组胺受体H1和H4在过敏性炎症中的作用：新型抗组胺药的研究

组胺在过敏性炎症中起关键性作用, 长期以来人们认为组胺释放引起的炎性反应是H₁受体介导的。H₁受体拮抗剂也称为抗组胺药, 用于治疗过敏性反应已很多年。但是在哮喘和慢性瘙痒症的病理状态下组胺的重要性可能被低估。已证明组胺的确在炎症和免疫调节疾病中起作用,特别是H₄受体的发现及其在多种免疫和炎性细胞中的表达,提示应重新评价组胺的作用,预示新型H₄受体拮抗剂将被发现,且H₁,H₄受体拮抗剂在许多炎性反应靶标上可能有协同作用。     

新型三环类地氯雷他定衍生物的合成、生物活性与分子对接

以三环类抗组胺药物地氯雷他定为母体,设计并合成了一系列取代的三环类衍生物。所有目标化合物均通过核磁共振氢谱和高分辨质谱表征确定。H₁受体结合活性测试结果表明：化合物7拮抗组胺H₁受体的活性显著优于先导化合物地氯雷他定。组胺诱导的豚鼠回肠收缩实验显示化合物7可显著抑制回肠收缩。构效关系研究表明：化合物的疏水参数lgP的计算值与拮抗H1受体的活性具有相关性。并进一步利用分子对接技术研究了化合物7与H₁受体的结合模式。     

血管紧张素Ⅱ受体2对心血管肾脏系统功能的影响

血管紧张素Ⅱ（AngⅡ）1型（AT₁）受体在心血管和肾脏功能方面具有重要作用,但有关AngⅡ2型（AT₂）受体的效应知之较少。近年来,采用AT₂受体缺失小鼠对该受体进行了较为深入的研究。一方面,激活AT2受体能抑制细胞增殖、促进凋亡,此效应在发育和组织重构中具有重要地位;另一方面,在心脏、动脉和肾脏,AngⅡ通过激活AT₂受体刺激NO/cGMP,可能通过对抗AT₁受体介导的效应而发挥潜在的保护作用。     

缺氧预适应小鼠脑组织中缺氧诱导因子-1的表达

为探讨缺氧诱导因子-1(HIF-1)在缺氧预适应小鼠脑组织中的表达,用Western印迹法检测慢性缺氧(H)和不缺氧(C)HeLa细胞、急性重复性缺氧0次(H₀)、1次(H₁)、4次(H₄)小鼠脑组织中的HIF-1α.结果:慢性缺氧HeLa细胞中可检测到较多的HIF-1α,H₀组脑组织中检测不到HIF-1α,H₁组检测到微量HIF-1α,H₄组检测到较多HIF-1α.结果显示:脑组织中HIF-1α 的含量随缺氧预适应的产生而逐步增加,提示HIF-1可能参与缺氧预适应的形成.     

大麻Ⅰ型受体抑制剂研究进展

临床试验表明,大麻Ⅰ型受体(CB₁)抑制剂利莫那班(rimonabant)在治疗肥胖和戒烟方面具有良好效果^［1］,CB₁受体抑制剂还具有治疗药物成瘾、认知和记忆紊乱、神经错乱等疾病的潜力。CB₁受体抑制剂与诸多疾病的相关性大大推进了新的CB₁受体抑制剂的发展。本文主要对各种CB₁受体抑制剂的结构及活性研究的最新进展进行综述。     

Erythrocytic or serum hydrogen sulfide association with hypertension development in untreated essential hypertension

Background  Endogenous hydrogen sulfide (H₂S) plays an important role in hypertension. The aim of this study was to investigate the role of erythrocyte and serum H₂S in patients with untreated essential hypertension.

Methods  We recruited 62 patients (age 22–74 years) with untreated prehypertension or hypertension, and 64 normotensive subjects (age 18–64 years). We assessed the 3-mercaptopyruvate sulphurtransferase (MPST) protein expression in erythrocytes and measured the H₂S production from erythrocytes and serum H₂S levels, then analyzed the association of erythrocytic or serum H₂S content and blood pressure or cardiovascular risk factors (e.g., age, body mass index (BMI) and dyslipidemia). A stepwise regression analysis was used to evaluate the possible relationship of erythrocytic H₂S in hypertension.

Results  In hypertensive patients, erythrocyte H₂S production ((111.04±29.20) nmol/min per 10⁸ erythrocytes) was higher than that in controls ((78.85±19.38) nmol/min per 10⁸ erythrocytes), and serum H₂S was also higher. The erythrocytic H₂S production was associated with increased systolic blood pressure (sBP), diastolic blood pressure (dBP), age, BMI, level of C-reactive protein (CRP), as well as triglycerides (TG) and high density lipoprotein cholesterol (HDL-C). Serum H₂S was not associated with age or CRP. Stepwise regression analysis showed that erythrocytic H₂S production was correlated with sBP, TG, HDL-C, low density lipoprotein cholesterol (LDL-C) and blood urea nitrogen (BUN) and serum H₂S was correlated with dBP and TG. Results of receiver-operating characteristic curve analysis suggested that erythrocytic H₂S production was a more sensitive predictor of hypertension development than serum H₂S.

Conclusion  Erythrocytic or serum H₂S production is sensitive predictor of hypertension.

     

促肾上腺皮质激素释放因子Ⅰ型受体：抗抑郁药物的新靶标

抑郁和焦虑患者常伴随应激激素调节失常,这与下丘脑神经肽促肾上腺皮质激素释放因子（CRF）和精氨酸加压素分泌过多密切相关。CRF主要通过激动促肾上腺皮质激素释放因子Ⅰ型（CRF₁）受体诱导抑郁或焦虑样症状,众多研究表明CRF₁受体是新型抗抑郁药的潜在靶标。目前已研发出很多基于此靶标的非肽类小分子化合物,但只有一部分进入临床试验,包括NBI-30775/R121919和NBI-34041等。值得注意的是,此类化合物显效与动物的应激水平和自身焦虑程度有关,即CRF1受体拮抗剂可在不影响下丘脑-垂体-肾上腺轴基础活性情况下对抗CRF介导的病理性应激反应,从而提示其副作用可能较低。总之,小分子CRF₁受体拮抗剂可能成为治疗应激相关精神疾病的新方法。本文重点综述CRF₁受体作为新靶标在抑郁症治疗中的潜在应用。     

Hydrogen sulfide and nervous system regulation

Objective  This review discusses the current status and progress in studies on the roles of hydrogen sulfide (H₂S) in regulation of neurotoxicity, neuroprotection, and neuromodulator, as well as its therapeutic potential for neurodegenerative disorders.

Data sources  The data used in this review were mainly from Medline and PubMed published in English from 2001 to August 2011. The search terms were “hydrogen sulfide”, “neuron”, and “neurodegenerative disorders”.

Study selection  Articles regarding the regulation of neuronal function, the protection against neuronal damage and neurological diseases, and their possible cellular and molecular mechanisms associated with H₂S were selected.

Results  The inhibited generation of endogenous H₂S is implicated in 1-methy-4-phenylpyridinium ion, 6-OHDA, and homocysteine-triggered neurotoxicity. H₂S elicits neuroprotection in Alzheimer’s disease and Parkinson’s disease models as well as protecting neurons against oxidative stress, ischemia, and hypoxia-induced neuronal death. H₂S offers anti-oxidant, anti-inflammatory and anti-apoptotic effects, as well as activates ATP-sensitive potassium channels and cystic fibrosis transmembrane conductance regulator Cl^- channels. H₂S regulates the long-term potentiation (LTP) and GABA_B receptors in the hippocampus, as well as intracellular calcium and pH homeostasis in neurons and glia cells.

Conclusions  These articles suggest that endogenous H₂S may regulate the toxicity of neurotoxin. H₂S not only acts as a neuroprotectant but also serves as a novel neuromodulator.

     

Hydrogen peroxide preconditioning enhances the therapeutic efficacy of Wharton’s Jelly mesenchymal stem cells after myocardial infarction

Background  Exposure of cells to sublethal concentrations of hydrogen peroxide (H₂O₂) can alleviate subsequent oxidative stress-induced apoptosis. We assessed the effects of H₂O₂ preconditioning on the therapeutic potential of human umbilical cord Wharton’s Jelly mesenchymal stem cells (WJ-MSCs) in a murine model of myocardial infarction.

Methods  WJ-MSCs were incubated in the media for 2 hours with or without 200 µmol/L H₂O₂. Mice underwent left anterior descending coronary artery ligation, and received injection of phosphate buffered saline, 1×10⁶ WJ-MSCs, or 1×10⁶ H₂O₂ preconditioned WJ-MSCs 3 hours later via tail vein. Echocardiography was performed 0, 7, 14 and 28 days after surgery, and the mice were euthanized on day 28 for histological analysis. In vitro cytokine concentrations in the WJ-MSC cell supernatant were measured by enzyme-linked immunosorbent assay (ELISA). The effect of WJ-MSC cell supernatant on the migration and proliferation of endothelial cells were observed by transwell migration and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazoliumbromide (MTT) assays.

Results  Echocardiographic measurements revealed a significant improvement in the left ventricular contractility of the WJ-MSCs-H₂O₂ group compared to the WJ-MSCs group. Histological analysis revealed increased neovascularization and reduced myocardial fibrosis in the WJ-MSCs-H₂O₂ group compared to the WJ-MSCs group. Pretreatment of WJ-MSCs with H₂O₂ increased the secretion of interleukin-6 (IL-6) into the cell culture supernatant by approximately 25-fold. The culture supernatant from WJ-MSCs-H₂O₂ significantly increased the migration and proliferation of endothelial cells; these effects could be blocked using an anti-IL-6 antibody.

Conclusions  This study demonstrates that H₂O₂ preconditioning significantly enhanced the therapeutic potential of WJ-MSCs, possibly by stimulating the production of IL-6 by WJ-MSCs, which may cause migration and proliferation of endothelial cells and increase neovascularization.

     

2-芳基咪唑并［1，2-a］吡啶-3-乙酰胺衍生物的合成与抗焦虑活性研究

目的 寻找水溶性较好、抗焦虑活性较强的新型化合物。方法 设计合成2-芳基咪唑并［1,2-a］吡啶-3-乙酰胺类化合物,通过体外苯二氮卓受体竞争结合实验及小鼠高架迷宫行为实验,评价化合物的体内外抗焦虑活性,分析化合物的构效关系。结果与结论 共合成28个新型化合物,通过¹H-NMR和 MS确证其结构,其中I8和I10水溶性良好。苯二氮受体竞争结合实验结果表明,化合物Ⅰ₁、Ⅰ₈、Ⅰ₁₀ 、Ⅰ₁₃ 、Ⅰ₁₉ 与苯二氮卓受体的亲和力与阳性对照药物Ro5-4864相当,在浓度为100 nmol/L时,其对放射性配体与受体结合的抑制率分别为87%、89%、85%、89%和76%,而Ro5-4864为82%。对水溶性及活性均较好的化合物Ⅰ₈和Ⅰ₁₀ 进行小鼠抗焦虑活性评价结果表明,其具有明显的体内抗焦虑作用。     

内皮素受体拮抗剂治疗肺动脉高压的临床应用进展

内皮素(ET)-1是强有力的内源性血管收缩剂,在肺动脉高压的发病机制中发挥重要作用。ET受体分为两种类型：ET_A和ET_B。本文综述近年来非选择性ET受体拮抗剂和选择性ET_A受体拮抗剂治疗肺动脉高压的临床应用进展。证明ET受体拮抗剂可以改善肺动脉高压患者的运动耐量,降低肺血管阻力,增加心输出量,改善心功能。其主要副作用是血清转氨酶增高。     

Hydrogen sulfide and vascular relaxation

Objective  To review the vasorelaxant effects of hydrogen sulfide (H₂S) in arterial rings in the cardiovascular system under both physiological and pathophysiological conditions and the possible mechanisms involved.

Data sources  The data in this review were obtained from Medline and Pubmed sources from 1997 to 2011 using the search terms “hydrogen sulfide” and “vascular relaxation”.

Study selection  Articles describing the role of hydrogen sulfide in the regulation of vascular activity and its vasorelaxant effects were selected.

Results  H₂S plays an important role in the regulation of cardiovascular tone. The vasomodulatory effects of H₂S depend on factors including concentration, species and tissue type. The H₂S donor, sodium hydrosulfide (NaHS), causes vasorelaxation of rat isolated aortic rings in a dose-dependent manner. This effect was more pronounced than that observed in pulmonary arterial rings. The expression of K_ATP channel proteins and mRNA in the aortic rings was increased compared with pulmonary artery rings. H₂S is involved in the pathogenesis of a variety of cardiovascular diseases. Downregulation of the endogenous H₂S pathway is an important factor in the pathogenesis of cardiovascular diseases. The vasorelaxant effects of H₂S have been shown to be mediated by activation of K_ATP channels in vascular smooth muscle cells and via the induction of acidification due to activation of the Cl^-/HCO₃^- exchanger. It is speculated that the mechanisms underlying the vasoconstrictive function of H₂S in the aortic rings involves decreased NO production and inhibition of cAMP accumulation.

Conclusion  H₂S is an important endogenous gasotransmitter in the cardiovascular system and acts as a modulator of vascular tone in the homeostatic regulation of blood pressure.

     

Changes in plasma hydrogen sulfide and nitric oxide levels and their clinical significance in children with Kawasaki disease

Background  Cardiac involvement is the most common complication of Kawasaki disease (KD); however, the underlying mechanisms are not understood. The present study was designed to investigate changes in plasma hydrogen sulfide (H₂S) and nitric oxide (NO) levels in the acute and recovery stages of KD children and to examine their clinical significance.

Methods  Thirty-five KD patients and 32 healthy children were enrolled in the study. KD patients were divided into two subgroups: a non-cardiac involvement group and a cardiac involvement group. Plasma H₂S levels were measured using the sulfur-sensitive electrode method and plasma NO levels and NO synthase activity were determined using the nitrate reductase method both before and after intravenous immune globulin (IVIG) therapy.

Results  Plasma H₂S levels significantly decreased in KD patients during the acute phase of the disease and NO levels were significantly increased, compared with the control group (P <0.01). After treatment with IVIG, both plasma H₂S and NO levels significantly increased (P <0.01). The plasma levels of H₂S were significantly lower in the cardiac involvement group compared with the non-cardiac involvement group (P <0.05).

Conclusion  H₂S and NO may play a role in the pathophysiological process of inflammation during the acute phase of KD. Endogenous H₂S may exert protective effects with respect to cardiac complications in KD.

     

抗组胺药研究进展

组胺是引起炎症和过敏性疾病的一类物质,是速发型过敏反应（临床最常见Ⅰ型变态反应疾病）的重要的化学介质之一。因而,在过去的70多年中,抗组胺药物出现了第一代、第二代,以及第二代的改良品种,在临床上被广泛应用。尤其是在非处方药方面,该类药常与其他药物,如解热镇痛剂、去鼻塞剂等组成复方制剂用于感冒发热等,深受医生和患者的欢迎。现对抗组胺药物（以组胺H₁受体拮抗剂为主）的研发进展做一介绍。     

治疗失眠症的一种GABAA受体激动剂indiplon

失眠症有很高的发病率，能使人生活质量下降并可能发生事故。传统用于治疗的苯二氮卓类药物易引起不良反应，因而仍在不断研发新型药物。目前，一种有应用前景的人工合成新药indiplon(NBI-34060)为GABA_A受体的部分激动剂，能与此受体的α1亚单位发生特异性结合。通过药理学实验及药代动力学研究，显示它的ED₅₀值较小、吸收快、作用时间长、生物半衰期短、易被耐受且无明显不良反应。已进行Ⅲ期临床试验，考察了不同释出速度的剂型。     

Kentanserin对大鼠心肌缺血-再灌注损伤的影响

为探讨5-HT₂受体与心肌缺血 再灌注损伤的关系,观察5-HT₂受体阻断剂kentanserin对心肌缺血 再灌注大鼠室颤及左室内压+dp/dt_max及-dp/dt_max的影响。结果表明,kentanserin可拮抗缺血性心功能障碍和再灌室颤。提示5-HT₂受体参与了缺血性心功能障碍和再灌室性心律失常的发生。     

毛兰素注射液在大鼠体内药动学研究

目的 阐明毛兰素注射液在SD大鼠体内药动学规律。方法 SD大鼠分别单次和隔天、每隔一个半衰期一次多剂量静脉注射毛兰素注射液。采用高效液相色谱-质谱联用(HPLC-MS)测定大鼠静脉注射后不同时间大鼠血浆中毛兰素的血药浓度。结果 大鼠单次静脉注射25,50,100 mg·kg^-1毛兰素注射液的主要药动学参数为：T_1/2β分别为3.66,3.75,3.89 h; AUC_0-12分别为1 453.0,3 041.6,6 731.6 ng·mL^-1·h;AUC_0-∞分别为1 462.0,3 077.3,6 788.7 ng·mL^-1·h;Vd分别为11.67,10.37,3.38 L·kg^-1;CL分别为0.049,0.089,0.024 L·kg^-1·h^-1;MRT分别为0.18,0.28,0.21 h;50 mg·kg^-1剂量的毛兰素注射液隔日给药5次其药动学参数与单次给药相近;而50 mg·kg^-1剂量的毛兰素注射液每隔一个半衰期一次给药5次的T_1/2β为5.43 h,AUC_(S0)(0-t)为9 800.8 ng·mL^-1·h。结论 毛兰素注射液在大鼠体内的动力学过程与剂量相关,毛兰素注射液单剂量给药的体内药动学符合开放型二房室模型,T_1/2β与给药剂量与关,表明毛兰素在大鼠体内的消除过程符合一级动力学规律。隔日多剂量给药的消除过程亦符合一级动力学规律;而每隔一个半衰期一次多剂量给予50 mg·kg^-1剂量的毛兰素其在大鼠体内则呈非线性消除。     

Electrophysiological effects of hydrogen sulfide on human atrial fibers

Background  It has been reported that endogenous or exogenous hydrogen sulfide (H₂S) exerts physiological effects in the vertebrate cardiovascular system. We have also demonstrated that H₂S acts as an important regulator of electrophysiological properties in guinea pig papillary muscles and on pacemaker cells in sinoatrial nodes of rabbits. This study was to observe the electrophysiological effects of H₂S on human atrial fibers.

Methods  Human atrial samples were collected during cardiac surgery. Parameters of action potential in human atrial specialized fibers were recorded using a standard intracellular microelectrode technique.

Results  NaHS (H₂S donor) (50, 100 and 200 μmol/L) decreased the amplitude of action potential (APA), maximal rate of depolarization (V_max), velocity of diastolic (phase 4) depolarization (VDD) and rate of pacemaker firing (RPF), and shortened the duration of 90% repolarization (APD₉₀) in a concentration-dependent manner. ATP-sensitive K⁺ (K_ATP) channel blocker glibenclamide (Gli, 20 μmol/L) partially blocked the effects of NaHS (100 μmol/L) on human atrial fiber cells. The L-type Ca²⁺ channel agonist Bay K8644 (0.5 μmol/L) also partially blocked the effects of NaHS (100 μmol/L). An inhibitor of cystathionine γ-lyase (CSE), DL-propargylglycine (PPG, 200 μmol/L), increased APA, V_max, VDD and RPF, and prolonged APD₉₀.

Conclusions  H₂S exerts a negative chronotropic action and accelerates the repolarization of human atrial specialized fibers, possibly as a result of increases in potassium efflux through the opening of K_ATP channels and a concomitant decrease in calcium influx. Endogenous H₂S may be generated by CSE and act as an important regulator of electrophysiological properties in human atrial fibers.

     

Beneficial effects of metformin on primary cardiomyocytes via activation of adenosine monophosphate-activated protein kinase

Background  Metformin has become a cornerstone in the treatment of patients with type-2 diabetes. Accumulated evidence suggests that metformin supports direct cardiovascular effects. The present study aimed to investigate if metformin has beneficial effects on primary cardiomyocytes damaged by H₂O₂, and reveal the potential mechanism of action of metformin.

Methods  Cardiomyocytes were incubated in the presence of 100 µmol/L H₂O₂ for 12 hours. Cardiomyocytes were pretreated with metformin at different concentrations and time and with aminoimidazole carboxamide ribonucleotide (AICAR) (500 µmol/L), an adenosine monophophate (AMP)-activated protein kinase (AMPK) agonist for 60 minutes before the addition of H₂O₂. Other cells were preincubated with compound C (an AMPK antagonist, 20 μmol/L) for 4 hours. The viability and apoptosis of cells were analyzed. AMPK, endothelial nitric oxide synthase (eNOS), and transforming growth factor (TGF)-β1 were analyzed using immunblotting.

Results  Metformin had antagonistic effects on the influences of H₂O₂ on cell viability and attenuated oxidative stress-induced apoptosis. Metformin also increased phosphorylation of AMPK and eNOS, and reduced the expression of TGF-β1, basic fibroblast growth factor (bFGF), and tumor necrosis factor (TNF)-α.

Conclusions  Metformin has beneficial effects on cardiomyocytes, and this effect involves activation of the AMPK-eNOS pathway. Metformin may be potentially beneficial for the treatment of heart disease.