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
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
Efficient and precise assembly of polypeptides into native functional states is critical for normal cellular processes. Understanding how a specific structure is encoded in the polypeptide sequence and what drives the...Efficient and precise assembly of polypeptides into native functional states is critical for normal cellular processes. Understanding how a specific structure is encoded in the polypeptide sequence and what drives the structural progression to the native state is essential to deciphering the folding problem. Several prokaryotic and eukaryotic proteins require their propeptide-domains to function as dedicated intramolecular chaperones (IMCs). In this manuscript, we investigate the elementary steps in the IMC mediated maturation of Subtilisin E, a bacterial serine protease, and a prototype for the eukaryotic proprotein convertases (PCs). Through detailed analyses, we have attempted to define the unimolecular folding energy landscape for SbtE to understand how the stabilization of folding intermediates influences the maturation process, an aspect that is difficult to study in eukaryotic PCs. Our studies demonstrate that a rapid hydrophobic collapse precedes acquisition of tertiary structure during the folding of Pro-SbtE and results in formation of a molten-globule like intermediate. Induction of structure within the IMC stabilizes both the molten globule-like folding intermediate and the native state, and appears to expedite initial stages of folding, purely through thermodynamic stabilization of the folded state. While the induced structure does not affect the activation energies in the unimolecular folding reaction, it is detrimental to the autoproteolytic cleavage of the precursor and subsequent release and degradation of the inhibitory IMC-domain since both these stages require some degree of unfolding. Completion of Pro-SbtE maturation results in the formation of a kinetically trapped and extremely stable native state. Hence, our results suggest that the SbtE IMC appears to have evolved to be intrinsically unstructured and to bind with its cognate protease with a specific affinity that is critical for biological regulation.展开更多
Hyperlipidemia is a well-established risk factor for developing cardiovascular disease(CVD). The recent American College of Cardiology and American Heart Association guidelines on lipid management emphasize treatment ...Hyperlipidemia is a well-established risk factor for developing cardiovascular disease(CVD). The recent American College of Cardiology and American Heart Association guidelines on lipid management emphasize treatment of individuals at increased risk for developing CVD events with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors(statins) at doses proven to reduce CVD events. However, there are limited options for patients who are either intolerant to statin therapy, develop CVD despite being on maximally tolerated statin therapy, or have severe hypercholesterolemia. Recently the Food and Drug Administration approved two novel medications for low-density lipoprotein(LDL)-cholesterol reduction: Evolocumab and Alirocumab. These agents target and inactivate proprotein convertase subtilsinkexin type 9(PCSK9), a hepatic protease that attaches and internalizes LDL receptors into lysosomes hence promoting their destruction. By preventing LDL receptor destruction, LDL-C levels can be lowered 50%-60% above that achieved by statin therapy alone. This review explores PCSK-9 biology and the mechanisms available to alter it; clinical trials targeting PCSK9 activity, and the current state of clinically available inhibitors 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
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
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
Proprotein convertase subtilisin/kexin type 9(PCSK9) plays a paramount role in the degradation of lowdensity lipoprotein(LDL) receptors(LDLR) on the hepatic cells surface and subsequently affects LDL particles catabol...Proprotein convertase subtilisin/kexin type 9(PCSK9) plays a paramount role in the degradation of lowdensity lipoprotein(LDL) receptors(LDLR) on the hepatic cells surface and subsequently affects LDL particles catabolism and LDL cholesterol(LDL-c) levels. The anti-PCSK9 monoclonal antibodies lead to substantial decrease of LDL-c concentration. PCSK9(which is also expressed in pancreatic delta-cells) can decrease LDLR and subsequently decrease cholesterol accumulation in pancreatic beta-cells, which impairs glucose metabolism and reduces insulin secretion. Thus, a possible adverse effect of PCSK9 inhibitors on carbohydrate metabolism may be expected by this mechanism, which has been supported by the mendelian studies results. On the other hand, clinical data have suggested a detrimental association of PCSK9 with glucose metabolism. So, the inhibition of PCSK9 may be seen as a double-edged sword regarding carbohydrate metabolism. Completed clinical trials have not shown a detrimental effect of PCSK9 inhibitors on diabetes risk, but their short-term duration does not allow definite conclusions.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
Statins have been shown to be effective in reducing cardiovascular events.Their magnitude of benefits has been proportionate to the reduction in low-density lipoprotein cholesterol(LDL-c).Intensive lipid-lowering ther...Statins have been shown to be effective in reducing cardiovascular events.Their magnitude of benefits has been proportionate to the reduction in low-density lipoprotein cholesterol(LDL-c).Intensive lipid-lowering therapies using ezetimibe and more recently proprotein convertase subtilisin kexin 9 inhibitors have further improved clinical outcomes.Unselective application of these treatments is undesirable and unaffordable and,therefore,has been guided by LDL-c level.Nonetheless,the residual risk in the post-statin era is markedly heterogeneous,including thrombosis and inflammation risks.Moreover,the lipoprotein related risk is increasingly recognised to be related to other non-LDL-c markers such as Lp(a).Emerging data show that intensive lipid-lowering therapy produce larger absolute risk reduction in patients with polyvascular disease,post coronary artery bypass graft and diabetes.Notably,these clinical entities share similar phenotype of large burden of atherosclerotic plaques.Novel plaque imaging may aid decision making by identifying patients with propensity to develop lipid rich plagues at multi-vascular sites.Those patients may be suitable candidates for intensive lipid lowering treatment.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
Background Relations of lipoprotein (a)(Lp[a]) and proprotein convertase substilisin/kexin type 9 (PCSK9) levels to coronary artery disease (CAD) have been well established in general population, while little is known...Background Relations of lipoprotein (a)(Lp[a]) and proprotein convertase substilisin/kexin type 9 (PCSK9) levels to coronary artery disease (CAD) have been well established in general population, while little is known about the association between Lp(a) or PCSK9 and atherosclerotic lesions of different artery sites in patients with familial hypercholesterolemia (FH).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
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
Background: Reported are increased risks for malignant transformation in human oral keratinocytes (HOK) from ethyl alcohol (ETOH), tobacco products or human papilloma virus oncogenic subtype 16 (HPV 16) infections. We...Background: Reported are increased risks for malignant transformation in human oral keratinocytes (HOK) from ethyl alcohol (ETOH), tobacco products or human papilloma virus oncogenic subtype 16 (HPV 16) infections. We examined various HOK cell responses to these factors to show inhibitors of epidermal growth factor receptor (EGFR) also inhibits furin;proprotein convertase (FC) and HPV 16 entry in HOK. Methods: Immortalized HOK by HPV 16 (HPV 16B) or human telomerase (hTERT);primary foreskin keratinocytes (NHFK), primary HOK, buccal keratinocytes (NHBK) and oral SCC-25 were treated with dibenz[a,l]pyrene (DBP), anthraquinone;nitrosamine (NNAL) or ethyl alcohol (ETOH) and acetaldehyde (AA). ETOH was tested for synthesis of malondialdehyde (MDA) and alcohol dehydrogenase expression (ADH). ETOH, and PAH were evaluated by Western immunoblot for oncogene changes, and phosphorylated EGFR expression. Inhibition of EGFR by WZ4002 and Erlotinib and/or carcinogens effect on HPV 16 entry were studied. A green fluorescent pseudovirus (PsV);chloromethylketone (CMK) an inhibitor of furin activity and Western immunoblot of furin cell distribution further characterized HPV 16 entry. Results: ETOH (10 μM) increased expression of phosphorylated EGFR and HPV 16 entry through furin activity, and membrane, nuclear and cytoskeletal accumulations. CMK suppressed HPV 16 entry and blockage of ADH while aldehyde dehydrogenase (ALDH) enhanced HPV 16 entry. Similarly PAH, DBP (4-8 nM), anthraquinone (98 nM) and NNAL (6.9 μM) enhanced HPV 16 entry through furin activity and membrane, nuclear and cytoskeletal accumulations. Furthermore, WZ4002 and Erlotinib suppressed expressions of phosphorylated EGFR, FC activity, and HPV 16 entry. ETOH and DBP treatments also enhanced expressions of protease activated receptor-1 (PAR-1), and p21waf1 while depressed p16 and p27KIP1 expressions in HOK/HPV 16B cells. Conclusion: EGFR inhibitors are candidates for suppression of alcohol and tobacco effects on EGFR phosphorylated expression;keratinocyte growth, and HPV 16 entry and prevention treatment for HPV related diseases.展开更多
Objective:To study the value of serum PCSK9 for evaluating the severity in patients with type 2 diabetes mellitus and atherosclerosis. Methods:Type 2 diabetic patients with carotid atherosclerosis who were treated in ...Objective:To study the value of serum PCSK9 for evaluating the severity in patients with type 2 diabetes mellitus and atherosclerosis. Methods:Type 2 diabetic patients with carotid atherosclerosis who were treated in our hospital between May 2014 and September 2016 were selected as group A (n=69), type 2 diabetic patients without carotid atherosclerosis were selected as group B (n=79) and healthy subjects were selected as group C (n=55). Serum levels of SPCSK9, lipid metabolism indexes and oxidative stress indexes of three groups of subjects were detected. Results:Serum proprotein convertase subtilisin kexin 9 (PCSK9), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), CyPA, paraoxonase-1 (PON-1), PON-3, malondialdehyde (MDA) and 8-iso-prostaglandin F-2α(8-iso-PGF2α) levels of group A and group B were significantly higher than those of group C (P<0.05) while high-density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (ApoAI) levels were significantly lower than those of group C (P<0.05);serum PCSK9, TG, TC, LDL-C, ApoB, CyPA, PON-1, PON-3, MDA and 8-iso-PGF2αlevels of group A were significantly higher than those of group B (P<0.05) while HDL-C and ApoAI levels were significantly lower than those of group B (P<0.05);serum TG, TC, LDL-C, ApoB, CyPA, PON-1, PON-3, MDA and 8-iso-PGF2αlevels of high PCSK9 level subgroup in group A were significantly higher than those of low PCSK9 level subgroup (P<0.05) while HDL-C and ApoAI levels were significantly lower than those of low PCSK9 level subgroup (P<0.05). Conclusions:Abnormally elevated serum PCSK9 can affect lipid metabolism and enhance oxidative stress in patients with type 2 diabetes mellitus and atherosclerosis.展开更多
Objective:This study aimed to assess the impact of proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitor treatment immediately after percutaneous coronary intervention(PCI)on the myocardial salvage index(MSI)i...Objective:This study aimed to assess the impact of proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitor treatment immediately after percutaneous coronary intervention(PCI)on the myocardial salvage index(MSI)in patients with anterior ST-segment elevation myocardial infarction(STEMI)5-10 d after the procedure.Methods:The early PCSK9 inhibitor thERapy Following pErcutaneous Coronary inTervention(PERFECT)trial is a prospective randomized controlled trial.From January 2021 to December 2023,32 patients with anterior STEMI from Tongren Hospital,Shanghai Jiao Tong University School of Medicine,Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,and Shanghai Tenth People’s Hospital were enrolled in the PERFECT trial.Patients were randomly assigned in a 1∶1 ratio to the PCSK9 inhibitor group(n=16)or the control group(n=16),and their baseline data were collected.Patients in the PCSK9 inhibitor group(ie,alirocumab group)received a subcutaneous injection of PCSK9 inhibitor(alirocumab,75 mg)immediately after PCI based on conventional treatment.In the control group,patients received only conventional treatment.The primary endpoint was the MSI measured by cardiovascular magnetic resonance 5-10 d after PCI.The secondary endpoints included the left ventricular ejection fraction measured by cardiovascular magnetic resonance 5-10 d after PCI and the time to peak of creatine kinase isoenzyme-MB and high-sensitivity cardiac troponin T.Safety endpoints included any clinical adverse events that occurred during the 6-month follow-up period.Results:Baseline data during admission showed no intergroup significance.No significant difference in MSI(55.54%±14.80%vs.44.72%±15.42%,P=0.056)and left ventricular ejection fraction(51.24%±8.91%vs.44.99%±8.84%,P=0.060)was observed.Additional,there was no significant difference in the time to peak of creatine kinase isoenzyme-MB((12.97±5.67)h vs.(14.31±7.04)h,P=0.557)and high-sensitivity cardiac troponin T((21.03±12.46)h vs.(21.44±9.99)h,P=0.920)between the 2 groups.During the 6-month follow-up period,only 1 patient in the PCSK9 inhibitor group developed cerebral hemorrhage 6 months after PCI.Conclusions:Early treatment with alirocumab did not exhibit a significant increase in MSI at 5-10 d in patients with anterior STEMI.Larger trials are necessary to evaluate the impact of early administration of PCSK9 inhibitors after myocardial infarction.展开更多
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.
文摘Efficient and precise assembly of polypeptides into native functional states is critical for normal cellular processes. Understanding how a specific structure is encoded in the polypeptide sequence and what drives the structural progression to the native state is essential to deciphering the folding problem. Several prokaryotic and eukaryotic proteins require their propeptide-domains to function as dedicated intramolecular chaperones (IMCs). In this manuscript, we investigate the elementary steps in the IMC mediated maturation of Subtilisin E, a bacterial serine protease, and a prototype for the eukaryotic proprotein convertases (PCs). Through detailed analyses, we have attempted to define the unimolecular folding energy landscape for SbtE to understand how the stabilization of folding intermediates influences the maturation process, an aspect that is difficult to study in eukaryotic PCs. Our studies demonstrate that a rapid hydrophobic collapse precedes acquisition of tertiary structure during the folding of Pro-SbtE and results in formation of a molten-globule like intermediate. Induction of structure within the IMC stabilizes both the molten globule-like folding intermediate and the native state, and appears to expedite initial stages of folding, purely through thermodynamic stabilization of the folded state. While the induced structure does not affect the activation energies in the unimolecular folding reaction, it is detrimental to the autoproteolytic cleavage of the precursor and subsequent release and degradation of the inhibitory IMC-domain since both these stages require some degree of unfolding. Completion of Pro-SbtE maturation results in the formation of a kinetically trapped and extremely stable native state. Hence, our results suggest that the SbtE IMC appears to have evolved to be intrinsically unstructured and to bind with its cognate protease with a specific affinity that is critical for biological regulation.
文摘Hyperlipidemia is a well-established risk factor for developing cardiovascular disease(CVD). The recent American College of Cardiology and American Heart Association guidelines on lipid management emphasize treatment of individuals at increased risk for developing CVD events with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors(statins) at doses proven to reduce CVD events. However, there are limited options for patients who are either intolerant to statin therapy, develop CVD despite being on maximally tolerated statin therapy, or have severe hypercholesterolemia. Recently the Food and Drug Administration approved two novel medications for low-density lipoprotein(LDL)-cholesterol reduction: Evolocumab and Alirocumab. These agents target and inactivate proprotein convertase subtilsinkexin type 9(PCSK9), a hepatic protease that attaches and internalizes LDL receptors into lysosomes hence promoting their destruction. By preventing LDL receptor destruction, LDL-C levels can be lowered 50%-60% above that achieved by statin therapy alone. This review explores PCSK-9 biology and the mechanisms available to alter it; clinical trials targeting PCSK9 activity, and the current state of clinically available inhibitors 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.
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.
文摘Proprotein convertase subtilisin/kexin type 9(PCSK9) plays a paramount role in the degradation of lowdensity lipoprotein(LDL) receptors(LDLR) on the hepatic cells surface and subsequently affects LDL particles catabolism and LDL cholesterol(LDL-c) levels. The anti-PCSK9 monoclonal antibodies lead to substantial decrease of LDL-c concentration. PCSK9(which is also expressed in pancreatic delta-cells) can decrease LDLR and subsequently decrease cholesterol accumulation in pancreatic beta-cells, which impairs glucose metabolism and reduces insulin secretion. Thus, a possible adverse effect of PCSK9 inhibitors on carbohydrate metabolism may be expected by this mechanism, which has been supported by the mendelian studies results. On the other hand, clinical data have suggested a detrimental association of PCSK9 with glucose metabolism. So, the inhibition of PCSK9 may be seen as a double-edged sword regarding carbohydrate metabolism. Completed clinical trials have not shown a detrimental effect of PCSK9 inhibitors on diabetes risk, but their short-term duration does not allow definite conclusions.
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.
文摘Statins have been shown to be effective in reducing cardiovascular events.Their magnitude of benefits has been proportionate to the reduction in low-density lipoprotein cholesterol(LDL-c).Intensive lipid-lowering therapies using ezetimibe and more recently proprotein convertase subtilisin kexin 9 inhibitors have further improved clinical outcomes.Unselective application of these treatments is undesirable and unaffordable and,therefore,has been guided by LDL-c level.Nonetheless,the residual risk in the post-statin era is markedly heterogeneous,including thrombosis and inflammation risks.Moreover,the lipoprotein related risk is increasingly recognised to be related to other non-LDL-c markers such as Lp(a).Emerging data show that intensive lipid-lowering therapy produce larger absolute risk reduction in patients with polyvascular disease,post coronary artery bypass graft and diabetes.Notably,these clinical entities share similar phenotype of large burden of atherosclerotic plaques.Novel plaque imaging may aid decision making by identifying patients with propensity to develop lipid rich plagues at multi-vascular sites.Those patients may be suitable candidates for intensive lipid lowering treatment.
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.
文摘Background Relations of lipoprotein (a)(Lp[a]) and proprotein convertase substilisin/kexin type 9 (PCSK9) levels to coronary artery disease (CAD) have been well established in general population, while little is known about the association between Lp(a) or PCSK9 and atherosclerotic lesions of different artery sites in patients with familial hypercholesterolemia (FH).
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.
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.
文摘Background: Reported are increased risks for malignant transformation in human oral keratinocytes (HOK) from ethyl alcohol (ETOH), tobacco products or human papilloma virus oncogenic subtype 16 (HPV 16) infections. We examined various HOK cell responses to these factors to show inhibitors of epidermal growth factor receptor (EGFR) also inhibits furin;proprotein convertase (FC) and HPV 16 entry in HOK. Methods: Immortalized HOK by HPV 16 (HPV 16B) or human telomerase (hTERT);primary foreskin keratinocytes (NHFK), primary HOK, buccal keratinocytes (NHBK) and oral SCC-25 were treated with dibenz[a,l]pyrene (DBP), anthraquinone;nitrosamine (NNAL) or ethyl alcohol (ETOH) and acetaldehyde (AA). ETOH was tested for synthesis of malondialdehyde (MDA) and alcohol dehydrogenase expression (ADH). ETOH, and PAH were evaluated by Western immunoblot for oncogene changes, and phosphorylated EGFR expression. Inhibition of EGFR by WZ4002 and Erlotinib and/or carcinogens effect on HPV 16 entry were studied. A green fluorescent pseudovirus (PsV);chloromethylketone (CMK) an inhibitor of furin activity and Western immunoblot of furin cell distribution further characterized HPV 16 entry. Results: ETOH (10 μM) increased expression of phosphorylated EGFR and HPV 16 entry through furin activity, and membrane, nuclear and cytoskeletal accumulations. CMK suppressed HPV 16 entry and blockage of ADH while aldehyde dehydrogenase (ALDH) enhanced HPV 16 entry. Similarly PAH, DBP (4-8 nM), anthraquinone (98 nM) and NNAL (6.9 μM) enhanced HPV 16 entry through furin activity and membrane, nuclear and cytoskeletal accumulations. Furthermore, WZ4002 and Erlotinib suppressed expressions of phosphorylated EGFR, FC activity, and HPV 16 entry. ETOH and DBP treatments also enhanced expressions of protease activated receptor-1 (PAR-1), and p21waf1 while depressed p16 and p27KIP1 expressions in HOK/HPV 16B cells. Conclusion: EGFR inhibitors are candidates for suppression of alcohol and tobacco effects on EGFR phosphorylated expression;keratinocyte growth, and HPV 16 entry and prevention treatment for HPV related diseases.
基金National Natural Science Foundation of China(81601373).
文摘Objective:To study the value of serum PCSK9 for evaluating the severity in patients with type 2 diabetes mellitus and atherosclerosis. Methods:Type 2 diabetic patients with carotid atherosclerosis who were treated in our hospital between May 2014 and September 2016 were selected as group A (n=69), type 2 diabetic patients without carotid atherosclerosis were selected as group B (n=79) and healthy subjects were selected as group C (n=55). Serum levels of SPCSK9, lipid metabolism indexes and oxidative stress indexes of three groups of subjects were detected. Results:Serum proprotein convertase subtilisin kexin 9 (PCSK9), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), CyPA, paraoxonase-1 (PON-1), PON-3, malondialdehyde (MDA) and 8-iso-prostaglandin F-2α(8-iso-PGF2α) levels of group A and group B were significantly higher than those of group C (P<0.05) while high-density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (ApoAI) levels were significantly lower than those of group C (P<0.05);serum PCSK9, TG, TC, LDL-C, ApoB, CyPA, PON-1, PON-3, MDA and 8-iso-PGF2αlevels of group A were significantly higher than those of group B (P<0.05) while HDL-C and ApoAI levels were significantly lower than those of group B (P<0.05);serum TG, TC, LDL-C, ApoB, CyPA, PON-1, PON-3, MDA and 8-iso-PGF2αlevels of high PCSK9 level subgroup in group A were significantly higher than those of low PCSK9 level subgroup (P<0.05) while HDL-C and ApoAI levels were significantly lower than those of low PCSK9 level subgroup (P<0.05). Conclusions:Abnormally elevated serum PCSK9 can affect lipid metabolism and enhance oxidative stress in patients with type 2 diabetes mellitus and atherosclerosis.
基金supported by the National Natural Science Foundation of China(82270276)the Xinxin Heart Foundation from China Cardiovascular Association(2021-CCA-ACCESS-73).
文摘Objective:This study aimed to assess the impact of proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitor treatment immediately after percutaneous coronary intervention(PCI)on the myocardial salvage index(MSI)in patients with anterior ST-segment elevation myocardial infarction(STEMI)5-10 d after the procedure.Methods:The early PCSK9 inhibitor thERapy Following pErcutaneous Coronary inTervention(PERFECT)trial is a prospective randomized controlled trial.From January 2021 to December 2023,32 patients with anterior STEMI from Tongren Hospital,Shanghai Jiao Tong University School of Medicine,Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,and Shanghai Tenth People’s Hospital were enrolled in the PERFECT trial.Patients were randomly assigned in a 1∶1 ratio to the PCSK9 inhibitor group(n=16)or the control group(n=16),and their baseline data were collected.Patients in the PCSK9 inhibitor group(ie,alirocumab group)received a subcutaneous injection of PCSK9 inhibitor(alirocumab,75 mg)immediately after PCI based on conventional treatment.In the control group,patients received only conventional treatment.The primary endpoint was the MSI measured by cardiovascular magnetic resonance 5-10 d after PCI.The secondary endpoints included the left ventricular ejection fraction measured by cardiovascular magnetic resonance 5-10 d after PCI and the time to peak of creatine kinase isoenzyme-MB and high-sensitivity cardiac troponin T.Safety endpoints included any clinical adverse events that occurred during the 6-month follow-up period.Results:Baseline data during admission showed no intergroup significance.No significant difference in MSI(55.54%±14.80%vs.44.72%±15.42%,P=0.056)and left ventricular ejection fraction(51.24%±8.91%vs.44.99%±8.84%,P=0.060)was observed.Additional,there was no significant difference in the time to peak of creatine kinase isoenzyme-MB((12.97±5.67)h vs.(14.31±7.04)h,P=0.557)and high-sensitivity cardiac troponin T((21.03±12.46)h vs.(21.44±9.99)h,P=0.920)between the 2 groups.During the 6-month follow-up period,only 1 patient in the PCSK9 inhibitor group developed cerebral hemorrhage 6 months after PCI.Conclusions:Early treatment with alirocumab did not exhibit a significant increase in MSI at 5-10 d in patients with anterior STEMI.Larger trials are necessary to evaluate the impact of early administration of PCSK9 inhibitors after myocardial infarction.
