第3种内源性气体信号分子

越来越多的证据支持内源性的H2 S是第 3种气体信号分子。H2 S通过cAMP途径调节神经突触功能 ,H2 S是一种神经调节因子或神经递质 ;H2 S亦是一种重要的内源性血管舒张因子 ,它通过激活血管平滑肌KATP通道和使血管平滑肌膜电位去极化 ,或通过能降低外Ca2 + 内流而实现其血管调节功能     

内源性硫化氢对心肺循环系统作用研究进展

提及硫化氢(hydrogen sulfide,H2S),人们的第一反应就是有毒、带有臭鸡蛋气味的气体,然而近年来的研究发现H2S不但可以在包括人类在内的哺乳动物许多细胞中经酶促作用产生,而且还起着重要的生理作用,并且参与了多系统的病理生理变化.越来越多的研究显示H2S在神经系统、循环系统起着重要的生理及病理意义,从而使H2S成为继一氧化氮(NO)和一氧化碳(CO)后第三种气体信号分子[1].尤其是研究发现H2S具有通过减少KATP通道通透性以舒张血管平滑肌的作用,这使H2S在心肺循环系统具有重要的病生理意义.现就其在心肺循环系统作用研究进展作一综述.     

IL-33/ST2信号通路及相关药物研究进展

目的：介绍IL-33/ST2信号通路,总结其与各项疾病的发生发展机制之间的关系以及相关药物的研发进展,为相关疾病的治疗策略提供新的思路。方法：通过汇总分析现有的研究IL-33/ST2信号通路与多种疾病的发病机制关联的文献,对IL-33/ST2信号通路与各项疾病之间的关系以及相关药物的研发进展进行讨论总结。结果与结论：IL-33作为免疫反应和细胞损伤的警报分子,其信号转导通路在过敏性疾病、慢性炎症性疾病、恶性肿瘤和心血管疾病等多种疾病的发病过程中发挥了十分关键的作用,这些研究成果为多种疾病的治疗策略提供了新的思路。多家国内外公司已经开始研发针对IL-33/ST2的靶向药物,绝大多数为单抗药物,且已经进入不同的临床试验阶段,具有重要的应用前景。     

人参蛋白协同H2O2诱导SH-SY5Y细胞氧化损伤

目的:探讨人参蛋白(GP)协同H₂O₂诱导人神经母细胞瘤(SH-SY5Y)氧化应激损伤的作用,并筛选二者的最佳联合浓度。方法:首先采用不同浓度H₂O₂诱导SH-SY5Y细胞氧化损伤,然后采用不同浓度GP联合200 μmol·L^-1H₂O₂诱导SH-SY5Y细胞氧化损伤;采用倒置荧光显微镜观察细胞形态,MTT法检测细胞存活,Hoechst 33342染色法检测细胞凋亡。结果:SH-SY5Y细胞经GP-H₂O₂作用后,细胞数量减少,轴突缩短或消失,胞体变圆、缩小,大小不等;细胞存活率降低;Heochst 33342染色呈现高蓝光;GP 60 mg·L^-1+H₂O₂ 200 μmol·L^-1为联合诱导氧化应激损伤的最佳浓度。结论:GP有协同H₂O₂诱导SH-SY5Y细胞氧化损伤的作用,抑制细胞增殖、促进细胞凋亡是其可能的作用机制。     

新的抗肝癌分子靶及相关药物研究

目前临床上有效的抗肝癌药物很少,普遍存在着疗效差、毒性大、易产生耐药性等问题,发现新的肝癌分子靶,并以此发展高效低毒的抗肝癌药物是解决问题的关键之一。相关研究表明启动子甲基化、肝细胞生长因子及其受体、血管内皮生长因子及其受体、环氧化酶 2可能是抗肝癌药物有效的分子靶,相应的配体化合物已展示了潜在的应用前景。此外三氧化二砷等其他类型的化合物也显示了一定的抗肝癌疗效。     

分子靶向药物治疗宫颈癌研究进展

宫颈癌是女性生殖系统发病率第二的恶性肿瘤。主要的治疗方法为手术、放疗或化疗。近年来,分子靶向药物的蓬勃发展为晚期恶性肿瘤的治疗提供了一个新途径,在宫颈癌的治疗上也取得了一定的成绩,本文就靶向药物治疗宫颈癌的研究进展作一简要综述。     

白藜芦醇激活Nrf-2信号抑制H2O2诱导的骨关节炎软骨细胞凋亡、氧化损伤和炎症反应

目的 研究白藜芦醇在H₂O₂诱导骨关节炎软骨细胞凋亡、氧化损伤和炎症反应中的作用。方法 通过MTT试验检测H₂O₂和（或）白藜芦醇处理原代软骨细胞增殖活性,流式细胞仪检测细胞凋亡情况;通过实时定量荧光PCR和Western blotting检测各处理组Nrf2-HO-1/NQO-1信号因子,抗氧化酶基因SOD-2、GPx4和CAT,炎症信号因子NF-κB、COX-2和iNOS的表达水平;流式细胞仪检测细胞ROS水平和脂质氧化水平;ELISA检测各处理组细胞炎症因子IL-6、IL-8、TNF-α的释放情况。结果 白藜芦醇能够恢复H₂O₂诱导的原代软骨细胞凋亡,增加细胞增殖活性;上调Nrf2-HO-1/NQO-1信号因子和抗氧化酶基因SOD-2、GPx4和CAT的表达,降低H₂O₂诱导的ROS和脂质氧化水平;降低H₂O₂诱导的炎症信号因子NF-κB、COX-2和iNOS的表达水平,降低炎症因子IL-6、IL-8、TNF-α的释放。结论 白藜芦醇可能通过增加转录因子Nrf-2的激活以及其直接抗氧化和抗炎作用来发挥对软骨细胞的保护作用,以改善骨关节炎的氧化损伤和炎症反应。     

丁香酚对H2O2诱导H9C2心肌细胞损伤的保护作用

目的 研究丁香酚对H₂O₂诱导H9C2心肌细胞损伤的影响。方法 使用不同浓度H₂O₂建立H9C2心肌细胞氧化损伤模型,将建立好的心肌细胞氧化损伤模型分为对照组、50 μg/mL丁香酚处理组、100 μg/mL丁香酚处理组和200 μg/mL丁香酚处理组,采用MTT法观察吸光度值（OD）变化来评价丁香酚对H9C2心肌细胞活力的影响;采用Hoechst染色法观察细胞核形态变化,评价丁香酚对H9C2心肌细胞凋亡的影响;为进一步研究丁香酚的抗氧化损伤作用,采用比色法检测试剂盒观察丁香酚对H9C2心肌细胞乳酸脱氢酶（LDH）、丙二醛（MDA）及超氧化物歧化酶（SOD）含量的影响。结果 400 μmol/L H₂O₂显著降低H9C2细胞活力,增加细胞凋亡,适宜建立H9C2心肌细胞氧化损伤模型。100 μg/mL和200 μg/mL的丁香酚增加H9C2细胞活力,减少细胞凋亡（P<0.05）;同时,H₂O₂诱导H9C2细胞LDH及MDA含量增加和SOD含量减少的效应也可被100 μg/mL和200 μg/mL的丁香酚抑制。结论 丁香酚对H₂O₂诱导H9C2心肌细胞损伤具有保护作用。     

药物分子聚集体及其作用机理研究进展

近年来,药物分子聚集体是国外研究的一大热点。本文概述了单一药物分子、多组分药物分子以及药物分子聚集体与胃肠吸收的研究进展,综述了中药分子聚集体的研究概况及其前景。     

酸性鞘磷脂酶活性调控及相关药物研究进展

酸性鞘磷脂酶(ASM)是鞘磷脂代谢的关键酶,调节细胞增殖、分化、衰老和凋亡等.ASM过少或缺陷易引起尼曼-匹克病,过多会导致神经性病变、抑郁症、脓毒症和糖尿病等.研究发现,ASM的激活受环境因素、药物因素和其他因素的影响,细菌、病毒、电离辐射、重金属、心理压力、乙醇和细胞因子等可激活ASM,诱发上述疾病发生.应用ASM...     

特发性肺纤维化相关信号通路及治疗药物研究进展

特发性肺纤维化是一种慢性的进行性肺部疾病,它也是特发性间质性肺炎最常见的形式之一,具有很高死亡率,自诊断之日起中位生存期仅为2～3年。尽管其发病机制尚不明确,但已发现多条信号通路在该疾病发生发展过程中起重要作用。目前FDA批准用于治疗特发性肺纤维化的药物主要有吡非尼酮和尼达尼布,另外还有10余种药物处于临床研究阶段。综述与特发性肺纤维化相关的信号通路及其临床在研药物的研究进展。     

硫酸乙酰肝素及其相关药物的研究新进展

硫酸乙酰肝素是存在于所有动物组织细胞及胞外基质中的一类多糖物质,它通过与蛋白的相互作用参与各种生理病理过程,而其结构的改变,特别是硫酸化程度的改变,可干扰其与蛋白的相互作用,从而影响多种疾病的发生和发展。鉴于硫酸乙酰肝素在疾病进程中扮演的重要角色,硫酸乙酰肝素相关药物的设计与合成引起了药学研究者的广泛兴趣。综述硫酸乙酰肝素的结构、形成和功能以及与蛋白相互作用的机制,介绍硫酸乙酰肝素相关药物的研究与开发新进展。     

Low micromolar zinc exerts cytotoxic action under H2O2-induced oxidative stress: Excessive increase in intracellular Zn concentration

The ability of zinc to retard oxidative processes has been recognized for many years. However, zinc is cytotoxic under certain oxidative stress. In this study, we investigated the effect of H₂O₂ on intracellular Zn²⁺ concentration of rat thymocytes and its relation to the cytotoxicity. Experiments were cytometrically performed by the use of fluorescent probes, propidium iodide, FluoZin-3-AM, and 5-chloromethylfluorescein diacetate. ZnCl₂ potentiated cytotoxicity of H₂O₂ while TPEN, a chelator for intracellular Zn²⁺, attenuated it. Results suggested an involvement of intracellular Zn²⁺ in the cytotoxicity of H₂O₂. H₂O₂ at concentrations of 30 μM or more (up to 1000 μM) significantly increased intracellular Zn²⁺ concentration. There were two mechanisms. (1) H₂O₂ decreased cellular content of nonprotein thiols, possibly resulting in release of Zn²⁺ from thiols as cellular Zn²⁺ binding sites. (2) H₂O₂ increased membrane Zn²⁺ permeability because external ZnCl₂ application further elevated intracellular Zn²⁺ concentration. Micromolar H₂O₂ may induce excessive elevation of intracellular Zn²⁺ concentration that is harmful to cellular functions. However, the incubation with micromolar ZnCl₂ alone increased cellular content of nonprotein thiols, one of the factors protecting cells against oxidative stress. Though zinc is generally considered to be protective with its antioxidant property, this study reveals the toxic effect of zinc even in micromolar range under oxidative stress induced by H₂O₂.     

Activation of phospholipase D involved in both injury and survival in A549 alveolar epithelial cells exposed to H2O2

To determine the role of the phospholipase D (PLD) pathway in injury and survival of alveolar epithelial cells, A549 cells were exposed to H₂O₂ (500 μM) which resulted in time-dependent injury and bi-phasic increase of PLD activity at 5 min and at 3 h, respectively. n-Butanol (0.5%) inhibited PLD activation, attenuated cell injury at 5 min of H₂O₂ exposure, but enhanced injury at 3 h of exposure. This activation was inhibited by treatment with catalase (500 units/ml). Exogenous phosphatidic acid mimicked the effects of PLD activation, and diphenyliodonium (NADPH oxidase inhibitor) reversed the decline in cell viability induced by H₂O₂ exposure. Propranolol (phosphatidic acid phospholydrolase inhibitor) and quinacrine (phospholipase A2 inhibitor) had weak effects on H₂O₂-induced PLD activation but reversed H₂O₂-induced injury. We speculate that PLD activation at the initiation of H₂O₂ exposure predominantly results in NAPDH oxidase activation, which mediates A549 cell injury, but turns to mediating cell survival as the H₂O₂ attack continues, which might be mainly due to the accumulation of intracellular phosphatidic acid.     

trans-Resveratrol inhibits H2O2-induced adenocarcinoma gastric cells proliferation via inactivation of MEK1/2-ERK1/2-c-Jun signalling axis

In this report we investigate the signalling pathway activated by H₂O₂ in human adenocarcinoma gastric cells (AGS) and we evaluate the anti-proliferative action of the natural stilbene trans-resveratrol. We demonstrate that H₂O₂ accelerates cell growth and induces a prompt MEK1/2-ERK1/2 activation. Such events are also associated with the activation of c-Jun and its translocation into the nuclear compartment. A specific inhibitor of ERK1/2 phosphorylation by MEK1/2 (U0126) abrogates these phenomena. On the contrary, specific inhibition of JNK activity does not influence H₂O₂-mediated growth, suggesting that cell proliferation likely proceeds via MEK1/2-ERK1/2-Jun signalling axis. trans-Resveratrol is also able to completely suppress the increase in proliferation. We demonstrate that this property is not due to its antioxidant capacity but rather due to a specific inhibition of ERK1/2 phosphorylation by MEK1/2 and repression of c-Jun activation.     

超声心动图评价外源性硫化氢对糖尿病心肌病大鼠心功能的影响

摘 要 目的：采用超声心动图来检测外源性硫化氢（H₂S）对糖尿病大鼠心功能的影响。方法: 将SD大鼠随机分为对照组、模型组和治疗组,每组5只。一次性腹腔注射链脲佐菌素（STZ）制备糖尿病大鼠模型。治疗组腹腔注射NaHS,对照组和模型组给予等量生理盐水。12周后通过超声心动图进行检测。结果: 与模型组比较,治疗组的收缩期室间隔厚度（IVSd）、舒张期室间隔厚度（IVSs）、收缩期左室内径（LVIDs）和舒张期左室后壁厚度（LVPWd）明显降低（P<0.01）, 收缩期左室后壁厚度（LVPWs）明显降低（P<0.05）,治疗组心功能指标射血分数（EF）和缩短分数(FS)明显升高（P<0.01）。结论:通过超声心动图证明,外源性H₂S能够有效减少糖尿病心肌病大鼠心肌重构,改善糖尿病心肌病大鼠心功能。     

淫羊藿苷对H2O2诱导的软骨细胞氧化损伤的保护作用及其机制

目的 探究淫羊藿苷（icariin,ICA）对H₂O₂诱导的软骨细胞氧化损伤的保护作用及相关机制。方法 分离SD新生大鼠软骨细胞,随机分为对照组、H₂O₂模型组、ICA低剂量组、ICA中剂量组、ICA高剂量组;采用CCK8法检测各组细胞增殖能力的变化;采用ELISA试剂盒检测各组细胞中活性氧（reactive oxygen,ROS）、超氧化物歧化酶（superoxide dismutase,SOD）、丙二醛（malondialdehyde,MDA）、过氧化氢酶（catalase,CAT）以及谷胱甘肽过氧化物酶（glutathione peroxidase,GSH-Px）的表达情况;流式细胞术检测各组细胞周期情况,并计算增殖指数（proliferation index,PI）;Hoechst染色观察各组细胞核凋亡情况;分别采用荧光定量PCR （qRT-PCR）和Western blotting检测凋亡相关因子及Nrf2/HO-1通路的表达情况。结果 与对照组相比,H₂O₂模型组细胞增殖能力降低,ROS、MDA含量升高,SOD、CAT及GSH-Px含量下降,细胞凋亡情况加重;经ICA干预后,软骨细胞的增殖能力上升,ROS、MDA含量下降,SOD、CAT及GSH-Px含量增加,并且ICA能够有效抑制软骨细胞凋亡,上调Nrf2和HO-1蛋白的表达。结论 ICA对H₂O₂诱导的软骨细胞氧化损伤具有保护作用,能够抑制软骨细胞凋亡,其机制跟Nrf2/HO-1信号通路有关。     

我国《药品管理法》与美国相关法规中关于假劣药界定的比较分析及启示

目的：全面理解假劣药的界定,为完善药品管理法规提供参考。方法：将现行2001年版《药品管理法》与1984年版《药品管理法》和美国1983年《联邦食品、药品和化妆品法案》（FDCA）中关于假劣药的界定进行了分析比较,并提出相关的建议。结果与结论：现行版《药品管理法》与1984年版《药品管理法》相比,其中关于假药的界定取消了“与省、自治区、直辖市药品标准规定不符合的”情况,取消了地方标准;按假药论处的情形新增加了2条。FDCA和现行版《药品管理法》对假劣药品的规定有着本质的区别,FDCA将药品划分为违标药品和伪劣药的分类标准既明确又科学,我国对假劣药品的划分标准借鉴了FDCA的划分方法。但现行版《药品管理法》还存在将劣药的一种情形作为劣药的界定,犯了内涵过大、外延过小的错误。建议有必要增加新的款项来有效打击假劣药品,同时还应当增加包括无需检验即可判断和确定的劣药具有相同或相似危害性的所有药品的相关内容。     

Some central effects of impromidine,a potent agonist of histamine H2 receptors

Intraventricular injection of impromidine (10–40 μg) in rats produced a dose-dependent hypothermia, which was antagonized by cimetidine and metiamide. Impromidine produced hypothermia at doses 5–10 times lower than doses of other H₂ stimulants, therefore it can be regarded as a potent agonist of histamine H₂ receptors in the central nervous system. Impromidine did not change the gross behavior of animals, but reduced the exploratory activity of rats, although this action was not antagonized by cimetidine. Impromidine also reduced the level of serotonin in the hypothalamus with a concomitant increase in levels of 5-HIAA, but did not produce head twitches in tranylcypromine-treated rats.     

Histamine-induced excitation of spontaneously active medullary neurones in the rat brain is mediated by H2-receptors : A microiontophoretic study using H1 and H2-agonists and antagonists

The effects of histamine, applied by microiontophoresis onto spontaneously-active medullary neurones were investigated in the rat. Histamine caused current-dependent excitation of these neurones, an action that is at variance with previous studies in the cat. The nature of the receptor mediating these effects was examined using a number of agonists with differing potencies at peripheral H₁- and H₂-receptors. The precursor of histamine, l-histidine and the metabolite, N-telemethylhistamine did not mimic the effects of histamine while the H₂-agonist, 4-methylhistamine caused similar but weaker excitation. The extent of excitations produced by the H₁-agonists, 2-pyridylethylamine, 2-methylhistamine and 2-thiazolylethylamine could be related to their activity at H₂-receptors. Metiamide was ineffective in antagonising responses to histamine and related agonists as was mepyramine. The H₂-antagonist ranitidine, however, proved a good antagonist of responses to histamine and the H₁- and H₂-agonists, despite an unrelated excitatory action which may be linked to inhibition of cholinesterase. It is concluded that the excitatory effects of microiontophoretically-applied histamine and the agonists on medullary neurones in the rat is probably a result of activation of H₂-receptors.