姜黄素防治心力衰竭的药理作用研究进展

心力衰竭是高血压、缺血性心脏病、瓣膜性心脏病、冠心病等各种心血管事件常见的终末期临床表现,病理特征以进行性心功能不全和心肌重塑为主。姜黄素可通过抗心肌肥大和纤维化,增强细胞自噬,降低氧化应激反应,减轻心肌炎性损伤,调节Ca²⁺-ATP酶活性,上调Dickkopf相关蛋白3的表达,多途径防治心力衰竭,进一步阻止心肌重塑,改善心功能。总结了姜黄素防治心力衰竭的研究情况,分析其作用机制,为姜黄素的临床运用提供支持。     

丹参素治疗心肌梗死的药理作用研究进展

心肌梗死已成为威胁人类生命健康的主要心血管疾病之一。及时挽救濒死心肌组织、减轻心肌细胞再缺血灌注损伤对改善心肌梗死患者预后具有重要临床意义。丹参素是丹参中提取的水溶性酚性芳香酸类化合物,可通过抑制心肌纤维化、降低心肌细胞凋亡、改善心肌细胞代谢、降低炎症反应、减轻氧化应激反应、改善血液流变学、促进新血管形成以治疗心肌梗死。综述了丹参素治疗心肌梗死的药理作用研究进展,归纳其作用机制,为丹参素治疗心肌梗死的临床应用提供参考。     

红景天苷防治帕金森病的药理作用研究进展

帕金森病已成为威胁老年人身心健康的主要疾病之一。红景天苷是从红景天中提取的主要活性化合物之一,具有多种药理作用。红景天苷可通过抑制细胞凋亡、增强细胞自噬、降低氧化应激反应、降低炎症反应、促进胶质细胞源性神经营养因子的表达、提高多巴胺转运蛋白的表达以达到防治帕金森病的作用。总结了红景天苷防治帕金森病的药理作用及其作用机制,为红景天苷的临床使用提供参考。     

黄芩素防治感染性肺炎的作用机制研究进展

感染性肺炎已成为重大的全球健康问题,抗感染是临床治疗感染性肺炎最主要的治疗方式。黄芩素是黄芩中的黄酮类成分,具有多种活性,可减轻病原微生物感染介导的炎症反应,抑制多种炎症因子的分泌,直接抗病毒和协同抗病毒作用,抗细胞凋亡,促进肺上皮细胞修复减轻肺部病理损伤。总结了黄芩素防治感染性肺炎的作用机制,为指导黄芩素的临床使用提供参考。     

黄芩苷防治结肠炎作用机制的研究进展

结肠炎是多种因素引起的结肠炎症性病变,发病率逐年上升,病程冗长,有并发结肠癌风险。黄芩苷是黄芩中重要的黄酮类化合物之一,可通过降低炎症反应、抗氧化应激反应、调节细胞凋亡、调节肠道菌群、调节细胞自噬等多种途径发挥抗结肠炎作用。归纳了黄芩苷防治结肠炎的作用机制研究进展,为黄芩苷的临床应用提供参考。     

视网膜静脉阻塞病人血清胶质纤维酸性蛋白和水通道蛋白 4水平变化及其与预后的关系

目的检测视网膜静脉阻塞( RVO)病人血清中胶质纤维酸性蛋白( GFAP)、水通道蛋白 4(AQP4)水平,探究二者表达水平与 RVO病人预后的关系。方法回顾性选取 2019年 8月至 2021年 8月西安医学院第二附属医院收治的 94例 RVO病人为研究组,另取同期体检健康者 85例为对照组。收集病人一般临床资料,对研究组和对照组的血清 GFAP、AQP4水平进行检测;根据研究组病人预后情况将其分为预后良好组( 39例)和预后不良组( 55例);多因素 logistic回归分析 RVO病人预后的影响因素;绘制血清 GFAP、AQP4对 RVO病人预后评估的受试者操作特征曲线( ROC曲线)。结果研究组血清 GFAP水平( 3.56±0.74)μg/L显著高于对照组( 1.85±0.41)μg/L,研究组血清 AQP4水平( 15.97±2.82)μg/L显著高于对照组( 10.56±2.54)μg/L(P<0.05)。预后不良组血清 GFAP水平(3.91±0.84)μg/L显著高于预后良好组( 3.06±0.62)μg/L;预后不良组血清 AQP4水平(17.25±3.29)μg/L显著高于预后良好组( 14.18±2.18)μg/L(P<0.05)。预后良好组与预后不良组病人高血压史、空腹血糖、总胆固醇(TC)、三酰甘油( TG)、高密度脂蛋白胆固醇( HDL-C)和低密度脂蛋白胆固醇( LDL-C)差异有统计学意义( P<0.05)。 logistic回归分析显示,血清 GFAP、AQP4、高血压史、空腹血糖、 TC、TG、LDL-C和 HDL-C均是 RVO病人预后不良的影响因素( P<0.05)。血清中 GFAP、AQP4、二者联合预测 RVO病人预后的 AUC分别是 0.73、0.79、0.92,灵敏度分别为 47.27%、78.85%、77.08%,特异度分别为 89.74%、72.97%、97.14%,约登指数分别为 0.370、0.518、0.742;二者联合优于 GFAP、AQP4各自单独预测(均 P<0.05)。结论 RVO病人血清 GFAP、AQP4水平显著升高,对病人的预后状况具有较高的预测效能,可为临床的合理干预和改善病人预后提供依据。     

白藜芦醇防治脑梗死的作用机制研究进展

脑梗死是人类第三大死因和第一大致残原因,如何提高防治脑梗死的疗效成为社会广泛关注的焦点。白藜芦醇属于二苯乙烯类多酚,具有广泛的生物活性,可通过抑制炎症反应、抗氧化应激反应、增强细胞自噬和能量代谢、促进突触生长、降低脑缺血区神经细胞凋亡、保护血脑屏障的功能和结构等途径发挥防治脑梗死的作用。对白藜芦醇防治脑梗死的作用机制进行综述,为白藜芦醇临床治疗脑梗死提供新思路。     

哇巴因和华蟾毒配基通过调节ERK信号通路诱导人肝癌HepG2细胞凋亡的研究

目的:通过检测钠钾泵(Na+/K+-ATPase)抑制剂哇巴因和华蟾毒配基对肿瘤细胞存活的影响,研究其通过调节ERK信号通路诱导肿瘤细胞凋亡的机制。方法:以人肝癌细胞HepG2为靶细胞,检测Na+/K+-ATPase的活性变化,Hochest33342荧光染色检测细胞形态学变化;单细胞电泳检测细胞DNA损伤程度,钙离子荧光探针检测Ca2+浓度变化;Westernblot检测Caspase-3、ERK的表达变化。结果:哇巴因和华蟾毒配基可抑制Na+/K+-ATPase的活性;可使HepG2细胞呈典型的凋亡形态特征;单细胞电泳显示其可损伤HepG2细胞DNA双链;Fluo-3AM检测显示哇巴因和华蟾毒配基促进了Ca2+浓度增高;Western blot显示其可促进Caspase-3的活化,上调ERK磷酸化水平。结论:Na+/K+-ATPase抑制剂可诱导肝癌HepG2细胞凋亡,导致细胞DNA损伤,诱导细胞内游离Ca2+浓度增高,促进细胞凋亡途径中主要蛋白Caspase-3的活化。而ERK信号通路在哇巴因和华蟾毒配基诱导的HepG2细胞凋亡过程中发挥着关键调控作用。     

钠盐及其调控因素对骨骼影响的研究进展

高盐的摄入可以引发高血压已有很多研究,随着研究的深入,越来越多的证据表明高盐的摄入还引起骨量丢失,导致骨质疏松和骨折。Na+在生理和病理过程中起着很重要的作用,细胞凋亡、肿瘤生长以及离子转运都与细胞内外的Na+有关,而且Na+与骨骼的关系目前越来越受到关注。该文综述了钠盐及其调控因素:Na+,K+-ATP酶、钠氯共同转运体(NCC)、上皮钠离子通道(ENaC)、肾素-血管紧张素-醛固酮系统(RAAS)对骨骼的影响。     

Acute and chronic effects of lithium in therapeutically relevant concentrations on potassium uptake into astrocytes

Potassium uptake into astrocytes in primary cultures was measured by the aid of ⁴²K. Acute application of lithium in concentrations of 1 and 5 mM, but not 0.5 und 0.25 mM, exerted a significant inhibition of the potassium uptake rates. This effect is due to a partial impairment of the ouabain-sensitive part of the uptake into the cells caused by a lithium interaction with the extracellular K⁺-activated site of the Na⁺, K⁺-ATPase. After 14 days of exposure of the astrocytes to 1 mM lithium, the potassium uptake remained lower in the presence of lithium than in its absence. However, the cells had adjusted to the chronic presence of lithium by increasing their potassium uptake to such an extent that, during the exposure to 1 mM lithium, it was indistiguishable from that in cultures from the same batches grown in the absence of lithium and measured in the absence of this compound. The interference by lithium with potassium uptake into astrocytes may well be related to the inhibition of potassium clearance in the CNS described in the literature.     

Effects of monovalent cations on cardiac Na+, K+-ATPase activity and on contractile force

Summary The relationship between Na⁺, K⁺-ATPase inhibition by monovalent cations and their inotropic effect was studied in guinea pig hearts. The activity of partially purified cardiac enzyme was assayed in the presence of 5.8 mM KCl and either 20 or 150 mM NaCl. Rb⁺ and Tl⁺ inhibited Na⁺, K⁺-ATPase activity, the magnitude of the inhibition by these cations being greater in the assay media containing lower Na⁺ concentrations. Tl⁺ produced a dose-dependent inhibition of Na⁺, K⁺-ATPase activity in the presence of 20 mM Na⁺ and 75 mM K⁺, a cationic condition similar to that of intracellular fluid. Other monovalent cations such as K⁺, Cs⁺, NH₄ ⁺, Na⁺ or Li⁺ produced essentially no effect on the Na⁺, K⁺-ATPase activity or slightly stimulated it. In left atrial strips stimulated with field electrodes and bathed in Krebs-Henseleit solution (5.8 mM K⁺ and 145 mM Na⁺), addition of Cs⁺ failed to alter the isometric contractile force significantly. NH₄ ⁺ and K⁺ caused a transient positive inotropic effect which was partially blocked by propranolol. The positive inotropic response to K⁺ was followed by a negative inotropic response. Rb⁺ produced a sustained, dose-dependent inotropic response reaching a plateau at 1–2 min, whereas Tl⁺ produced a dose-dependent positive inotropic effect which developed slowly over a 30-min period. The positive inotropic effects produced by Rb⁺ and Tl⁺ were insensitive to propranolol pretreatment. Concentrations of Tl⁺ and cardiac glycosides which produce similar inotropic effects appear to cause the same degree of Na⁺-pump inhibition. The onset of the positive inotropic response to Rb⁺ or Tl⁺ was not dependent on the number of contractions which is in contrast to the cardiac glycoside-induced inotropic response. Substitution of 20 mM LiCl for an equimolar amount of NaCl in Krebs-Henseleit solution produced a significantly greater inotropic response than that observed when sucrose was substituted for NaCl. It appears that, among monovalent cations, only sodium pump inhibitors produce a sustained positive inotropic response.     

Reduction of the equilibrium binding of cardiac glycosides and related compounds to Na+, K+-ATPase as a possible mechanism for the potassium-induced reversal of their toxicity

Summary The influence of potassium ions on the equilibrium state of the binding of cardiac glycosides and their derivatives to partially purified dog heart and rat brain enzyme preparations was studied in vitro. The addition of potassium to the incubation mixture containing enzyme preparation, ³H-ouabain, Na⁺, Mg²⁺ and ATP, at the time when the binding reaction is close to equilibrium, caused an immediate reduction of the bound drug concentration; the concentration apparently shifting toward a lower equilibrium state. The degree of the potassium-induced reduction in bound drug concentration was dependent on the potassium concentration and on the chemical structure of the compound. The binding of aglycones, pentacetyl-gitoxin and cassaine was affected to a greater extent than that of the glycosides. These data suggest that one of the mechanisms by which potassium antagonizes the toxic actions of digitalis on the heart is to reduce the drug binding to cardiac Na⁺, K⁺-ATPase.This work was supported by a U.S. Public Health Service Grant, HL-16052     

Comparative studies of the influence of various K+ concentration on the action of K-strophthidin, digitoxin and strophanthidin-3-bromoacetate on papillary muscle and on membrane-ATPSA of guinea pig hearts

The influence of increasing K⁺ concentrations (5, 16, and 50 mM) on the effects of different cardenolides — digitoxin (DIG), k-strophanthidin (STR) and strophanthidin-3-bromoacetate (SBA) — on the contractile force of isolated electrically stimulated papillary muscles and on the activity of the Na⁺, K⁺-activated ATPase of guinea pig hearts was studied under comparable experimental conditions.     

Neurochemical changes on oxidative stress in rat hippocampus during acute phase of pilocarpine-induced seizures

Using the epilepsy model obtained by systemic administration of pilocarpine in rats in the present study we investigated the changes caused by seizures on content and species of gangliosides and phospholipids, as well as on cholesterol concentration, glutathione reduced contents, Na⁺, K⁺-ATPase activity and lipid peroxidation levels in rat hippocampus. Wistar rats received pilocarpine hydrochloride (400 mg/kg, i.p., pilocarpine group), and other group received 0.9% saline (i.p., control group). Results showed that seizures significantly decreased the total content of lipids and glutathione reduced concentration in rat hippocampus. We also observed that seizures significantly reduced the absolute quantity of the major brain gangliosides (GM1, GD1a, GD1b and GT1b) and phospholipids (sphingomyelin, phosphatidylcholine and phosphatidylethanolamine). Our data also showed a decreased Na⁺, K⁺-ATPase activity and an increased TBARS levels in hippocampus of seized rats. If confirmed in human beings, these data could suggest that the alteration in lipid composition, Na⁺, K⁺-ATPase activity, glutathione reduced content and TBARS levels caused by seizures might contribute to the neurophysiopathology of seizures observed in epileptic patients.     

Evaluation of endomorphin-1 on the activity of Na(+),K(+)-ATPase using in vitro and in vivo studies

The goal of this study was to investigate the effects of endomorphin-1 on Na(+),K(+)-ATPase activity in mouse brain synaptosome in vitro, and its antinociceptive interaction with the Na(+),K(+)-ATPase inhibitor ouabain. Endomorphin-1 (0.1 nM-10 microM) produced a concentration-dependent (EC(50): 43.19 nM, CI: 23.38-65.71 nM, E(max): 25.86%, CI: 24.53-27.20%), naloxone-reversible increase of the synaptosomal Na(+),K(+)-ATPase activity. The intrathecally (i.t.) administered endomorphin-1 (2-20 microg) produced a dose-dependent short-lasting increase in the tail-flick latency. Ouabain itself (1-1000 ng, i.t.) did not cause antinociception. Treatment with 10 ng ouabain significantly decreased the antinociceptive effect of 2 microg endomorphin-1, but none of the other combinations did significantly differ from the endomorhin-1-treated groups. These data indicate that endomorphin-1 increases the activity of Na(+),K(+)-ATPase in vitro but this effect may play a weak role in the antinociception induced by intrathecal endomorphin-1.     

Differential neurotoxic effects of methylmercury and mercuric sulfide in rats

Methylmercury (MeHg) is an environmental toxicant, while mercuric sulfide (HgS) is a main active component of cinnabar, a Chinese mineral medicine used as a sedative. Because the neurotoxicological effects of HgS were not clearly understood, in this study, we attempted to compare HgS with MeHg in various physiological responses in Sprague-Dawley rats. After oral administration (2 mg/(kg day)) for consecutive 5 and 14 days, MeHg reversibly decreased both of motor nerve conduction velocity (MNCV) and tail flick response, whereas irreversibly inhibited all of the motor equilibrium performance, recovery of compound muscle action potentials (CMAP) following exhaustic tetanic stimuli and Na+/K+-ATPase activity of the isolated sciatic nerve. These toxic effects of MeHg were found in well correlation of Hg contents of various tissues (blood, cerebral cortex, liver and kidney) in rats. For comparison, a dose of 1g/(kg day) of HgS was orally administered to the rats based on our previous findings on ototoxicity of HgS. The results revealed that HgS only reversibly delayed the recovery of suppressed CMAP and inhibited sciatic nerve Na+/K+-ATPase activity in accordance to the lower Hg contents of the tissues. These findings provide the important information on the differential susceptibility of various nervous tissues to MeHg and HgS. The neruotoxic effects produced by HgS was estimated to be about 1000 of those induced by MeHg found in this study and our previous reports.     

Correlation between inhibition of (Na+, K+)-membrane-ATPase and positive inotropic activity of cardenolides in isolated papillary muscles of guinea pig

Summary Concentrations of 17 cardenolides, cardenolide glucuronides and sulfates producing halfmaximal inhibition of (Na⁺, K⁺)-membrane-ATPase from different organs and animal species were determined in vitro. In addition the concentrations that increased the contractility of guinea pig isolated papillary muscles to a particular level were investigated. Comparisons between ATPase-inhibiting and positive inotropic cardiac activities showed extensive parallelism: the correlation coefficients after log/log transformation were between 0.92 and 0.97. The same close correlations are found if dissociation constants of cardenolide receptor complexes and concentrations causing ⁸⁶Rb-uptake inhibition in human erythrocytes are examined.The concentrations necessary for inhibition of (Na⁺, K⁺)-membrane-ATPase of the guinea pig heart and the concentrations required to achieve a defined positive inotropic effect in guinea pig papillary muscle showed a log/log correlation coefficient of 0.97 (P<0.001). In both tests the potencies covered more than three orders of magnitude. The results support Repke's hypothesis on the digitalis receptor.     

Toxic effects of diazinon and its photodegradation products

The toxic effects of diazinon and its irradiated solutions were investigated using cultivated human blood cells (lymphocytes and erythrocytes) and skin fibroblasts. Ultra Performance Liquid Chromatography (UPLC)–UV/VIS system was used to monitor the disappearance of starting diazinon during 115-min photodegradation and formation of its by-products (diazoxon and 2-isopropyl-6-methyl-4-pyrimidinol (IMP)) as a function of time. Dose-dependent AChE and Na⁺/K⁺-ATPase inhibition by diazinon was obtained for all investigated cells. Calculated IC₅₀ (72 h) values, in M, were: 7.5 × 10⁻⁶/3.4 × 10⁻⁵, 8.7 × 10⁻⁵/6.6 × 10⁻⁵, and 3.0 × 10⁻⁵/4.6 × 10⁻⁵ for fibroblast, erythrocyte and lymphocyte AChE/Na⁺/K⁺-ATPase, respectively. Results obtained for reference commercially purified target enzymes indicate similar sensitivity of AChE towards diazinon (IC₅₀ (20 min)-7.8 × 10⁻⁵M), while diazinon concentrations below 10 mM did not noticeably affect Na⁺/K⁺-ATPase activity. Besides, diazinon and IMP induced increasing incidence of micronuclei (via clastogenic mode of action) in a dose-dependent manner up to 2 × 10⁻⁶ M and significant inhibition of cell proliferation and increased level of malondialdehyde at all investigated concentrations. Although after 15-min diazinon irradiation formed products do not affect purified commercial enzymes activities, inhibitory effect of irradiated solutions on cell enzymes increased as a function of time exposure to UV light and resulted in significant reduction of AChE (up to 28–45%) and Na⁺/K⁺-ATPase (up to 35–40%) at the end of irradiation period. Moreover, photodegradation treatment strengthened prooxidative properties of diazinon as well as its potency to induce cytogenetic damage.