Pharmacological research最新文献_第10页

Paracetamol metabolism by endothelial cells – Potential mechanism underlying intravenous paracetamol-induced hypotension 内皮细胞对扑热息痛的代谢——静脉注射扑热息痛诱导低血压的潜在机制。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-01 DOI: 10.1016/j.phrs.2024.107540

Johs Dannesboe, Joakim A. Bastrup, Kathrine Holm Nielsen, Pelle Munck, Morten B. Thomsen, Clare L. Hawkins, Thomas A. Jepps

It was shown previously that a metabolite of acetaminophen (APAP), N-acetyl-p-benzoquinone imine (NAPQI), is a potent vasodilator, which could underlie the hypotension observed when APAP is administered intravenously. However, it is unknown whether APAP metabolism to NAPQI is possible in the vasculature. In this study, we examine the hypothesis that APAP is metabolized by cytochrome P450 enzymes within the endothelium, which may be accelerated in critically ill patients by the presence of elevated myeloperoxidase (MPO). Exposure of human coronary artery endothelial cells (HCAECs) to APAP resulted in the formation of protein-bound APAP adducts. Proteomic analysis of HCAECs exposed to APAP showed upregulation of CYP20A1, together with proteins involved in the pentose phosphate pathway and maintaining redox homeostasis. Proteomic analyses of mesenteric arteries from rats administered intravenous APAP are consistent with a key role of the vascular wall in APAP metabolism, with similar proteomic pathway changes identified in HCAECs. These changes occurred over a short timeframe and were not seen in the corresponding proteomic analyses of liver tissue. Intracellular thiols were depleted in HCAECs upon APAP treatment, which was partially attenuated by ketoconazole, consistent with the involvement of cytochrome P450 enzymes in the metabolism of APAP to a thiol-reactive metabolite such as NAPQI. Evidence was also obtained for the metabolism of APAP to a thiol-reactive intermediate by MPO in the absence of chloride ions, consistent with NAPQI formation. Taken together, these data provide a putative mechanism to explain the presentation of hypotension in critically ill patients following IV APAP administration.

先前的研究表明，对乙酰氨基酚（APAP）的代谢物n -乙酰基-对苯醌亚胺（NAPQI）是一种有效的血管舒张剂，这可能是静脉注射APAP时观察到的低血压的基础。然而，APAP代谢为NAPQI是否可能在脉管系统中存在尚不清楚。在这项研究中，我们检验了APAP是由内皮细胞色素P450酶代谢的假设，在危重患者中，髓过氧化物酶（MPO）升高可能会加速APAP代谢。人冠状动脉内皮细胞（HCAECs）暴露于APAP可形成蛋白结合的APAP加合物。暴露于APAP的hcaec的蛋白质组学分析显示，CYP20A1以及参与戊糖磷酸途径和维持氧化还原稳态的蛋白质上调。静脉注射APAP的大鼠肠系膜动脉的蛋白质组学分析与血管壁在APAP代谢中的关键作用一致，在hcaec中发现了类似的蛋白质组学途径变化。这些变化发生在短时间内，在相应的肝组织蛋白质组学分析中未见。在APAP处理后，hcaec细胞内硫醇被耗尽，酮康唑部分减弱，这与细胞色素P450酶参与APAP代谢为硫醇反应性代谢物（如NAPQI）的过程一致。在没有氯离子的情况下，MPO将APAP代谢为巯基反应中间体，这与NAPQI的形成一致。综上所述，这些数据提供了一个假定的机制来解释重症患者在静脉注射APAP后出现低血压。

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引用次数: 0

The multifaceted anti-atherosclerotic properties of herbal flavonoids: A comprehensive review 草药类黄酮的多方面抗动脉粥样硬化特性综述

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-01 DOI: 10.1016/j.phrs.2024.107551

Meiwen Huang , Xuena Xie , Rong Yuan , Qiqi Xin , Shudong Ma , Hongai Guo , Yu Miao , Chunyu Hu , Yizhun Zhu , Weihong Cong

Atherosclerosis (AS) is a major etiological factor underpinning a spectrum of cardiovascular diseases, leading to cerebral infarction, coronary artery disease, and peripheral vascular disease. The chronic progression of AS, spanning from initial plaque formation to the occurrence of acute cardiovascular events, underscores the complexity of AS and the challenges it presents in terms of treatment. Currently, the clinical management of AS relies predominantly on statins and proprotein convertase subtilisin/kexin type 9 inhibitors, which primarily aim to reduce low-density lipoprotein levels and have demonstrated some therapeutic efficacy. Nevertheless, due to their potential side effects, there is a pressing need to actively investigate alternative treatment approaches. Researches on natural compounds derived from herbal medicines, such as flavonoids, hold significant promise in combating AS by regulating lipid metabolism, reducing oxidative stress and inflammation, inhibiting the proliferation of vascular smooth muscle cells, modulating autophagy and additional pathways. Various targets participate in these physiological processes, encompassing acyl-CoA: cholesterol acyltransferase (ACAT), ATP citrate lyase (ACLY), nuclear factor erythroid 2-related factor 2 (Nrf2), krüppel-like factor 2 (KLF2), NOD-like receptor protein 3 (NLRP3), transcription factor EB (TFEB) and so on. This comprehensive review endeavors to synthesize and analyse the most recent findings on herbal flavonoids, shedding light on their anti-atherosclerotic potential and the underlying protective mechanisms and related-targets, which might pave the way for the development of novel drug candidates or the optimization of flavonoid-based therapies.

动脉粥样硬化（AS）是一系列心血管疾病的主要病因，可导致脑梗死、冠状动脉疾病和周围血管疾病。AS的慢性进展，从最初的斑块形成到急性心血管事件的发生，强调了AS的复杂性及其在治疗方面提出的挑战。目前，AS的临床治疗主要依赖于他汀类药物和蛋白转化酶枯草杆菌素/kexin 9型抑制剂，其主要目的是降低低密度脂蛋白水平，并已显示出一定的治疗效果。然而，由于其潜在的副作用，迫切需要积极研究替代治疗方法。从草药中提取的天然化合物，如黄酮类化合物的研究，通过调节脂质代谢、减少氧化应激和炎症、抑制血管平滑肌细胞的增殖、调节自噬和其他途径，在对抗as方面具有重要的前景。参与这些生理过程的靶标多种多样，包括酰基辅酶a：胆固醇酰基转移酶（ACAT）、ATP柠檬酸裂解酶（ACLY）、核因子红细胞2相关因子2 （Nrf2）、kr pel样因子2 （KLF2）、nod样受体蛋白3 （NLRP3）、转录因子EB （TFEB）等。本文综合分析了近年来有关中草药类黄酮的最新研究成果，揭示了其抗动脉粥样硬化的潜力、潜在的保护机制和相关靶点，为开发新的候选药物或优化基于黄酮的治疗方法铺平了道路。

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引用次数: 0

Efficacy and safety of selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors in FGFR-altered urothelial carcinoma 选择性泛成纤维细胞生长因子受体（FGFR）酪氨酸激酶抑制剂在FGFR改变的尿路上皮癌中的疗效和安全性。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-01 DOI: 10.1016/j.phrs.2024.107543

Yuxuan Song, Yiqing Du, Shan Jiang, Yun Peng, Xing Luo, Tao Xu

Fibroblast growth factor receptor (FGFR) alteration is one of the common driver alterations in urothelial carcinoma (UC). FGFR alterations contribute to anti-tumor immunity inhibition and are associated with attenuated response to immune checkpoint inhibitor (ICI) or chemotherapy. Selective pan-FGFR tyrosine kinase inhibitor (FGFRi) has been approved for FGFR-altered UC. However, the comparative efficacy and safety of FGFRi with ICI or chemotherapy remains under debate. We analyzed 865 UC patients including 447 with FGFRi and 418 with ICI or chemotherapy. FGFRi showed better recurrence-free survival for non-muscle invasive UC and higher objective response for advanced UC than ICI or chemotherapy. However, FGFRi demonstrated no benefit for the survival of advanced UC and led to more treatment-related adverse events, especially adverse events causing dose interruptions. It is worth noting that patients with liver metastasis might benefit from FGFRi in terms of both prognosis and response. In summary, FGFRi offered higher efficacy and lower safety in second-line treatment of FGFR-altered UC. It is crucial for clinicians to balance the efficacy and safety in different tumor stages when considering the use of FGFRi for UC treatment.

成纤维细胞生长因子受体（FGFR）改变是尿路上皮癌（UC）中常见的驱动改变之一。FGFR改变有助于抗肿瘤免疫抑制，并与免疫检查点抑制剂（ICI）或化疗反应减弱有关。选择性泛fgfr酪氨酸激酶抑制剂（FGFRi）已被批准用于fgfr改变的UC。然而，FGFRi与ICI或化疗的相对疗效和安全性仍存在争议。我们分析了865例UC患者，其中447例伴有FGFRi， 418例伴有ICI或化疗。FGFRi在非肌肉侵袭性UC中显示出更好的无复发生存期，在晚期UC中显示出比ICI或化疗更高的客观反应。然而，FGFRi对晚期UC患者的生存没有益处，并导致更多与治疗相关的不良事件，尤其是导致剂量中断的不良事件。值得注意的是，肝转移患者在预后和疗效方面可能受益于FGFRi。综上所述，FGFRi在fgfr改变的UC的二线治疗中提供了更高的疗效和更低的安全性。当临床医生考虑使用FGFRi治疗UC时，平衡不同肿瘤阶段的疗效和安全性是至关重要的。

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引用次数: 0

Unveiling the link between NADPH oxidase 2 activation and mitochondrial superoxide formation in leukemic cell killing induced by arsenic trioxide 揭示三氧化二砷致白血病细胞死亡中NADPH氧化酶2活化与线粒体超氧化物形成之间的联系

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-01 DOI: 10.1016/j.phrs.2024.107554

Andrea Spina , Andrea Guidarelli , Gloria Buffi, Mara Fiorani, Orazio Cantoni

This study focused on the interplay between NADPH oxidase 2 (NOX 2) activation and mitochondrial superoxide (mitoO₂^.-) formation induced by clinically relevant concentrations of arsenic trioxide (ATO; As₂O₃) in acute promyelocytic leukemia (APL) cells.

Carefully controlled inhibitor studies and small interfering RNA mediated downregulation of p47^phox (a component of the NOX 2 complex) expression demonstrated that, in an APL cell line, ATO promotes upstream NOX 2 activation critically connected with the formation of mitoO₂^.- and with the ensuing mitochondrial permeability transition (MPT)-dependent apoptosis.

Instead, acute myeloid leukemia (AML) cell lines respond to ATO with low NOX 2 activation, resulting in a state that is non-permissive for mitoO₂^.- formation. Consistently, through rescue experiments, we demonstrate that pharmacological stimulation of NOX 2 overcomes resistance in these cells, thereby initiating the same cascade of downstream events observed in APL cells.

As a final note, several lines of evidence, including measurement of glutathione, catalase and glutathione peroxidase levels, indicated that the antioxidant machinery was similar in APL and AML cells. The results regarding nuclear factor erythroid 2 p45-related factor 2-dependent antioxidant responses were instead of more complex interpretation as NB4 cells appeared particularly responsive to ATO.

Our findings allow a novel interpretation of the interplay between NOX 2 activation and mitoO₂^.- formation induced by ATO, ultimately steering leukemic cells towards MPT-dependent apoptosis. These mechanistic insights provide a rationale for the disparate responses of APL and AML cells to ATO, offering potential avenues for the development of therapeutic intervention tailored to specific leukemia subtypes.

本研究的重点是NADPH氧化酶2 （NOX 2）的激活和线粒体超氧化物（mitoO2.-）形成之间的相互作用，由临床相关浓度的三氧化二砷(ATO；急性早幼粒细胞白血病（APL）细胞中的As2O3。精心控制的抑制剂研究和小干扰RNA介导的p47phox （NOX 2复合物的一个组成部分）表达下调表明，在APL细胞系中，ATO促进与mitoO2形成密切相关的上游NOX 2激活。-以及随之而来的线粒体通透性转变（MPT）依赖性细胞凋亡。相反，急性髓性白血病（AML）细胞系对ATO的反应是低NOX 2激活，导致mitoO2不允许的状态。——形成。一致地，通过救援实验，我们证明了NOX 2的药理刺激克服了这些细胞中的抗性，从而启动了在APL细胞中观察到的相同的下游级联事件。最后需要说明的是，一些证据，包括谷胱甘肽、过氧化氢酶和谷胱甘肽过氧化物酶水平的测量，表明APL和AML细胞的抗氧化机制是相似的。核因子红细胞2 p45相关因子2依赖性抗氧化反应的结果没有更复杂的解释，因为NB4细胞对ATO表现出特别的反应。我们的发现允许对NOX 2活化和mitoO2之间的相互作用进行新的解释。-由ATO诱导形成，最终引导白血病细胞走向mpt依赖性凋亡。这些机制见解为APL和AML细胞对ATO的不同反应提供了基本原理，为开发针对特定白血病亚型的治疗干预提供了潜在途径。

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引用次数: 0

A hepatocellular carcinoma model with and without parenchymal liver damage that integrates technical and pathophysiological advantages for therapy testing 一个肝细胞癌模型有和没有实质肝损伤，整合技术和病理生理优势的治疗测试。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-01 DOI: 10.1016/j.phrs.2024.107560

Karina Benderski , Paul Schneider , Panayiotis Kordeves , Michael Fichter , Jenny Schunke , Federica De Lorenzi , Feyza Durak , Barbara Schrörs , Özlem Akilli , Fabian Kiessling , Matthias Bros , Mustafa Diken , Stephan Grabbe , Jörn M. Schattenberg , Twan Lammers , Alexandros Marios Sofias , Leonard Kaps

Hepatocellular Carcinoma (HCC) is the most common form of primary liver cancer, with cirrhosis being its strongest risk factor. Interestingly, an increasing number of HCC cases is also observed without cirrhosis. We developed an HCC model via intrasplenic injection of highly tumorigenic HCC cells, which, due to cellular tropism, invade the liver and allow for a controllable disease progression. Specifically, C57BL/6JRj mice were intrasplenically inoculated with Dt81Hepa1–6 HCC cells, with a subgroup pre-treated with CCl₄ to induce cirrhosis (C-HCC). At four weeks post-inoculation, mice were sacrificed, and diseased livers were analyzed via histology, flow cytometry, and RT-qPCR to profile the extracellular matrix (ECM), angiogenesis, and immune cells. In addition, tumor-bearing mice were treated with the first-line therapy, AtezoBev, to assess therapeutic responsiveness of the model. Dt81Hepa1–6 cells displayed similar gene expression as human HCC. After intrasplenic injection, all mice developed multifocal disease. C-HCC mice had a significantly higher tumor load than non-cirrhotic HCC mice. Both HCC and C-HCC models displayed extensive ECM formation, increased levels of vascularization, and immune cell infiltration compared to healthy and non-cancerous cirrhotic livers. AtezoBev treatment produced robust antitumor efficacy, validating the model’s suitability for therapy testing. In conclusion, we established a rapidly developing and high-yield HCC model through a simple intrasplenic injection, with or without cirrhotic damage. The model overexpressed key human HCC genes and showed high responsiveness to first-line treatment. Our model uniquely combines all the above-mentioned features, promoting its use towards HCC therapy testing.

肝细胞癌（HCC）是原发性肝癌最常见的形式，肝硬化是其最强的危险因素。有趣的是，越来越多的HCC病例也没有肝硬化。我们通过脾内注射高度致瘤性HCC细胞建立了HCC模型，由于细胞的趋向性，HCC细胞侵入肝脏并允许可控的疾病进展。具体来说，C57BL/6JRj小鼠脾内接种Dt81Hepa1-6 HCC细胞，其中一个亚组用CCl4预处理以诱导肝硬化（C-HCC）。接种后4周，处死小鼠，通过组织学、流式细胞术和RT-qPCR分析病变肝脏，分析细胞外基质（ECM）、血管生成和免疫细胞。此外，荷瘤小鼠用一线药物AtezoBev治疗，以评估模型的治疗反应性。Dt81Hepa1-6细胞表现出与人类HCC相似的基因表达。脾内注射后，所有小鼠均出现多灶性疾病。C-HCC小鼠的肿瘤负荷明显高于非肝硬化HCC小鼠。与健康和非癌性肝硬化肝脏相比，HCC和C-HCC模型均表现出广泛的ECM形成、血管化水平增加和免疫细胞浸润。AtezoBev治疗产生了强大的抗肿瘤疗效，验证了该模型用于治疗测试的适用性。总之，我们通过简单的脾内注射建立了一个快速发展和高产量的HCC模型，有或没有肝硬化损害。该模型过表达人类HCC关键基因，并对一线治疗表现出高反应性。我们的模型独特地结合了上述所有特征，促进了其在HCC治疗测试中的应用。

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引用次数: 0

Deep proteomics and network pharmacology reveal sex- and age-shared neuropathic pain signatures in mouse dorsal root ganglia 深层蛋白质组学和网络药理学揭示了小鼠背根神经节中性别和年龄共享的神经性疼痛特征。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-01 DOI: 10.1016/j.phrs.2024.107552

Sabrina Grundtner , Julia R. Sondermann , Feng Xian , Daniel Malzl , Daniel Segelcke , Esther M. Pogatzki-Zahn , Jörg Menche , David Gómez-Varela , Manuela Schmidt

Our understanding of how sex and age influence chronic pain at the molecular level is still limited with wide-reaching consequences for adolescent patients. Here, we leveraged deep proteome profiling of mouse dorsal root ganglia (DRG) from adolescent (4-week-old) and adult (12-week-old) male and female mice to investigate the establishment of neuropathic pain in the spared nerve injury (SNI)-model in parallel. We quantified over 12,000 proteins, including notable ion channels involved in pain, highlighting the sensitivity of our approach. Differential expression revealed sex- and age-dependent proteome changes upon nerve injury. In contrast to most previous studies, our comprehensive dataset enabled us to determine differentially expressed proteins (DEPs), which were shared between male and female mice of both age groups. Among these, the vast majority (94 %) were also expressed and, in part, altered in human DRG of neuropathic pain patients, indicating evolutionary conservation. Proteome signatures represented numerous targets of FDA-approved drugs comprising both (i) known pain therapeutics (e.g. Pregabalin and opioids) and, importantly, (ii) compounds with high potential for future re-purposing, e.g. Ptprc-modulators and Epoetins. Protein network and multidimensional analysis uncovered distinct hubs of sex- and age-shared biological pathways impacted by neuropathic pain, such as neuronal activity and synaptic function, DNA-damage, and neuroimmune interactions. Taken together, our results capture the complexity of nerve injury-associated DRG alterations in mice at the network level, moving beyond single-candidate studies. Consequently, we provide an innovative resource of the molecular landscape of neuropathic pain, enabling novel opportunities for translational pain research and network-based drug discovery.

我们对性别和年龄如何在分子水平上影响慢性疼痛的理解仍然有限，对青少年患者的影响广泛。在这里，我们利用小鼠背根神经节（DRG）的深度蛋白质组分析，从青春期（4周龄）和成年（12周龄）的雄性和雌性小鼠，平行研究神经性疼痛在备用神经损伤（SNI）模型的建立。我们量化了超过12,000种蛋白质，包括与疼痛有关的著名离子通道，突出了我们方法的敏感性。差异表达揭示了神经损伤后蛋白质组的性别和年龄依赖性变化。与之前的大多数研究相比，我们的综合数据集使我们能够确定两个年龄组的雄性和雌性小鼠之间共享的差异表达蛋白（DEPs）。其中，绝大多数（94%）也在神经性疼痛患者的DRG中表达，部分改变，表明进化守恒。蛋白质组特征代表了fda批准的药物的许多靶标，包括(i)已知的疼痛治疗药物（例如普瑞巴林和阿片类药物），以及（ii）具有未来重新利用潜力的化合物，例如ptprc -调节剂和Epoetins。蛋白质网络和多维分析揭示了受神经性疼痛影响的不同性别和年龄共享的生物通路枢纽，如神经元活动和突触功能、dna损伤和神经免疫相互作用。综上所述，我们的结果在网络水平上捕获了小鼠神经损伤相关DRG改变的复杂性，超越了单一候选研究。因此，我们提供了神经性疼痛分子景观的创新资源，为转化疼痛研究和基于网络的药物发现提供了新的机会。

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引用次数: 0

Ginsenoside Ro prevents endothelial injury via promoting Epac1/AMPK- mediated mitochondria protection in early diabetic retinopathy 人参皂苷Ro通过促进Epac1/AMPK介导的线粒体保护在早期糖尿病视网膜病变中预防内皮损伤。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-01 DOI: 10.1016/j.phrs.2024.107562

Jia Liu , Yunqi Zhang , Xiaoyu Xu , Xi Dong , Yunfeng Pan , Xiaobo Sun , Yun Luo

Diabetic retinopathy (DR) is a blinding complication of microangiopathy. First-line therapeutic drugs are all focused on late-stage DR and have several side effects, which could not meet clinical needs. The plant-derived ginsenoside Ro (Ro) has a variety of effective anti-inflammatory, immune-regulating, and cardiovascular protective effects, but its microvascular protective effects are rarely studied. This study aimed to explore the protective effect and mechanism of Ro on retinal microvascular endothelial cells in early stage of DR. We demonstrated that Ro exerted endothelial cell protection by regulating mitochondrial oxidative stress and autophagy in AGEs-injured endothelial cells. Moreover, Ro alleviated DR progress through improving retinal thickness and pathological changes in STZ-induced diabetic mice. Mechanically, Ro promotes the activation of Epac1-mediated AMPK signaling. On the contrary, the protective effects of Ro were abolished by Epac1 inhibitor in vitro or Epac1 knock down in vivo. Our results revealed the important role of Ro on the treatment of DR and suggested that targeting Epac1 may be a promising approach to prevent and treat DR.

糖尿病视网膜病变（DR）是微血管病变的致盲并发症。一线治疗药物均以晚期DR为主，副作用较多，不能满足临床需要。植物源性人参皂苷Ro （Ro）具有多种有效的抗炎、免疫调节和心血管保护作用，但其微血管保护作用研究较少。本研究旨在探讨Ro对dr早期视网膜微血管内皮细胞的保护作用及其机制。我们发现Ro通过调节ages损伤的内皮细胞线粒体氧化应激和自噬来发挥内皮细胞保护作用。此外，Ro通过改善stz诱导的糖尿病小鼠视网膜厚度和病理改变来缓解DR进展。机械上，Ro促进epac1介导的AMPK信号的激活。相反，在体外Epac1抑制剂或体内敲低Epac1均可消除Ro的保护作用。我们的研究结果揭示了Ro在DR治疗中的重要作用，并提示靶向Epac1可能是预防和治疗DR的一种有希望的方法。

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引用次数: 0

Targeting protein-protein interactions in drug discovery: Modulators approved or in clinical trials for cancer treatment 药物发现中的靶向蛋白-蛋白相互作用：已批准或处于癌症治疗临床试验中的调节剂。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-01 DOI: 10.1016/j.phrs.2024.107544

Cristina Camps-Fajol , Debora Cavero , Jordi Minguillón , Jordi Surrallés

Protein-protein interactions (PPIs) form complex cellular networks fundamental to many key biological processes, including signal transduction, cell proliferation and DNA repair. In consequence, their perturbation is often associated with many human diseases. Targeting PPIs offers a promising approach in drug discovery and ongoing advancements in this field hold the potential to provide highly specific therapies for a wide range of complex diseases. Despite the development of PPI modulators is challenging, advances in the genetic, proteomic and computational level have facilitated their discovery and optimization. Focusing on anticancer drugs, in the last years several PPI modulators have entered clinical trials and venetoclax, which targets Bcl-2 family proteins, has been approved for treating different types of leukemia. This review discusses the clinical development status of drugs modulating several PPIs, such as MDM2–4/p53, Hsp90/Hsp90, Hsp90/CDC37, c-Myc/Max, KRAS/SOS1, CCR5/CCL5, CCR2/CCL2 or Smac/XIAP, in cancer drug discovery.

蛋白质-蛋白质相互作用（PPIs）形成了复杂的细胞网络，是许多关键生物过程的基础，包括信号转导、细胞增殖和DNA修复。因此，它们的扰动往往与许多人类疾病有关。靶向PPIs为药物发现提供了一种很有前途的方法，并且该领域的持续进展具有为广泛的复杂疾病提供高度特异性治疗的潜力。尽管PPI调节剂的开发具有挑战性，但遗传学、蛋白质组学和计算水平的进步促进了它们的发现和优化。专注于抗癌药物，在过去的几年里，几种PPI调节剂已经进入临床试验，而venetoclax，一种靶向Bcl-2家族蛋白的药物，已经被批准用于治疗不同类型的白血病。本文综述了MDM2-4/p53、Hsp90/Hsp90、Hsp90/CDC37、c-Myc/Max、KRAS/SOS1、CCR5/CCL5、CCR2/CCL2、Smac/XIAP等几种PPIs在肿瘤药物发现中的临床发展现状。

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引用次数: 0

Protective role of 3-mercaptopyruvate sulfurtransferase (MPST) in the development of metabolic syndrome and vascular inflammation 3-巯基丙酮酸硫转移酶（MPST）在代谢综合征和血管炎症发生中的保护作用

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-01 DOI: 10.1016/j.phrs.2024.107542

Paraskevas Zampas , Zhen Li , Antonia Katsouda , Aimilia Varela , Stelios Psarras , Constantinos H. Davos , David J. Lefer , Andreas Papapetropoulos

Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that occur concurrently and increase the risk of cardiovascular disease. 3-mercaptopyruvate sulfurtransferase (MPST) is a cysteine-catabolizing enzyme that yields pyruvate and hydrogen sulfide (H₂S) and plays a central role in the regulation of energy homeostasis. Herein, we seek to investigate the role of MPST/H₂S in MetS and its cardiovascular consequences using a mouse model of the disease. Mice were fed a high-fat diet (HFD) for 15 weeks to induce obesity and hyperglycemia and administrated a nitric oxide synthase inhibitor, during the last 5 weeks to induce hypertension and MetS. This model caused a mild left ventricular (LV) diastolic dysfunction and vascular endothelial dysfunction. Free H₂S and sulfane-sulfur levels were decreased in the aorta, but unaltered in the heart. Also, downregulation of MPST and thiosulfate sulfuretransferase (TST) were observed in the aorta. Global deletion of Mpst (Mpst^-/-) resulted in increased body weight and greater glucose intolerance in mice with MetS, without affecting their blood pressure, and caused an upregulation of genes involved in immune responses in the vasculature suggestive of T-cell infiltration and activation. Pharmacological restoration of H₂S levels ameliorated the comorbidities of MetS; GYY4137 administration reduced body weight and blood pressure, attenuated cardiac fibrosis and improved glucose handling and endothelium-dependent relaxation. In conclusion, this study found that reduced MPST/H₂S exacerbates the pathological changes associated with MetS and contributes to vascular inflammation. H₂S supplementation emerges as a potential therapeutic approach to treat the abnormalities associated with MetS.

代谢综合征（MetS）是一组同时发生并增加心血管疾病风险的代谢异常。3-巯基丙酮酸硫转移酶（MPST）是一种半胱氨酸分解代谢酶，产生丙酮酸和硫化氢（H2S），在调节能量稳态中起核心作用。在此，我们试图通过小鼠疾病模型研究MPST/H2S在MetS中的作用及其心血管后果。小鼠喂食高脂肪饮食（HFD） 15周以诱导肥胖和高血糖，并在最后5周给予一氧化氮合酶抑制剂以诱导高血压和MetS。该模型引起轻度左室舒张功能障碍和血管内皮功能障碍。主动脉中游离H2S和亚砜硫水平降低，但心脏中没有变化。此外，主动脉中MPST和硫代硫酸盐硫转移酶（TST）下调。Mpst （Mpst-/-）的整体缺失导致MetS小鼠体重增加和葡萄糖耐受不良加剧，但不影响血压，并导致参与血管免疫反应的基因上调，提示t细胞浸润和激活。药理恢复H2S水平可改善MetS的合并症；GYY4137可减轻体重和血压，减轻心脏纤维化，改善葡萄糖处理和内皮依赖性松弛。综上所述，本研究发现MPST/H2S减少会加剧与MetS相关的病理变化，并导致血管炎症。补充H2S是治疗与MetS相关的异常的潜在治疗方法。

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引用次数: 0

Advancing precision therapy for colorectal cancer: Developing clinical indications for multi-target kinase inhibitor BPR1J481 using patient-derived xenograft models 推进结直肠癌的精准治疗：利用患者来源的异种移植模型开发多靶点激酶抑制剂BPR1J481的临床适应症。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-01-01 DOI: 10.1016/j.phrs.2024.107556

Ya-Chu Tang , Jing-Jim Ou , Shu-Ching Hsu , Chih-Hsiang Huang , Li-Mei Lin , Hsin-Huei Chang , Yi-Hsin Wang , Zih-Ting Huang , Manwu Sun , Ko-Jiunn Liu , Yi-Mei Hung , Chi-Yun Lai , Chuan Shih , Chiung-Tong Chen , Jang-Yang Chang , Hsing-Pang Hsieh , Weir-Torn Jiaang , Ching-Chuan Kuo

The large and rapid increase in the incidence and mortality of colorectal cancer (CRC) demonstrates the urgent need for new drugs with higher efficacy to treat CRC. However, the lack of applicable and reliable preclinical models significantly hinders the progress of drug development. Patient-derived xenograft (PDX) models are currently considered reliable in vivo preclinical models for predicting drug efficacy in cancer patients. This study successfully uses the CRC PDX model to develop clinical indications for the new multi-target kinase inhibitor BPR1J481 and demonstrated the anti-cancer mechanism and competitive advantages of this drug candidate. The results demonstrate that BPR1J481 exhibits significant anticancer efficacy by inducing apoptosis in CRC PDX tumor tissues and corresponding PDX-derived CRC cells. Through kinase competitive binding and kinase activity assays, we discover that BPR1J481 effectively inhibits SRC kinase activity by directly binding to its active site. The reduction in SRC phosphorylation observed in CRC PDX tumor tissues and derived cells upon treatment with BPR1J481 further validates its inhibitory potential. Furthermore, the decrease in viable cells after SRC knockout and the poorer prognosis observed in patients with higher SRC expression, emphasizes the critical significance and clinical relevance of SRC in CRC. Additionally, BPR1J481 exhibits robust anti-angiogenic effects by suppressing VEGF- and PDGF-induced endothelial cell proliferation, migration, and capillary-like tube formation through inhibition of VEGFR2 and PDGFRβ phosphorylation. Remarkably, BPR1J481 appears to demonstrate greater efficacy against CRC compared to regorafenib. These findings highlight the therapeutic potential of BPR1J481 for patients with CRC.

结直肠癌（colorectal cancer， CRC）发病率和死亡率的大幅快速增长，表明迫切需要更高疗效的治疗结直肠癌的新药。然而，缺乏适用和可靠的临床前模型严重阻碍了药物开发的进展。患者来源的异种移植（PDX）模型目前被认为是预测癌症患者药物疗效的可靠的体内临床前模型。本研究成功利用CRC PDX模型建立了新的多靶点激酶抑制剂BPR1J481的临床适应症，并展示了该候选药物的抗癌机制和竞争优势。结果表明，BPR1J481通过诱导CRC PDX肿瘤组织和相应的PDX来源的CRC细胞凋亡而具有显著的抗癌作用。通过激酶竞争结合和激酶活性分析，我们发现BPR1J481通过直接结合其活性位点有效抑制SRC激酶活性。BPR1J481在CRC PDX肿瘤组织和衍生细胞中观察到SRC磷酸化降低，进一步证实了其抑制潜力。此外，SRC基因敲除后存活细胞减少，SRC高表达患者预后较差，强调了SRC在CRC中的关键意义和临床相关性。此外，BPR1J481通过抑制VEGFR2和PDGFRβ磷酸化，抑制VEGF和pdgf诱导的内皮细胞增殖、迁移和毛细血管样管形成，显示出强大的抗血管生成作用。值得注意的是，与regorafenib相比，BPR1J481似乎对结直肠癌表现出更大的疗效。这些发现强调了BPR1J481对结直肠癌患者的治疗潜力。

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引用次数: 0