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The epsilon toxin from Clostridium perfringens stimulates calcium-activated chloride channels, generating extracellular vesicles in Xenopus oocytes. 产气荚膜梭菌的epsilon毒素刺激钙激活的氯离子通道,在爪蟾卵母细胞中产生细胞外囊泡。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-01 DOI: 10.1002/prp2.70005
Mercè Cases, Jonatan Dorca-Arévalo, Marta Blanch, Sergi Rodil, Beatrice Terni, Mireia Martín-Satué, Artur Llobet, Juan Blasi, Carles Solsona

The epsilon toxin (Etx) from Clostridium perfringens has been identified as a potential trigger of multiple sclerosis, functioning as a pore-forming toxin that selectively targets cells expressing the plasma membrane (PM) myelin and lymphocyte protein (MAL). Previously, we observed that Etx induces the release of intracellular ATP in sensitive cell lines. Here, we aimed to re-examine the mechanism of action of the toxin and investigate the connection between pore formation and ATP release. We examined the impact of Etx on Xenopus laevis oocytes expressing human MAL. Extracellular ATP was assessed using the luciferin-luciferase reaction. Activation of calcium-activated chloride channels (CaCCs) and a decrease in the PM surface were recorded using the two-electrode voltage-clamp technique. To evaluate intracellular Ca2+ levels and scramblase activity, fluorescent dyes were employed. Extracellular vesicles were imaged using light and electron microscopy, while toxin oligomers were identified through western blots. Etx triggered intracellular Ca2+ mobilization in the Xenopus oocytes expressing hMAL, leading to the activation of CaCCs, ATP release, and a reduction in PM capacitance. The toxin induced the activation of scramblase and, thus, translocated phospholipids from the inner to the outer leaflet of the PM, exposing phosphatidylserine outside in Xenopus oocytes and in an Etx-sensitive cell line. Moreover, Etx caused the formation of extracellular vesicles, not derived from apoptotic bodies, through PM fission. These vesicles carried toxin heptamers and doughnut-like structures in the nanometer size range. In conclusion, ATP release was not directly attributed to the formation of pores in the PM, but to scramblase activity and the formation of extracellular vesicles.

来自产气荚膜梭菌的epsilon毒素(Etx)已被确定为多发性硬化症的潜在诱因,它是一种孔形成毒素,可选择性地靶向表达质膜(PM)髓鞘和淋巴细胞蛋白(MAL)的细胞。此前,我们观察到 Etx 可诱导敏感细胞株释放细胞内 ATP。在此,我们旨在重新研究该毒素的作用机制,并调查孔形成与 ATP 释放之间的联系。我们研究了 Etx 对表达人类 MAL 的爪蟾卵母细胞的影响。使用荧光素-荧光素酶反应评估了细胞外 ATP。使用双电极电压钳技术记录了钙激活氯通道(CaCCs)的激活和 PM 表面的下降。为了评估细胞内 Ca2+ 水平和加扰酶活性,使用了荧光染料。使用光镜和电子显微镜对细胞外囊泡进行成像,并通过 Western 印迹鉴定毒素寡聚体。在表达hMAL的爪蟾卵母细胞中,Etx引发细胞内Ca2+动员,导致CaCCs活化、ATP释放和PM电容降低。在爪蟾卵母细胞和对Etx敏感的细胞系中,毒素诱导了scramblase的活化,从而将磷脂从PM的内叶转移到外叶,使磷脂酰丝氨酸暴露在外面。此外,Etx 还能通过 PM 裂变形成细胞外囊泡,而这些囊泡并非来自凋亡体。这些囊泡携带毒素七聚体和纳米级的甜甜圈状结构。总之,ATP的释放并不直接归因于PM中孔隙的形成,而是归因于scramblase活性和细胞外囊泡的形成。
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引用次数: 0
Effect of vitamin D supplementation on clinical outcomes in adult patients with COVID-19: A GRADE-assessed systematic review and meta-analysis of randomized controlled trials. 补充维生素 D 对 COVID-19 成年患者临床疗效的影响:对随机对照试验进行GRADE评估的系统综述和荟萃分析。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-01 DOI: 10.1002/prp2.70013
Zohreh-Al-Sadat Ghoreshi, Javad Charostad, Nasir Arefinia, Mohsen Nakhaie, Mohammad Rezaei Zadeh Rukerd, Faranak Salajegheh

The COVID-19 pandemic has emerged as a major global health crisis. Vitamin D, a crucial fat-soluble vitamin, has been recommended for COVID-19 patients, though evidence of its effectiveness is inconsistent. This systematic literature review and meta-analysis aimed to evaluate the impact of vitamin D supplementation on COVID-19-related outcomes. A comprehensive search was conducted across PubMed, Scopus, Web of Science, Embase, and Cochrane databases. Primary outcomes included mortality and hospital length of stay, while secondary outcomes encompassed C-reactive protein (CRP), ferritin, D-dimer, hemoglobin (Hb) concentrations, and lymphocyte, neutrophil, and platelet counts. Data analysis was performed using Stata™ Version 14. A total of 16 trials were analyzed. The meta-analysis revealed that vitamin D supplementation significantly reduced hospital length of stay (mean difference = -1.16; 95% confidence interval [CI]: -2.23, -0.09; p = .033) with significant heterogeneity (I2 = 69.2%, p = .002). Subgroup analysis showed a more pronounced reduction in studies with vitamin D dosages ≤10 000 international units (IU) (mean difference = -1.27; 95% CI: -1.96, -0.57; p < .001) and in patients over 60 years old (mean difference = -1.84; 95% CI: -2.53, -1.14; p < .001). Additionally, vitamin D significantly reduced CRP concentrations in older adults (>60 years) (mean difference = -1.13; 95% CI: -2.07, -0.18; p = .019). No significant changes were found in ferritin, D-dimer, Hb concentrations, or in lymphocyte, neutrophil, and platelet counts (p > .05). In conclusion, while vitamin D supplementation did not significantly affect most COVID-19-related biomarkers, however, it reduces the length of hospital stay.

COVID-19 大流行已成为一场重大的全球健康危机。维生素 D 是一种重要的脂溶性维生素,已被推荐用于 COVID-19 患者,但有关其有效性的证据并不一致。本系统性文献综述和荟萃分析旨在评估补充维生素 D 对 COVID-19 相关结果的影响。我们在 PubMed、Scopus、Web of Science、Embase 和 Cochrane 数据库中进行了全面检索。主要结果包括死亡率和住院时间,次要结果包括 C 反应蛋白 (CRP)、铁蛋白、D-二聚体、血红蛋白 (Hb) 浓度以及淋巴细胞、中性粒细胞和血小板计数。数据分析使用 Stata™ Version 14 进行。共分析了 16 项试验。荟萃分析显示,补充维生素 D 可显著缩短住院时间(平均差异 = -1.16; 95% 置信区间 [CI]: -2.23, -0.09; p = .033),但存在显著的异质性(I2 = 69.2%, p = .002)。亚组分析表明,维生素 D 剂量≤10 000 国际单位 (IU) 的研究结果显示了更明显的降低(平均差异 = -1.27; 95% CI: -1.96, -0.57; p 60 years)(平均差异 = -1.13; 95% CI: -2.07, -0.18; p = .019)。铁蛋白、D-二聚体、血红蛋白浓度以及淋巴细胞、中性粒细胞和血小板计数均无明显变化(p > .05)。总之,虽然维生素 D 补充剂对大多数 COVID-19 相关生物标志物无明显影响,但却能缩短住院时间。
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引用次数: 0
The gut-brain axis in appetite, satiety, food intake, and eating behavior: Insights from animal models and human studies. 食欲、饱腹感、食物摄入量和进食行为中的肠脑轴:动物模型和人体研究的启示
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-01 DOI: 10.1002/prp2.70027
Georgia S Clarke, Amanda J Page, Sally Eldeghaidy

The gut-brain axis plays a pivotal role in the finely tuned orchestration of food intake, where both homeostatic and hedonic processes collaboratively control our dietary decisions. This interplay involves the transmission of mechanical and chemical signals from the gastrointestinal tract to the appetite centers in the brain, conveying information on meal arrival, quantity, and chemical composition. These signals are processed in the brain eventually leading to the sensation of satiety and the termination of a meal. However, the regulation of food intake and appetite extends beyond the realms of pure physiological need. Hedonic mechanisms, including sensory perception (i.e., through sight, smell, and taste), habitual behaviors, and psychological factors, exert profound influences on food intake. Drawing from studies in animal models and human research, this comprehensive review summarizes the physiological mechanisms that underlie the gut-brain axis and its interplay with the reward network in the regulation of appetite and satiety. The recent advancements in neuroimaging techniques, with a focus on human studies that enable investigation of the neural mechanisms underpinning appetite regulation are discussed. Furthermore, this review explores therapeutic/pharmacological strategies that hold the potential for controlling food intake.

肠道-大脑轴在食物摄入的微调过程中起着至关重要的作用,在这一过程中,平衡过程和享乐过程共同控制着我们的饮食决定。这种相互作用包括从胃肠道向大脑食欲中枢传递机械和化学信号,传达有关食物到达、数量和化学成分的信息。这些信号在大脑中经过处理,最终导致饱腹感和进餐终止。然而,食物摄入和食欲的调节超出了纯生理需求的范畴。包括感官知觉(即通过视觉、嗅觉和味觉)、习惯行为和心理因素在内的享乐机制对食物摄入产生了深远的影响。本综述从动物模型和人体研究中汲取营养,总结了肠脑轴的生理机制及其与奖赏网络在调节食欲和饱腹感方面的相互作用。本综述还讨论了神经成像技术的最新进展,重点关注能够研究食欲调节神经机制的人体研究。此外,本综述还探讨了有可能控制食物摄入量的治疗/药物策略。
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引用次数: 0
The endocannabinoid system in appetite regulation and treatment of obesity. 内源性大麻素系统在食欲调节和肥胖症治疗中的作用。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-01 DOI: 10.1002/prp2.70009
Marija Kurtov,Igor Rubinić,Robert Likić
The endocannabinoid system (ECS) is a complex cell-signaling system that is responsible for maintaining homeostasis by modulating various regulatory reactions in response to internal and environmental changes. The influence of ECS on appetite regulation has been a subject of much recent research, however, the full extent of its impact remains unknown. Current evidence links human obesity to ECS activation, increased endocannabinoid levels in both central and peripheral tissues, along with cannabinoid receptor type 1 (CBR1) up-regulation. These findings imply the potential pharmacological use of the ECS in the treatment of obesity. Here, we present various pathophysiological processes in obesity involving the ECS, highlighting different pharmacological options for modulating endocannabinoid activity to treat obesity. However, the potential of those pharmacological possibilities remains under investigation and requires further research.
内源性大麻素系统(ECS)是一个复杂的细胞信号系统,负责通过调节各种调节反应来应对内部和环境变化,从而维持体内平衡。ECS 对食欲调节的影响一直是近期研究的主题,但其影响的全面程度仍不得而知。目前有证据表明,人类肥胖与 ECS 激活、中枢和外周组织的内源性大麻素水平增加以及大麻素受体 1 型(CBR1)上调有关。这些发现意味着 ECS 在治疗肥胖症方面具有潜在的药理作用。在此,我们介绍了肥胖症中涉及 ECS 的各种病理生理过程,重点介绍了调节内源性大麻素活性以治疗肥胖症的不同药理选择。然而,这些药理学可能性的潜力仍在调查之中,需要进一步研究。
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引用次数: 0
Cromolyn sodium and masitinib combination inhibits fibroblast-myofibroblast transition and exerts additive cell-protective and antioxidant effects on a bleomycin-induced in vitro fibrosis model. 色甘酸钠和马西替尼复方制剂可抑制成纤维细胞-肌成纤维细胞转化,并对博莱霉素诱导的体外纤维化模型产生细胞保护和抗氧化作用。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-01 DOI: 10.1002/prp2.70018
Azize Yasemin Göksu, Hulya Dirol, Fatma Gonca Kocanci

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. While recent studies have suggested the potential efficacy of tyrosine kinase inhibitors in managing IPF, masitinib, a clinically used tyrosine kinase inhibitor, has not yet been investigated for its efficacy in fibrotic lung diseases. In a previous study on an in vitro neurodegenerative model, we demonstrated the synergistic antitoxic and antioxidant effects of masitinib combined with cromolyn sodium, an FDA-approved mast cell stabilizer. This study aims to investigate the anti-fibrotic and antioxidant effects of the masitinib-cromolyn sodium combination in an in vitro model of pulmonary fibrosis. Fibroblast cell cultures treated with bleomycin and/or hydrogen peroxide (H2O2) were subjected to masitinib and/or cromolyn sodium, followed by assessments of cell viability, morphological and apoptotic nuclear changes, triple-immunofluorescence labeling, and total oxidant/antioxidant capacities, besides ratio of Bax and Bcl-2 mRNA expressions as an indication of apoptosis. The combined treatment of masitinib and cromolyn sodium effectively prevented the fibroblast myofibroblast transition, a hallmark of fibrosis, and significantly reduced bleomycin / H2O2-induced apoptosis and oxidative stress. This study is the first to demonstrate the additive anti-fibrotic, cell-protective, and antioxidant effects of the masitinib-cromolyn sodium combination in an in vitro fibrosis model, suggesting its potential as an innovative therapeutic approach for pulmonary fibrosis. Combination therapy may be more advantageous in that both drugs could be administered in lower doses, exerting less side effects, and at the same time providing diverse mechanisms of action simultaneously.

特发性肺纤维化(IPF)是一种进行性致命肺纤维化疾病。虽然最近的研究表明酪氨酸激酶抑制剂在治疗 IPF 方面具有潜在疗效,但马西替尼作为一种临床常用的酪氨酸激酶抑制剂,其在肺纤维化疾病中的疗效尚未得到研究。在之前的一项体外神经退行性模型研究中,我们证实了马西替尼与美国食品及药物管理局(FDA)批准的肥大细胞稳定剂色甘宁钠(cromolyn sodium)联用具有协同解毒和抗氧化作用。本研究旨在体外肺纤维化模型中研究马西替尼与色甘酸钠联合用药的抗纤维化和抗氧化作用。用博莱霉素和/或过氧化氢(H2O2)处理成纤维细胞培养物后,再用马西替尼和/或色甘酸钠处理成纤维细胞培养物,然后评估细胞活力、形态学和细胞凋亡核变化、三重免疫荧光标记、总氧化剂/抗氧化剂能力,以及作为细胞凋亡指标的 Bax 和 Bcl-2 mRNA 表达比值。马西替尼与色甘酸钠联合治疗可有效阻止纤维化的标志--成纤维细胞向肌成纤维细胞转化,并显著减少博莱霉素/H2O2诱导的细胞凋亡和氧化应激。本研究首次在体外纤维化模型中证明了马西替尼-色甘酸钠联合疗法具有抗纤维化、细胞保护和抗氧化的叠加效应,表明它有可能成为治疗肺纤维化的一种创新疗法。联合疗法的优势在于两种药物的用药剂量较低,副作用较小,同时还能提供多种作用机制。
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引用次数: 0
A dose-adjusted, open-label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis. 一项关于脓毒症重症患者使用 STC3141 的安全性、耐受性和药代动力学的剂量调整、开放标签试验研究。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-01 DOI: 10.1002/prp2.70015
Rinaldo Bellomo, John Patava, Ruth Van Lancker, Nathalie Layios, Marijke Peetermans, Mark Plummer, Rachid Attou, Robert McNamara, Andrew Udy, Bradley Wibrow, Adam Deane, Edward Litton, Marcel Tanudji, Fuhong Su, Zhang Zhong, Linda Shi, Li Ning

Increased circulating histones correlate with sepsis severity and are a potential therapeutic target. Pre-clinical studies showed benefit with a histone-neutralizing polyanion molecule (STC3141). We aimed to investigate the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis. We studied 26 patients with sepsis divided into four cohorts of one, five, ten, and ten subjects, respectively. We conducted a dose-adjusted, open-label study to determine the safety, tolerability, and pharmacokinetics of STC3141 administered as an IV infusion for up to 72 h, with rate adjusted to estimated creatinine clearance. Four steady-state concentrations were targeted. Twenty of the 26 subjects (77%) in the study experienced at least one adverse event (AE). The most frequently reported study drug-related AE was a mildly prolonged aPTT (four events). Only one AE (pulmonary hemorrhage) led to discontinuation of the drug. After excluding patients receiving renal replacement therapy (RRT) patients, clearance ranged from 3.3 to 4.2 L/h across cohorts and was essentially completely renal in nature. Half-life values ranged from 5 to 7 h. The mean (±SD) terminal half-life for non-RRT subjects and for whom it was possible to calculate was approximately 9 (±4.77) h but increased to 19 (±7.94) h for subjects on RRT. Overall, 18 (69.2%) patients completed the study to day eight in the ICU, and 22 (84.6%) survived to 28 days. STC3141 administration appeared to have an acceptable degree of safety and tolerability and expected pharmacokinetics. Cautious, larger randomized efficacy trials in sepsis appear justified.

循环组蛋白的增加与败血症的严重程度相关,是一个潜在的治疗目标。临床前研究显示,组蛋白中和多负离子分子(STC3141)可带来益处。我们旨在研究 STC3141 在脓毒症重症患者中的安全性、耐受性和药代动力学。我们对 26 名脓毒症患者进行了研究,分为四组,每组分别有 1 名、5 名、10 名和 10 名受试者。我们进行了一项剂量调整后的开放标签研究,以确定 STC3141 的安全性、耐受性和药代动力学,该药以静脉输注方式给药长达 72 小时,并根据估计的肌酐清除率调整给药速度。目标浓度为四种稳态浓度。该研究的 26 位受试者中有 20 位(77%)至少出现过一次不良事件 (AE)。最常见的研究药物相关不良反应是 aPTT 轻度延长(4 例)。只有一次 AE(肺出血)导致停药。排除接受肾脏替代疗法(RRT)的患者后,各组群的清除率为 3.3 至 4.2 升/小时,基本上完全由肾脏清除。非 RRT 受试者的平均(±SD)终末半衰期约为 9(±4.77)小时,而接受 RRT 治疗的受试者则增至 19(±7.94)小时。总体而言,18 名(69.2%)患者在重症监护室中完成了研究至第 8 天,22 名(84.6%)患者存活至 28 天。STC3141用药的安全性、耐受性和预期的药代动力学似乎都可以接受。在脓毒症中进行谨慎、更大规模的随机疗效试验似乎是合理的。
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引用次数: 0
Disposition of orally administered atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor in healthy participants. 口服新型 5-脂氧合酶激活蛋白抑制剂 Atuliflapon 在健康参与者体内的分布情况。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-01 DOI: 10.1002/prp2.70029
Xue-Qing Li, Bo Lindmark, Carl Amilon, Kristin Samuelsson, Lars Weidolf, Karin Nelander, Jane Knöchel, Maria Heijer, Ryan A Bragg, Malin Gränfors, Eva-Lotte Lindstedt, Sharan Sidhu, Pavlo Garkaviy, Hans Ericsson

In this study, the mass balance, pharmacokinetics (PK) and metabolism of atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor, were investigated in healthy male subjects. A single oral dose of 200 mg [14C]atuliflapon suspension was administered to six healthy male subjects. Mass balance, PK and metabolite profiles of atuliflapon were analyzed using radioactivity monitoring and liquid chromatography with mass spectrometry analysis. The safety of atuliflapon was assessed during the study. Atuliflapon was rapidly absorbed with a median tmax of 1.5 h, followed by a biphasic decline in plasma exposure rendering a terminal half-life of ~20 h. Unchanged atuliflapon was the predominant radioactive component in plasma, accounting for 40.1% of the total drug-related exposure (DRE), while a direct N-glucuronide was the only metabolite exceeding 10% of DRE, accounting for 20.9%. Renal excretion of intact atuliflapon accounted for <1% of the administered dose. In total 85.2% of administered radioactivity was recovered over 312 h with 79.3% and 5.9% in feces and urine, respectively. Parent atuliflapon contributed to approximately 40% of the recovered dose in excreta, while metabolites resulting from phase 1 oxidative pathways accounted for more than 30% of the excreted dose. Overall, a single oral dose of 200 mg [14C]atuliflapon suspension was well tolerated in healthy male subjects. The human metabolism and disposition data obtained will support future development and submissions of atuliflapon as a potential candidate drug for the treatment of cardiovascular, cardiorenal, and respiratory indications.

本研究调查了健康男性受试者体内新型 5-脂氧合酶激活蛋白抑制剂阿托利夫拉朋(atuliflapon)的质量平衡、药代动力学(PK)和代谢情况。六名健康男性受试者单次口服 200 毫克 [14C]atuliflapon 悬浮液。采用放射性监测和液相色谱-质谱分析法对阿托利福平的质量平衡、PK 和代谢物谱进行了分析。研究期间还对阿托利夫拉朋的安全性进行了评估。阿托利夫拉朋吸收迅速,中位tmax为1.5小时,随后血浆暴露量呈双相下降,最终半衰期约为20小时。未发生变化的阿托利夫拉朋是血浆中最主要的放射性成分,占药物相关总暴露量(DRE)的40.1%,而直接N-葡萄糖醛酸是唯一超过DRE 10%的代谢物,占20.9%。在健康男性受试者中,肾脏排泄的完整阿托利夫拉蓬占 14C]atuliflapon 悬浮液总排泄量的 10%,耐受性良好。所获得的人体代谢和处置数据将支持阿托利夫拉朋今后作为治疗心血管、心肾和呼吸系统疾病的潜在候选药物进行开发和申报。
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引用次数: 0
Study on the mechanism of echinacoside in preventing and treating hypoxic pulmonary hypertension based on proteomic analyses. 基于蛋白质组分析的紫锥菊苷防治缺氧性肺动脉高压的机制研究
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-01 DOI: 10.1002/prp2.70025
Xiangyun Gai, Qingqing Xia, Hongmai Wang, Hongtao Bi, Jinyu Wang, Yuefu Zhao

Hypoxic pulmonary hypertension (HPH), a chronic condition affecting the cardiopulmonary system, has high mortality. Echinacoside (ECH) is a phenylethanoid glycoside, which is used to ameliorate pulmonary vascular remodeling and pulmonary vasoconstriction in rats. Accordingly, we aimed to explore the mechanism of ECH in preventing and treating HPH. Sprague Dawley rats were housed in a hypobaric hypoxia chamber for 28 days to obtain the HPH model. The experimental rats were randomly allocated into the following several groups: normoxia group, chronic hypoxia group, and ECH group. The therapeutic results of ECH (10, 20, and 40 mg/kg) showed that ECH reduced mPAP, Hb, Hct, and RVHI in HPH rats. Then this work employed label-free quantitative proteomic analysis, western blotting, and RT-PCR to investigate the mechanism by which ECH prevents HPH. The results found that in the chronic hypoxia group, the levels of ACSL1, COL6A1, COL4A2, COL1A1, and PC increased compared to the normoxia group. However, the opposite effect was observed in the chronic hypoxia group treated with ECH. The study indicates that the administration of ECH may slow the pathological progression of HPH by suppressing the inflammatory response, inhibiting smooth muscle cell proliferation, and minimizing the deposition of extracellular matrix.

缺氧性肺动脉高压(HPH)是一种影响心肺系统的慢性疾病,死亡率很高。棘白甙是一种苯乙醇苷,可用于改善大鼠肺血管重塑和肺血管收缩。因此,我们旨在探索ECH预防和治疗HPH的机制。将 Sprague Dawley 大鼠饲养在低压缺氧箱中 28 天,以获得 HPH 模型。实验大鼠被随机分为以下几组:常氧组、慢性缺氧组和 ECH 组。ECH(10、20和40 mg/kg)的治疗结果显示,ECH可降低HPH大鼠的mPAP、Hb、Hct和RVHI。随后,本研究采用无标记定量蛋白质组分析、Western印迹和RT-PCR等方法研究了ECH预防HPH的机制。结果发现,在慢性缺氧组中,ACSL1、COL6A1、COL4A2、COL1A1和PC的水平比正常缺氧组升高。然而,在接受 ECH 治疗的慢性缺氧组中却观察到了相反的效果。该研究表明,服用 ECH 可抑制炎症反应、抑制平滑肌细胞增殖并减少细胞外基质的沉积,从而减缓 HPH 的病理进展。
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引用次数: 0
Plasma and urinary CP I and CP III concentrations in chimeric mice with human hepatocytes after rifampicin administration. 人肝细胞嵌合小鼠服用利福平后血浆和尿液中的 CP I 和 CP III 浓度。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-01 DOI: 10.1002/prp2.70017
Yurina Shishido, Tomohiro Yoshida, Keiyu Oshida, Masashi Uchida

The interest in transporter-mediated drug interactions has been increasing in the field of drug development. In this study, we measured the plasma and urinary concentrations of coproporphyrin (CP) I and CP III as endogenous substrates for organic anion-transporting polypeptide (OATP) using chimeric mice with human hepatocytes (PXB mice) and examined the influence of an OATP inhibitor, rifampicin (RIF). CP I and CP III were actively taken up intracellularly, and RIF inhibited the uptake in a concentration-dependent manner for both CP I and CP III in human hepatocytes (PXB-cells). Single doses of RIF at 10 and 30 mg/kg were orally or intravenously administered to PXB mice and wild-type ICR mice. Plasma concentrations (AUC0-8h) of CP I increased in both mice. However, a marked increase in CP III was only observed in ICR mice, after intravenous administration of RIF at 30 mg/kg. The IC50 values of RIF for intracellular CP I/III uptake and the unbound plasma concentrations of RIF suggested that the increase in plasma CP I is associated with the exposure of RIF to OATPs. The 24-h cumulative urinary excretions of CP I and CP III increased in both mice, but more markedly in PXB mice. Thus, RIF increased the plasma and urinary concentrations of CP I and CP III in the mice, as reported in humans, and CP I may be a more sensitive biomarker of OATP-mediated drug interactions in PXB mice.

在药物开发领域,人们对转运体介导的药物相互作用的兴趣与日俱增。在这项研究中,我们利用具有人类肝细胞的嵌合小鼠(PXB 小鼠)测定了作为有机阴离子转运多肽(OATP)内源性底物的共卟啉(CP)Ⅰ和CPⅢ的血浆和尿液浓度,并考察了 OATP 抑制剂利福平(RIF)的影响。在人肝细胞(PXB-细胞)中,CP I 和 CP III 在细胞内被主动摄取,RIF 以浓度依赖的方式抑制了 CP I 和 CP III 的摄取。给 PXB 小鼠和野生型 ICR 小鼠口服或静脉注射单剂量 RIF(10 毫克/千克和 30 毫克/千克)。两种小鼠血浆中 CP I 的浓度(AUC0-8h)均有所增加。然而,只有在静脉注射 30 毫克/千克的 RIF 后,ICR 小鼠的 CP III 浓度才会显著增加。RIF 在细胞内摄取 CP I/III 的 IC50 值和 RIF 的非结合血浆浓度表明,血浆 CP I 的增加与 RIF 暴露于 OATPs 有关。两种小鼠 24 小时尿液中 CP I 和 CP III 的累积排泄量都有所增加,但 PXB 小鼠的情况更为明显。因此,RIF 增加了小鼠血浆和尿液中 CP I 和 CP III 的浓度,正如在人类身上所报道的那样,CP I 可能是 PXB 小鼠体内 OATP 介导的药物相互作用的更敏感的生物标志物。
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引用次数: 0
Histamine H1-receptor-mediated modulation of NMDA receptors signaling responses. 组胺 H1 受体介导的 NMDA 受体信号反应调节。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-01 DOI: 10.1002/prp2.1216
J-M Arrang, V Armand

This study attempted to clarify the role of histamine H1 receptors in epilepsy by exploring the effects of agonists and inverse agonists on the rundown of the current induced by iterative applications of NMDA or GABA in primary neuronal culture. Mepyramine, a classical H1-receptor antagonist/inverse agonist, increased the NMDA current by about 40% during the first minutes of recording. This effect was concentration-dependent, maximal at 10 nM, and mimicked by triprolidine, another antagonist/inverse agonist. No endogenous histamine was detected in the cultures by a selective immunoassay; both compounds were acting as inverse agonists. Indicating a high constitutive activity of the H1 receptor in this system, histamine did not affect the NMDA rundown, including its settlement, but significantly reversed the effect of mepyramine. A similar pattern was obtained with 2,3 bromophenyl histamine, a selective H1-receptor agonist. The initial increase induced by the two inverse agonists was followed by the same rundown as in controls. H1- and NMDA receptors are colocalized in most cultured neuronal cells. Mepyramine and histamine did not affect the GABA rundown. Our findings suggest an interaction between H1- and NMDA receptors. Inactivation of the H1-receptor by its inverse agonists delays the settlement of the NMDA rundown, which may underlie their proconvulsant effect reported in clinics. Therefore, H1-receptor constitutive activity and the effect of histamine revealed in its absence, tend to facilitate the initiation of the rundown, which is consistent with the anticonvulsant properties of histamine via activation of H1-receptors reported in many studies.

本研究试图通过探讨激动剂和反向激动剂对原代神经元培养中迭代应用 NMDA 或 GABA 所诱导的电流骤降的影响,来阐明组胺 H1 受体在癫痫中的作用。经典的 H1 受体拮抗剂/反向激动剂美吡胺能在记录的最初几分钟内使 NMDA 电流增加约 40%。这种效应是浓度依赖性的,在 10 nM 时达到最大,并被另一种拮抗剂/反向激动剂曲普利啶模拟。通过选择性免疫测定,培养物中没有检测到内源性组胺;这两种化合物都是反向激动剂。组胺不影响 NMDA 崩溃(包括其沉降),但却能显著逆转甲氧苄啶的作用,这表明该系统中 H1 受体具有很高的组成活性。选择性 H1 受体激动剂 2,3-溴苯组胺也有类似的作用。这两种反向激动剂引起的最初升高随后出现了与对照组相同的下降。在大多数培养的神经细胞中,H1 受体和 NMDA 受体是共定位的。美吡胺和组胺并不影响 GABA 的隆升。我们的研究结果表明,H1-和NMDA受体之间存在相互作用。H1-受体的反向激动剂使H1-受体失活,从而延迟了NMDA的释放,这可能是临床上报道的H1-受体促惊厥效应的原因。因此,H1-受体的组成活性和组胺在其缺失时显示的效应往往会促进 "破环 "的启动,这与许多研究报告的组胺通过激活 H1-受体而产生的抗惊厥特性是一致的。
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Pharmacology Research & Perspectives
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