Cardioprotective effects of sinomenine in myocardial ischemia/reperfusion injury in a rat model

BackgroundIschemia reperfusion (I/R) play an imperative role in the expansion of cardiovascular disease. Sinomenine (SM) has been exhibited to possess antioxidant, anticancer, anti-inflammatory, antiviral and anticarcinogenic properties. The aim of the study was scrutinized the cardioprotective effect of SM against I/R injury in rat.MethodsRat were randomly divided into normal control (NC), I/R control and I/R + SM (5, 10 and 20 mg/kg), respectively. Ventricular arrhythmias, body weight and heart weight were estimated. Antioxidant, inflammatory cytokines, inflammatory mediators and plasmin system indicator were accessed.ResultsPre-treated SM group rats exhibited the reduction in the duration and incidence of ventricular fibrillation, ventricular ectopic beat (VEB) and ventricular tachycardia along with suppression of arrhythmia score during the ischemia (30 and 120 min). SM treated rats significantly (P < 0.001) altered the level of antioxidant parameters. SM treatment significantly (P < 0.001) repressed the level of creatine kinase MB (CK-MB), creatine kinase (CK) and troponin I (Tnl). SM treated rats significantly (P < 0.001) repressed the tissue factor (TF), thromboxane B2 (TXB2), plasminogen activator inhibitor 1 (PAI-1) and plasma fibrinogen (Fbg) and inflammatory cytokines and inflammatory mediators.ConclusionOur result clearly indicated that SM plays anti-arrhythmia effect in I/R injury in the rats via alteration of oxidative stress and inflammatory reaction.     

Sickle cell nephropathy: A review of novel biomarkers and their potential roles in early detection of renal involvement

Whether the underlying mutations are homozygous, heterozygous, or co-inherited with other hemoglobinopathies, sickle cell disease is known to afflict the kidneys, leading to the clinical entity known as sickle cell nephropathy (SCN). Although common, SCN remains diagnostically elusive. Conventional studies performed in the context of renal disorders often fail to detect early stage SCN. This makes the quest for early diagnosis and treatment more challenging, and it increases the burden of chronic kidney disease-related morbidity among patients. Novel diagnostic tools have been employed to overcome this limitation. In this study, we discuss various biomarkers of SCN, including those employed in clinical practice and others recently identified in experimental settings, such as markers of vascular injury, endothelial dysfunction, tubulo-glomerular damage, and oxidative stress. These include kidney injury molecule-1, monocyte chemoattractant protein-1, N-acetyl-B-D-glucosaminidase, ceruloplasmin, orosomucoid, nephrin, and cation channels, among others. Furthermore, we explore the potential of novel biomarkers for refining diagnostic and therapeutic approaches and describe some obstacles that still need to be overcome. We highlight the importance of a collaborative approach to standardize the use of promising new biomarkers. Finally, we outline the limitations of conventional markers of renal damage as extensions of the pathogenic process occurring at the level of the organ and its functional subunits, with a discussion of the expected pattern of clinical and biochemical progression among patients with SCN.     

靶向MLL1-WDR5蛋白-蛋白相互作用抑制剂的研究进展

Mixed lineage leukemia 1(MLL1)是组蛋白甲基转移酶SET家族的成员之一。MLL1与WDR5、RbBP5、Ash2L和DPY-30组成MLL1甲基转移酶复合物调控组蛋白H3的第4位赖氨酸的甲基化水平，对造血系统的发育和血细胞的更新至关重要。部分白血病患者体内存在因MLL1基因易位而产生的致癌蛋白——MLL1融合蛋白，MLL1融合蛋白在发挥其致癌作用时需要功能完整的MLL1酶复合物，故靶向MLL1-WDR5的蛋白-蛋白相互作用成为治疗MLL1融合型白血病的潜在策略。本文对MLL1-WDR5蛋白-蛋白相互作用的生物学机制、结构信息以及抑制剂进行了系统的总结，并结合已报道数据对该领域进行了展望，以期为后续研究提供参考。     

Analysis of AcrB in Klebsiella pneumoniae reveals natural variants promoting enhanced multidrug resistance

Infections caused by Klebsiella pneumoniae are often difficult to manage due to the high frequency of multidrug resistance, often conferred by efflux pumps. In this study, we analyzed sequence variations of the major RND family multidrug efflux pump AcrB from 387 assembled K. pneumoniae genomes. We confirm that AcrB is a highly-conserved efflux pump in K. pneumoniae, and identified several variants that were prevalent in clinical isolates. Molecular dynamics analyses on two of these variants (L118M and S966A) suggested conformational changes that may correlate with increased drug efflux capabilities. The L118M change resulted in enhanced protein rigidity while the flexibility of drug binding pockets was stable or increased, and the interactions between the proximal pockets and water molecules were stronger. For S966A, the significantly enlarged proximal pocket suggested higher drug accommodation ability. Consistent with these predictions, the L118M and S966A variants conferred a slightly increased ability to grow in the presence of tetracycline and to survive cefoxitin exposure when overexpressed. In summary, our results suggest that the emergence of enhanced-function AcrB variants may be a potential risk for increased antibiotic resistance in clinical K. pneumoniae isolates.     

黄芩素调控 NLRP3 / Caspase-1 通路对牙周炎大鼠牙槽骨吸收的影响

目的 探索黄芩素调控核苷酸结合寡聚化结构域样受体蛋白 3 ( nucleotide-binding oligomerization domain-like receptor protein 3, NLRP3) / 半胱氨酸天冬氨酸蛋白酶 1 ( cysteine aspartate protease 1, Caspase1) 通路对牙周炎大鼠牙槽骨吸收的影响。 方法 将 40 只牙周炎大鼠随机分为模型组、 黄芩素组、 激活剂 组、 黄芩素 + 激活剂组, 另取 10 只正常作为对照组。 检测大鼠釉牙骨质界到牙槽嵴顶 (CEJ-AC) 的距离、 血清中白细胞介素-6 (IL-6)、 转化生长因子-β (TGF-β) 含量以及牙周组织病理变化、 IL-6、 TGF-β 阳性 表达和 NLRP3、 Caspase-1 蛋白表达。 结果 模型组大鼠 CEJ-AC、 NLRP3、 Caspase-1、 IL-6、 TGF-β 水平及 阳性表达水平以及蛋白表达水平均升高 (P< 0. 05); 经黄芩素干预后, 各项指标均降低 (P< 0. 05); 引入 激活剂明显削弱了黄芩素对牙周炎大鼠的抗炎作用。 结论 黄芩素通过抑制 NLRP3 / Caspase-1 通路减轻炎性反应, 控制牙槽骨吸收。