Overexpression of low-density lipoprotein receptor prevents neurotoxic polarization of astrocytes via inhibiting NLRP3 inflammasome activation in experimental ischemic stroke

Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.

Low-density lipoprotein receptor-related protein 2(LRP2)is required for lipid export in the midgut of the migratory locust,Locusta migratoria

Low-density lipoprotein receptor-related protein 2(LRP2)is a multifunctional endocytic receptor expressed in epithelial cells.In mammals,it acts as an endocytic receptor that mediates the cellular uptake of cholesterol-containing apolipoproteins to maintain lipid homeostasis.However,little is known about the role of LRP2 in lipid homeostasis in insects.In the present study,we investigated the function of LRP2 in the migratory locust Locusta migratoria(LmLRP2).The mRNA of LmLRP2 is widely distributed in various tissues,including integument,wing pads,foregut,midgut,hindgut,Malpighian tubules and fat body,and the amounts of LmLRP2 transcripts decreased gradually in the early stages and then increased in the late stages before ecdysis during the nymphal developmental stage.Fluorescence immunohistochemistry revealed that the LmLRP2 protein is mainly located in cellular membranes of the midgut and hindgut.Using RNAi to silence LmLRP2 caused molting defects in nymphs(more than 60%),and the neutral lipid was found to accumulate in the midgut and surface of the integument,but not in the fat body,of dsLmLRP2-treated nymphs.The results of a lipidomics analysis showed that the main components of lipids(diglyceride and triglyceride)were significantly increased in the midgut,but decreased in the fat body and hemolymph.Furthermore,the content of total triglyceride was significantly increased in the midgut,but markedly decreased in the fat body and hemolymph in dsLmLRP2-injected nymphs.Our results indicate that LmLRP2 is located in the cellular membranes of midgut cells,and is required for lipid export from the midgut to the hemolymphand fat body in locusts.

Synthetic high-density lipoprotein(sHDL):a bioinspired nanotherapeutics for managing periapical bone inflammation

Apical periodontitis(AP)is a dental-driven condition caused by pathogens and their toxins infecting the inner portion of the tooth(i.e.,dental pulp tissue),resulting in inflammation and apical bone resorption affecting 50%of the worldwide population,with more than 15 million root canals performed annually in the United States.Current treatment involves cleaning and decontaminating the infected tissue with chemo-mechanical approaches and materials introduced years ago,such as calcium hydroxide,zinc oxide–eugenol,or even formalin products.Here,we present,for the first time,a nanotherapeutics based on using synthetic highdensity lipoprotein(sHDL)as an innovative and safe strategy to manage dental bone inflammation.sHDL application in concentrations ranging from 25μg to 100μg/mL decreases nuclear factor Kappa B(NF-κB)activation promoted by an inflammatory stimulus(lipopolysaccharide,LPS).Moreover,sHDL at 500μg/mL concentration markedly decreases in vitro osteoclastogenesis(P<0.001),and inhibits IL-1α(P=0.027),TNF-α(P=0.004),and IL-6(P<0.001)production in an inflammatory state.Notably,sHDL strongly dampens the Toll-Like Receptor signaling pathway facing LPS stimulation,mainly by downregulating at least 3-fold the pro-inflammatory genes,such as Il1b,Il1a,Il6,Ptgs2,and Tnf.In vivo,the lipoprotein nanoparticle applied after NaOCl reduced bone resorption volume to(1.3±0.05)mm^(3) and attenuated the inflammatory reaction after treatment to(1090±184)cells compared to non-treated animals that had(2.9±0.6)mm^(3)(P=0.0123)and(2443±931)cells(P=0.004),thus highlighting its promising clinical potential as an alternative therapeutic for managing dental bone inflammation.

Monocyte to High-density Lipoprotein Cholesterol Ratio as a Predictor of Nonalcoholic Fatty Liver Disease in Childhood Obesity

Objective Inflammation is involved in the development and progression of nonalcoholic fatty liver disease(NAFLD).The monocyte to high-density lipoprotein cholesterol ratio(MHR)has emerged as a marker for various inflammation-related diseases.The aim of the present study was to investigate the association between the MHR and NAFLD in a population with childhood obesity.Methods Based on hepatic ultrasound,a total of 504 children with obesity(357 with NAFLD and 147 without NAFLD)were included in the study.The correlation between the MHR and NAFLD risk factors was assessed by Pearson’s and Spearman’s analyses.Multivariate stepwise logistic regression analyses were conducted to explore the association between the MHR and the risk of NAFLD.Results The MHR in patients with NAFLD was significantly greater than that in patients without NAFLD[0.52(0.44-0.67)versus 0.44(0.34-0.57),P<0.001].Multivariate stepwise logistic regression analysis demonstrated that the MHR[odds ratio(OR):1.033,95%confidence interval(CI):1.015-1.051;P<0.001]was an independent predictor of NAFLD in childhood obesity patients,as were age(OR:1.205,95%CI:1.059-1.371;P=0.005],waist circumference[OR:1.037,95%CI:1.008-1.067;P=0.012],and alanine transaminase[OR:1.067,95%CI:1.045-1.089;P<0.001].Additionally,MHR quartiles showed a significant positive association with the incidence of NAFLD after adjusting for potential confounding factors.Conclusion The present study showed that the MHR may serve as an available and useful indicator of NAFLD in individuals with childhood obesity.

Monocyte to high-density lipoprotein cholesterol ratio as a predictor of the activity of thyroid-associated ophthalmopathy

AIM:To evaluate the relationship between monocyte to high-density lipoprotein cholesterol ratio(MHR)and the disease activity of thyroid-associated ophthalmopathy(TAO).METHODS:A total of 87 patients were classified into two groups based on clinical activity score(CAS)scoring criteria:high CAS group(n=62,the CAS score was≥3);low CAS group(n=25,the CAS score was<3).In addition,a group of healthy people(n=114)were included to compared the MHR.Proptosis,MHR,average signal intensity ratio(SIR),average lacrimal gland(LG)-SIR,average extraocular muscles(EOM)area from 87 patients with TAO were calculated in magnetic resonance imaging(MRI),and compared between these two groups.Correlation testing was utilized to evaluate the association of parameters among the clinical variables.RESULTS:Patients in high CAS group had a higher proptosis(P=0.041)and MHR(P=0.048).Compared to the healthy group,the MHR in the TAO group was higher(P=0.001).Correlation testing declared that CAS score was strongly associated with proptosis and average SIR,and MHR was positively associated with CAS score,average SIR,and average LG-SIR.The area under the receiver operating characteristic curve(AUC)of MHR was 0.6755.CONCLUSION:MHR,a novel inflammatory biomarker,has a significant association with CAS score and MRI imaging(average SIR and LG-SIR)and it can be a new promising predictor during the active phase of TAO.

Initial decrease in the lipoprotein(a)level is a novel prognostic biomarker in patients with acute coronary syndrome

BACKGROUND Lipoprotein(a)[Lp(a)]is a causal risk factor for atherosclerotic cardiovascular diseases;however,its role in acute coronary syndrome(ACS)remains unclear.AIM To investigate the hypothesis that the Lp(a)levels are altered by various conditions during the acute phase of ACS,resulting in subsequent cardiovascular events.METHODS From September 2009 to May 2016,377 patients with ACS who underwent emergent coronary angiography,and 249 who completed≥1000 d of follow-up were enrolled.Lp(a)levels were measured using an isoform-independent assay at each time point from before percutaneous coronary intervention(PCI)to 48 h after PCI.The primary endpoint was the occurrence of major adverse cardiac events(MACE;cardiac death,other vascular death,ACS,and non-cardiac vascular events).RESULTS The mean circulating Lp(a)level decreased significantly from pre-PCI(0 h)to 12 h after(19.0 mg/dL to 17.8 mg/dL,P<0.001),and then increased significantly up to 48 h after(19.3 mg/dL,P<0.001).The changes from 0 to 12 h[Lp(a)Δ0-12]significantly correlated with the basal levels of creatinine[Spearman’s rank correlation coefficient(SRCC):-0.181,P<0.01]and Lp(a)(SRCC:-0.306,P<0.05).Among the tertiles classified according to Lp(a)Δ0-12,MACE was significantly more frequent in the lowest Lp(a)Δ0-12 group than in the remaining two tertile groups(66.2%vs 53.6%,P=0.034).A multivariate analysis revealed that Lp(a)Δ0-12[hazard ratio(HR):0.96,95%confidence interval(95%CI):0.92-0.99]and basal creatinine(HR:1.13,95%CI:1.05-1.22)were independent determinants of subsequent MACE.CONCLUSION Circulating Lp(a)levels in patients with ACS decreased significantly after emergent PCI,and a greater decrease was independently associated with a worse prognosis.

Association between sensitivity to thyroid hormones and non-highdensity lipoprotein cholesterol levels in patients with type 2 diabetes mellitus

BACKGROUND Dyslipidemia and type 2 diabetes mellitus(T2DM)are chronic conditions with substantial public health implications.Effective management of lipid metabolism in patients with T2DM is critical.However,there has been insufficient attention given to the relationship between thyroid hormone sensitivity and dyslipidemia in the T2DM population,particularly concerning non-high-density lipoprotein cholesterol(non-HDL-C).AIM To clarify the association between thyroid hormone sensitivity and dyslipidemia in patients with T2DM.METHODS In this cross-sectional study,thyroid hormone sensitivity indices,the thyroid feedback quantile-based index(TFQI),the thyroid-stimulating hormone index(TSHI),the thyrotrophic T4 resistance index(TT4RI),and the free triiodothyronine(FT3)/free thyroxine(FT4)ratio were calculated.Logistic regression analysis was performed to determine the associations between those composite indices and non-HDL-C levels.Random forest variable importance and Shapley Additive Explanations(SHAP)summary plots were used to identify the strength and direction of the association between hyper-non-HDL-C and its major predictor.RESULTS Among the 994 participants,389(39.13%)had high non-HDL-C levels.Logistic regression analysis revealed that the risk of hyper-non-HDL-C was positively correlated with the TFQI(OR:1.584;95%CI:1.088-2.304;P=0.016),TSHI(OR:1.238;95%CI:1.034-1.482;P=0.02),and TT4RI(OR:1.075;95%CI:1.006-1.149;P=0.032)but was not significantly correlated with the FT3/FT4 ratio.The relationships between composite indices of the thyroid system and non-HDL-C levels differed according to sex.An increased risk of hyper-non-HDL-C was associated with elevated TSHI levels in men(OR:1.331;95%CI:1.003-1.766;P=0.048)but elevated TFQI levels in women(OR:2.337;95%CI:1.4-3.901;P=0.001).Among the analyzed variables,the average SHAP values were highest for TSHI,followed by TT4RI.CONCLUSION Impaired sensitivity to thyroid hormones was associated with high non-HDL-C levels in patients with T2DM.

Correlation of Helicobacter pylori infection with high-density lipoprotein cholesterol levels and pulse wave conduction velocity

Background:Helicobacter pylori(HP)is associated with several gastrointestinal diseases,including peptic ulcer diseases and gastric cancer,and non-gastrointestinal diseases such as hypertension and Alzheimer's disease.However,the relationship between HP and lipid metabolism and atherosclerosis remains unclear.This study aims to investigate the association between H.pylori infection and high-density lipoprotein cholesterol levels and pulse wave conduction velocity.Methods:This is a report of a cross-sectional study that collected data from 2,827 participants.The data collected included results of life questionnaires,laboratory tests,13C-urea breath test(13C-UBT),and pulse wave conduction velocity test.Based on the results of the 13C-UBT test,the subjects were divided into two groups:the HP-uninfected group(HP−)and the HP-infected group(HP+).The study compared the differences in HDL-C levels and brachial-ankle pulse wave velocity(baPWV)between the two groups.One-way regression analysis was used to identify potential factors affecting HDL-C levels in the study population.Multiple regression equations were presented to analyze whether HP infection was an independent risk factor for abnormal HDL-C metabolism in the population.Results:Univariate analysis demonstrated that high-density lipoprotein cholesterol(HDL-C)levels were significantly lower in the HP+group compared to the HP−group,with a mean difference ofβ=−18.1 mg/dl(95%CI:−19.3 to−17.0,P<0.001).After adjusting for all variables,the HDL-C levels remained lower in the HP+group compared to the HP-group,with a mean difference ofβ=−17.4 mg/dl(95%CI:−18.2 to−16.7,P<0.001).These findings suggest that H.pylori infection is independently associated with abnormal HDL-C metabolism.Additionally,brachial-ankle pulse wave velocity(baPWV)was higher in the HP+group than in the HP−group on both sides.On the right side,the baPWV was 1,713.4±231.4 cm/s in the HP+group compared to 1,542.8±237.5 cm/s in the HP−group(t=−18.30,P<0.001).On the left side,the baPWV was 1,743.7±238.8 cm/s in the HP+group compared to 1,562.8±256.3 cm/s in the HP−group(t=−18.23,P<0.001).These results indicate a significant association between H.pylori infection and increased arterial stiffness,as measured by baPWV.Conclusion:Helicobacter pylori infection is associated with a decrease in high-density lipoprotein cholesterol levels and an increase in pulse wave conduction velocity.

基于NOD样受体3炎性小体通路对利拉鲁肽在氧化低密度脂蛋白诱导内皮细胞损伤的作用机制研究

背景动脉粥样硬化是世界范围内引起心脑血管疾病最主要的原因,炎症是目前研究热点,其中NOD样受体3(NLRP3)是研究最为深入的炎症小体。胰高糖素样肽1(GLP-1)受体激动剂有抗动脉粥样硬化作用,具体机制尚不明确。目的研究利拉鲁肽通过拮抗氧化低密度脂蛋白(ox-LDL)诱导的内皮细胞损伤的作用机制。方法2022-03-25—05-19培养人脐静脉内皮细胞(HUVEC),取HUVEC加空白血清作为对照组,100μg/mL的ox-LDL干预HUVEC 48 h作为模型组,100μg/mL的ox-LDL干预HUVEC 24 h后分别加入100、200、400 nmol/L利拉鲁肽处理24 h作为利拉鲁肽低浓度组、利拉鲁肽中浓度组、利拉鲁肽高浓度组。CCK-8法计算细胞增殖率。通过扫描电镜观察焦亡细胞形态。检测乳酸脱氢酶(LDH)活力。酶联免疫吸附试验(ELISA)检测白介素(IL)-1β、IL-18表达水平。蛋白质免疫印迹试验(Western blot)检测NLRP3、接头蛋白凋亡相关斑点样蛋白(ASC)、天冬氨酸蛋白水解酶1(Caspase-1)、焦亡执行蛋白(GSDMD)、N端结构域的焦亡执行蛋白(N-GSDMD)表达水平。结果模型组、利拉鲁肽低浓度组和利拉鲁肽中浓度组细胞增殖率低于对照组,利拉鲁肽低浓度组、利拉鲁肽中浓度组、利拉鲁肽高浓度组细胞增殖率高于模型组(P<0.05)。细胞扫描电镜结果示模型组细胞焦亡明显,利拉鲁肽低浓度组、利拉鲁肽中浓度组、利拉鲁肽高浓度组细胞焦亡情况明显改善。模型组、利拉鲁肽低浓度组LDH活力高于对照组,利拉鲁肽低浓度组、利拉鲁肽中浓度组、利拉鲁肽高浓度组低于模型组(P<0.05)。模型组、利拉鲁肽低浓度组IL-1β表达水平高于对照组,利拉鲁肽中浓度组、利拉鲁肽高浓度组IL-1β表达水平低于模型组(P<0.05);模型组IL-18表达水平高于对照组,利拉鲁肽低浓度组、利拉鲁肽中浓度组、利拉鲁肽高浓度组IL-18表达水平低于模型组(P<0.05)。模型组NLRP3、ASC、Caspase-1、GSDMD、N-GSDMD表达水平高于对照组,利拉鲁肽低浓度组ASC、Caspase-1表达水平高于对照组,利拉鲁肽中浓度组NLRP3、ASC表达水平低于模型组,利拉鲁肽高浓度组NLRP3、ASC、Caspase-1表达水平低于模型组(P<0.05)。结论利拉鲁肽显著抑制ox-LDL诱导的内皮细胞NLRP3炎性小体活化,并且能够抑制内皮细胞的焦亡,具有抗动脉粥样硬化作用。

阿司匹林抵抗和脂蛋白相关磷脂酶A2与复发性缺血性脑卒中的相关性分析

目的探讨非心源性卒中患者阿司匹林抵抗和脂蛋白相关磷脂酶A2(Lp-PLA2)与缺血性脑卒中复发的相关性。方法选取2021-10—2022-10在永城市人民医院住院的发病7 d内的急性非心源性缺血性脑卒中患者72例,基于临床病史和神经影像学证据分为初发组(n=36)和复发组(n=36),入院后规律服用阿司匹林7 d。采用血栓弹力图测定阿司匹林抵抗,并测定血清Lp-PLA2水平。比较初发组和复发组阿司匹林抵抗、Lp-PLA2水平,分析阿司匹林抵抗、Lp-PLA2与缺血性脑卒中复发之间的相关性。采用多元Logistic回归分析筛选复发性卒中独立危险因素,ROC曲线下面积评价相关危险因素的预测价值。结果36.1%的复发性卒中患者存在阿司匹林抵抗,19.4%的初发患者存在阿司匹林抵抗,2组比较差异有统计学意义(P<0.001)。复发性卒中患者血清PLA2水平中位数160.0μg/L,初次发病患者为125.0μg/L,2组比较差异有统计学意义(P=0.008)。多元Logistic回归分析显示阿司匹林抵抗和高PLA2水平是复发性缺血性脑卒中的影响因素,阿司匹林抵抗患者卒中复发风险增加4.06倍(P=0.042),高于Lp-PLA2中位值患者的4.37倍(P=0.011)。阿司匹林抵抗和Lp-PLA2预测卒中复发的ROC曲线下面积分别为0.753(95%CI:0.641~0.873)和0.683(95%CI:0.559~0.807)。结论与初发卒中患者相比,复发性卒中患者阿司匹林抵抗的比率和血清Lp-PLA2水平均明显升高,可作为复发性卒中的预测因素。

Genetic Screening of the Lipoprotein Lipase Gene for Mutations in Chinese Subjects with or without Hypertriglyceridemia

Objective： To investigate the association between the mutations in lipoprotein lipase gene and hypertriglyceridemia （HTG）. Methods： The lipoprotein lipase （LPL） gene was screened for mutations in 386 Chinese subjects with （108 cases in the HTG group） or without HTG （278 cases in the control group）, by single-strand conformation polymorphism （SSCP） analysis and DNA sequencing. Results： One novel silent mutation L103L, one missense mutation P207L, three splicing mutations Int3/3＇ -ass/C（-6）→T, and the common S447X polymorphism has been identified in the whole coding region and exon-intron junctions of the LPL gene were examined. Heterozygous P207L found in the HTG group was the first case reported in Asia and subsequently another P207L heterozygote was found in the proband＇s family, all of which suggested that P207L was one of the causes of familial combined hyperlipidemia, but was not so prevalent as that in French Canadian. Int3/3＇-ass/C（-6）→T was found in both groups in the present study although it was regarded as a pathogenic variant to HTG earlier on. Moreover about the beneficial polymorphism S447X, there was also some supportive evidence that the levels of triglycerides （TG） in S447X carriers were significantly lower than noncarders in the subjects without HTG. Conclusions： The association between the LPL variants and HTG is quite complicated and versatile, genotyping of LPL in a larger-scale screening should be necessary and justifiable.

TyG-BMI、HAR、GRI与糖尿病视网膜病变的关系

目的探讨甘油三酯葡萄糖体重指数(TyG-BMI)、高密度脂蛋白胆固醇与载脂蛋白A比值(HAR)、血糖风险指数(GRI)与糖尿病视网膜病变(DR)的关系。方法将159例2型糖尿病(T2DM)并发DR患者(DR组)根据DR国际临床分级标准分为非增殖期视网膜病变组(NPDR组,66例)和增殖期视网膜病变组(PDR组,93例),另择159例未发生DR的T2DM患者为对照组。记录临床信息和基线实验室检查结果,计算TyG-BMI、HAR、GRI。多因素Logistic回归分析DR发病的影响因素,受试者工作特征(ROC)曲线分析TyG-BMI、HAR、GRI对DR的诊断价值。结果DR组T2DM病程,合并高血压、糖尿病肾病、糖尿病足比例,糖化血红蛋白(HbA1c)、稳态模型胰岛素抵抗指数(HOMA-IR)、总胆固醇(TC)、C反应蛋白(CRP)、TyG-BMI、HAR和GRI水平均高于对照组(P<0.05)。PDR组TyGBMI、HAR和GRI均高于NPDR组(P<0.05)。多因素Logistic回归分析结果显示,T2DM病程较长[OR(95%CI):2.781(1.398~5.534)]、高TyG-BMI[2.036(1.169~3.546)]、高HAR[1.890(1.090~3.280)]、高GRI[1.836(1.065~3.167)]是DR患病的危险因素(P<0.05)。ROC曲线分析结果显示,联合TyG-BMI、HAR、GRI诊断DR的曲线下面积(AUC)高于单独诊断[分别为0.940(0.908~0.964)、0.864(0.821~0.900)、0.796(0.747~0.839)、0.836(0.790~0.875),均P<0.05]。结论T2DM患者TyG-BMI、HAR、GRI增高与DR发病及病情严重程度有关,可用于评估DR的发病风险。

家蚕孤雌生殖差异脂蛋白30K lipoprotein precursor基因的克隆与生物信息学分析

应用二维凝胶电泳（2-DE）技术分离家蚕孤雌生殖蚁蚕总蛋白，并和正常蚁蚕总蛋白进行比较，得到46个可能与家蚕孤雌生殖相关的差异蛋白点。对这些差异蛋白点进行胶内酶解后基质辅助激光解吸电离串联飞行时间质谱（MALDI-TOF-TOFMS）分析，经数据库搜索鉴定，确定其中一个差异蛋白点为脂蛋白30Klipoprotein precursor（30KLPP）。通过5′-RACE技术克隆到30KLPP脂蛋白的全长cDNA序列。生物信息学分析显示该差异蛋白基因全长917bp。编码261个氨基酸，理论分子质量为30．013kD，等电点为7．193；结构域和三级结构预测显示该蛋白包含1个Lipoprotein_11结构域和12个β-折叠。预测其信号肽概率为1．000，定位在1～20aa区域，即可能存在信号肽。细胞定位预测显示该蛋白可能分泌到胞外（SP值为0．934）。分析结果有助于进一步研究30KLPP脂蛋白结构与功能的关系。

Decreased levels of phosphorylated synuclein in plasma are correlated with poststroke cognitive impairment

Poststro ke cognitive impairment is a major secondary effect of ischemic stroke in many patients;however,few options are available for the early diagnosis and treatment of this condition.The aims of this study were to(1)determine the specific relationship between hypoxic andα-synuclein during the occur of poststroke cognitive impairment and(2)assess whether the serum phosphorylatedα-synuclein level can be used as a biomarker for poststro ke cognitive impairment.We found that the phosphorylatedα-synuclein level was significantly increased and showed pathological aggregation around the cerebral infa rct area in a mouse model of ischemic stroke.In addition,neuronalα-synuclein phosphorylation and aggregation were observed in the brain tissue of mice subjected to chronic hypoxia,suggesting that hypoxia is the underlying cause ofα-synuclein-mediated pathology in the brains of mice with ischemic stroke.Serum phosphorylatedα-synuclein levels in patients with ischemic stroke were significantly lower than those in healt hy subjects,and were positively correlated with cognition levels in patients with ischemic stroke.Furthermore,a decrease in serum high-density lipoprotein levels in stroke patie nts was significantly correlated with a decrease in phosphorylatedα-synuclein levels.Although ischemic stroke mice did not show significant cognitive impairment or disrupted lipid metabolism 14 days after injury,some of them exhibited decreased cognitive function and reduced phosphorylatedα-synuclein levels.Taken together,our results suggest that serum phosphorylatedα-synuclein is a potential biomarker for poststroke cognitive impairment.

单核细胞/高密度脂蛋白胆固醇比值对原发性非病毒性肝细胞癌患者预后的影响:一项回顾性队列研究

背景原发性非病毒性肝细胞癌(NBNC-HCC)的发病率持续增加,脂质代谢异常伴随炎症是NBNCHCC发生的主要原因之一,炎性指标的检测和评估可能是预测NBNC-HCC预后的重要方法。目的 本研究探讨单核细胞/高密度脂蛋白比值(MHR)预测NBNC-HCC患者的预后价值。方法 收集2013年1月—2020年2月在河北医科大学第三医院被诊断为NBNC-HCC的患者119例,收集患者的基线资料和实验室检查结果。将患者依据MHR值四分位数分为Q1(MHR<0.33,n=28)、Q2(0.33≤MHR<0.66,n=31)、Q3(0.66≤MHR<1.59,n=30)、Q4(MHR≥1.59,n=30)组。对患者进行定期随访,记录患者的生存状态、死亡时间等资料,主要观察终点为NBNC-HCC患者的总生存期(OS)。绘制限制性立方样图(RCS)评估入院时MHR与患者死亡的相关性。绘制受试者工作特征曲线(ROC曲线)分析入院时MHR对NBNC-HCC患者36个月预后的预测价值。采用Cox比例风险模型和BP神经网络模型分析NBNC-HCC患者的独立危险因素。采用Kaplan-Meier法绘制NBNC-HCC患者预后的生存曲线并进行Log-rank检验。结果 Q1~Q4组患者糖尿病、接受手术比例、巴塞罗那分期(BCLC分期)、天冬氨酸氨基转氨酶(AST)、C反应蛋白(CRP)、谷氨酰转肽酶(γ-GT)、胆碱酯酶(CHE)、尿素(UREA)、肌酐(Scr)、高密度脂蛋白胆固醇(HDL-C)、白细胞计数(WBC)、红细胞计数(RBC)、单核细胞计数(MONO)、中性粒细胞计数(NEUT)、白蛋白-胆红素评分(ALBI评分)比较,差异有统计学意义(P<0.05)。绘制MHR、MONO、HDL-C预测NBNC-HCC患者预后的ROC曲线,结果显示MHR(AUC=0.822,95%CI=0.742~0.903,P<0.05)对患者预后的预测作用优于MONO(AUC=0.723,95%CI=0.618~0.828)(Z=4.34,P<0.05)和HDL-C(AUC=0.216,95%CI=0.119~0.313)(Z=2.088,P<0.05)。多因素Cox回归分析结果显示BCLC分期B~D期、CRP和MHR是NBNC-HCC患者全因死亡的独立危险因素(P<0.05)。调整高血压、吸烟、饮酒、糖尿病、ALT、AST后,Q2(OR=1.926,95%CI=1.005~3.689,P=0.015)、Q3(OR=3.418,95%CI=1.774~6.586,P<0.05)、Q4组(OR=7.677,95%CI=3.773~15.621,P<0.05)是患者死亡的危险因素。RCS结果显示,入院时MHR与NBNC-HCC患者预后的死亡风险存在非线性剂量-反应关系(P_(总趋势)<0.001,P_(非线性)<0.001),当入院时MHR>0.67时,HR>1,入院时MHR为NBNC-HCC患者死亡的危险因素(P<0.05)。BP神经网络模型分析发现影响NBNC-HCC患者预后的主要因素包括BCLC分期(100.0%)、血管侵犯(76.3%)、肝外转移(40.6%)、MHR(39.3%)、CRP(38.7%)、ALBI评分(35.5%)、总胆红素(35.0%)、MONO(34.8%)、NEUT(29.8%)等。Q1~Q4组累积生存率比较,差异有统计学意义(χ^(2)=61.86,P<0.001)。结论 MHR是NBNC-HCC患者不良预后的独立危险因素,具有较好的预测价值。

Liver as a new target organ in Alzheimer's disease:insight from cholesterol metabolism and its role in amyloid-beta clearance

Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.

非常规血脂指标在2型糖尿病患者心血管风险评估中的应用进展

动脉粥样硬化性血脂异常与心血管疾病的发病率和死亡率之间的残余风险密切相关,即使2型糖尿病(T2DM)患者的低密度脂蛋白胆固醇(LDL-C)水平达标后,这种风险依然存在。非常规血脂指标[如非高密度脂蛋白胆固醇(HDL-C)、三酰甘油/HDL-C比值、LDL-C/HDL-C比值、总胆固醇/HDL-C比值]在T2DM患者的心血管风险预测中逐渐受到重视。心血管风险的早期识别对于优化T2DM管理至关重要。随着心血管疾病预防策略的不断细化,研究的重点逐渐转向简便、全面且有效的心血管疾病风险分层方法。未来将进一步评估上述指标与其他代谢参数的协同作用,精确区分阈值,优化个体化治疗,并通过动态监测上述指标加强精准的心血管风险管理。

血脂指标介导糖尿病与脑卒中因果关系的两样本双向孟德尔随机化研究

目的应用孟德尔随机化(MR)研究探索血脂指标[高密度脂蛋白胆固醇(HDLC)、甘油三酯(TG)等]在糖尿病与脑卒中因果关系中的中介效应。方法在全基因组关联研究(GWAS)汇总数据中选取单核苷酸多态性(SNP)作为工具变量,以逆方差加权法作为主分析方法,结合MR-Egger回归法、加权中位数法、简单模式和加权模式进行分析,探索糖尿病、血脂指标与脑卒中的因果关系。利用反向MR探索糖尿病、血脂指标与脑卒中是否存在反向因果关系。利用MR-Egger回归法进行多效性检验,利用MR-Egger和IVW进行Cochran′s Q异质性检验,利用留一法分析排除个别SNP对于整体结果的影响。采用中介分析探讨血脂指标的中介效应。结果IVW结果显示,糖尿病(OR=17.017,95%CI 7.377~39.252)、HDLC(OR=0.724,95%CI 0.069~0.862)、TG(OR=1.137,95%CI 1.047~1.235)均与脑卒中有因果关系,糖尿病与HDLC(OR=0.652,95%CI 0.501~0.849)、TG(OR=3.046,95%CI 1.467~6.323)有因果关系。MR-Egger回归法的P均>0.05,表明遗传工具不存在多效性。反向MR显示,脑卒中与糖尿病不存在因果关系,HDLC、TG与糖尿病不存在因果关系。HDLC在糖尿病与脑卒中中介效应为0.137,中介效应比例为4.851%。TG在糖尿病与脑卒中中介效应为0.143,中介效应比例为5.031%。结论糖尿病与脑卒中存在正向因果关系,HDLC、TG在糖尿病与脑卒中的因果关系中存在中介效应。

大豆卵磷脂和低密度脂蛋白在山羊精液冷冻保存中的应用研究进展

精液冷冻保存技术是现代畜牧业中用于遗传资源保护和繁殖管理的重要手段。本文从山羊精液冷冻保存技术及其保存过程中的冷冻损伤和冷冻保护剂的应用,大豆卵磷脂(SL)和低密度脂蛋白(LDL)在精液冷冻保存中的作用机理及应用,以及两者的联合应用等方面,探讨了SL和LDL在山羊精液冷冻保存中的研究进展。山羊精液冷冻保存技术是指通过构建极低温环境使山羊精液中的精子生理活动处于静止状态。精液在保存过程中受低温环境的影响导致细胞受损,活性氧积累导致精子质量下降,而冷冻保护剂的使用如甘油和卵黄可以减少精液冷冻保存过程中冰晶的形成,保护精子细胞膜免受冰晶的刺破。SL作为一种天然磷脂,在山羊精液冷冻保存过程中,能够减少冰晶形成,减轻活性氧对精子的伤害,从而降低对精子的损伤;LDL作为一种存在于鸡蛋黄中的脂蛋白,可与精液中的有害阳离子肽竞争性结合,保护精子免受有害蛋白的损伤;两者具有协同效应,LDL增强了SL的冷冻保护作用,而SL提供额外的抗氧化保护,共同提高精子在冷冻和解冻过程中的存活率,提高冷冻保护剂的整体效果。本文为山羊精液冷冻保存提供思路和参考。

真方白丸子加减治疗中风(风痰入络证)临床疗效及对血清Lp-PLA2、IL-6、Hcy水平的影响

目的 观察真方白丸子加减治疗中风风痰入络证的疗效及对患者血清人脂蛋白相关磷脂酶A2(Lp-PLA2)、白细胞介素-6(IL-6)、同型半胱氨酸(Hcy)水平的影响。方法 参照随机数字表法将80例患者分为对照组与试验组各40例。对照组予以西医常规对症治疗,试验组在此基础上给予真方白丸子加减治疗。治疗4周后观察对比两组患者的临床疗效、中医证候积分、神经功能[改良Rankin量表(MRS)评分和美国国立卫生研究院卒中量表(NIHSS)评分]、血清Lp-PLA2、IL-6与Hcy水平,统计治疗期间出现药物不良反应的情况。结果 治疗后,试验组的总有效率高于对照组(P<0.05),中医证候积分、MRS评分和NIHSS评分均明显降低且低于对照组(P<0.05)。与对照组比较,试验组治疗后血清Lp-PLA2、IL-6与Hcy水平均显著降低(P<0.05)。治疗期间实验组不良反应总发生率与对照组比较差异无统计学意义(P> 0.05)。结论 应用真方白丸子加减治疗中风风痰入络证具有良好的临床效果,在缓解患者临床症状、恢复其机体神经功能和改善血清Lp-PLA2、IL-6与Hcy水平方面均表现良好,且不良反应少。