钾离子通道在抑郁症中的作用

抑郁症是一种常见的心理性疾病,随着社会压力的日益加大,发病率逐渐升高。以往研究证实,抑郁症主要与脑内神经递质(5-羟色胺,去甲肾上腺素等)系统紊乱有关,目前又发现脑内电压依赖性钾离子通道以及双孔钾离子通道也与该疾病有着紧密关系。该文综述了钾离子通道与抑郁症的相关研究进展,为新型抗抑郁药物的研发提出了新的思路。     

滤泡调节性T细胞及其在自身免疫病中的研究进展

 滤泡调节性T细胞（follicular regulatory T cell, Tfr）是一类新发现的调节性T细胞亚群,其特点是表面表型与滤泡辅助性T细胞（T follicular helper cell,Tfh）和效应调节性T细胞（regulatory T cell, Treg）细胞均有重叠,因此,Tfr在功能上具有Tfh和Treg的双重特性。近年来,Tfr在原发性免疫性血小板减少、重症肌无力、强直性脊柱炎和多发性硬化等自身免疫病中的研究得到了广泛关注,此文对Tfr及其在自身免疫病中的研究进展做一概述。     

调节性 T细胞在脓毒症中的作用研究进展

脓毒症是急诊及各大重症监护室( ICU)的常见疾病,免疫功能紊乱作为其发病机制是目前研究的热点,其中关于 T淋巴细胞的相关研究居多。病原体一旦入侵机体时,机体会同时启动固有免疫和适应性免疫系统,其中 CD4+T淋巴细胞在适应性免疫系统中起核心作用。 CD4+T淋巴细胞亚群中的调节性 T细胞( Treg细胞)作为一种负性免疫分子,在脓毒症中扮演着重要角色。该研究就 Treg细胞的来源、机制及在脓毒症中的作用展开综述,为临床上脓毒症的诊治及预后提供参考依据。     

调节性T淋巴细胞的研究进展

调节性T淋巴细胞是机体免疫系统的重要组成部分,在防止自身免疫,保持机体的自身耐受性中发挥着决定性作用,但同时也具有减弱机体对肿瘤和感染免疫反应的作用。转录因子FoxP3（forkhead box p3）是forkhead家族成员,是近年来发现的一种影响调节性T细胞发育和生物功能发挥的关键转录因子,是调节性T淋巴细胞表面特异性标志。FoxP3＋调节性T淋巴细胞是机体保持内环境稳定的关键环节,在维持机体免疫耐受状态、防止自身免疫病发生、抗移植物排斥以及肿瘤免疫中发挥重要作用。本文就近年来调节性T淋巴细胞的研究进展综述如下。     

前列腺癌患者调节性T细胞的表达及意义

目的探讨CD4^＋CD25^high调节性T细胞在前列腺癌患者外周血及肿瘤组织中的存在及其意义。方法检测45例前列腺癌患者外周血及肿瘤组织中CD4^＋CD25^high调节性T细胞的表达，并进一步检测CD4^＋CD25high调节性T细胞胞内FoxP3的表达。同时检测肿瘤来源的CD4^＋CD25^high调节性T细胞在体外的抑制功能。结果前列腺癌患者外周血及肿瘤组织中存在大量CD4^＋CD25^high调节性T细胞，正常供者外周血中CD4^＋CD25^T细胞的比例仅为（0．5±0．1）％，患者外周血为（2．3±0．7）％，两者比较，P〈0．01；患者良性组织CD4^＋CD25^highT细胞的比例也显著低于恶性肿瘤组织[分别为（6．9±0．8）％和（11．3±1．3）％，P〈0．05].结论CD4^＋CD25^high调节性T细胞可能有助于肿瘤的生长，提示抑制或清除CD4^＋CD25^high调节性T细胞可能为前列腺癌的治疗提供新的途径。     

白芍总甙对T细胞调节功能的影响

本文用超适量免疫及~(60)Co照射加输注受训胸腺细胞等方法,诱导抗原特异性T_s和T_h细胞,并经过继性转移系统测定其功能及自芍总甙的作用,结果表明,白芍总甙(5 mg·kg~(-1)·d~(-1)×8 d,ip)对超适量2,4-二硝基氯苯(3 mg)或羊红细胞(SRBC,4×10~9)诱导的环磷酰胺敏感的T_s细胞均有促进作用,前者表现为受体鼠的耳肿度(Δwt7.4±s2.8mg)与ConA诱导的脾淋巴细胞增殖反应(3.4±s0.9)×10~(-3)cpm明显分别低于溶媒对照组的耳肿度(Δwt13.6±s3.2mg)和淋巴细胞转化(10.9±s2.8)×10~(-3)cpm,后者表现为溶血素抗体生成(A 0.26±s0.05)明显低于溶媒对照组,白芍总甙(5mg·kg~(-1)·d~(-)×10 d,ip)对小鼠辐照后低剂量SRBC(2×10~8)诱导的T_h细胞亦有增强作用,使受体鼠的溶血素抗体生成(A 0.74±s 0.10)明显高于溶媒对照组(A 0.57±s 0.06),提示白芍总甙对不同条件下分别诱导的T_s和T_h细胞均有促进作用,这可能是其发挥免疫调节作用的机理之一。     

肝硬化患者外周血B细胞和T细胞及其亚群的研究

目的　探讨了肝硬化患者外周血 B细胞和 T淋巴细胞及其亚群的变化。方法　应用单克隆技术测定了 33例肝硬化患者外周血 B细胞和 T淋巴细胞亚群的水平并以 30名正常健康人作比较。结果　肝硬化患者外周血B细胞数显著地高于正常人组 (P<0 .0 0 1 ) ,CD3、CD4 、CD4 / CD8显著地低于正常人 (P<0 .0 1 )。结论　肝硬化患者是一种自身免疫调节异常的疾病     

小儿心脏手术前后TB淋巴细胞及T细胞亚群的动态变化及麻醉的影响

小儿心脏手术前后ＴＢ淋巴细胞及Ｔ细胞亚群的动态变化及麻醉的影响山西省儿童医院（０３００１３）程燕生，张鸿毅，吕改华山西医学院第一附属医院刘德平麻醉、手术、体外循环对ＴＢ淋巴细胞的影响已有人进行了观察［１］，但仅限于成人的资料．我们观察了４０例小儿心脏...     

钾离子通道作为肿瘤治疗靶点的研究

钾离子通道是细胞膜上重要的离子通道,在肿瘤细胞中有不同的表达,有些钾离子通道参与肿瘤细胞的增殖和分化,对肿瘤细胞的凋亡也起作用,通过了解钾离子通道在肿瘤细胞中的表达和可能的应用,为肿瘤治疗提供新的靶点。     

T细胞恶性肿瘤的嵌合抗原受体T细胞治疗研究进展

T细胞恶性肿瘤具有高度恶性、预后差等特点,对于复发 / 难治性患者当前最有效的治疗手段是造血干细胞移植,但往往伴随着诸多移植相关风险,故探索更多安全、有效的疗法迫在眉睫。嵌合抗原受体T细胞治疗(chimeric antigen receptor T cell therapy,CAR-T cell therapy)作为一种近年来较新颖的免疫疗法,在复发/难治性B细胞恶性肿瘤及多发性骨髓瘤中已展现出了巨大临床受益。然而对于T细胞恶性肿瘤,CAR-T 细胞治疗仍处于临床前和早期临床阶段,并面临着重重困难。现阐述目前T细胞恶性肿瘤的CAR-T细胞治疗的研究进展,旨在为临床治疗相关疾病提供一定参考。     

血管平滑肌ATP敏感性钾通道研究进展

ATP敏感性钾通道 (KATP)广泛存在于各类细胞和组织中 ,是药物作用的重要靶点。KATP是由内向整流钾通道Kir和磺酰脲类受体SUR亚基组成。与血管舒缩特性密切相关的是SUR2B/Kir6 1,电导值小 ,对ATP的抑制作用不敏感 ,需要有NDP才能被开放 ,故这类血管平滑肌KATP又被称为NDP依赖性钾通道。内源性和外源性的很多因子引起的血管舒缩反应与血管平滑肌上的KATP有关 ,此信号途径与PKA、PKC等磷酸化激酶有密切联系。不同血管对钾通道开放剂(potassiumchannelopeners,KCO)的反应有差异 ,KCO对血管的选择性作用机制仍不明确。本文就血管平滑肌KATP的分子结构、电生理、药理学特征、信号转导途径和KCO对血管的选择性作用进行综述     

Oxidative stress and potassium channel function

1. Modulation of K+ channel activities by cellular oxidative stress has emerged as a significant determinant of vasomotor function in multiple disease states. 2. Evidence from in vitro and in vivo studies suggest that superoxide (O2-) and hydrogen peroxide (H2O2) enhance BKCa channel activity in rat and cat cerebral arterioles; however, activity is decreased by peroxynitrite (ONOO-) in rat cerebral arteries. The mechanisms of changes in BKCa channel properties are not fully understood and may involve oxidation of cysteine residues that are located in the cell membranes. 3. Studies further suggest that O2- increases KATP channel activity in guinea-pig cardiac myocytes, but decreases opening in cerebral vasculature. Both H2O2 and ONOO- enhance KATP channel activity in the myocardium and in coronary, renal, mesenteric and cerebral vascular beds. Alteration of KATP channels by free radicals may be due to oxidation of SH groups or changes in the cytosolic concentration of ATP. 4. It does appear that O2- produced by either reaction of xanthine and xanthine oxidase or elevated levels of glucose reduces Kv channel activity and the impairments can be partially restored by free radical scavengers, superoxide dismutase and catalase. 5. Thus, redox modulation of potassium channel activity is an important mechanism regulating cell vascular smooth muscle membrane potential.     

The role of potassium channels in antihistamine analgesia

The effect of the administration of pertussis toxin as well as modulators of different subtypes of K⁺ channels on the antinociception induced by the H₁-antihistamines pyrilamine, diphenhydramine and promethazine was evaluated in the mouse hot plate test. Pretreatment with pertussis toxin (0.25 μg/mouse i.c.v.) prevented pyrilamine, diphenhydramine and promethazine antinociception. The K_ATP channel openers minoxidil and pinacidil potentiated the antinociception produced by the H₁-antihistamines whereas the K_ATP channel blocker gliquidone prevented the anti H₁-induced analgesia. The Ca²⁺-gated K⁺ channel blocker apamin antagonized pyrilamine, diphenhydramine and promethazine analgesia. Pretreatment with an antisense oligonucleotide (aODN) to mKv1.1, a voltage-gated K⁺ channel, at the dose of 3.0 nmol/single i.c.v. injection, never modified the antinociception induced by the H₁-antihistamines in comparison with degenerate oligonucleotide (dODN)-treated mice. At the highest effective doses, none of the drugs used modified animals’ gross behaviour nor impaired motor coordination, as revealed by the rota rod test. The present data demonstrate that both K_ATP and Ca²⁺-gated K⁺ channels, contrary to voltage-gated K⁺ channel Kv1.1, represent an important step in the transduction mechanism underlying central antinociception induced by H₁-antihistamines.     

Peripheral channelopathies as targets for potassium channel openers

Potassium channel openers (KCOs) are important tools that are often used to gain a greater understanding of K⁺ channels. Agents that can induce or maintain the opening of K⁺ channels also offer a therapeutic approach to controlling of cell excitability and offer a means of producing stability in biological systems. The pathogenesis of a broad range of peripheral disorders (e.g., LQT syndrome, hypokalemic periodic paralysis, hyperinsulinism in infancy and erectile dysfunction) are associated with dysfunctional K⁺ channels due to mutations in genes encoding channel proteins. The therapeutic potential of KCOs in peripheral K⁺ channelopathies is discussed. The identification of K⁺ channel subtype-specific openers offers discrete modulation of cellular systems creating a realistic therapeutic advance in the treatment of K⁺ channelopathies.     

Action of a novel potassium channel opener,SR 47063, on human bronchi and on guinea-pig trachea in vitro: comparison with cromakalim

Potassium channels are present on airway smooth muscle cells and their activation results in hyperpolarization and relaxation. Because these effects may have therapeutic relevance to asthma, the aim of our study was to examine the activity of SR 47063, a potassium channel opener (KCO), against a variety of spasmogens or against electrical field stimulation in guinea-pig isolated trachea and in human isolated bronchi in vitro; the effects of SR 47063 were compared with those of cromakalim, isoprenaline, and theophylline. Like cromakalim, SR 47063 reduced the contractility of guinea-pig isolated trachea and the human isolated bronchus in basal tone with pD₂ of 7.79 ± 0.01 and 7.83 ± 0.09, respectively, or during precontractions induced by acetylcholine 10^?4 M, histamine 10^?5 M, or low concentrations of KCl (<30 mM), but not by high KCl concentrations (≥30 mM); these effects were antagonized by glibenclamide 10^?5 M. This spectrum of action is typical of the compounds known as potassium channel openers. Electrical field stimulation (EFS: 16 Hz, 1 ms, 320 mA for 10 sec in the presence of indomethacin 10^?6 M and propranolol 10^?6 M) of guinea-pig isolated main bronchi induced 2 successive contractile responses. Both contractions were reduced significantly by SR 47063 and cromakalim. Although we have not studied the effects of KCOs on exogenous neurokinin A- or substance P-induced contractions, it might be suggested as a hypothesis that this inhibition seems to take place presynaptically and to affect the release of neuromediators produced by electrical field stimulation. In conclusion, SR 47063 exerts in vitro on the bronchial smooth muscle an inhibitory effect which seems to be due to the opening of glibenclamide-sensitive potassium channels. SR 47063 is 3- to 10-fold more potent than cromakalim. © 1993 Wiley-Liss, Inc.     

作用于钾离子通道的抗心律失常药物的研发实例

鉴于心律失常病因的复杂性, 如何通过药物安全有效地控制心律失常疾病一直是亟待攻克的医药学难题。本文介绍了作用于钾离子通道的抗心律失常药物的研发实例, 并对抗心律失常药物的研究现状进行了综述和展望。     

Calcium-activated potassium currents in mammalian neurons

1. Influx of calcium via voltage-dependent calcium channels during the action potential leads to increases in cytosolic calcium that can initiate a number of physiological processes. One of these is the activation of potassium currents on the plasmalemma. These calcium-activated potassium currents contribute to action potential repolarization and are largely responsible for the phenomenon of spike frequency adaptation. This refers to the progressive slowing of the frequency of discharge of action potentials during sustained injection of depolarizing current. In some cell types, this adaptation is so marked that despite the presence of depolarizing current, only a single spike (or a few spikes) is initiated. Following cessation of current injection, slow deactivation of calcium-activated potassium currents is also responsible for the prolonged hyperpolarization that often follows. 2. A number of macroscopic calcium-activated potassium currents that can be separated on the basis of kinetic and pharmacological criteria have been described in mammalian neurons. At the single channel level, several types of calcium-activated potassium channels also have been characterized. While for some macroscopic currents the underlying single channels have been unambiguously defined, for other currents the identity of the underlying channels is not clear. 3. In the present review we describe the properties of the known types of calcium-activated potassium currents in mammalian neurons and indicate the relationship between macroscopic currents and particular single channels.     

钾通道阻滞剂及毒毛花甙G对依血管内皮舒张作用的影响

四乙铵(TEA),Ba~(2+),格列本脲(可阻滞ATP敏感K~+通道)及毒毛花甙G均显著抑制Ach诱发的兔主动脉环依内皮舒血管效应.cromakalim的舒血管作用是不依赖内皮的,且为上述药物所抑制,本实验结果提示离体兔主动脉环上ACh诱发的依内皮舒张中,可能有ATP敏感的K~+通道及Na~-—K~+泵参与.     

The effect of K channel openers on submucosal gland function and epithelial transport of the ferret trachea, in vitro

The effects of three K⁺ channel openers on lysozyme output from submucosal gland serous cells and epithelial albumin transport following maintained submaximal stimulation by the secretagogues methacholine and phenylephrine were examined in the ferret trachea in vitro preparation. The K⁺ channel openers Ro 31-6930, 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-pyridine 1-oxide (10 nM-10 μM), levcromakalim, BRL38227 (10 nM-10 μM) and pinacidil (100 nM-10 μM) produced a concentration dependent inhibition of (20 μM) methacholine-induced lysozyme output, with pD₂ values of 7.64, 7.72 and 7.28 respectively. Ro 31-6930 (10 nM-10 μM), levcromakalim (10 nM-10 μM) and pinacidil (1 nM-10 μM) also produced a concentration dependent inhibition of (100 μM) phenylephrine-induced lysozyme output, with pD₂ values of 7.64, 6.55 and 9.16 respectively. Furthermore, glibenclamide (1 μM) produced a modest attenuation of the K⁺ channel opener effects on secretagogue-induced lysozyme output. All three K⁺ channel openers failed to produce any significant change in either methacholine or phenylephrine-induced albumin outputs. The K⁺ channel openers exerted marked effects on airway secretion processes, suggesting that these compounds may have an antisecretory effect. The relevance of the use of the K⁺ channel openers in airway disease remains to be determined.     

小胶质细胞钾通道的表达与功能

小胶质细胞作为中枢神经系统的免疫细胞在阿尔采末病的慢性炎症过程中起关键作用。在小胶质细胞中有多种钾通道亚型的表达 ,钾通道可能是小胶质细胞对微环境变化作出反应的重要途径 ,钾通道的变化是小胶质细胞是否处于激活状态的重要标志 ,钾通道可能在如维持膜电位、细胞增生、分化等小胶质细胞的生理及病理过程中起关键作用