Tumor is one of the major diseases that endanger people's health.At present,the treatments used for tumor include surgery,chemotherapy,radiotherapy and so on.Nonetheless,the traditional treatments have some disadvantages,such as insufficient treatment effect,liable to cause multidrug resistance,toxicity and side effect.Further research and exploration of tumor treatment schemes are still necessary.As the energy converter of cells,mitochondria are currently considered to be one of the most important targets for the design of new drugs for tumor,cardiovascular and neurological diseases.Nano-drug delivery carriers have the characteristics of being easily modified with active targeting groups,and it can achieve accurate targeted drug delivery to cells and organelles.This paper reviews the application of mitochondrial targeted nanoparticles in tumor diagnosis and treatment from the aspects of inhibiting tumor cell proliferation,promoting tumor cell apoptosis,inhibiting tumor recurrence and metastasis,and inducing cell autophagy.

目的 利用网络药理学方法探索延胡索(Corydalis Rhizoma)治疗心绞痛的主要有效成分和作用靶点,为阐明延胡索药理作用机制提供参考.方法 利用 TCMSP、GeneCards数据库,参考有关文献收集延胡索防治心绞痛的活性成分和交叉靶点;再利用Cytoscape 3.9.1 软件,建立延胡索有效成分和心绞痛共同作用靶点的网络图;STRING数据库进行PPI网络的生成与分析.采用DAVID数据库进行GO分析、KEGG通路富集分析;结合AutoDockTools软件和 PyMOL 软件进行分子对接验证其作用靶点.结果 共获得16 个延胡索有效成分和141 个靶点与治疗心绞痛相关,这些靶点包括细胞外间隙组分、酶体系、HIF-1、肿瘤坏死因子等信号通路等.分子对接表明,所筛选出的延胡索主要有效成分与核心作用靶点均有良好的亲和力,结合能较低.结论 延胡索多种成分与机体内多个信号通路、多个靶点相互作用是其治疗心绞痛的重要作用机制.

目的:研究游泳运动对糖尿病小鼠肾脏的保护作用及机制.方法:正常小鼠随机分成正常对照组、正常游泳组、2型糖尿病(T2DM)小鼠模型组、糖尿病游泳组和二甲双胍组.用链脲佐菌素(STZ)法建立T2DM小鼠模型.正常游泳组和糖尿病游泳组小鼠给予游泳运动(每天1 h),二甲双胍组小鼠给予二甲双胍(200 mg/kg)每天一次灌胃,持续7周.测定小鼠空腹血糖、血清胰岛素值,计算胰岛素抵抗指数值.测定血清尿酸、尿素及肌酐的含量.计算肾质量/体质量比值,观察肾组织病理结构变化,Western blot法检测肾组织自噬相关蛋白LC3和p62的相对表达.结果:与正常对照组比,模型组胰岛素抵抗指数、肾质量/体质量比值显著升高;血清尿酸、尿素及肌酐含量升高,肾小球病理变化明显;LC3II/LC3I比值显著降低;p62的表达显著增加.与模型组比,糖尿病游泳组胰岛素抵抗指数、肾质量/体质量比值显著降低;血清尿酸、尿素及肌酐含量降低,肾小球病理改变也减轻;LC3II/LC3I比值显著升高;p62的表达显著下降(均P<0.05).结论:游泳运动保护T2DM小鼠的肾脏损伤,其机制可能与促进肾组织细胞自噬过程有关.

Nanoparticles (NPs)-based on various ionic polysaccharides, including chitosan, hyaluronic acid, and alginate have been frequently summarized for controlled release applications, however, most of the published reviews, to our knowledge, focused on the delivery of a single therapeutic agent. A comprehensive summarization of the co-delivery of multiple therapeutic agents by the ionic polysaccharides-based NPs, especially on the optimization of the polysaccharide structure for overcoming various extracellular and intracellular barriers toward maximized synergistic effects, to our knowledge, has been rarely explored so far. For this purpose, the strategies used for overcoming various extracellular and intracellular barriers in vivo were introduced first to provide guidance for the rational design of ionic polysaccharides-based NPs with desired features, including long-term circulation, enhanced cellular internalization, controllable drug/gene release, endosomal escape and improved nucleus localization. Next, four preparation strategies were summarized including three physical methods of polyelectrolyte complexation, ionic crosslinking, and self-assembly and a chemical conjugation approach. The challenges and future trends of this rapidly developing field were finally discussed in the concluding remarks. The important guidelines on the rational design of ionic polysaccharides-based NPs for maximized synergistic efficiency drawn in this review will promote the future generation and clinical translation of polysaccharides-based NPs for cancer therapy.

Pulmonary hypertension (PH) is a critical and dangerous disease in cardiovascular system. Pulmonary vascular remodeling is an important pathophysiological mechanism for the development of pulmonary arterial hypertension. Pulmonary artery smooth muscle cell (PASMC) proliferation, hypertrophy, and enhancing secretory activity are the main causes of pulmonary vascular remodeling. Previous studies have proven that various active substances and inflammatory factors, such as interleukin 6 (IL-6), IL-8, chemotactic factor for monocyte 1, etc., are involved in pulmonary vascular remodeling in PH. However, the underlying mechanisms of these active substances to promote the PASMC proliferation remain to be elucidated. In our study, we demonstrated that PASMC senescence, as a physiopathologic mechanism, played an essential role in hypoxia-induced PASMC proliferation. In the progression of PH, senescence PASMCs could contribute to PASMC proliferation via increasing the expression of paracrine IL-6 (senescence-associated secretory phenotype). In addition, we found that activated mTOR/S6K1 pathway can promote PASMC senescence and elevate hypoxia-induced PASMC proliferation. Further study revealed that the activation of mTOR/S6K1 pathway was responsible for senescence PASMCs inducing PASMC proliferation via paracrine IL-6. Targeted inhibition of PASMC senescence could effectively suppress PASMC proliferation and relieve pulmonary vascular remodeling in PH, indicating a potential for the exploration of novel anti-PH strategies.

目的 探讨弱氧化性低密度脂蛋白(minimally modified low density lipoprotein,mmLDL)上调在体小鼠肠系膜动脉ETA受体的作用(endothelin type A receptors,ETA)并考察自噬是否参与这一过程.方法 小鼠尾静脉注射mmLDL,腹腔注射Class ⅢPI3K自噬通路抑制剂6-氨基-3-甲基嘌呤(3-methyladenine,3-MA),探究自噬在mmLDL给药处理小鼠中的作用,微血管张力描记仪观察内皮素-1(endothelin-1,ET-1)引起的小鼠肠系膜动脉收缩量效曲线的变化,RT-PCR定量ETA受体mRNA,Western blot检测ETA受体和Class Ⅲ PI3K、Beclin-1、LC3-Ⅱ/Ⅰ、p62及p-NF-κB、NF-κB的蛋白水平表达.结果 mmLDL引起ET-1收缩量效曲线明显增强,表现为Emax值由生理盐水(NS)组的(184.87±7.46)％上升为(319.91 ±20.31)％ (P＜0.001),pEC50值由NS组的(8.05±0.05)上升为(9.11±0.09)(P＜0.01).mmLDL在上调Class Ⅲ PI3K、beclin-1、LC3-Ⅱ/Ⅰ和下调p62蛋白水平的同时,也引起ETA受体mRNA水平、蛋白表达明显增加,增加了p-NF-κB的蛋白水平;腹腔注射3-MA抑制了mmLDL的这些作用.结论 mmLDL能通过Class Ⅲ PI3K/Beclin-1通路激活自噬及下游NF-κB通路上调ETA受体.

目的 探讨马铃薯糖苷生物碱和芦荟蒽醌类物质的提取方法及其联合使用对静脉炎的治疗效果.方法 利用超声提取马铃薯糖苷生物碱和芦荟蒽醌类物质,将提取物按1:1质量浓度配置成待试药.将32只昆明小鼠连续3 d尾静脉注射5-氟尿嘧啶建立静脉炎模型,随机分成4组,即对照组、模型组、硫酸镁组及待试药组,每组8只.硫酸镁组和待试药组分别湿敷50％硫酸镁和待试药液,对照组和模型组湿敷等体积生理盐水,并观察鼠尾肿胀程度和形态学变化.结果 与对照组相比,模型组鼠尾肿胀度显著增加,尾静脉病理形态学显示血管壁变厚,炎性细胞增多,硫酸镁和待试药湿敷后第2,3天鼠尾肿胀度和血管壁变厚均显著减轻(P<0.05).结论 马铃薯糖苷生物碱和芦荟蒽醌类物质联合使用能有效减轻化疗性静脉炎.

该文旨在探讨信号转导和转录激活因子3(signal transducer and activator of transcrip?tion 3,STAT3)在血管紧张素Ⅱ(Angiotensin Ⅱ,AngⅡ)诱导的血管平滑肌细胞(vascular smooth muscle cells,VSMCs)自噬中的作用.体外培养VSMCs,经STAT3磷酸化抑制剂预处理以及小干扰RNA技术沉默STAT3基因后检测AngⅡ对其自噬活性的影响.LC3蛋白turnover实验检测自噬潮,West-em blot检测通路蛋白ph-STAT3(Tyr795)、STAT3及自噬标志性蛋白LC3-Ⅱ、Beclin1的表达.结果显示,AngⅡ促进自噬标志性蛋白LC3-Ⅱ、Beclin1的表达,且呈AngⅡ浓度和时间依赖性,以10-7 mol/L AngⅡ刺激VSMCs 24 h后LC3-Ⅱ、Beclin1增加最明显(P＜0.01).Chloroquine(氯喹)的预处理能进一步增加AngⅡ诱导的LC3-Ⅱ表达(P＜0.05).STAT3磷酸化抑制剂Cryptotanshinone(隐丹酮)和STAT3-siRNA都能逆转AngⅡ诱导的自噬标志性蛋白LC3-Ⅱ、Beclin1的表达(P＜0.05).该项研究结果表明,AngⅡ诱导的VSMCs自噬与STAT3信号通路活化有关,抑制STAT3的磷酸化及基因沉默可逆转AngⅡ诱导的VSMCs自噬.

<span id="ChDivSummary" name="ChDivSummary" class="abstract-text">目的探讨适度游泳运动对2型糖尿病小鼠骨骼肌损伤的作用及机制。方法采用高脂高糖饲料加小剂量注射链脲佐菌素的方法建立T2DM小鼠模型。随机分为正常对照组、正常运动组、糖尿病组、糖尿病运动组和糖尿病二甲双胍组,并分别给予6周适度游泳运动(1 h·d^-1, 5 d·w^-1)和二甲双胍(200 mg·kg^-1)干预。对小鼠体质量、饮食饮水量、空腹血糖、胰岛素抵抗指数、骨骼肌形态和自噬蛋白（LC3、P62）进行测定。结果与正常对照组小鼠比较,2型糖尿病小鼠骨骼肌细胞变形明显,自噬蛋白LC3表达下降,P62表达上调;与糖尿病组比较,适度游泳运动或二甲双胍干预可促进骨骼肌细胞形态恢复,自噬蛋白LC3表达上调,P62表达下调。结论适度游泳运动可减轻STZ介导的2型糖尿病小鼠骨骼肌损伤,可能与上调骨骼肌细胞自噬有关。</span>

目的:探讨弱氧化修饰低密度脂蛋白(mmLDL)是否通过激活p38 MAPK炎症通路上调小鼠肠系膜动脉内皮素(ET)A型(ETA)和B型(ETB)受体.方法:将昆明小鼠分为正常对照组(尾静脉注射生理盐水)、mmLDL组(尾静脉注射mmLDL)、LDL组(尾静脉注射LDL)、mmLDL+SB 203580组(尾静脉注射mmLDL及腹腔注射p38 MAPK抑制剂SB 203580)和mmLDL+DMSO组(尾静脉注射mmLDL及腹腔注射DMSO).微血管张力描记仪记录ETB受体激动剂角蝰毒素6c和ET-1引起肠系膜动脉收缩的量效曲线;RT-qPCR检测ETB受体、ETA受体和白细胞介素(IL-6)的mRNA表达;ELISA检测血清IL-6的水平;Western blot检测ETB受体、ETA受体、IL-6、p38 MAPK、p-p38 MAPK、NF-κB和p-NF-κB的蛋白水平.结果:mmLDL引起ETB受体和ETA受体介导的血管收缩反应显著增强(P＜0. 01),ETB受体、ETA受体和IL-6的mRNA和蛋白表达显著增加(P＜0. 01),p-p38 MAPK和p-NF-κB蛋白水平显著升高(P＜0. 01),血清中IL-6水平显著升高(P＜0. 01);腹腔注射SB 203580抑制了mmLDL的作用.mmLDL引起的IL-6血清浓度升高分别与ETB受体和ETA受体介导的最大收缩率呈正相关.结论:mmLDL通过激活p38 MAPK通路及下游NF-κB转录因子,提高炎症因子IL-6血清水平,增加小鼠肠系膜动脉IL-6、ETA受体和ETB受体表达,增强ETA受体和ETB受体介导的血管收缩功能.

Caveolin-1 is considered an important pathophysiological factor in atherosclerosis development. Previous studies indicate that caveolin-1 exhibits a pathogenic capacity in atherosclerosis via the regulation of membrane trafficking, cholesterol metabolism and cellular signal transduction. Accumulating evidence shows that autophagy activation influences the progression and development of atherosclerosis in multiple ways, including cholesterol metabolism, inflammatory responses and lipid transcytosis. However, how caveolin-1 is involved in autophagy activation in atherosclerosis remains unclear, and the precise mechanisms of caveolin-1 on autophagic flux in atherosclerosis need to be further investigated. Clarifying the roles and mechanisms of caveolin-1 in the regulation of autophagy activation is of great importance, contributing to the ability to manipulate caveolin-1 as a novel therapeutic approach for atherosclerosis. In this review, we summarize the understanding of the molecular structure, biological roles and biochemical functions of caveolin-1 to date and discuss the roles and mechanisms of caveolin-1 in autophagy activation. The emphasis on the potential of caveolin-1 to be a novel therapeutic target in atherosclerosis and understanding its precise functions and exact mechanisms in autophagic flux will provide evidence for future experimental research and aid in the development of novel therapeutic strategies for atherosclerosis.

Objectives Cardiovascular disease (CVD) remains the primary cause of morbidity and mortality worldwide. The abnormal proliferation of vascular smooth muscle cells (VSMCs) is a key event in the pathogenesis of CVD. The functional and phenotypic changes in vascular cells are mediated by complex signaling cascades that initiate and control genetic reprogramming. Many studies have demonstrated that signal transducer and activator of transcription 3 (STAT3) regulates a diverse array of functions relevant to atherosclerosis. Methods In this review, we summarize the studies on the STAT3-mediated proliferation of VSMCs and subsequent CVDs such as hypertension, atherosclerosis, stroke, coronary artery disease, and myocardial infarction. Furthermore, we describe the general background of STAT3, its structure, function and regulation as well as the STAT3 signaling pathway. Finally, we highlight some potential issues and propose some solutions to these issues. Results and conclusions: STAT3 activation promotes the proliferation of VSMCs by regulating the transcription of genes. Studying the mechanism of VSMC proliferation induced by the STAT3 pathway is valuable for finding therapeutic targets for CVD.

目的 探讨预先使用TLR4单克隆抗体(TLR4mAb)对轻度氧化修饰低密度脂蛋白(mmLDL)诱发小鼠肠系膜动脉内皮依赖性舒张功能损伤的影响及作用机制.方法 实验分为:空白对照组、mmLDL处理组、TLR4mAb干预组.采用ELISA方法测定血浆中白细胞介素(IL)-1β和肿瘤坏死因子(TNF)-α的浓度水平,微血管张力描记技术测定血管内皮依赖性舒张功能,Western blot技术和RT-PCR技术分别考察血管组织蛋白表达量和mRNA表达水平,透射电镜观察肠系膜动脉内皮细胞超显微结构.结果 TLR4mAb剂量依赖性改善mmLDL损伤血管内皮依赖性舒张功能的损伤作用,显著上调Kca3.1-通道、Kca2.3-通道蛋白表达和下调炎症因子TNF-α和IL-1β 表达.TLR4mAb改善mmLDL损伤血管内皮细胞及内皮依赖性舒张功能,可能与其竞争性拮抗mmLDL激活TLR4信号转导通路及其下游的NF-κBp65和p-38MAPK通路有关.结论 预先使用TLR4mAb可以减轻mmLDL所诱发的内皮细胞损伤和内皮依赖性舒张功能降低,以及抑制炎症因子的过度表达,调控TLR4通路及其下游的NF-κBp65和p-38MAPK通路可能是预防治疗心血管疾病的有效靶点.

Enterobacter aerogene is a facultative anaerobic Gram-negative bacilli. In recent years, its drug resistant phenomenon is clinically prominent, and the infection caused has become a main concern worldwide. The mechanism of drug resistance of Enterobacter aerogenes included active efflux system, change of membrane pore protein, and production of β-lactamase and biofilm formation. Understanding the resistance mechanism of Enterobacter aerogenes helps provide theoretical basis for the rational use of antibiotics. This paper summarized the research progress in its resistance mechanism.

Rutaecarpine attenuates hypertensive cardiac hypertrophy in the rats with abdominal artery constriction (AAC); however, its mechanism of action remains largely unknown. Our previous study indicated that NADPH oxidase 4 (Nox4) promotes angiotensin II (Ang II)‐induced cardiac hypertrophy through the pathway between reactive oxygen species (ROS) and a disintegrin and metalloproteinase‐17 (ADAM17) in primary cardiomyocytes. This research aimed to determine whether the Nox4‐ROS‐ADAM17 pathway is involved in the protective action of rutaecarpine against hypertensive cardiac hypertrophy. AAC‐induced hypertensive rats were adopted to evaluate the role of rutaecarpine in hypertensive cardiac hypertrophy. Western blotting and real‐time PCR were used to detect gene expression. Rutaecarpine inhibited hypertensive cardiac hypertrophy in AAC‐induced hypertensive rats. These findings were confirmed by the results of in vitro experiments that rutaecarpine significantly inhibited Ang II‐induced cardiac hypertrophy in primary cardiomyocytes. Likewise, rutaecarpine significantly suppressed the Nox4‐ROS‐ADAM17 pathway and over‐activation of extracellular signal‐regulated kinase (ERK) 1/2 pathway in the left ventricle of AAC‐induced hypertensive rats and primary cardiomyocytes stimulated with Ang II. The inhibition of Nox4‐ROS‐ADAM17 pathway and over‐activation of ERK1/2 might be associated with the beneficial role of rutaecarpine in hypertensive cardiac hypertrophy, thus providing additional evidence for preventing hypertensive cardiac hypertrophy with rutaecarpine.

血管平滑肌细胞异常增殖是血管增殖性疾病的病理基础,自噬是真核生物维持细胞内环境稳态的一种自我保护机制.近年来的研究发现,自噬参与多种细胞因子、血管活性物质、剪切应力、ncRNA等诱导的血管平滑肌细胞增殖,一些抗血管增生性疾病的药物往往通过调节自噬通量和自噬活性发挥抗血管平滑肌细胞增殖作用.本文综述了自噬对血管平滑肌细胞增殖的影响,为探索血管增生性疾病的病理生理机制提供新的思路.

血管重构是血管增殖性疾病的重要病理特征,血管平滑肌细胞的增殖与增生是血管重构的主要细胞学基础.环氧合酶2(COX-2)是合成前列腺素类(PGs)中间体的一类诱导型酶,其表达高低与血管重构密切相关.不同的诱导因素通过激活不同的信号通路上调COX-2的表达水平,进而激活不同的前列腺素PGE2或PGI2及其受体EP或IP,以相同或相反的作用调控血管重构.本文通过分析COX-2的结构与功能,探讨不同的刺激因子激活COX-2及其产生的前列腺素类及其受体在血管重构中的作用,期望能为防治血管增殖类疾病提供新策略和新思路.

目的:探讨降钙素基因相关肽(CGRP)对人脐静脉内皮细胞胰岛素抵抗的保护作用及其机制.方法:用人脐静脉内皮细胞(HUVEC)建立胰岛素抵抗细胞模型(irHUVEC),分别用葡萄糖氧化酶法和蒽酮-硫酸法检测细胞葡萄糖消耗能力和糖原合成能力;RT-PCR和Western blot分别检测目的蛋白和基因表达.结果:33.3 mmol/L的高糖和5μmol/L的胰岛素处理24 h可以成功诱导内皮细胞产生胰岛素抵抗.与正常HUVEC相比,irHUVEC体积变大,边界模糊,形态异常;当细胞用高糖和高胰岛素分别诱导24 h和48 h时,irHUVEC的葡萄糖消耗量分别减少20％和31％,并且糖原合成分别减少了55％和64％,差异都具有显著性;同时,过氧化物酶增殖体激活受体 γ(PPARγ)和还原型一氧化氮合酶(eNOS)的表达均降低.CGRP可以明显增加irHUVEC葡萄糖的消耗量约20％和糖原合成增加约70％,并能增加PPARγ 和eNOS蛋白及mRNA表达;SQ22536(cAMP阻断剂)能使PPARγ和eNOS的蛋白和基因表达量明显减少.结论:CGRP可以改善内皮细胞的胰岛素抵抗,其机制可能与上调环磷酸腺苷(cAMP),增加PPARγ和eNOS表达有关.

二甲双胍是一种临床上使用最广泛的抗糖尿病药,用于治疗Ⅱ型糖尿病已有几十年的历史.近年来发现二甲双胍的药理作用除降血糖的作用外,还存在降糖外作用.本文综述二甲双胍的药理作用及其作用机制,为探索老药新用及某些疾病发病机制提供新认识.

OBJECTIVES:Protein arginine methyltransferase 2 (PRMT2) protects against vascular injury-induced intimal hyperplasia; however, little is known about the role of PRMT2 in angiotensin II (Ang II)-induced VSMCs proliferation and inflammation. This research aims to determine whether PRMT2 inhibits Ang II-induced proliferation and inflammation of vascular smooth muscle cells (VSMCs).MATERIALS AND METHODS:PRMT2 overexpression was used to elucidate the role of PRMT2 in Ang II-induced VSMCs proliferation and inflammation. Western blotting and reverse transcriptional PCR were adopted to detect protein and mRNA expression severally. Cell viability was evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay and cell cycle distribution by flow cytometry.RESULTS:Ang II significantly reduced mRNA and protein levels of PRMT2 in VSMCs in time-dependent and dose-dependent manner. Results of PRMT2 overexpression indicated that PRMT2 inhibited proliferation of VSMCs stimulated with 100 nmol/L Ang II for 24 hours. Furthermore, overexpression of PRMT2 reduced Ang II-induced production of proinflammatory cytokines such as interleukin 6 (IL-6) and interleukin 1β (IL-1β) in VSMCs.CONCLUSIONS:These findings suggest that PRMT2 alleviates Ang II-induced VSMCs proliferation and inflammation, providing a new mechanism about how Ang II mediated VSMCs proliferation and inflammation.