运动预适应与力竭运动大鼠心肌损伤：Rho/ROCK信号通路的作用

背景:目前,关于运动预适应的心肌保护机制尚未完全阐明,据报道Rho/ROCK信号通路在心血管疾病中起到关键作用,运动预适应是否通过Rho/ROCK信号通路对心肌起到保护作用有待研究。目的:基于Rho/ROCK信号通路探讨运动预适应在力竭运动大鼠心肌损伤中的作用。方法:将60只5周龄的SPF级SD雄性大鼠随机分为3组:安静对照组、单纯力竭运动组、运动预适应+力竭运动组,各组建模结束后1 h,取血清进行全生化分析检测心肌酶谷草转氨酶、磷酸肌酸激酶、乳酸脱氢酶水平,取心肌组织标本进行苏木精-碱性复红-苦味酸染色观察心肌组织病理变化,分析缺血缺氧程度,TUNEL法观察心肌细胞凋亡情况,ELISA法检测心肌组织肿瘤坏死因子α和白细胞介素10水平,Western blot检测心肌组织RhoA、ROCK1、ROCK2、Bax和Bcl-2蛋白的表达。结果与结论:①单纯力竭运动组谷草转氨酶、磷酸肌酸激酶、乳酸脱氢酶水平显著高于安静对照组(P<0.05);而运动预适应+力竭运动组谷草转氨酶、磷酸肌酸激酶、乳酸脱氢酶水平显著低于单纯力竭运动组(P<0.05);②单纯力竭运动组心肌细胞界限不清楚,呈现出较多斑块状或片状艳红色样区域,与安静对照组相比,有明显的缺血缺氧改变;运动预适应+力竭运动组部分心肌细胞界限不清楚,出现部分斑块状艳红色染色,较单纯力竭运动组缺血缺氧程度明显减轻;③单纯力竭运动组较安静对照组凋亡指数值明显升高,运动预适应+力竭运动组与单纯力竭运动组相比凋亡指数值明显下降(P<0.05);④单纯力竭运动组的肿瘤坏死因子α和白细胞介素10水平显著高于安静对照组(P<0.05),运动预适应+力竭运动组肿瘤坏死因子α和白细胞介素10水平显著低于单纯力竭运动组(P<0.05);⑤单纯力竭运动组的Bcl-2/Bax显著低于安静对照组(P<0.05),运动预适应+力竭运动组Bcl-2/Bax显著高于单纯力竭运动组(P<0.05);⑥与安静对照组相比,单纯力竭运动组RhoA、ROCK1、ROCK2蛋白水平明显升高,而运动预适应+力竭运动组RhoA、ROCK1、ROCK2蛋白水平显著低于单纯力竭运动组(P<0.05);⑦结果表明,运动预适应对心肌损伤具有保护作用,可改善大鼠的心脏功能,其作用机制可能与Rho/ROCK通路有关。     

Recent achievements in developing selective Gq inhibitors

G proteins are key mediators of G protein-coupled receptor (GPCR) signaling, facilitating a plethora of important physiological processes. The role of G proteins is much less understood than other aspects of GPCR function, which is largely due to the shortage of potent and selective G protein inhibitors. The natural cyclic depsipeptides YM-254890 and FR900359 are two of the very few known selective inhibitors of the G_q subfamily, and are used as unique pharmacological tools in the study of G _q-mediated signaling. Moreover, a peptide-based G protein antagonist-2A (GP-2A), a 27-residue peptide (27mer(I860A)) derived from phospholipase C-β3 (PLC-β3), and the small molecule BIM-46187 have also been characterized as selective G _q inhibitors within the past 5 years. In this review, we highlight the recent development in chemical syntheses, characterization, and mechanism of action of these selective G _q inhibitors. The development and application of G _q-selective inhibitors will expand our knowledge of the structure and function of G protein-mediated signaling, shed light on the development of inhibitors for other G protein classes, and feed in to drug discovery for diseases where G proteins are implicated, including various forms of cancer.     

miRNAs in lung cancer: A link to aging

Lung cancer is a leading cause of cancer deaths worldwide. Development of lung cancer is associated with exposure to carcinogens such as tobacco smoke and some environmental factors. The incidence of lung cancer increases with age, particularly after age 60. It was estimated that less than 2% of all lung cancer cases occurred in patients younger than 45; therefore, this type of tumor can be considered as an aging-related disease. MicroRNAs (miRNAs) are small non-coding RNA molecules capable of regulating expression of over 50% of protein-coding genes. miRNAs were shown to play an extremely important role in cell functioning, affecting all biological processes, as well as development of various diseases. Expression profiles of miRNAs are known to be altered in cancer, including lung cancer, and also exhibit changes during aging. These RNA molecules are stable in tissue sections and blood and reflect tumor origin, histotype, and stage, which make them candidate diagnostic and prognostic biomarkers. miRNA mimetics or inhibitors can be delivered into a cell, with possible therapeutic implications. Here, we review the results obtained during the last several years that demonstrate the aging-related regulation of miRNAs expression, in association with their role in lung cancer initiation, progression, and resistance to anticancer therapy, as well as the possibility to use miRNAs as predictive biomarkers for treatment response.     

BioAge: Toward a multi-determined,mechanistic account of cognitive aging

The search for reliable early indicators of age-related cognitive decline represents a critical avenue for progress in aging research. Chronological age is a commonly used developmental index; however, it offers little insight into the mechanisms underlying cognitive decline. In contrast, biological age (BioAge), reflecting the vitality of essential biological systems, represents a promising operationalization of developmental time. Current BioAge models have successfully predicted age-related cognitive deficits. Research on aging-related cognitive function indicates that the interaction of multiple risk and protective factors across the human lifespan confers individual risk for late-life cognitive decline, implicating a multi-causal explanation. In this review, we explore current BioAge models, describe three broad yet pathologically relevant biological processes linked to cognitive decline, and propose a novel operationalization of BioAge accounting for both moderating and causal mechanisms of cognitive decline and dementia. We argue that a multivariate and mechanistic BioAge approach will lead to a greater understanding of disease pathology as well as more accurate prediction and early identification of late-life cognitive decline.     

Simultaneous detection of acetaminophen and 4-aminophenol with an electrochemical sensor based on silver–palladium bimetal nanoparticles and reduced graphene oxide

In this paper, Ag–Pd bimetallic nanoparticles uniformly distributed on reduced graphene oxide (rGO) were synthesized by redox reaction between Pd²⁺, Ag⁺and GO, and were characterized by X-ray diffractometry, field emission scanning electron microscopy, electrochemical impedance spectroscopy and thermal gravimetric analyses. A novel electrochemical sensor was constructed based on these nanocomposites using glassy carbon as a substrate. Under optimal conditions, the linear ranges were 0.50–300.00 μM for PA and 1.00–300.00 μM for 4-AP, with the detection limits of 0.23 μM for PA and 0.013 μM for 4-AP, respectively. This sensor was successfully applied to the determination of PA in pharmaceutical formulations and gave satisfactory results with a lower detection limit, wider linear range and good reproducibility.

Simultaneous detection of acetaminophen and 4-aminophenol with a highly sensitive electrochemical sensor based on silver–palladium bimetal nanoparticles and reduced graphene oxide.     

Secondary glaucoma as initial manifestation of ring melanoma: a case report and review of literature

Melanomas account for over 70% of adult malignancies in the eye and occur primarily in the choroid. Melanomas rarely originate in the ciliary body, with an annual incidence of approximately 1.6 cases per million. While the incidence rate of these tumors is low, malignant melanomas metastasize at early stages of disease development and show poor prognoses. Malignant melanomas of the ciliary body are often deeply hidden and have complex clinical manifestations, which are easily misdiagnosed and affect the prognosis. Here, we report a case of monocular ciliary body melanoma in an elderly Asian woman. Using this case as an example, we perform a systematic review of the disease’s clinical symptoms, signs, diagnoses, differential diagnoses, treatment and prognosis.     

Retracted Article: Long noncoding RNA ANRIL protects cardiomyocytes against hypoxia/reoxygenation injury by sponging miR-195-5p and upregulating Bcl-2

Long noncoding RNAs have been widely accepted to play important roles in acute myocardial infarction (AMI). The dysregulation of cyclin-dependent kinase inhibitor 2B antisense RNA 1 (ANRIL) was discovered in AMI patients. Nevertheless, the detailed role and molecular mechanisms of ANRIL in AMI remain indistinct. The levels of ANRIL, miR-195-5p and Bcl-2 mRNA were determined by qRT-PCR. western blot was performed to assess the expression of Bcl-2, Bax, Cyclin D1 and p21. Cell proliferation was detected by CCK-8 assay, and cell apoptosis was measured by flow cytometry. The targeted correlation between ANRIL and miR-195-5p was confirmed by the dual-luciferase reporter and RNA pull-down assays. Our data revealed that ANRIL was downregulated and miR-195-5p was upregulated in the serum of AMI patients and hypoxia/reoxygenation (H/R)-induced myocardial cells. ANRIL upregulation or miR-195-5p knockdown alleviated H/R-induced myocardial cell injury. Moreover, ANRIL sequestered miR-195-5p by acting as a sponge of miR-195-5p. ANRIL upregulated Bcl-2 expression by sponging miR-195-5p. Additionally, ANRIL overexpression alleviated H/R-induced myocardial cell injury by upregulating Bcl-2. In conclusion, our study indicated that ANRIL upregulation alleviated H/R-induced myocardial cell injury partially through sponging miR-195-5p and upregulating Bcl-2, highlighting its role as a promising mediator for new therapies for AMI treatment.

Long noncoding RNAs have been widely accepted to play important roles in acute myocardial infarction (AMI).