Heat shock protein 27 as a neuroprotective biomarker and a suitable target for stem cell therapy and pharmacotherapy in ischemic stroke

Ischemic stroke is a major common cause of death and long‐term disability worldwide. Several pathophysiological events including excitotoxicity, oxidative/nitrative stress, inflammation, and apoptosis are involved in ischemic injuries. Recently, the molecular mechanisms involved in cerebral ischemia through a focus on a member of small heat shock proteins family, Hsp27, has been developed. Notably, following exposure to ischemia, Hsp27 expression in the brain could be increased rather than the normal condition and it may play an important role in neuroprotection after ischemic stroke. The neuroprotection effects of Hsp27 may arise from its anti‐oxidant, anti‐inflammatory, anti‐apoptotic, and chaperonic properties. Moreover, some therapeutic strategies such as stem cell therapy and pharmacotherapy have been developed with Hsp27 targeting. In this review, we describe the function and structure of Hsp27 and its possible role in neuroprotection after ischemic stroke. Finally, we present current studies in stroke therapy, which focused on Hsp27 targeting.     

Verification of a proteomic biomarker panel to diagnose minor stroke and transient ischaemic attack: phase 1 of SpecTRA,a large scale translational study

Objective: To derive a plasma biomarker protein panel from a list of 141 candidate proteins which can differentiate transient ischaemic attack (TIA)/minor stroke from non-cerebrovascular (mimic) conditions in emergency department (ED) settings.

Design: Prospective clinical study (#NCT03050099) with up to three timed blood draws no more than 36?h following symptom onset. Plasma samples analysed by multiple reaction monitoring-mass spectrometry (MRM-MS).

Participants: Totally 545 participants suspected of TIA enrolled in the EDs of two urban medical centres.

Outcomes: 90-day, neurologist-adjudicated diagnosis of TIA informed by clinical and radiological investigations.

Results: The final protein panel consists of 16 proteins whose patterns show differential abundance between TIA and mimic patients. Nine of the proteins were significant univariate predictors of TIA [odds ratio (95% confidence interval)]: L-selectin [0.726 (0.596–0.883)]; Insulin-like growth factor-binding protein 3 [0.727 (0.594–0.889)]; Coagulation factor X [0.740 (0.603–0.908)]; Serum paraoxonase/lactonase 3 [0.763 (0.630–0.924)]; Thrombospondin-1 [1.313 (1.081–1.595)]; Hyaluronan-binding protein 2 [0.776 (0.637–0.945)]; Heparin cofactor 2 [0.775 (0.634–0.947)]; Apolipoprotein B-100 [1.249 (1.037–1.503)]; and von Willebrand factor [1.256 (1.034–1.527)]. The scientific plausibility of the panel proteins is discussed.

Conclusions: Our panel has the potential to assist ED physicians in distinguishing TIA from mimic patients.     

添加益生菌的早期滋养量肠内营养对 重症脑卒中患者呼吸机相关性肺炎的影响

目的探讨早期给予添加益生菌的滋养量肠内营养(EN)对重症脑卒中患者呼吸机相关性肺炎(VAP)的影响。方法选择2015年10月1日至2017年10月1日我院神经内科收治的接受鼻饲饮食及机械通气的重症脑卒中患者56例,随机分为对照组和观察组各28例。对照组患者在入院48h内给予早期肠内营养支持治疗,观察组在对照组基础上常规给予双歧杆菌乳杆菌三联活菌片鼻饲,并给予滋养量肠内营养支持治疗(起始量10～20mL鼻饲低速泵入)。比较两组患者治疗后肠内营养达标时间、肠内营养并发症发生率、营养状态指标、炎症因子水平、呼吸机相关性肺炎发生率、脱机成功率及病死率。结果治疗后,观察组患者腹胀、腹泻、应激性高血糖发生率较低,肠内营养达标时间较短。同时观察组患者血清白蛋白、前白蛋白、淋巴细胞计数均高于对照组,血WBC、CRP、PCT水平均低于对照组。观察组患者脱机成功率相对较高,呼吸机相关性肺炎发生率相对较低。观察组患者GCS评分、APACHEⅡ评分及病死率相对较低,但差异均无统计学意义(P0.05)。结论早期给予添加益生菌的滋养量肠内营养有助于提高患者肠内营养的耐受性,改善患者营养状态,降低炎性因子水平,有助于减少呼吸机相关性肺炎发生率。     

急性缺血性脑卒中患者血浆Lp-PLA2 的表达及与斑块稳定性及神经功 能缺损的关系

目的：探讨急性缺血性脑卒中患者血浆脂蛋白相关磷脂酶（Lp-PLA2）的表达及与斑块稳定性及神经功能缺损的关系。方法： 按照颈动脉彩超结果将2014 年5 月-2015 年1 月我院收治的80 例急性缺血性脑卒中患者分为斑块稳定组（25 例）、斑块不稳定 组（39 例）和无斑块组（16 例）,并于同期随机抽取120 例健康体检者为对照组。采用散射比浊法测定各组血浆Lp-PLA2,同时采 用美国国立卫生研究所中风量表（NIHSS 评分）对三组的神经功能缺损情况进行评估。结果：斑块稳定组、斑块不稳定组以及无斑 块组血浆Lp-PLA2 高于对照组,斑块稳定组、斑块不稳定组高于无斑块组,斑块不稳定组高于斑块稳定组,差异均有统计学意义 （P<0.05）,患者血浆Lp-PLA2水平与动脉粥样硬化斑块的稳定性呈正相关性（rs=0.638,P<0.05）。神经功能缺损中型组、重型组血 浆Lp-PLA2 高于轻型组,重型组高于中型组,差异有统计学意义（P<0.05）,患者血浆Lp-PLA2 水平与神经功能缺损程度呈正相关 性（rs=0.715,P<0.05）。结论：血浆Lp-PLA2 可作为预测急性缺血性脑卒中患者颈动脉硬化斑块稳定性以及评估患者神经功能缺 损程度的重要指标。     

中美生物医学合作研究计划及其前景

中美生物医学合作研究计划实施3年来,收到了来自中美双方科学家共657项申请.这些申请在研究内容上涉及肿瘤、感染性疾病(包括HIV感染和艾滋病相关研究)、过敏性疾病、医学免疫学、精神健康及神经性疾病(中风和帕金森病).经过国家自然科学基金委员会和美国国立卫生研究院的联合评审程序,有109项申请项目获得了资助.联合评审的机制和获资助的109个研究项目的合作研究为今后中美双方的进一步合作奠定了基础.     

Cardiovascular and cerebrovascular risk factors and events associated with second-generation antipsychotic compared to antidepressant use in a non-elderly adult sample: results from a claims-based inception cohort study

This is a study of the metabolic and distal cardiovascular/cerebrovascular outcomes associated with the use of second-generation antipsychotics (SGAs) compared to antidepressants (ADs) in adults aged 18-65 years, based on data from Thomson Reuters MarketScan® Research Databases 2006-2010, a commercial U.S. claims database. Interventions included clinicians'' choice treatment with SGAs (allowing any comedications) versus ADs (not allowing SGAs). The primary outcomes of interest were time to inpatient or outpatient claims for the following diagnoses within one year of SGA or AD discontinuation: hypertension, ischemic and hypertensive heart disease, cerebrovascular disease, diabetes mellitus, hyperlipidemia, and obesity. Secondary outcomes included the same diagnoses at last follow-up time point, i.e., not censoring observations at 365 days after SGA or AD discontinuation. Cox regression models, adjusted for age, gender, diagnosis of schizophrenia and mood disorders, and number of medical comorbidities, were run. Among 284,234 individuals, those within one year of exposure to SGAs versus ADs showed a higher risk of essential hypertension (adjusted hazard ratio, AHR+1.16, 95% CI: 1.12-1.21, p<0.0001), diabetes mellitus (AHR+1.43, CI: 1.33-1.53, p<0.0001), hypertensive heart disease (AHR+1.34, CI: 1.10-1.63, p<0.01), stroke (AHR+1.46, CI: 1.22-1.75, p<0.0001), coronary artery disease (AHR+1.17, CI: 1.05-1.30, p<0.01), and hyperlipidemia (AHR+1.12, CI: 1.07-1.17, p<0.0001). Unrestricted follow-up results were consistent with within one-year post-exposure results. Increased risk for stroke with SGAs has previously only been demonstrated in elderly patients, usually with dementia. This study documents, for the first time, a significantly increased risk for stroke and coronary artery disease in a non-elderly adult sample with SGA use. We also confirm a significant risk for adverse metabolic outcomes. These findings raise concerns about the longer-term safety of SGAs, given their widespread and chronic use.     

Proteomic analysis of hypothalamic injury in heatstroke rats

Ischemic and oxidative damage to the hypothalamus may be associated with decreased heat tolerance as well as heatstroke formation. The present study explores the hypothalamic proteome mechanisms associated with heatstroke‐mediated hypothalamic ischemia, and oxidative damage. Heatstroke rats had hypotension, hypothalamic ischemia, and lethality. In addition, they had hyperthermia and hypothalamic blood–brain–barrier disruption, oxidative stress, activated inflammation, and neuronal apoptosis and degeneration. 2DE combined LC‐MS/MS revealed that heatstroke‐induced ischemic injury and apoptosis were associated with upregulation of L‐lactate dehydrogenase but downregulation of both dihydropyriminase‐related protein and 14‐3‐3 Zeta isoform protein. Heat‐induced blood–brain–barrier disruption might be related to upregulation of glial fibrillary acidic protein. Oxidative stress caused by heatstroke might be related to upregulation of cytosolic dehydrogenase‐1. Also, heat‐induced overproduction of proinflammatory cytokines might be associated with downregulation of stathmin 1. Heat‐induced hypothalamic ischemia, apoptosis, injury (or upregulation of L‐lactate dehydrogenase), blood–brain–barrier disruption (or upregulation of glial fibrillary acidic protein), oxidative stress (or upregulation of cytosolic dehydrogenase‐1), and activated inflammation (or downregulation of stathmin 1) were all significantly reversed by whole body cooling. Our data indicate that cooling therapy improves outcomes of heatstroke by modulating hypothalamic proteome mechanisms.     

GFAP and antibodies against NMDA receptor subunit NR2 as biomarkers for acute cerebrovascular diseases

We studied whether the serum levels of glial fibrillary acidic protein (GFAP) and of antibodies against the N‐methyl‐d ‐aspartate receptor subunit NR2 (NR2 R_NMDA) can discriminate between intracerebral haemorrhage (ICH) and ischaemic stroke (IS) in stroke patients. We prospectively recruited patients with suspected stroke (72 confirmed) and 52 healthy controls. The type of brain lesion (ICH or IS) was established using brain imaging. The levels of GFAP and of antibodies against NR2 R_NMDA were measured in blood samples obtained within 12 hrs after stroke onset and 24, 48 and 72 hrs and 1 and 2 weeks later using ELISA immunoassay. Improvement in diagnostic performance was assessed in logistic regression models designed to predict the diagnosis and the type of stroke. GFAP peaks early during haemorrhagic brain lesions (at significantly higher levels), and late in ischaemic events, whereas antibodies against NR2 R_NMDA have significantly higher levels during IS at all time‐points. Neither of the two biomarkers used on its own could sufficiently discriminate patients, but when they are used in combination they can differentiate at 12 hrs after stroke, between ischaemic and haemorrhagic stroke with a sensitivity and specificity of 94% and 91%, respectively.     

Plasma desmoplakin I biomarker of vascular recurrence after ischemic stroke

Stroke patients have a high risk of vascular recurrence. Biomarkers related to vascular recurrence, however, remain to be identified. The aim of the study was to identify, through proteomic analysis, plasma biomarkers associated with vascular recurrence within one year after the first ischemic stroke. This is a substudy (n = 134) of a large prospective multicenter study of post-stroke patients with an ischemic stroke. Plasma samples were obtained at inclusion. Among the identified proteins, only plasma levels of desmoplakin I were associated with protection against a new vascular event (Odds ratio: 0.64; 95% CI: 0.46-0.89; p = 0.009) after adjustment for hypercholesterolemia, statins and previous atherothrombotic stroke subtype. A greater number of patients without vascular recurrence had been treated with statins within three months of the recent ischemic stroke. Only patients who had been taking statins for 3 months after the ischemic stroke and did not suffer vascular recurrence over a follow-up year, have higher levels of desmoplakin I at the time of inclusion (Odds ratio 0.49; 95% CI: 0.28-0.86; p = 0.013). Increased desmoplakin I levels, determined within 1-3 months of the first ischemic stroke, could be a biomarker for statin responsiveness against a new vascular event in post-ischemic stroke patients taking statins early (1-3 months) after the ischemic stroke.