Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity

Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mitochondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence/absence of the prodrug NV118. Statins concentration-dependently inhibited mitochondrial respiration in both intact and permeabilized cells. Further, statins caused an increase in non-ATP generating oxygen consumption (uncoupling), severely limiting the OXPHOS coupling efficiency, a measure of the ATP generating capacity. Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct complex I inhibition. NV118 increased succinate-supported mitochondrial oxygen consumption in atorvastatin/cerivastatin-exposed platelets leading to normalization of coupled (ATP generating) respiration. The results acquired in isolated human platelets were validated in a limited set of experiments using atorvastatin in HepG2 cells, reinforcing the generalizability of the findings.     

Coenzyme Q10: Novel Formulations and Medical Trends

The aim of this review is to shed light over the most recent advances in Coenzyme Q₁₀ (CoQ₁₀) applications as well as to provide detailed information about the functions of this versatile molecule, which have proven to be of great interest in the medical field. Traditionally, CoQ₁₀ clinical use was based on its antioxidant properties; however, a wide range of highly interesting alternative functions have recently been discovered. In this line, CoQ₁₀ has shown pain-alleviating properties in fibromyalgia patients, a membrane-stabilizing function, immune system enhancing ability, or a fundamental role for insulin sensitivity, apart from potentially beneficial properties for familial hypercholesterolemia patients. In brief, it shows a remarkable amount of functions in addition to those yet to be discovered. Despite its multiple therapeutic applications, CoQ₁₀ is not commonly prescribed as a drug because of its low oral bioavailability, which compromises its efficacy. Hence, several formulations have been developed to face such inconvenience. These were initially designed as lipid nanoparticles for CoQ₁₀ encapsulation and distribution through biological membranes and eventually evolved towards chemical modifications of the molecule to decrease its hydrophobicity. Some of the most promising formulations will also be discussed in this review.     

The Effect of Deflazacort Treatment on the Functioning of Skeletal Muscle Mitochondria in Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a severe hereditary disease caused by a lack of dystrophin, a protein essential for myocyte integrity. Mitochondrial dysfunction is reportedly responsible for DMD. This study examines the effect of glucocorticoid deflazacort on the functioning of the skeletal-muscle mitochondria of dystrophin-deficient mdx mice and WT animals. Deflazacort administration was found to improve mitochondrial respiration of mdx mice due to an increase in the level of ETC complexes (complexes III and IV and ATP synthase), which may contribute to the normalization of ATP levels in the skeletal muscle of mdx animals. Deflazacort treatment improved the rate of Ca²⁺ uniport in the skeletal muscle mitochondria of mdx mice, presumably by affecting the subunit composition of the calcium uniporter of organelles. At the same time, deflazacort was found to reduce the resistance of skeletal mitochondria to MPT pore opening, which may be associated with a change in the level of ANT2 and CypD. In this case, deflazacort also affected the mitochondria of WT mice. The paper discusses the mechanisms underlying the effect of deflazacort on the functioning of mitochondria and contributing to the improvement of the muscular function of mdx mice.     

姜黄素对辐射诱导的胰腺外分泌细胞损伤的保护作用

将大鼠胰腺外分泌细胞(AR42J)分为实验组与对照组,两组细胞根据姜黄素处理水平又分为A/B/C/D/E 5个姜黄素处理组,分别经0、2、4、8、16 μM姜黄素处理,实验组予以一次性大剂量X射线照射(6 Gy),模拟急性辐射损伤事件。照后收集细胞蛋白行免疫印迹试验(Wensten-blot)检测凋亡相关蛋白PARP、BCL-2,应激及能量代谢相关因子HIF-1ɑ、LDHA、PDH表达情况,MTT法检测细胞增殖活力,荧光酶标仪检测细胞ATP及ROS生成情况。清洁级大鼠24只随机分为对照组、单纯加药组、单纯照射组、照射+加药组,予以12 Gy X射线照射或假照射,射后24小时处死并解剖取出胰腺组织,Wensten-blot检查能量代谢相关蛋白表达情况,以探讨姜黄素在胰腺外分泌细胞辐射损伤中的作用及其机制。结果表明,与对照组相比,单纯照射组细胞在受照24 h后,凋亡蛋白PARP表达升高,BCL-2蛋白下调,线粒体膜电位下降表明线粒体受损。辐照促使缺氧诱导因子HIF-1α表达上调,介导糖酵解的关键因子LDHA表达增强,PDH表达下调。细胞增殖活力下降,ROS生成增多,沉默HIF-1表达在一定程度上抑制了辐照诱导的这种能量代谢转变。经姜黄素预处理,纠正了HIF-1α及LDHA的表达上调,部分恢复PDH表达,有效清除氧自由基,并且对细胞的增殖能力及ATP生成具有正向作用。动物实验显示辐照诱导HIF-1α表达加强,调控能量代谢相关蛋白表达发生改变,LDHA表达增强,PDH表达下调;经姜黄素预处理,纠正了HIF-1α上调所介导的能量代谢相关蛋白的表达变化,趋势与细胞实验相符。以上结果说明,胰腺外分泌细胞在电离辐射损伤下,通过上调HIF-1α表达,促使能量代谢发生转变,糖酵解途径加强,而经线粒体的有氧氧化受到抑制。姜黄素通过下调HIF-1α,纠正了辐射诱导的细胞能量代谢紊乱,并有效清除氧自由基,保护线粒体,从而发挥其对胰腺外分泌细胞的辐射损伤的保护作用。     

Gui-A-Gra Attenuates Testicular Dysfunction in Varicocele-Induced Rats via Oxidative Stress,ER Stress and Mitochondrial Apoptosis Pathway

Gui-A-Gra, a commercial insect powder from Gryllus bimaculatus, is registered as an edible insect by the Korean food and drug administration. The aim of this study was to investigate the effect of Gui-A-Gra on testicular damage induced by experimental left varicocele in male Sprague Dawley rats. A total of 72 rats were randomly divided into the following six groups (12 rats in each group): a normal control group (CTR), a group administrated with Gui-A-Gra 1.63 gm/kg (G1.63), a group administrated with Gui-A-Gra 6.5 gm/kg (G6.5), a varicocele (VC)-induced control group (VC), a VC-induced group administrated with Gui-A-Gra 1.63 gm/kg (VC + G1.63), and a VC-induced group administrated with Gui-A-Gra 6.5 gm/kg (VC + G6.5). Rats were administrated 1.63 or 6.5 gm/kg Gui-A-Gra once daily for 42 days. Indicators of sperm parameters, histopathology, reproductive hormones, oxidative stress, endoplasmic reticulum (ER) stress, inflammation, and mitochondrial apoptosis were analyzed to evaluate effects of Gui-A-Gra on VC-induced testicular dysfunction. Gui-A-Gra administration to VC-induced rats significantly (p < 0.05) increased sperm count and sperm motility, Johnsen score, spermatogenic cell density, serum testosterone, testicular superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, GPx4, and steroidogenic acute regulatory protein (StAR) level. Moreover, pretreatment with Gui-A-Gra significantly (p < 0.05) decreased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) positive cells/tubules, serum luteinizing hormone (LH), serum follicle-stimulating hormone (FSH), testicular tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde (MDA), reactive oxygen species (ROS)/reactive nitrogen species (RNS) level, glucose-regulated protein-78 (Grp-78), phosphorylated c-Jun-N-terminal kinase (p-JNK), phosphorylated inositol-requiring transmembrane kinase/endoribonuclease 1α (p-IRE1α), cleaved caspase-3, and BCL2 associated X protein: B-cell lymphoma 2 (Bax: Bcl2) ratio in VC rats. These results suggest that protective effects of Gui-A-Gra on VC-induced testicular injury might be due to its antioxidant, anti-inflammatory, and androgenic activities that might be mediated via crosstalk of oxidative stress, ER stress, and mitochondrial apoptosis pathway.     

Dual Inhibition of Pyruvate Dehydrogenase Complex and Respiratory Chain Complex Induces Apoptosis by a Mitochondria-Targeted Fluorescent Organic Arsenical in vitro and in vivo

Based on the potential therapeutic value in targeting mitochondria and the fluorophore tracing ability, a fluorescent mitochondria-targeted organic arsenical PDT-PAO-F16 was fabricated, which not only visualized the cellular distribution, but also exerted anti-cancer activity in vitro and in vivo via targeting pyruvate dehydrogenase complex (PDHC) and respiratory chain complexes in mitochondria. In details, PDT-PAO-F16 mainly accumulated into mitochondria within hours and suppressed the activity of PDHC resulting in the inhibition of ATP synthesis and thermogenesis disorder. Moreover, the suppression of respiratory chain complex I and IV accelerated the mitochondrial dysfunction leading to caspase family-dependent apoptosis. In vivo, the acute promyelocytic leukemia was greatly alleviated in the PDT-PAO-F16 treated group in APL mice model. Our results demonstrated the organic arsenical precursor with fluorescence imaging and target-anticancer efficacy is a promising anticancer drug.     

葡萄糖诱导的线粒体蛋白氧化应激及调控机制概述

食品中的葡萄糖是人体细胞获取能量的重要来源,细胞中的线粒体是重要的能量代谢场所,在维持人体正常生理代谢功能中起重要作用。但葡萄糖代谢异常会导致线粒体功能紊乱,这是通过葡萄糖诱导的氧化应激导致的线粒体蛋白功能异常,进而引发相关疾病,例如糖尿病、阿尔茨海默症和脑中风。所以维持线粒体生理功能,研究氧化应激调控机制,探究相关疾病更有效的治疗手段至关重要。本文综述了氧化应激涉及的主要线粒体蛋白(包括顺乌头酸酶、腺嘌呤核苷酸转位酶、二氢硫辛酰胺脱氢酶、线粒体蛋白复合物Ⅰ、雌激素受体β、热休克转录因子1和缺氧诱导因子2a)、氧化应激调控机制(包括丙酮酸调节、线粒体蛋白之间的协同调节)和人工干预过程(包括乙醇戒断、亚甲蓝作电子受体和5-甲氧基吲哚-2-羧酸预处理)。     

Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Renoprotective Mechanisms beyond Glycemic Control

Diabetes mellitus is a major cause of chronic kidney disease and end-stage renal disease. However, the management of chronic kidney disease, particularly diabetes, requires vast improvements. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for the treatment of diabetes, have been shown to protect against kidney injury via glycemic control, as well as various other mechanisms, including blood pressure and hemodynamic regulation, protection from lipotoxicity, and uric acid control. As such, regulation of these mechanisms is recommended as an effective multidisciplinary approach for the treatment of diabetic patients with kidney disease. Thus, SGLT2 inhibitors are expected to become key drugs for treating diabetic kidney disease. This review summarizes the recent clinical evidence pertaining to SGLT2 inhibitors as well as the mechanisms underlying their renoprotective effects. Hence, the information contained herein will advance the current understanding regarding the pleiotropic effects of SGLT2 inhibitors, while promoting future research in the field.