生长因子Progranulin的结合受体和生物学功能

生长因子颗粒素蛋白前体（progranulin, PGRN）广泛存在于动物和植物组织中.研究证明,哺乳动物的PGRN是一个多功能分子,在组织/器官发育、细胞分化、肿瘤发生发展、炎症应答以及神经退行性疾病中均具有重要的作用.PGRN发挥生物学功能需要和多种结合蛋白相互结合,例如sortilin、Toll样受体9（TLR9）、肿瘤坏死因子受体（TNFR）及分泌性淋巴细胞蛋白酶抑制因子（SLPI）等. 本文将对PGRN的结合受体和生物学功能进行综述.     

多个生物标志物预测宫颈上皮内瘤和宫颈癌的风险

目的:研究生物蛋白指标是否可以作为宫颈癌和高分级宫颈上皮内瘤样病变(CIN)的肿瘤标志物。方法:采用免疫组织化学方法检测包括宫颈内皮瘤和宫颈癌在内的292例标本中9个蛋白指标的表达,包括E-钙粘素(E-cadherin),细胞外信号调节激酶-1(ERK-1),基质金属蛋白酶-2(MMP-2),nm23-H1,核因子NF-κB,p16INK4A,存活素(survivin),人端粒酶逆转录酶(hTERT),血管内皮生长因子(VEGF-C),然后采用统计方法进行分析,构建变量模型,计算反映指标,与靶受体反应的特征曲线进行比较,确定上述蛋白标记物在预测宫颈癌存活率以及高分级CIN的作用。结果:所有个标记物中,nm23-H1及p16 INK4a对宫颈癌的生存率的单变量分析有明显的意义,在对所有标记物做细致详尽的分析后发现,其中3个标记物(E-钙粘素、VEGF-C、survivin)可对高分级的CIN进行预测。宫颈癌的生存率的有效的预测因子中,只有nm23-H1可以作为有效的预测因素。结论:联合检测多个生物蛋白,如E-钙粘素、VEGF-C、survivin指标可以有效的预测高危CIN的恶变风险,同时nm23-H1则可以为宫颈癌的预后提供参考。     

网膜素在神经关联疾病中的生物标记物作用

网膜素(omentin)是一种新型的脂肪因子,由内脏脂肪组织分泌。研究发现,网膜素在脑梗死、成神经细胞瘤、多发性硬化等神经关联疾病中发挥着重要作用,并与疾病的发生、发展具有良好相关性。因此,网膜素或可成为神经关联疾病的生物标记物,为相关疾病的诊断、治疗和预后评估提供新指标。     

科研新闻

肾上腺髓质素前体中段(Prepro-ADM45~92):脓毒败血症的预测标志物肾上腺髓质素前体肽原(Prepro-adrenomedullin,Prepro-ADM)由185个氨基酸残基组成,经剪切后形成多个片断,包括氨基端信号肽(1~21位氨基酸)、肾上腺髓质素前体N端20肽(PAMP)、肾上腺髓质素前体中段(Prepro-ADM45~9     

促泌素在胃肠道神经内分泌肿瘤中的表达及其临床意义

目的 比较促泌素(secretagogin,SCGN)与传统的神经内分泌标记物在胃肠道神经内分泌肿瘤中的表达差异.方法 收集胃肠道手术标本共88例,其中实验组为8例类癌和20例非典型类癌,对照组为40例腺癌伴神经内分泌分化和20例腺癌.所有标本均使用SCGN、PGP9.5、CD56、NSE、Syn及CgA进行免疫组织化学SP两步法染色.结果 SCGN可在胃肠道粘膜同有层腺体的弥散性神经内分泌细胞中表达,多显示“开放型”的神经内分泌细胞.除CD56和NSE各在1例胃肠道腺癌中阳性表达外,SCGN及其它标记物在20例腺癌中均无表达,所有标记物之间均无统计学差异(P＞0.05).SCGN在40例胃肠道腺癌伴神经内分泌分化、20例非典型类癌和8例类癌巾的阳性表达率均最高,分别为62.5％ (25/40)、90％(18/20)和100％(8/8),PGP9.5阳性表达率均最低分别为32.5％(13/40)、45％ (9/20)和37.5％(3/8),两标记物在这三组肿瘤中的表达均有显著统计学差异(P＜0.01),而CD56、NSE、Syn和CgA在以上三组肿瘤中的表达率均较高,与SCGN比较均无统计学差异(P＞0.05).所有标记物在腺癌伴神经内分泌分化、非典型类癌和类癌中的阳性表达率均明显高于腺癌(P＜0.01);SCGN、Syn和CgA在非典型类癌和类癌巾的阳性表达均高于腺癌伴神经内分泌分化(P＜0.05);所有标记物在非典型类癌和类癌之间的阳性表达率均无统计学差异(P＞0.05).结论 SCGN作为一种新型的神经内分泌标记物与传统标记物Syn和CgA联合,可应用于胃肠道神经内分泌肿瘤的临床病理诊断.     

沙库巴曲缬沙坦联合胺碘酮对老年HF伴PAF患者心功能、炎症因子及神经内分泌激素的影响

目的:探讨沙库巴曲缬沙坦联合胺碘酮对老年心力衰竭(HF)伴阵发性房颤(PAF)患者心功能、神经内分泌激素以及炎症因子的影响。方法:选取2017年2月~2019年1月期间我院收治的80例老年HF伴PAF患者,根据随机数字表法分为研究组(n=40,沙库巴曲缬沙坦联合胺碘酮治疗)和对照组(n=40,胺碘酮治疗),比较两组患者疗效、心功能指标[左心室舒张末期内径(LVEDD)、左心室射血分数(LVEF)、左心室收缩末期内径(LVESD)]、炎症因子[白介素-33(IL-33)、肿瘤坏死因子-α(TNF-α)、细胞间黏附分子-1(ICAM-1)]及神经内分泌激素(去甲肾上腺素、醛固酮和血管紧张素Ⅱ)水平及不良反应发生情况。结果:研究组治疗3个月后的临床总有效率90.00%(36/40)高于对照组67.50%(27/40)(P<0.05)。两组治疗3个月后LVEDD、ICAM-1、TNF-α、LVESD、IL-33均较治疗前降低,且研究组较对照组低(P<0.05);LVEF较治疗前提高,且研究组高于对照组(P<0.05)。两组不良反应总发生率比较无差异(P>0.05)。两组治疗3个月后去甲肾上腺素、醛固酮、血管紧张素Ⅱ水平均较治疗前降低,且研究组低于对照组(P<0.05)。结论:老年HF伴PAF患者在胺碘酮的基础上联合沙库巴曲缬沙坦治疗,心功能指标改善显著,血清炎症因子及神经内分泌激素水平有所降低,且安全可靠,疗效显著。     

NLRP3炎症小体在真菌感染中的作用机制研究进展

炎症小体(Inflammasome)是细胞内识别危险信号的多蛋白复合体,是固有免疫的重要组成部分,NOD样受体家族含热蛋白结构域蛋白3炎症小体(NLRP3)是目前研究最多的一种炎症小体。真菌感染中,NLRP3炎症小体通路募集半胱天冬蛋白酶的前体半胱氨酸天冬氨酸蛋白酶1(pro-caspase-1)自身剪切活化,活化后的半胱天冬蛋白酶(Caspase-1),通过对促炎因子IL-1β(interleukin-1β, IL-1β)和IL-18(interleukin-18, IL-18)的激活,引起宿主的炎症反应,在宿主免疫应答中发挥了重要作用。     

脂肪细胞因子对代谢的调节

脂肪组织可将多余能量以甘油三酯(triglycerides,TG)形式储存,在饥饿状态下可分解TG产生游离脂肪酸(free fatty acids,FFAs)为机体供能。此外,脂肪组织还具有体温调节和器官保护功能,并且越来越多的证据表明,脂肪组织也是一种重要的内分泌组织。脂肪组织分泌的蛋白质物质被称为脂肪细胞因子(adipokine),可通过自分泌、旁分泌和内分泌方式发挥多种生物学功能,例如调节能量摄入和能量消耗,调节糖脂代谢,抗炎和促炎反应。对整体而言,脂肪细胞因子可调节大脑、肝、肌肉、血管系统、心、胰腺和免疫系统等不同靶器官的生物反应。其中,脂肪细胞因子在糖脂代谢中发挥特定的作用,包括:葡萄糖代谢[瘦素(leptin)、脂联素(adiponectin)、抵抗素(resistin)];胰岛素敏感性 [瘦素、脂联素、锌-α2-糖蛋白(zinc-α2-glycoprotein,ZAG)];脂肪形成[骨形成蛋白4(bone morphogenetic protein 4,BMP4)]等生物反应过程。但目前对脂肪组织功能障碍与代谢之间机制的理解尚不完善。脂肪组织功能发生紊乱时,脂肪细胞因子的分泌会发生改变,并可能导致一系列与肥胖相关的代谢性疾病的发生。临床前和临床研究表明,激活或抑制特定脂肪细胞因子的信号转导可能是一种适合干预代谢疾病的方法。本文就部分脂肪细胞因子对代谢的调控作用做出综述,以增强对脂肪细胞因子功能的理解。     

多标记物法在心力衰竭风险评估中的应用

心力衰竭的发生发展涉及多条生理病理通路,选择不同通路中的多个生物标记物能够提高对心力衰竭风险评估的准确性。总结了心 力衰竭发生发展过程中与心肌损伤、内皮功能障碍、神经激素紊乱、炎症反应、氧化应激过程相关的生物标记物,基于多标记物评价方法 的数学模型及多标记物法在心力衰竭和药物心脏毒性风险评估中的应用。     

炎性小体在诱导脊髓损伤神经炎症中的作用

脊髓损伤的治疗与康复一直是医学领域的重大难题,尤其是在改善损伤的神经功能方面进展甚微。继发性损伤是造成脊髓损伤后神经功能障碍的主要原因,炎症反应是继发性损伤阶段最重要的病理过程。急性期通过抑制神经炎症来减轻继发性损伤被认为可减轻神经功能损害而达到神经保护作用。炎性小体是一类蛋白质复合体,由模式识别受体中的NLRs家族和PHYIN家族的受体蛋白质作为主要框架组装并命名,常见的炎性小体包括NLRP1、NLRP3、NLRC4(IPAF)、AIM2等。在感染或受到损伤刺激时,炎性小体在细胞质内组装,并激活促炎症蛋白酶胱天蛋白酶1(caspase-1),活化的胱天蛋白酶1一方面促进促炎症细胞因子IL-1β和IL-18的前体成熟和分泌,另一方面介导细胞焦亡。细胞焦亡以细胞肿胀破裂并释放细胞内容物为特征,是在炎症和应激的病理条件下诱导的程序性细胞死亡方式。促炎症细胞因子和焦亡释放的胞内物质都可作为促炎信号引发炎症反应。近期发现,炎性小体通过诱导促炎因子释放以及介导细胞焦亡等途径, 参与激活脊髓损伤后的炎症级联反应,加重继发性神经炎症。靶向抑制炎性小体的激活可减轻炎症反应,促进神经细胞存活,达到神经保护作用。因此,炎性小体有望成为脊髓损伤治疗的新靶点。本文拟从炎性小体的结构及其在脊髓损伤中的作用、激活机制和治疗前景进行综述,以期为后续研究提供思路。     

Biomarkers and diagnostics in heart failure

Heart failure (HF) biomarkers have dramatically impacted the way HF patients are evaluated and managed. B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are the gold standard biomarkers in determining the diagnosis and prognosis of HF, and studies on natriuretic peptide-guided HF management look promising. An array of additional biomarkers has emerged, each reflecting different pathophysiological processes in the development and progression of HF: myocardial insult, inflammation and remodeling. Novel biomarkers, such as mid-regional pro atrial natriuretic peptide (MR-proANP), mid-regional pro adrenomedullin (MR-proADM), highly sensitive troponins, soluble ST2 (sST2), growth differentiation factor (GDF)-15 and Galectin-3, show potential in determining prognosis beyond the established natriuretic peptides, but their role in the clinical care of the patient is still partially defined and more studies are needed. This article is part of a Special Issue entitled: Heart failure pathogenesis and emerging diagnostic and therapeutic interventions.     

The effect of diabetes on the diagnostic and prognostic performance of mid-region pro-atrial natriuretic peptide and mid-region pro-adrenomedullin in patients with acute dyspnea

Serum mid-regional pro-atrial natriuretic peptide (MR-proANP) and pro-adrenomedullin (MR-proADM) are novel biomarkers for acute heart failure (AHF). Like other AFH biomarkers, the performance of these tests are affected by the presence of clinical variables such as renal failure and obesity. In a substudy of the Biomarkers from Acute Heart Failure Study, we show that diabetes did not influence the performance of these markers with regards to AHF diagnosis or 90-day all cause death. However, in patients without AHF, increased MR-proADM alone was associated with the presence of diabetes.     

The effect of diabetes on the diagnostic and prognostic performance of mid-region pro-atrial natriuretic peptide and mid-region pro-adrenomedullin in patients with acute dyspnea

Serum mid-regional pro-atrial natriuretic peptide (MR-proANP) and pro-adrenomedullin (MR-proADM) are novel biomarkers for acute heart failure (AHF). Like other AFH biomarkers, the performance of these tests are affected by the presence of clinical variables such as renal failure and obesity. In a substudy of the Biomarkers from Acute Heart Failure Study, we show that diabetes did not influence the performance of these markers with regards to AHF diagnosis or 90-day all cause death. However, in patients without AHF, increased MR-proADM alone was associated with the presence of diabetes.     

Regulation of expression of atrial and brain natriuretic peptide,biomarkers for heart development and disease

The mammalian heart expresses two closely related natriuretic peptide (NP) hormones, atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). The excretion of the NPs and the expression of their genes strongly respond to a variety of cardiovascular disorders. NPs act to increase natriuresis and decrease vascular resistance, thereby decreasing blood volume, systemic blood pressure and afterload. Plasma levels of BNP are used as diagnostic and prognostic markers for hypertrophy and heart failure (HF), and both ANF and BNP are widely used in biomedical research to assess the hypertrophic response in cell culture or the development of HF related diseases in animal models. Moreover, ANF and BNP are used as specific markers for the differentiating working myocardium in the developing heart, and the ANF promoter serves as platform to investigate gene regulatory networks during heart development and disease. However, despite decades of research, the mechanisms regulating the NP genes during development and disease are not well understood. Here we review current knowledge on the regulation of expression of the genes for ANF and BNP and their role as biomarkers, and give future directions to identify the in vivo regulatory mechanisms. This article is part of a Special Issue entitled: Heart failure pathogenesis and emerging diagnostic and therapeutic interventions.     

Biomarkers in heart failure with preserved ejection fraction

Biomarkers are widely used and studied in heart failure. Most studies have described the utility and performance of biomarkers in sub-studies of randomised clinical trials, where the vast majority of the patients suffered from heart failure with reduced ejection fraction (HFrEF), and not with preserved ejection fraction (HFpEF). As a result, there is a scarcity of data describing the levels, dynamics, clinical and biochemical correlates, and biology of biomarkers in patients suffering from HFpEF, whereas HFpEF is in fact a very frequent clinical entity. This article discusses the value of different biomarkers in HFpEF. We describe various aspects of natriuretic peptide measurements in HFpEF patients, with a focus on diagnosis, prognosis and the risk prediction of developing heart failure. Further, we will discuss several emerging biomarkers such as galectin-3 and suppression of tumorigenicity 2, and recently discovered ones such as growth differentiation factor-15 and syndecan-1.     

Comparative proteomics profiling of a phospholamban mutant mouse model of dilated cardiomyopathy reveals progressive intracellular stress responses

Defective mobilization of Ca2+ by cardiomyocytes can lead to cardiac insufficiency, but the causative mechanisms leading to congestive heart failure (HF) remain unclear. In the present study we performed exhaustive global proteomics surveys of cardiac ventricle isolated from a mouse model of cardiomyopathy overexpressing a phospholamban mutant, R9C (PLN-R9C), and exhibiting impaired Ca2+ handling and death at 24 weeks and compared them with normal control littermates. The relative expression patterns of 6190 high confidence proteins were monitored by shotgun tandem mass spectrometry at 8, 16, and 24 weeks of disease progression. Significant differential abundance of 593 proteins was detected. These proteins mapped to select biological pathways such as endoplasmic reticulum stress response, cytoskeletal remodeling, and apoptosis and included known biomarkers of HF (e.g. brain natriuretic peptide/atrial natriuretic factor and angiotensin-converting enzyme) and other indicators of presymptomatic functional impairment. These altered proteomic profiles were concordant with cognate mRNA patterns recorded in parallel using high density mRNA microarrays, and top candidates were validated by RT-PCR and Western blotting. Mapping of our highest ranked proteins against a human diseased explant and to available data sets indicated that many of these proteins could serve as markers of disease. Indeed we showed that several of these proteins are detectable in mouse and human plasma and display differential abundance in the plasma of diseased mice and affected patients. These results offer a systems-wide perspective of the dynamic maladaptions associated with impaired Ca2+ homeostasis that perturb myocyte function and ultimately converge to cause HF.     

MiR-590-5p inhibits pathological hypertrophy mediated heart failure by targeting RTN4

Journal of Molecular Histology - Heart failure (HF) is a rising epidemic and public health burden in modern society. It is of great need to find new biomarkers to ensure a timely diagnosis and to...     

Cardiac gene expression profiling – the quest for an atrium-specific biomarker

Biomarkers are gaining increasing interest to predict risk but also to aid in diagnostics. Tissue-specific biomarkers are of utmost importance to detect diseases of respective organs. As of yet there are no atriumspecific biomarkers for risk stratification of atrial disease, such as atrial fibrillation. Bioinformatics such as mRNA microarrays can help to detect tissue-enriched and possibly tissue-specific expressed genes that can be targets for biomarkers. We describe an approach to identify genes preferably expressed in atrial cardiomyocytes compared with ventricular cardiomyocytes by RNA microarray and confirmed by quantitative real-time polymerase chain reaction. By this approach we identified several atrium-enriched genes but also ventricle-enriched genes. As expected atrial natriuretic peptide (ANP) mRNA showed higher expression in atrial cardiomyocytes while with adrenergic stimulation expression was almost as high in ventricular as in atrial cells. Brain-type natriuretic peptide (BNP), however, was not different between atrial and ventricular cells giving a possible explanation for increased levels of NT-proBNP in atrial fibrillation patients. Interesting identified candidates are serpine1 and ltbp2 as atrium-enriched genes whereas alpha-adrenergic receptor subtype 1b and S100A1 expression was significantly higher in ventricular cells. The identified genes need to be confirmed in human tissue and might ultimately be tested as potential biomarkers for atrial stress. (Neth Heart J 2010;18:610–4.)     

Comprehensive plasma metabolomic and lipidomic analyses reveal potential biomarkers for heart failure

Heart failure is a syndrome with symptoms or signs caused by cardiac dysfunction. In clinic, four stages (A, B, C, and D) were used to describe heart failure progression. This study was aimed to explore plasma metabolomic and lipidomic profiles in different HF stages to identify potential biomarkers. Metabolomics and lipidomics were performed using plasma of heart failure patients at stages A (n?=?49), B (n?=?61), and C+D (n?=?26). Analysis of Variance (ANOVA) was used for screening dysregulated molecules. Bioinformatics was used to retrieve perturbed metabolic pathways. Univariate and multivariate receiver operating characteristic curve (ROC) analyses were used for potential biomarker screening. Stage A showed significant difference to other stages, and 142 dysregulated lipids and 134 dysregulated metabolites were found belonging to several metabolic pathways. Several marker panels were proposed for the diagnosis of heart failure stage A versus stage B-D. Several molecules, including lysophosphatidylcholine 18:2, cholesteryl ester 18:1, alanine, choline, and Fructose, were found correlated with B-type natriuretic peptide or left ventricular ejection fractions. In summary, using untargeted metabolomic and lipidomic profiling, several dysregulated small molecules were successfully identified between HF stages A and B-D. These molecules would provide valuable information for further pathological researches and biomarker development.

     

Galectin 3 complements BNP in risk stratification in acute heart failure

Background: Galectin 3 (G3) is a mediator of fibrosis and remodeling in heart failure.

Methods: Patients diagnosed with and treated for Acute Heart Failure Syndromes were prospectively enrolled in the Decision Making in Acute Decompensated Heart Failure multicenter trial.

Results: Patients with a higher G3 had a history of renal disease, a lower heart rate and acute kidney injury. They also tended to have a history of HF and 30-day adverse events compared with B-type natriuretic peptide.

Conclusion: In Acute Heart Failure Syndromes, G3 levels do not provide prognostic value, but when used complementary to B-type natriuretic peptide, G3 is associated with renal dysfunction and may predict 30-day events.