European journal of pharmacology最新文献_第5页

microRNA-18a-5p promotes vascular smooth muscle cell phenotypic switch by targeting Notch2 as therapeutic targets in vein grafts restenosis microRNA-18a-5p通过靶向Notch2促进血管平滑肌细胞表型转换，成为静脉移植物再狭窄的治疗靶点。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-08 DOI: 10.1016/j.ejphar.2024.177097

Xu Zhan , Chang-Ming Zhong , Hao Tang , Hansong Xiao , Yongzheng Guo , Cheng Zhang , Can Qu , Xiaowen Wang , Chun Huang

Vascular smooth muscle cells (VSMCs) phenotype switching plays a crucial role in vein graft restenosis following coronary artery bypass grafting (CABG) surgery. To discover novel clinically relevant therapeutic targets for vein graft restenosis after CABG, we therefore investigated whether miRNA-18a-5p mediated phenotype switching plays a critical role in the development of vein graft restenosis. We studied miRNA-18a-5p expression in plasma samples of patients with or without vein graft restenosis at 1, 3 and 5 years after coronary artery bypass graft surgery, and in normal vs. atherosclerotic human femoral artery samples, to prove its role in VSMC phenotype switching. We found that the expression of miRNA-18a-5p significantly increased in vein grafts restenosis rat model after bypass surgery at 7, 14, 28 days and human blood specimens with vein grafts failure after grafting surgery. Through gain- and loss-of-function approaches, we determined that miRNA-18a-5p affects VSMC proliferation, migration, differentiation, and contractility. Notch2 was found to be a direct target of miRNA-18a-5p, which is critical for VSMC phenotype switching. Finally, miRNA-18a-5p knockdown used miRNA sponge via AAV6 locally delivery in vivo, miRNA-18a-5p sponge gene transfer therapy reduced the neointimal area, neointimal thickness, and intimal/media area ratio in vein grafts compared with the controls and improved vein graft hemodynamics. miRNA-18a-5p is a critical modulator of VSMC phenotypic switch during development of vein graft restenosis by downregulating Notch2, therefore targeting miRNA-18a-5p may be a helpful strategy for the treatment of vein grafts restenosis or failure after CABG surgery.

血管平滑肌细胞（VSMC）表型转换在冠状动脉旁路移植术（CABG）术后静脉移植物再狭窄中起着至关重要的作用。为了发现治疗 CABG 术后静脉移植物再狭窄的临床相关新靶点，我们研究了 miRNA-18a-5p 介导的表型转换是否在静脉移植物再狭窄的发生中起关键作用。我们研究了冠状动脉旁路移植术后 1 年、3 年和 5 年有或无静脉移植物再狭窄患者血浆样本中 miRNA-18a-5p 的表达，以及正常与动脉粥样硬化人股动脉样本中 miRNA-18a-5p 的表达，以证明其在 VSMC 表型转换中的作用。我们发现，miRNA-18a-5p 的表达在搭桥手术后 7、14、28 天的静脉移植物再狭窄大鼠模型和移植手术后静脉移植物失败的人体血液标本中明显增加。通过功能增益和功能缺失的方法，我们确定 miRNA-18a-5p 会影响 VSMC 的增殖、迁移、分化和收缩能力。研究发现，Notch2 是 miRNA-18a-5p 的直接靶标，而 miRNA-18a-5p 对 VSMC 表型转换至关重要。最后，miRNA-18a-5p基因敲除疗法通过AAV6在体内局部传递miRNA海绵，与对照组相比，miRNA-18a-5p海绵基因转移疗法减少了静脉移植物的新生内膜面积、新生内膜厚度和内膜/中膜面积比，并改善了静脉移植物的血流动力学。miRNA-18a-5p通过下调Notch2是静脉移植物再狭窄发展过程中VSMC表型转换的关键调节因子，因此靶向miRNA-18a-5p可能是治疗CABG手术后静脉移植物再狭窄或失败的一种有效策略。

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引用次数: 0

AdipoRon improves mitochondrial homeostasis and protects dopaminergic neurons through activation of the AMPK signaling pathway in the 6-OHDA-lesioned rats AdipoRon通过激活AMPK信号通路，改善6-OHDA缺失大鼠的线粒体稳态并保护多巴胺能神经元。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-06 DOI: 10.1016/j.ejphar.2024.177111

Seyed Zanyar Athari , Rana Keyhanmanesh , Fereshteh Farajdokht , Mohammad Karimipour , Negin Azizifar , Soraya Alimohammadi , Gisou Mohaddes

The progressive decline of dopaminergic neurons in Parkinson's disease (PD) has been linked to an imbalance in energy and the failure of mitochondrial function. AMP-activated protein kinase (AMPK), the major intracellular energy sensor, regulates energy balance, and damage to nigral dopaminergic neurons induced by 6-hydroxydopamine (6-OHDA) is exacerbated in the absence of AMPK activity. This study aimed to examine the potential therapeutic advantages of AdipoRon, an AMPK activator, on motor function and mitochondrial homeostasis in a 6-OHDA-induced PD model. Male Wistar rats were subjected to unilateral injection of 6-OHDA (10 μg) into the left medial forebrain bundle at two points, and after 7 days, they were treated with intranasal AdipoRon (0.1, 1, and 10 μg) or Levodopa (10 mg/kg, p. o.) for 21 successive days. Following the last treatment day, motor behavior was evaluated through the Murprogo's test, bar test, beam walking test, and apomorphine-induced rotation test. After euthanasia, the left substantia nigra (SN) was separated for evaluation of ATP, mitochondrial membrane potential (MMP), and protein expressions of AMPK, p-AMPK, and mitochondrial dynamics markers (Mfn-2 and Drp-1). Moreover, the number of tyrosine hydroxylase-positive (TH⁺) cells was quantified in the left substantia nigra. Intranasal AdipoRon effectively reversed muscle rigidity, akinesia, bradykinesia, and rotation caused by 6-OHDA. Moreover, AdipoRon increased the phospho-AMPK/AMPK ratio, mitigated mitochondrial dysfunction, and improved mitochondrial dynamics in the SN. Furthermore, AdipoRon increased the number of TH⁺ cells in the SN of PD animals. These findings suggest that AdipoRon could protect dopaminergic neurons by activating the AMPK pathway and improving mitochondrial dysfunction.

帕金森病（PD）中多巴胺能神经元的逐渐衰退与能量失衡和线粒体功能衰竭有关。AMP激活蛋白激酶（AMPK）是细胞内主要的能量传感器，可调节能量平衡，而在缺乏AMPK活性的情况下，6-羟基多巴胺（6-OHDA）诱导的黑质多巴胺能神经元损伤会加剧。本研究旨在探讨 AMPK 激活剂 AdipoRon 对 6-OHDA 诱导的帕金森病模型的运动功能和线粒体稳态的潜在治疗优势。雄性Wistar大鼠单侧左侧前脑内侧束两点注射6-OHDA（10 μg），7天后连续21天鼻内注射AdipoRon（0.1、1和10 μg）或左旋多巴（10 mg/kg，p.o.）。在最后一个治疗日之后，通过默普罗戈试验、单杠试验、横梁行走试验和阿朴吗啡诱导的旋转试验对小鼠的运动行为进行评估。安乐死后，分离左侧黑质（SN）以评估ATP、线粒体膜电位（MMP）以及AMPK、p-AMPK和线粒体动力学标记物（Mfn-2和Drp-1）的蛋白表达。此外，还对左侧黑质中酪氨酸羟化酶阳性（TH+）细胞的数量进行了量化。鼻内注射 AdipoRon 能有效逆转 6-OHDA 引起的肌肉僵硬、运动迟缓和旋转。此外，AdipoRon 还能提高磷酸-APK/APK 比率，缓解线粒体功能障碍，并改善黑质中线粒体的活力。此外，AdipoRon 还能增加 PD 动物神经窦中 TH+ 细胞的数量。这些研究结果表明，AdipoRon 可通过激活 AMPK 途径和改善线粒体功能障碍来保护多巴胺能神经元。

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引用次数: 0

Berberine ameliorates inflammation by inhibiting MrgprB2 receptor-mediated activation of mast cell in mice 小檗碱可抑制小鼠肥大细胞受体介导的肥大细胞活化，从而改善炎症。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-06 DOI: 10.1016/j.ejphar.2024.177109

Yun Huang , Jian Zhang , Huan You , Fan Ye , Yan Yang , Chan Zhu , Yu-Cui Jiang , Zong-Xiang Tang

Background

Berberine, an isoquinoline alkaloid, is known for anti-inflammatory activities. However, the research on the anti-inflammatory mechanism of berberine is not comprehensive. Recently, studies have shown that MrgprB2 (Mas-related G-protein-coupled receptor B2) in mice and MrgprX2 (Mas-related G-protein-coupled receptor X2) in humans play vital roles in inflammation. Therefore, this study aims to investigate whether the anti-inflammatory activity of berberine is related to MrgprB2 receptor.

Methods

The anti-inflammatory activity of BH (berberine hydrochloride) was evaluated by hindpaw edema analysis, pathological analysis and RT-qPCR. Transgenic mice (MrgprB2^−/− mice), HEK293T cell transfection, calcium imaging, electrophysiology, molecular docking and other methods were employed to investigate the potential relationship between the anti-inflammatory activity of BH and the MrgprB2 receptor.

Results

The results demonstrated that BH significantly alleviated C48/80 (compound 48/80)-induced local inflammation in vivo. This was evidenced by a decrease in paw edema, reduced infiltration of inflammatory cells, inhibition of mast cell activation, and down-regulation of inflammatory factors such as CXCL13 (CXC subfamily 13) and TNF-α (tumor necrosis factor-α). It was also found that knockout of MrgprB2 receptor could block the anti-inflammatory activity of BH in mice. Furthermore, calcium imaging revealed that BH effectively inhibited the activity of MrgprB2 receptor in overexpressed HEK293T cells in vitro. Additionally, it was observed that BH also inhibited MrgprB2-mediated voltage-dependent current changes in mouse peritoneal mast cells. Molecular docking results further indicated that BH had affinity with MrgprX2 protein.

Conclusions

The anti-inflammatory mechanism of BH may be partially attributed to the inhibition of MrgprB2 receptor-mediated mast cell activation.

背景：小檗碱是一种异喹啉生物碱，具有抗炎活性。然而，关于小檗碱抗炎机制的研究并不全面。最近的研究表明，小鼠的MrgprB2（与Mas相关的G蛋白偶联受体B2）和人类的MrgprX2（与Mas相关的G蛋白偶联受体X2）在炎症中发挥着重要作用。因此，本研究旨在探讨小檗碱的抗炎活性是否与 MrgprB2 受体有关：方法：通过后爪水肿分析、病理分析和 RT-qPCR 评估 BH（盐酸小檗碱）的抗炎活性。采用转基因小鼠（MrgprB2-/-小鼠）、HEK293T 细胞转染、钙成像、电生理学、分子对接等方法研究 BH 的抗炎活性与 MrgprB2 受体的潜在关系：结果表明，BH 能显著减轻 C48/80（化合物 48/80）诱导的体内局部炎症。这表现在爪水肿减轻、炎症细胞浸润减少、肥大细胞活化受到抑制、CXCL13（CXC 亚家族 13）和 TNF-α（肿瘤坏死因子-α）等炎症因子下调。研究还发现，敲除 MrgprB2 受体可阻断 BH 在小鼠体内的抗炎活性。此外，钙成像显示，在体外过表达的 HEK293T 细胞中，BH 能有效抑制 MrgprB2 受体的活性。此外，还观察到 BH 还抑制了小鼠腹膜肥大细胞中由 MrgprB2 介导的电压依赖性电流变化。分子对接结果进一步表明，BH 与 MrgprX2 蛋白具有亲和性：结论：BH的抗炎机制可能部分归因于抑制了MrgprB2受体介导的肥大细胞活化。

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引用次数: 0

Unleashing the future: The revolutionary role of machine learning and artificial intelligence in drug discovery 释放未来：机器学习和人工智能在药物发现中的革命性作用。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-06 DOI: 10.1016/j.ejphar.2024.177103

Manoj Kumar Yadav , Vandana Dahiya , Manish Kumar Tripathi , Navaneet Chaturvedi , Mayank Rashmi , Arabinda Ghosh , V. Samuel Raj

Drug discovery is a complex and multifaceted process aimed at identifying new therapeutic compounds with the potential to treat various diseases. Traditional methods of drug discovery are often time-consuming, expensive, and characterized by low success rates. Because of this, there is an urgent need to improve the drug development process using new technologies. The integration of the current state-of-art of artificial intelligence (AI) and machine learning (ML) approaches with conventional methods will enhance the efficiency and effectiveness of pharmaceutical research. This review highlights the transformative impact of AI and ML in drug discovery, discussing current applications, challenges, and future directions in harnessing these technologies to accelerate the development of innovative therapeutics. We have discussed the latest developments in AI and ML technologies to streamline several stages of drug discovery, from target identification and validation to lead optimization and preclinical studies.

药物发现是一个复杂而多面的过程，旨在找出有可能治疗各种疾病的新治疗化合物。传统的药物发现方法往往耗时长、成本高、成功率低。因此，迫切需要利用新技术改进药物开发过程。将当前最先进的人工智能（AI）和机器学习（ML）方法与传统方法相结合，将提高药物研究的效率和效果。本综述强调了人工智能和 ML 对药物发现的变革性影响，讨论了利用这些技术加快创新疗法开发的当前应用、挑战和未来方向。我们讨论了人工智能和 ML 技术的最新发展，以简化药物发现的几个阶段，从靶点识别和验证到先导优化和临床前研究。

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引用次数: 0

The role for ω-3 polyunsaturated and short chain fatty acids in hypertension: An updated view on the interaction with gut microbiota ω-3多不饱和脂肪酸和短链脂肪酸在高血压中的作用：与肠道微生物群相互作用的最新观点。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-06 DOI: 10.1016/j.ejphar.2024.177107

Gabriele Brosolo , Andrea Da Porto , Stefano Marcante , Filippo Capilupi , Nicole Bertin , Cinzia Vivarelli , Luca Bulfone , Antonio Vacca , Cristiana Catena , Leonardo A. Sechi

As of 2024, arterial hypertension is still considered the leading modifiable cardiovascular risk factor and, due to high rates of undertreatment and poor blood pressure control, the major contributor to human morbidity and mortality. Development of new treatment options and better interventions in lifestyle correction have become a priority of experimental and clinical research. In the last decades, dietary supplementation of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) and generation of gut microbiota-derived short chain fatty acids (SCFAs) have surged as potential and promising interventions for hypertension and cardiovascular prevention. ω-3 PUFAs are considered “essential” fatty acids that can be obtained only from dietary sources. Although previous intervention trials were not consistent in reporting a significant benefit of ω-3 PUFAs, the recent REDUCE-IT trial has provided robust evidence in support of their role in cardiovascular prevention. Recent studies have also identified the intestinal microbiota as a potential player in the pathophysiology and progression of hypertension. Although this might occur through many pathways, generation of SCFAs that is highly dependent on dietary fiber intake is primarily involved, providing an additional target for the development of novel therapeutic strategies. For these reasons, some scientific societies currently recommend dietary supplementation of ω-3 PUFAs and fiber-containing foods in patients with hypertension. In this narrative review, we summarize the results of studies that examined the effects of ω-3 PUFAs and SCFAs on blood pressure, highlighting the mechanisms of action on the vascular system and their possible impact on hypertension, hypertension-related organ damage and, ultimately, cardiovascular outcomes.

截至 2024 年，动脉高血压仍被认为是最主要的可改变的心血管风险因素，而且由于治疗不足率高和血压控制不佳，动脉高血压还是导致人类发病和死亡的主要因素。开发新的治疗方案和更好的生活方式矫正干预措施已成为实验和临床研究的重点。在过去的几十年中，ω-3 多不饱和脂肪酸（ω-3 PUFAs）的膳食补充和肠道微生物群衍生的短链脂肪酸（SCFAs）作为高血压和心血管预防的潜在和有前途的干预措施得到了迅猛发展。尽管之前的干预试验并未一致报告ω-3 PUFAs 有明显的益处，但最近的 REDUCE-IT 试验提供了有力的证据，支持ω-3 PUFAs 在心血管预防中的作用。最近的研究还发现，肠道微生物群在高血压的病理生理学和发展过程中可能扮演重要角色。虽然这可能通过多种途径发生，但 SCFAs 的生成主要依赖于膳食纤维的摄入，这为新型治疗策略的开发提供了另一个目标。出于这些原因，一些科学协会目前建议高血压患者从膳食中补充ω-3 PUFAs 和含纤维的食物。在这篇叙述性综述中，我们总结了有关 ω-3 PUFAs 和 SCFAs 对血压影响的研究结果，强调了它们对血管系统的作用机制，以及它们对高血压、高血压相关器官损伤和最终心血管后果可能产生的影响。

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引用次数: 0

The involvement and possible targeting of cardiolipins degradation and disturbed linoleic acid metabolism in cardiac atrophy under cancer cachexia 心磷脂降解和亚油酸代谢紊乱参与了癌症恶病质下的心脏萎缩，并可能是其靶点。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-06 DOI: 10.1016/j.ejphar.2024.177108

Yue-ping Wang , Rui-qin Zhang , Nan Li , Qiong-sen Wang , Ke Yu , Meng Fan , Xiong-wen Zhang , Li-xing Feng , Xuan Liu

Cardiac atrophy is one of the critical characteristics of cancer cachexia though its mechanisms had not been fully clarified. In the present study, to study the mechanisms of cardiac atrophy in cancer cachexia and search for possible drug targets, cancer cachexia mice bearing C26 colon tumor cells and cultured H9c2 cardiomyocytes induced with simulated cancer cachexia injuries were used as in vivo and in vitro model, respectively. Results of both spatial metabolomics and LC-MS non-targeted metabolomics analysis of heart tissues suggested the disturbance of glycerophospholipid and fatty acid metabolism in the cancer cachexia hearts. Results of lipidomic analysis confirmed that the fatty acid composition of glycerophospholipids changed and the levels of linoleic acid (LA)-rich cardiolipins (CLs) significantly decreased. GC-MS analysis of fatty acids profile confirmed that the level of LA significantly increased and the ratio value of ω-6/ω-3 polyunsaturated fatty acids (PUFA) also increased in the cancer cachexia hearts. In H9c2 cardiomyocytes induced by simulated cancer cachexia injuries, degradation of CLs were also observed. Furthermore, SS-31, a tetrapeptide targeting CLs, could protect the H9c2 cardiomyocytes under simulated cancer cachexia injury by ameliorating the degradation of CLs, inhibiting apoptosis and attenuating the decrease in cell size. Collectively, these results have provided new insights into the cardiac atrophy in cancer cachexia, in which degradation of glycerophospholipids such as CLs and increase in LA and AA-related oxylipins might be important contributing factors and possible therapy targets.

心脏萎缩是癌症恶病质的重要特征之一，但其机制尚未完全阐明。为了研究癌症恶病质中心脏萎缩的机制并寻找可能的药物靶点，本研究分别以携带C26结肠肿瘤细胞的癌症恶病质小鼠和模拟癌症恶病质损伤诱导培养的H9c2心肌细胞为体内和体外模型。心脏组织的空间代谢组学和LC-MS非靶向代谢组学分析结果表明，癌症恶病质心脏的甘油磷脂和脂肪酸代谢紊乱。脂质体分析结果证实，甘油磷脂的脂肪酸组成发生了变化，富含亚油酸（LA）的心磷脂（CLs）水平显著下降。对脂肪酸谱的气相色谱-质谱（GC-MS）分析证实，癌症恶病质心脏中的亚油酸水平明显升高，ω-6/ω-3 多不饱和脂肪酸（PUFA）的比值也升高。在模拟癌症恶病质损伤诱导的 H9c2 心肌细胞中，也观察到了 CL 的降解。此外，靶向 CLs 的四胜肽 SS-31 可通过改善 CLs 降解、抑制细胞凋亡和减轻细胞体积缩小来保护模拟癌症恶病质损伤下的 H9c2 心肌细胞。总之，这些结果为癌症恶病质中的心脏萎缩提供了新的见解，其中CLs等甘油磷脂的降解以及LA和AA相关氧脂的增加可能是重要的诱因和可能的治疗靶点。

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引用次数: 0

Phenyllactic acid modulates the gut microbiota, enhances intestinal health, and alleviates physical frailty in aging mice 苯乳酸能调节肠道微生物群，增强肠道健康，缓解衰老小鼠的体质虚弱。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-06 DOI: 10.1016/j.ejphar.2024.177105

Dayoung Kim , Han Xu , Ouyang Li , Mengjuan Xue , Zhijun Bao , Fan Yang

Phenyllactic acid (PLA) is a natural antibiotic-like compound derived from certain foods and probiotics. PLA levels have been associated with age-related sarcopenia and provide benefits to metabolic health when derived from probiotics. However, the specific regulatory effects of PLA in aging remain largely unexplored. In this study, aging mice were administered PLA via gavage, followed by fecal 16S rRNA sequencing, measurements of targeted metabolites, glucose metabolism monitoring, and physical performance assessments. Our results indicate that PLA administration significantly altered gut microbiota composition, increased the abundance of short-chain fatty acids (SCFAs) and succinate producing microbiota, and enhanced gut integrity in aging mice. Furthermore, PLA treatment raised fasting blood glucose levels and improved physical activity. Mechanistically, PLA intake elevated the levels of circulating SCFAs and succinate, promoting glycogen metabolic homeostasis and maintaining skeletal muscle oxidative capacity. This study provides evidence that PLA modulates the gut microbiota in aging mice, supports intestinal health, promotes glucose homeostasis, and enhances physical activity.

苯乳酸（PLA）是从某些食物和益生菌中提取的天然抗生素类化合物。聚乳酸水平与年龄相关的肌肉疏松症有关，从益生菌中提取的聚乳酸有益于新陈代谢健康。然而，聚乳酸对衰老的具体调节作用在很大程度上仍未得到探索。在这项研究中，通过灌胃给衰老小鼠服用聚乳酸，然后进行粪便 16S rRNA 测序、目标代谢物测量、葡萄糖代谢监测和体能评估。我们的研究结果表明，服用聚乳酸能显著改变肠道微生物群的组成，增加短链脂肪酸（SCFAs）和产琥珀酸微生物群的丰度，并增强衰老小鼠肠道的完整性。此外，聚乳酸还能提高空腹血糖水平，改善体力活动。从机理上讲，摄入聚乳酸可提高循环中 SCFAs 和琥珀酸盐的水平，促进糖代谢平衡并维持骨骼肌的氧化能力。这项研究提供了证据，证明聚乳酸能调节衰老小鼠的肠道微生物群，支持肠道健康，促进葡萄糖平衡，并增强体力活动。

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引用次数: 0

The power of three: Retatrutide's role in modern obesity and diabetes therapy 三的力量雷特鲁肽在现代肥胖症和糖尿病治疗中的作用。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-06 DOI: 10.1016/j.ejphar.2024.177095

Toufik Abdul-Rahman , Poulami Roy , Fatma Kamal Ahmed , Jann Ludwig Mueller-Gomez , Sarmistha Sarkar , Neil Garg , Victor Oluwafemi Femi-Lawal , Andrew Awuah Wireko , Hala Ibrahim Thaalibi , Muhammad Usman Hashmi , Andrew Sefenu Dzebu , Sewar Basheer Banimusa , Aayushi Sood

The increasing prevalence of obesity and type 2 diabetes mellitus has resulted in a significant challenge to public health throughout the globe. It required the development of novel therapeutic approaches. Retatrutide is a groundbreaking triple agonist that targets glucagon receptors, gastric inhibitory polypeptide, and glucagon-like peptide-1. Retatrutide's complex mechanism of action involves a synergistic interaction among these receptors, resulting in increased insulin secretion, improved glucose homeostasis, and refined appetite modulation. Clinical trials in phases 1 to 3 have demonstrated significant efficacy, highlighted by significant reductions in body weight and favorable glycemic control outcomes. Additionally, retatrutide shows promise in mitigating cardiovascular risk factors and addressing metabolic dysfunction-associated steatotic liver disease. However, careful attention is required to delineate its long-term safety profile, explore its potential in special populations, unravel its adjunctive therapeutic roles, and elucidate its mechanisms in pediatric cohorts. As a transformative therapeutic modality, retatrutide represents a beacon of hope, signifying transformative changes in the management landscape of obesity and type 2 diabetes mellitus (T2DM), and warranting continued exploration and refinement in clinical practice. This narrative review examines the therapeutic potential of retatrutide in the management of obesity and T2DM.

肥胖症和 2 型糖尿病的发病率不断上升，给全球公共卫生带来了重大挑战。这就需要开发新的治疗方法。雷特鲁肽是一种突破性的三重激动剂，靶向胰高血糖素受体、胃抑制多肽和胰高血糖素样肽-1。雷特鲁肽的复杂作用机制包括这些受体之间的协同作用，从而增加胰岛素分泌、改善葡萄糖稳态和调节食欲。1 至 3 期临床试验已证明其疗效显著，突出表现为体重明显减轻，血糖控制结果良好。此外，雷塔曲肽在减轻心血管风险因素和解决代谢功能障碍相关的脂肪性肝病方面也大有可为。然而，还需要仔细研究其长期安全性，探索其在特殊人群中的潜力，揭示其辅助治疗作用，并阐明其在儿科群体中的作用机制。作为一种变革性的治疗方式，雷特鲁肽代表着希望的灯塔，标志着肥胖症和2型糖尿病（T2DM）治疗领域的变革，值得在临床实践中不断探索和完善。这篇叙述性综述探讨了雷他曲肽在肥胖症和 T2DM 治疗中的治疗潜力。

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引用次数: 0

Exendin-4, a glucagon-like peptide-1 receptor agonist, regulates ductus arteriosus by vasodilation and anti-remodeling through the PKA pathway 胰高血糖素样肽-1受体激动剂 Exendin-4 通过 PKA 途径扩张血管和抗重塑调节动脉导管。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-06 DOI: 10.1016/j.ejphar.2024.177106

Yi-Ching Liu , Yu-Hsin Tseng , Yen-Hsien Wu , Lorraine Tong , Siao-Ping Tsai , Shang-En Huang , Bin-Nan Wu , Shih-Hsing Lo , I-Chen Chen , Zen-Kong Dai , Jwu-Lai Yeh , Jong-Hau Hsu

The mechanisms of ductus arteriosus (DA) closure involve vasoconstriction and vascular remodeling. Previous findings indicate that the glucagon-like peptide-1 receptor agonist (GLP-1RA) exhibits antihypertensive and anti-remodeling effects in the pulmonary circulation. However, its role in the DA remains unknown. This study aimed to investigate whether exendin-4 (Ex-4), a GLP-1RA, can regulate DA patency and elucidate its mechanisms. After confirming the presence of GLP-1R in neonatal rat DA tissue in vivo, the effects of Ex-4 on DA patency in neonatal rats were sequentially examined. Two hours after birth, we observed spontaneous closure of the DA in control rats. In contrast, Ex-4 prevented the closure of DA, accompanied by reduced intimal thickening. Ex-4 attenuated oxygen-induced vasoconstriction in isolated DA rings ex vivo. This effect was diminished in the presence of H89, a PKA inhibitor. In vitro, Ex-4 inhibited platelet-derived growth factor (PDGF)-BB-induced proliferation and migration of DA smooth muscle cells. Additionally, Ex-4 inhibited PDGF-BB-induced reactive oxygen species (ROS) production, calcium mobilization, and signal transduction of MAPK and Akt pathways. Furthermore, Ex-4 preserved the nuclear expression of Nrf2 attenuated by PDGF-BB. Similarly, all these in vitro effects of Ex-4 were blunted by H89. In conclusion, Ex-4 maintains postnatal DA patency through vasodilatation and anti-remodeling via the PKA pathway. The GLP-1R/PKA pathway emerges as a promising target of DA patency in clinical management.

动脉导管（DA）关闭的机制包括血管收缩和血管重塑。之前的研究结果表明，胰高血糖素样肽-1 受体激动剂（GLP-1RA）在肺循环中具有降压和抗重塑作用。然而，它在DA中的作用仍然未知。本研究旨在探讨一种 GLP-1RA --- exendin-4（Ex-4）是否能调节肺动脉瓣的通畅，并阐明其作用机制。在确认体内新生大鼠DA组织中存在GLP-1R后，我们依次研究了Ex-4对新生大鼠DA通畅性的影响。出生两小时后，我们观察到对照组大鼠的 DA 自发闭合。与此相反，Ex-4 可阻止 DA 闭合，同时减少内膜增厚。Ex-4 可减轻体内离体 DA 环的氧诱导血管收缩。在使用 PKA 抑制剂 H89 的情况下，这种作用会减弱。在体外，Ex-4 可抑制血小板衍生生长因子（PDGF）-BB 诱导的 DA 平滑肌细胞的增殖和迁移。此外，Ex-4 还抑制了 PDGF-BB 诱导的活性氧（ROS）产生、钙动员以及 MAPK 和 Akt 通路的信号转导。此外，Ex-4 还保留了被 PDGF-BB 削弱的 Nrf2 核表达。同样，Ex-4 的所有这些体外效应都被 H89 削弱。总之，Ex-4通过PKA途径扩张血管和抗重塑，维持了出生后DA的通畅。在临床治疗中，GLP-1R/PKA通路有望成为DA通畅的靶点。

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引用次数: 0

Potential mechanism of perillaldehyde in the treatment of nonalcoholic fatty liver disease based on network pharmacology and molecular docking 基于网络药理学和分子对接的紫苏醛治疗非酒精性脂肪肝的潜在机制

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-06 DOI: 10.1016/j.ejphar.2024.177092

Qian-qian Niu , Yu-ting Xi , Chun-rui Zhang , Xi-yue Li , Cheng-zhi Li , Hui-dan Wang , Peng Li , Ya-ling Yin

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic metabolic liver diseases worldwide. Perillaldehyde (4-propyl-1-en-2-ylcyclohexene-1-aldehyde, PA) is a terpenoid compound extracted from Perilla, which has effective pharmacological activities such as anti-inflammatory, antidepressant, and anticancer. This study aimed to explore the pharmacological effects of PA in intervening with NAFLD and reveal its potential mechanisms. Firstly, we identified the core targets of PA intervention therapy for NAFLD through network pharmacology and molecular docking techniques. After that, in vitro animal experiments such as H&E and Masson staining, immunofluorescence, immunohistochemistry, and Western blot were conducted to validate the results network effectively pharmacology predicted. Network pharmacology analysis suggested that PPAR-α may be the core target of PA intervention in NAFLD. H&E and Masson staining showed that after low-dose (50 mg/kg) PA administration, there was a noticeable improvement in fat deposition in the livers of NAFLD mice, and liver tissue fibrosis was alleviated. Immunohistochemical and immunofluorescence analysis showed that low dose (50 mg/kg) PA could reduce hepatocyte apoptosis, decrease the content of pro-apoptosis protein Bax, and increase the expression of anti-apoptosis protein Bcl-2 in NAFLD mice. Western blot results confirmed that low-dose (50 mg/kg) PA could increase the expression of PPAR-α and inhibit the expression of NF-κB in NAFLD mice. Our study indicated that PA could enhance the activity of PPAR-α and reduce the level of NF-κB in NAFLD mice, which may positively affect the prevention of NAFLD.

非酒精性脂肪肝（NAFLD）是全球最常见的慢性代谢性肝病之一。紫苏醛（4-丙基-1-烯-2-基环己烯-1-甲醛，PA）是从紫苏中提取的一种萜类化合物，具有抗炎、抗抑郁、抗癌等有效药理活性。本研究旨在探索PA干预非酒精性脂肪肝的药理作用，并揭示其潜在机制。首先，我们通过网络药理学和分子对接技术确定了 PA 干预治疗非酒精性脂肪肝的核心靶点。随后，通过H&E和Masson染色、免疫荧光、免疫组化和Western blot等体外动物实验验证了网络药理学预测的结果。网络药理学分析表明，PPAR-α可能是PA干预非酒精性脂肪肝的核心靶点。H&E和Masson染色显示，小剂量（50mg/kg）PA给药后，非酒精性脂肪肝小鼠肝脏脂肪沉积明显改善，肝组织纤维化减轻。免疫组化和免疫荧光分析表明，低剂量（50 毫克/千克）PA 可减少非酒精性脂肪肝小鼠肝细胞凋亡，降低促凋亡蛋白 Bax 的含量，增加抗凋亡蛋白 Bcl-2 的表达。Western印迹结果证实，低剂量（50 毫克/千克）PA 可增加非酒精性脂肪肝小鼠 PPAR-α 的表达，抑制 NF-κB 的表达。我们的研究表明，PA能增强非酒精性脂肪肝小鼠体内PPAR-α的活性，降低NF-κB的水平，这可能对预防非酒精性脂肪肝有积极作用。

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引用次数: 0