclerosis in the peripheral arteries,associated with concomitant coronary and cerebrovascular diseases.Proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitors are a class of drugs that have shown potential in hypercholesterolemic patients.This review focuses on the efficacy,safety,and clinical outcomes of PCSK9 inhibitors in PAD based on the literature indexed by PubMed.Trials such as FOURIER and ODYSSEY demonstrate the efficacy of evolocumab and alirocumab in reducing cardiovascular events,offering a potential treatment option for PAD patients.Safety evaluations from trials show few adverse events,most of which are injection-site reactions,indicating the overall safety profile of PCSK9 inhibitors.Clinical outcomes show a reduction in cardiovascular events,ischemic strokes,and major adverse limb events.However,despite these positive findings,PCSK9 inhibitors are still underutilized in clinical practice,possibly due to a lack of awareness among care providers and cost concerns.Further research is needed to establish the long-term effects and cost-effectiveness of PCSK9 inhibitors in PAD patients.展开更多
OBJECTIVE: To evaluate the efficacy of Shoushen granule, prepared with four Chinese medicinals, on the targeted regulation of adenosine triphosphate binding cassette transporter A1(ABCA1) through proprotein convertase...OBJECTIVE: To evaluate the efficacy of Shoushen granule, prepared with four Chinese medicinals, on the targeted regulation of adenosine triphosphate binding cassette transporter A1(ABCA1) through proprotein convertase subtilisin/kexin type 9(PCSK9) and toll-like receptor 4(TLR4)/nuclear factor kappa-B(NF-κB) signaling pathway to affect atherosclerosis(AS) in ApoE-knockout(ApoE-/-) mice.METHODS: ApoE-/-mice fed with a high-fat diet were used for AS modeling and divided into Model,Shoushen, and Atorvastatin groups. C57 BL/6 J mice at the same age and background strain were included in the Control group. Western blot and immunohistochemistry were used to measure ABCA1, PCSK9, TLR4, and NF-κB protein expression in mouse aortas. Enzyme-linked immuno sorbent assay was used to measure mouse serum tumor necrosis factor-α(TNF-α), interleukin-10(IL-10), monocyte chemoattractant protein 1(MCP-1), and intercellular cell adhesion molecule-1(ICAM-1) expression. Serum lipid profiles and histopathology were also assessed. Shoushen granule were composed of Heshouwu(Radix Polygoni Multiflori) 15 g, Gouqizi(Fructus Lycii) 15 g, Sheng shanzha(Raw Fructus Crataegus Pinnatifidae) 10 g, and Sanqi(Radix Notoginseng) 3 g.RESULTS: ApoE-/-mice fed with a high-fat diet had notable AS lesions, with reduced ABCA1 and IL-10 levels, elevated PCSK9, TLR4, NF-κB, TNF-α, MCP-1,and ICAM-1 expression, and increased total cholesterol(TC) and low density lipoprotein cholesterol(LDL-C) contents. With drug interventions, the areas of AS plaques were significantly reduced,the ABCA1 and IL-10 levels were increase, while the PCSK9, TLR4, NF-κB, TC, and LDL-C contents,and the TNF-α, MCP-1, and ICAM-1 expression were reduced.CONCLUSION: Shoushen granule effectively interfered with AS development by antagonizing the expression of key factors of the PCSK9 and TLR4/NF-κB signaling pathway to upregulate ABCA1 expression.展开更多
Atherosclerotic cardiovascular disease is the main cause of mortality and morbidity in the world. Plasma levels of low density lipoprotein cholesterol （LDL-C） are positively correlated with the risk of atheroscleros...Atherosclerotic cardiovascular disease is the main cause of mortality and morbidity in the world. Plasma levels of low density lipoprotein cholesterol （LDL-C） are positively correlated with the risk of atherosclerosis. High plasma LDL concentrations in patients with hypercholesterolemia lead to build-up of LDL in the inner walls of the arteries, which becomes oxidized and promotes the formation of foam cells, consequently initiating atherosclerosis. Plasma LDL is mainly cleared through the LDL receptor （LDLR） pathway. Mutations in the LDLR cause familiar hyperch- olesterolemia and increase the risk of premature coronary heart disease. The expression of LDLR is regulated at the transcriptional level via the sterol regulatory element binding protein 2 （SREBP-2） and at the posttranslational levels mainly through proprotein convertase subtilisin/kexin-type 9 （PCSK9） and inducible degrader of the LDLR （IDOL）. In this review, we summarize the latest advances in the studies of PCSK9.展开更多
Brain-derived neurotrophic factor(BDNF)has robust effects on synaptogenesis,neuronal differentiation and synaptic transmission and plasticity.The maturation of BDNF is a complex process.Proprotein convertase 1/3(PC1/3...Brain-derived neurotrophic factor(BDNF)has robust effects on synaptogenesis,neuronal differentiation and synaptic transmission and plasticity.The maturation of BDNF is a complex process.Proprotein convertase 1/3(PC1/3)has a key role in the cleavage of protein precursors that are directed to regulated secretory pathways;however,it is not clear whether PC1/3 mediates the change in BDNF levels caused by ischemia.To clarify the role of PC1/3 in BDNF maturation in ischemic cortical neurons,primary cortical neurons from fetal rats were cultured in a humidified environment of 95%N_2 and 5%CO_2 in a glucose-free Dulbecco's modified Eagle's medium at 37℃for3 hours.Enzyme-linked immunosorbent assays and western blotting showed that after oxygen-glucose deprivation,the secreted and intracellular levels of BDNF were significantly reduced and the intracellular level of PC1/3 was decreased.Transient transfection of cortical neurons with a PC1/3 overexpression plasmid followed by oxygen-glucose deprivation resulted in increased PC1/3 levels and increased BDNF levels.When levels of the BDNF precursor protein were reduced,the concentration of BDNF in the culture medium was increased.These results indicate that PC 1/3 cleavage of BDNF is critical for the conversion of pro-BDNF in rat cortical neurons during ischemia.The study was approved by the Animal Ethics Committee of Wuhan University School of Basic Medical Sciences.展开更多
Proprotein convertase 1 （PC1） is a member of the family of proprotein convertases （PCs）, which are the processing enzymes of neuropeptides. Previous studies have addressed PC1 effects with regard to the neuroendoc...Proprotein convertase 1 （PC1） is a member of the family of proprotein convertases （PCs）, which are the processing enzymes of neuropeptides. Previous studies have addressed PC1 effects with regard to the neuroendocrine system. In this study, the developing changes of PC1 mRNA and PC1 protein in rat cortices after transient focal cerebral ischemia were investigated by fluorescent double labeling （both in situ hybridization and immunocytochemistry） using a transient focal cerebral ischemia model in rats. The results were compared with those of sham-operated rat cortices. Both the mRNA and protein levels of PC1 in ischemic cortices decreased gradually at 4, 8, and 16 hours of reperfusion after 100 minutes of middle cerebral artery occlusion. After 24 hours of reperfusion, enhanced intensities of signals for PC1 protein were observed, while signals for PC1 mRNA remained low. These results suggest that transient focal cerebral ischemia influences PC1 mRNA and protein expression in cortices of ischemic rats. Thus, PC1 is regulated by ischemic stress.展开更多
BACKGROUND Many studies have investigated the progression of nonalcoholic fatty liver disease(NAFLD)and its predisposing risk factors,but the conclusions from these studies have been conflicting.More challenging is th...BACKGROUND Many studies have investigated the progression of nonalcoholic fatty liver disease(NAFLD)and its predisposing risk factors,but the conclusions from these studies have been conflicting.More challenging is the fact that no effective treatment is currently available for NAFLD.AIM To determine the effects of proprotein convertase subtilisin/kexin type-9(PCSK9)inhibitors on fatty infiltration of the liver.METHODS This retrospective,chart review-based study was conducted on patients,18-yearold and above,who were currently on PCSK9 inhibitor drug therapy.Patients were excluded from the study according to missing pre-or post-treatment imaging or laboratory values,presence of cirrhosis or rhabdomyolysis,or development of acute liver injury during the PCSK9 inhibitor treatment period;the latter being due to false elevation of liver function markers,alanine aminotransferase(ALT)and aspartate aminotransferase(AST).Radiographic improvement was assessed by a single radiologist,who read both the pre-and post-treatment images to minimize reading bias.Fatty infiltration of the liver was also assessed by changes in ALT and AST,with pre-and post-treatment levels compared by paired t-test(alpha criterion:0.05).RESULTS Of the 29 patients included in the study,8 were male(27.6%)and 21 were female(72.4%).Essential hypertension was present in 25(86.2%)of the patients,diabetes mellitus in 18(62.1%)and obesity in 15(51.7%).In all,patients were on PCSK9 inhibitors for a mean duration of 23.69±11.18 mo until the most recent ALT and AST measures were obtained.Of the 11 patients who received the radiologic diagnosis of hepatic steatosis,8(72.73%)achieved complete radiologic resolution upon use of PCSK9 inhibitors(mean duration of 17.6 mo).On average,the ALT level(IU/L)decreased from 21.83±11.89 at pretreatment to 17.69±8.00 at posttreatment(2-tailed P=0.042)and AST level(IU/L)decreased from 22.48±9.00 pretreatment to 20.59±5.47 post-treatment(2-tailed P=0.201).CONCLUSION PCSK9 inhibitors can slow down or even completely resolve NAFLD.展开更多
Background The association of E670G polymorphism in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and serum lipid profiles is inconsistent in dif- ferent ethnic groups.Bai Ku Yao is a special subgroup...Background The association of E670G polymorphism in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and serum lipid profiles is inconsistent in dif- ferent ethnic groups.Bai Ku Yao is a special subgroup of the Yao minority in China.The present study was undertaken association of PCSK9 E670G polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations.Methods A total of 649 subjects of Bai Ku Yao and 646 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples.Genotyping of the PCSK9 E670G polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis,and then confirmed by direct sequencing. Results The levels of serum total cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C) and apolipoprotein(Apo) AI were lower in Bai Ku Yao than in Han(P【0.01 for all).The frequency of A and G alleles was 98.00%and 2.00%in Bai Ku Yao,and 95.20%and 4.80%in Han(P【0.01);respectively. The frequency of AA,AG and GG genotypes was 95.99%,4.01%and 0%in Bai Ku Yao,and 91.02%, 8.36%and 0.62%in Han(P【0.01);respectively.There were also significant differences in the genotypic and allelic frequencies between n and the ratio of ApoAI to ApoB in Han Chinese but not in Bai Ku Yao were different between the AA and AG/GG genotypes(P【0.05 for all).The G allele carriers had higher serum HDL-C and higher ApoAI to ApoB ratio than the G allele noncarriers.When serum lipid parameters in Han were analyzed according to sex,the G allele carriers had higher serum HDL and ApoAI levels in males (P【0.05),and lower ApoB level and higher ApoAI to ApoB ratio in females(P【0.05 for all).Multiple linear regression analysis showed that serum HDL-C levels were correlated with genotypes in both ethnic groups(P【0.05 each).Serum lipid parameters were also correlated with sex,age,body massindex,alcohol consumption,cigarette smoking,and blood pressure in both ethnic groups(P【0.05-0.001).Conclusions These results suggest that the PCSK9 E670G polymorphism is mainly associated with some serum lipid parameters in the Han population,both gender show different relations to different serum lipid parameters.The G allele carriers might have higher serum lipid profiles than the G allele noncarriers. ormal LDL-C(≤3.20 mmol/L) and high LDL-C subgroups (】 3.20 mmol/L,P【0.01;respectively) in Bai Ku Yao, and between normal ApoB(≤1.14 g/L) and high ApoB subgroups(】 1.14 g/L,P 【 0.01;respectively) in Han.展开更多
BACKGROUND Familial hypercholesterolemia(FH)is an autosomal dominant disorder that is characterized by severely increased low-density lipoprotein(LDL)cholesterol levels.At the same time,elevated LDL levels accelerated...BACKGROUND Familial hypercholesterolemia(FH)is an autosomal dominant disorder that is characterized by severely increased low-density lipoprotein(LDL)cholesterol levels.At the same time,elevated LDL levels accelerated the development of coronary heart disease.Several classes of drugs are currently in use to treat FH.Proprotein convertase subtilisin/kexin type 9 inhibitor(PCSK9i)is novel one of these.CASE SUMMARY This manuscript reports a case of FH that responded modestly after treatment with PCSK9i and statin drugs.Of even more concern is that the patient frequently admitted to the hospital during a 12-year follow-up period.Subsequently,we identified a heterozygous mutation,1448G>A(W483X)of the LDL receptor(LDLR)in this patient.The serum levels of PCSK9(proprotein convertase subtilisin/kexin type 9)in the patient was 71.30±26.66 ng/mL,which is close the average level reported in the literature.This LDLR mutation affects LDLR metabolism or structure,which may make it unsuitable for use of PCSK9i.CONCLUSION Our outcome demonstrates that LDLR-W483X represents a partial loss-of-function LDLR and may contribute to PCSK9i ineffective. In the meanwhile, additional measures aretherefore required (particularly with gene sequencing or change the treatment plan) must beinitiated as early as possible. Genetic testing for clinically challenging cases who do not respond toPCSK9i therapy is very helpful.展开更多
In this study, a rat model of transient focal cerebral ischemia was established by performing 100 minutes of middle cerebral artery occlusion, and an in vitro model of experimental oxygen-glucose deprivation using cul...In this study, a rat model of transient focal cerebral ischemia was established by performing 100 minutes of middle cerebral artery occlusion, and an in vitro model of experimental oxygen-glucose deprivation using cultured rat cortical neurons was established. Proprotein convertase 2 activity gradually decreased in the ischemic cortex with increasing duration of reperfusion. In cultured rat cortical neurons, the number of terminal deoxynucleotidyl transferase-mediated 2＇-deoxyuridine 5＇-triphosphate-biotin nick end labeling-positive neurons significantly increased and proprotein convertase 2 activity also decreased gradually with increasing duration of oxygen-glucose deprivation. These experimental findings indicate that proprotein convertase 2 activity decreases in ischemic rat cortex after reperfusion, as well as in cultured rat cortical neurons after oxygen-glucose deprivation. These changes in enzyme activity may play an important pathological role in brain injury.展开更多
Oxidized low density lipoprotein is a risk factor for cerebrovascular disease. Proprotein convertase subtilisin/kexin type 9 （PCSK9） can increase the level of low density lipoprotein. Therefore, this study assumed t...Oxidized low density lipoprotein is a risk factor for cerebrovascular disease. Proprotein convertase subtilisin/kexin type 9 （PCSK9） can increase the level of low density lipoprotein. Therefore, this study assumed that PCSK9 plays important roles in ischemic cerebrovascular disease. The present study established transient focal cerebral ischemia models after 100 minutes of middle cerebral artery occlusion. In situ hybridization demonstrated that PCSK9 mRNA expression increased gradually with prolonged reperfusion time in ischemic cortices. This indicated that transient focal cerebral ischemia upregulated PCSK9 mRNA expression in ischemic cortices.展开更多
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the proprotein convertase (PCs) family, which facilitates the degradation of low-density lipoprotein receptors (LDL-R) via intracellular and cell su...Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the proprotein convertase (PCs) family, which facilitates the degradation of low-density lipoprotein receptors (LDL-R) via intracellular and cell surface pathways, consequently elevating serum LDL-C levels. PCSK9 is implicated in various processes such as lipid metabolism, atherosclerosis, oxidative stress, inflammatory responses, thrombosis, and apoptosis. It is closely linked to ischemic stroke through its role in inducing and advancing atherosclerosis. PCSK9 inhibitors play a useful role in both acute and secondary prevention of ischemic stroke and can reduce the risk of ischemic stroke. This review examines the influence of PCSK9 on the risk factors associated with ischemic stroke and explores its potential mechanisms, and briefly describes the application of PCSK9 inhibitors in ischemic stroke.展开更多
目的:探究前蛋白转化酶枯草杆菌蛋白酶/溶菌素9(proprotein convertase subtilisin/kexin type 9,PCSK9)抑制剂药物经济性评价的方法。方法:检索从建库至2024年1月15日PubMed,Embase,Scopus,Cochrane Library和Web of science数据库中有...目的:探究前蛋白转化酶枯草杆菌蛋白酶/溶菌素9(proprotein convertase subtilisin/kexin type 9,PCSK9)抑制剂药物经济性评价的方法。方法:检索从建库至2024年1月15日PubMed,Embase,Scopus,Cochrane Library和Web of science数据库中有关PCSK9抑制剂经济学研究的文献,并使用2022年版综合卫生经济评价报告标准(Consolidated Health Economic Evaluation Reporting Standards,CHEERS)对纳入的文献进行评估。结果:30篇关于PCSK9抑制剂药物治疗心血管疾病的经济学评价研究中27篇采用了模型法进行经济学评价,主要使用马尔可夫模型,涵盖了多个研究时限和健康状态数量。23篇文献通过低密度脂蛋白胆固醇(low-density lipoproteins-cholesterol,LDL-C)水平降低进行外推来评估药效,23篇文献未考虑药物的不良反应。结论:现有文献主要通过马尔可夫模型对药物的经济性进行评价,在药物效果指标的选择、药物不良反应是否纳入分析等方面存在局限性。展开更多
文摘Peripheral artery disease(PAD)is a common condition characterized by atherosclerosis in the peripheral arteries,associated with concomitant coronary and cerebrovascular diseases.Proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitors are a class of drugs that have shown potential in hypercholesterolemic patients.This review focuses on the efficacy,safety,and clinical outcomes of PCSK9 inhibitors in PAD based on the literature indexed by PubMed.Trials such as FOURIER and ODYSSEY demonstrate the efficacy of evolocumab and alirocumab in reducing cardiovascular events,offering a potential treatment option for PAD patients.Safety evaluations from trials show few adverse events,most of which are injection-site reactions,indicating the overall safety profile of PCSK9 inhibitors.Clinical outcomes show a reduction in cardiovascular events,ischemic strokes,and major adverse limb events.However,despite these positive findings,PCSK9 inhibitors are still underutilized in clinical practice,possibly due to a lack of awareness among care providers and cost concerns.Further research is needed to establish the long-term effects and cost-effectiveness of PCSK9 inhibitors in PAD patients.
基金Supported by the National Natural Science Foundation of China(The Role of TLR4/MyD88/NF-κB Signal Transduction Pathway and Expression of miRNA-146a in Atherosclerosis and the Intervention Mechanism of Shen Invigorating Compounds,No.81202731Bushen Jiangzhi Recipe Protects Against Atherosclerosis via miR-27a-mediated PCSK9/ABCA1 Pathway,No.81873348)+2 种基金the Shanghai Natural Science Found(Inhibitory Mechanism of Chinese Herbal Compound,Shoushen Granule,for Invigorating Kidney in ApoE-/-Atherosclerosis Mouse Model by mir-19b Target Regulating ABCA1,No.16ZR1433900)the Shanghai Municipal Commission of Health and Family Planning Found(Effect of Kidney Invigoration and Lipid Intervention on the Atherosclerosis in ApoE-knockout Mice Based on mT OR signaling pathway of Autophagy System,No.201640217)Shanghai University of Traditional Chinese Medicine graduate"innovation ability training"special research projects(Mechanism of Bushen Jiangzhi Recipe Regulating TLR4/NF-κB Signaling Pathway Mediated by CD36 Through PCSK9 Targeted Regulation of apoE-/-mice Atherosclerosis,No.Y201858)
文摘OBJECTIVE: To evaluate the efficacy of Shoushen granule, prepared with four Chinese medicinals, on the targeted regulation of adenosine triphosphate binding cassette transporter A1(ABCA1) through proprotein convertase subtilisin/kexin type 9(PCSK9) and toll-like receptor 4(TLR4)/nuclear factor kappa-B(NF-κB) signaling pathway to affect atherosclerosis(AS) in ApoE-knockout(ApoE-/-) mice.METHODS: ApoE-/-mice fed with a high-fat diet were used for AS modeling and divided into Model,Shoushen, and Atorvastatin groups. C57 BL/6 J mice at the same age and background strain were included in the Control group. Western blot and immunohistochemistry were used to measure ABCA1, PCSK9, TLR4, and NF-κB protein expression in mouse aortas. Enzyme-linked immuno sorbent assay was used to measure mouse serum tumor necrosis factor-α(TNF-α), interleukin-10(IL-10), monocyte chemoattractant protein 1(MCP-1), and intercellular cell adhesion molecule-1(ICAM-1) expression. Serum lipid profiles and histopathology were also assessed. Shoushen granule were composed of Heshouwu(Radix Polygoni Multiflori) 15 g, Gouqizi(Fructus Lycii) 15 g, Sheng shanzha(Raw Fructus Crataegus Pinnatifidae) 10 g, and Sanqi(Radix Notoginseng) 3 g.RESULTS: ApoE-/-mice fed with a high-fat diet had notable AS lesions, with reduced ABCA1 and IL-10 levels, elevated PCSK9, TLR4, NF-κB, TNF-α, MCP-1,and ICAM-1 expression, and increased total cholesterol(TC) and low density lipoprotein cholesterol(LDL-C) contents. With drug interventions, the areas of AS plaques were significantly reduced,the ABCA1 and IL-10 levels were increase, while the PCSK9, TLR4, NF-κB, TC, and LDL-C contents,and the TNF-α, MCP-1, and ICAM-1 expression were reduced.CONCLUSION: Shoushen granule effectively interfered with AS development by antagonizing the expression of key factors of the PCSK9 and TLR4/NF-κB signaling pathway to upregulate ABCA1 expression.
基金D.W.Z.is a Scholar of the Alberta Heritage Foundation for Medical Research and is supported in part by a Canadian Institutes of Health Research New Investigator AwardZhang laboratory is supported by Canadian Foundation for Innovation,grants from a Grant-in-Aidfor Heart and Stroke Foundation of CanadaPfizer Canada, the Canadian Institutes of Health Research(MOP 93794), and Mazankowski Alberta Heart Institute
文摘Atherosclerotic cardiovascular disease is the main cause of mortality and morbidity in the world. Plasma levels of low density lipoprotein cholesterol （LDL-C） are positively correlated with the risk of atherosclerosis. High plasma LDL concentrations in patients with hypercholesterolemia lead to build-up of LDL in the inner walls of the arteries, which becomes oxidized and promotes the formation of foam cells, consequently initiating atherosclerosis. Plasma LDL is mainly cleared through the LDL receptor （LDLR） pathway. Mutations in the LDLR cause familiar hyperch- olesterolemia and increase the risk of premature coronary heart disease. The expression of LDLR is regulated at the transcriptional level via the sterol regulatory element binding protein 2 （SREBP-2） and at the posttranslational levels mainly through proprotein convertase subtilisin/kexin-type 9 （PCSK9） and inducible degrader of the LDLR （IDOL）. In this review, we summarize the latest advances in the studies of PCSK9.
基金supported by the National Nature Science Foundation of China,No.81501053(to YC)
文摘Brain-derived neurotrophic factor(BDNF)has robust effects on synaptogenesis,neuronal differentiation and synaptic transmission and plasticity.The maturation of BDNF is a complex process.Proprotein convertase 1/3(PC1/3)has a key role in the cleavage of protein precursors that are directed to regulated secretory pathways;however,it is not clear whether PC1/3 mediates the change in BDNF levels caused by ischemia.To clarify the role of PC1/3 in BDNF maturation in ischemic cortical neurons,primary cortical neurons from fetal rats were cultured in a humidified environment of 95%N_2 and 5%CO_2 in a glucose-free Dulbecco's modified Eagle's medium at 37℃for3 hours.Enzyme-linked immunosorbent assays and western blotting showed that after oxygen-glucose deprivation,the secreted and intracellular levels of BDNF were significantly reduced and the intracellular level of PC1/3 was decreased.Transient transfection of cortical neurons with a PC1/3 overexpression plasmid followed by oxygen-glucose deprivation resulted in increased PC1/3 levels and increased BDNF levels.When levels of the BDNF precursor protein were reduced,the concentration of BDNF in the culture medium was increased.These results indicate that PC 1/3 cleavage of BDNF is critical for the conversion of pro-BDNF in rat cortical neurons during ischemia.The study was approved by the Animal Ethics Committee of Wuhan University School of Basic Medical Sciences.
基金supported by the National Natural Science Foundation of China(The study on brain ischemia-induced changes and effects of proprotein convertase 1 and proprotein convertase subtilisin kexin9),No.81070999the Grant of National Institutes of Health(America)(Brain ischemia attenuates neuropeptide biosynthesis),No.NS046560the Grant of American Heart Association(Quantitative proteomics reveals a novel mechanism of brain ischemic tolerance),No.0450142Z
文摘Proprotein convertase 1 （PC1） is a member of the family of proprotein convertases （PCs）, which are the processing enzymes of neuropeptides. Previous studies have addressed PC1 effects with regard to the neuroendocrine system. In this study, the developing changes of PC1 mRNA and PC1 protein in rat cortices after transient focal cerebral ischemia were investigated by fluorescent double labeling （both in situ hybridization and immunocytochemistry） using a transient focal cerebral ischemia model in rats. The results were compared with those of sham-operated rat cortices. Both the mRNA and protein levels of PC1 in ischemic cortices decreased gradually at 4, 8, and 16 hours of reperfusion after 100 minutes of middle cerebral artery occlusion. After 24 hours of reperfusion, enhanced intensities of signals for PC1 protein were observed, while signals for PC1 mRNA remained low. These results suggest that transient focal cerebral ischemia influences PC1 mRNA and protein expression in cortices of ischemic rats. Thus, PC1 is regulated by ischemic stress.
基金Data for this research project was obtained from Health System of the University of Kansas Medical Center,Kansas City,KS 66160,United States.The authors are grateful to the Department of Clinical Informatics at the University of Kansas Medical Center for their help in accessing the patient medical record database.Data extraction was conducted by the HERON automated data extraction tool.
文摘BACKGROUND Many studies have investigated the progression of nonalcoholic fatty liver disease(NAFLD)and its predisposing risk factors,but the conclusions from these studies have been conflicting.More challenging is the fact that no effective treatment is currently available for NAFLD.AIM To determine the effects of proprotein convertase subtilisin/kexin type-9(PCSK9)inhibitors on fatty infiltration of the liver.METHODS This retrospective,chart review-based study was conducted on patients,18-yearold and above,who were currently on PCSK9 inhibitor drug therapy.Patients were excluded from the study according to missing pre-or post-treatment imaging or laboratory values,presence of cirrhosis or rhabdomyolysis,or development of acute liver injury during the PCSK9 inhibitor treatment period;the latter being due to false elevation of liver function markers,alanine aminotransferase(ALT)and aspartate aminotransferase(AST).Radiographic improvement was assessed by a single radiologist,who read both the pre-and post-treatment images to minimize reading bias.Fatty infiltration of the liver was also assessed by changes in ALT and AST,with pre-and post-treatment levels compared by paired t-test(alpha criterion:0.05).RESULTS Of the 29 patients included in the study,8 were male(27.6%)and 21 were female(72.4%).Essential hypertension was present in 25(86.2%)of the patients,diabetes mellitus in 18(62.1%)and obesity in 15(51.7%).In all,patients were on PCSK9 inhibitors for a mean duration of 23.69±11.18 mo until the most recent ALT and AST measures were obtained.Of the 11 patients who received the radiologic diagnosis of hepatic steatosis,8(72.73%)achieved complete radiologic resolution upon use of PCSK9 inhibitors(mean duration of 17.6 mo).On average,the ALT level(IU/L)decreased from 21.83±11.89 at pretreatment to 17.69±8.00 at posttreatment(2-tailed P=0.042)and AST level(IU/L)decreased from 22.48±9.00 pretreatment to 20.59±5.47 post-treatment(2-tailed P=0.201).CONCLUSION PCSK9 inhibitors can slow down or even completely resolve NAFLD.
文摘Background The association of E670G polymorphism in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and serum lipid profiles is inconsistent in dif- ferent ethnic groups.Bai Ku Yao is a special subgroup of the Yao minority in China.The present study was undertaken association of PCSK9 E670G polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations.Methods A total of 649 subjects of Bai Ku Yao and 646 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples.Genotyping of the PCSK9 E670G polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis,and then confirmed by direct sequencing. Results The levels of serum total cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C) and apolipoprotein(Apo) AI were lower in Bai Ku Yao than in Han(P【0.01 for all).The frequency of A and G alleles was 98.00%and 2.00%in Bai Ku Yao,and 95.20%and 4.80%in Han(P【0.01);respectively. The frequency of AA,AG and GG genotypes was 95.99%,4.01%and 0%in Bai Ku Yao,and 91.02%, 8.36%and 0.62%in Han(P【0.01);respectively.There were also significant differences in the genotypic and allelic frequencies between n and the ratio of ApoAI to ApoB in Han Chinese but not in Bai Ku Yao were different between the AA and AG/GG genotypes(P【0.05 for all).The G allele carriers had higher serum HDL-C and higher ApoAI to ApoB ratio than the G allele noncarriers.When serum lipid parameters in Han were analyzed according to sex,the G allele carriers had higher serum HDL and ApoAI levels in males (P【0.05),and lower ApoB level and higher ApoAI to ApoB ratio in females(P【0.05 for all).Multiple linear regression analysis showed that serum HDL-C levels were correlated with genotypes in both ethnic groups(P【0.05 each).Serum lipid parameters were also correlated with sex,age,body massindex,alcohol consumption,cigarette smoking,and blood pressure in both ethnic groups(P【0.05-0.001).Conclusions These results suggest that the PCSK9 E670G polymorphism is mainly associated with some serum lipid parameters in the Han population,both gender show different relations to different serum lipid parameters.The G allele carriers might have higher serum lipid profiles than the G allele noncarriers. ormal LDL-C(≤3.20 mmol/L) and high LDL-C subgroups (】 3.20 mmol/L,P【0.01;respectively) in Bai Ku Yao, and between normal ApoB(≤1.14 g/L) and high ApoB subgroups(】 1.14 g/L,P 【 0.01;respectively) in Han.
基金the Doctor Start-up fund of Jiangxi provincial People's Hospital,The First Affiliated Hospital of Nanchang Medical College,No.19-236.
文摘BACKGROUND Familial hypercholesterolemia(FH)is an autosomal dominant disorder that is characterized by severely increased low-density lipoprotein(LDL)cholesterol levels.At the same time,elevated LDL levels accelerated the development of coronary heart disease.Several classes of drugs are currently in use to treat FH.Proprotein convertase subtilisin/kexin type 9 inhibitor(PCSK9i)is novel one of these.CASE SUMMARY This manuscript reports a case of FH that responded modestly after treatment with PCSK9i and statin drugs.Of even more concern is that the patient frequently admitted to the hospital during a 12-year follow-up period.Subsequently,we identified a heterozygous mutation,1448G>A(W483X)of the LDL receptor(LDLR)in this patient.The serum levels of PCSK9(proprotein convertase subtilisin/kexin type 9)in the patient was 71.30±26.66 ng/mL,which is close the average level reported in the literature.This LDLR mutation affects LDLR metabolism or structure,which may make it unsuitable for use of PCSK9i.CONCLUSION Our outcome demonstrates that LDLR-W483X represents a partial loss-of-function LDLR and may contribute to PCSK9i ineffective. In the meanwhile, additional measures aretherefore required (particularly with gene sequencing or change the treatment plan) must beinitiated as early as possible. Genetic testing for clinically challenging cases who do not respond toPCSK9i therapy is very helpful.
基金supported by the National Natural Science Foundation of China,No.81070999the foundation of Xi’an Jiaotong University,No.95,2009+2 种基金Foundation of the Second Affiliated Hospital of Xi’an Jiaotong University,No.RC(GG)201109the US National Institutes of Health,No.NS046560the American Heart Association,No.0450142Z
文摘In this study, a rat model of transient focal cerebral ischemia was established by performing 100 minutes of middle cerebral artery occlusion, and an in vitro model of experimental oxygen-glucose deprivation using cultured rat cortical neurons was established. Proprotein convertase 2 activity gradually decreased in the ischemic cortex with increasing duration of reperfusion. In cultured rat cortical neurons, the number of terminal deoxynucleotidyl transferase-mediated 2＇-deoxyuridine 5＇-triphosphate-biotin nick end labeling-positive neurons significantly increased and proprotein convertase 2 activity also decreased gradually with increasing duration of oxygen-glucose deprivation. These experimental findings indicate that proprotein convertase 2 activity decreases in ischemic rat cortex after reperfusion, as well as in cultured rat cortical neurons after oxygen-glucose deprivation. These changes in enzyme activity may play an important pathological role in brain injury.
基金the National Natural Science Foundation of China,No.81070999the National Institutes of Health (America),No.NS046560the American Heart Association,No.0450142Z
文摘Oxidized low density lipoprotein is a risk factor for cerebrovascular disease. Proprotein convertase subtilisin/kexin type 9 （PCSK9） can increase the level of low density lipoprotein. Therefore, this study assumed that PCSK9 plays important roles in ischemic cerebrovascular disease. The present study established transient focal cerebral ischemia models after 100 minutes of middle cerebral artery occlusion. In situ hybridization demonstrated that PCSK9 mRNA expression increased gradually with prolonged reperfusion time in ischemic cortices. This indicated that transient focal cerebral ischemia upregulated PCSK9 mRNA expression in ischemic cortices.
文摘Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the proprotein convertase (PCs) family, which facilitates the degradation of low-density lipoprotein receptors (LDL-R) via intracellular and cell surface pathways, consequently elevating serum LDL-C levels. PCSK9 is implicated in various processes such as lipid metabolism, atherosclerosis, oxidative stress, inflammatory responses, thrombosis, and apoptosis. It is closely linked to ischemic stroke through its role in inducing and advancing atherosclerosis. PCSK9 inhibitors play a useful role in both acute and secondary prevention of ischemic stroke and can reduce the risk of ischemic stroke. This review examines the influence of PCSK9 on the risk factors associated with ischemic stroke and explores its potential mechanisms, and briefly describes the application of PCSK9 inhibitors in ischemic stroke.
文摘目的:探究前蛋白转化酶枯草杆菌蛋白酶/溶菌素9(proprotein convertase subtilisin/kexin type 9,PCSK9)抑制剂药物经济性评价的方法。方法:检索从建库至2024年1月15日PubMed,Embase,Scopus,Cochrane Library和Web of science数据库中有关PCSK9抑制剂经济学研究的文献,并使用2022年版综合卫生经济评价报告标准(Consolidated Health Economic Evaluation Reporting Standards,CHEERS)对纳入的文献进行评估。结果:30篇关于PCSK9抑制剂药物治疗心血管疾病的经济学评价研究中27篇采用了模型法进行经济学评价,主要使用马尔可夫模型,涵盖了多个研究时限和健康状态数量。23篇文献通过低密度脂蛋白胆固醇(low-density lipoproteins-cholesterol,LDL-C)水平降低进行外推来评估药效,23篇文献未考虑药物的不良反应。结论:现有文献主要通过马尔可夫模型对药物的经济性进行评价,在药物效果指标的选择、药物不良反应是否纳入分析等方面存在局限性。
