Pharmacological research最新文献_第4页

Low, non-psychedelic doses of psilocybin as a novel treatment for MASLD, obesity and type 2 diabetes via 5-HT2B receptor-dependent mechanisms 低剂量、非致幻剂裸盖菇素通过5-HT2B受体依赖机制作为MASLD、肥胖和2型糖尿病的新治疗方法。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-29 DOI: 10.1016/j.phrs.2025.108080

Martina Colognesi , Daniela Gabbia , Anna Signor , Miles Sarill , Lucia Centofanti , Andrea Rinaldi , Luciano Cascione , Sara Nunziata , Marco Banzato , Andrea Mattarei , Giovanna Finzi , Sonia Sonda , Diana Pendin , Ilaria Zanotto , Stefano Comai , Gianfranco Pasut , Abdullah Alajati , Miriam Saponaro , Loredana Bucciarelli , Maria Elena Lunati , Sara De Martin

The therapeutic potential of low, non-psychedelic doses of psilocybin, a fungal tryptamine alkaloid, was investigated in metabolic disorders including obesity, type 2 diabetes mellitus (T2DM), and liver steatosis. Mice fed a high-fat/high-fructose diet received chronic treatment with psilocybin (0.05 mg/kg) for 12 weeks. Body weight, liver histology, insulin sensitivity, and skeletal muscle function were assessed, and hepatic and muscle tissues underwent transcriptomic and lipidomic analyses. The role of three serotonin receptors (5-HT2A, 5-HT2B, and 5-HT2C) in psilocybin-induced metabolic effects was examined in human cell lines using pharmacological and CRISPR/Cas9-based genetic approaches. Low-dose psilocybin reduced body-weight gain, liver steatosis, hyperglycaemia, and insulin resistance without eliciting central nervous system effects. Multi-omics analyses revealed near-complete normalization of disrupted hepatic lipid and carbohydrate metabolism pathways. Psilocybin also improved muscle strength and function, potentially through restoration of leptin sensitivity. Mechanistic studies demonstrated that these metabolic benefits were independent of the canonical psychedelic target 5-HT2A and instead resulted from antagonism of the serotonin 5-HT2B receptor in the liver. Overall, chronic low-dose psilocybin exerts broad metabolic benefits via a hepatic 5-HT2B-dependent mechanism, distinct from its psychedelic effects, supporting its potential as a novel therapeutic strategy for liver steatosis, obesity, T2DM, and sarcopenia.

低剂量的非致幻剂裸盖菇素（一种真菌色胺生物碱）治疗代谢紊乱包括肥胖、2型糖尿病（T2DM）和肝脂肪变性的潜力进行了研究。饲喂高脂肪/高果糖饮食的小鼠给予裸盖菇素（0.05mg/kg）慢性治疗12周。评估体重、肝脏组织学、胰岛素敏感性和骨骼肌功能，并对肝脏和肌肉组织进行转录组学和脂质组学分析。在人类细胞系中，使用药理学和基于CRISPR/ cas9的遗传方法检测了三种5-羟色胺受体（5-HT2A、5-HT2B和5-HT2C）在裸盖菇素诱导的代谢效应中的作用。低剂量裸盖菇素可减少体重增加、肝脂肪变性、高血糖和胰岛素抵抗，而不会引起中枢神经系统的影响。多组学分析显示，肝脏脂质和碳水化合物代谢途径几乎完全正常化。裸盖菇素还能改善肌肉力量和功能，可能是通过恢复瘦素敏感性来实现的。机制研究表明，这些代谢益处与典型的迷幻靶点5-HT2A无关，而是由肝脏中5-HT2B受体的5-羟色胺的拮抗作用引起的。总的来说，慢性低剂量裸盖菇素通过肝脏5- ht2b依赖机制发挥广泛的代谢益处，不同于其迷幻作用，支持其作为肝脏脂肪变性、肥胖、2型糖尿病和肌肉减少症的新治疗策略的潜力。

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引用次数: 0

PHGDH as a therapeutic node: Natural modulators from TCM, degradation pathways, and emerging TPD strategies PHGDH作为治疗节点：来自中医的天然调节剂、降解途径和新兴的TPD策略。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-23 DOI: 10.1016/j.phrs.2025.108079

Song-Song Shi , Yu-Dan Du , Si-Yi Chen , Wen Zhang , Guo-Wu Rao , Quan Zheng

Phosphoglycerate dehydrogenase (PHGDH) has emerged as a promising therapeutic target due to its critical roles in the pathogenesis of cancer and neurological disorders. Targeting PHGDH holds significant theoretical and translational potential for cancer therapy and the amelioration of cognitive impairments. However, currently available PHGDH inhibitors are limited in number and primarily function through inhibition of the enzyme's catalytic activity. This review systematically summarizes PHGDH modulators identified from traditional Chinese medicine, including both inhibitors and activators, and presents a detailed analysis of their structure–activity relationships (SAR) and mechanisms of action. It also comprehensively outlines the signaling pathways that regulate PHGDH degradation through the ubiquitin–proteasome system and autophagy–lysosome pathway. Importantly, it also discusses emerging targeted protein degradation (TPD) technologies, including PROTACs, LYTACs, AUTACs, and ATTECs. The development of these frontier technologies has opened new pathways for mitigating the limitations of existing inhibitors.

磷酸甘油酸脱氢酶（Phosphoglycerate dehydrogenase， PHGDH）由于在癌症和神经系统疾病的发病机制中起着关键作用而成为一个有希望的治疗靶点。靶向PHGDH在癌症治疗和改善认知障碍方面具有重要的理论和转化潜力。然而，目前可用的PHGDH抑制剂数量有限，主要通过抑制酶的催化活性起作用。本文系统综述了中药中发现的PHGDH调节剂，包括抑制剂和激活剂，并详细分析了它们的构效关系（SAR）和作用机制。它还全面概述了通过泛素-蛋白酶体系统和自噬-溶酶体途径调节PHGDH降解的信号通路。重要的是，它还讨论了新兴的靶向蛋白降解（TPD）技术，包括PROTACs， lytac， autac和attec。这些前沿技术的发展为减轻现有抑制剂的局限性开辟了新的途径。

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引用次数: 0

Multi-target neuroprotective effects of notoginsenoside R1 in neurodegenerative diseases: From pharmacokinetics to translational prospects 三七皂苷R1在神经退行性疾病中的多靶点神经保护作用：从药代动力学到转化前景。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-18 DOI: 10.1016/j.phrs.2025.108074

Hao-wen Lin , Shi-pian Li , Jia-xin Wen , Jia-xuan Zhang , Bi-meng Zhang , Yong-jun Wang , Xue-jun Cui , Min Yao

Neurodegenerative diseases impose a heavy social and economic burden, and effective therapeutic strategies are essential for slowing disease progression and improving patient quality of life. Notoginsenoside R1 (NGR1), a key saponin derived from Panax notoginseng (Burk. F.H. Chen), has been widely studied in experimental models of neurodegenerative diseases, such as stroke and Alzheimer’s disease (AD). Based on a rigorous literature screening and a meta-analysis of animal studies, we confirmed that NGR1 significantly reduces infarct volumes in cerebral ischemia-reperfusion models and improves escape latency in AD mice. Mechanistically, NGR1 confers neuroprotection by attenuating oxidative stress, suppressing neuroinflammation, inhibiting apoptosis, and preserving the neurovascular unit. Furthermore, using network pharmacology, reverse virtual screening, and molecular docking, we preliminarily identified potential targets and signaling pathways, providing a theoretical basis for future studies. However, clinical translation of NGR1 remains limited due to poor oral bioavailability and restricted permeability across the blood-brain and blood-spinal cord barriers. To address these challenges, we summarized delivery strategies, including nanoparticle-based carriers, intranasal administration, and permeability enhancers, to facilitate NGR1 entry into the central nervous system. We also discussed additional potential approaches, such as structural modification and targeted delivery, analyzing their respective advantages and limitations. Collectively, these findings highlight NGR1 as a promising candidate for the prevention and treatment of neurodegenerative diseases.

神经退行性疾病造成沉重的社会和经济负担，有效的治疗策略对于减缓疾病进展和改善患者生活质量至关重要。三七皂苷R1 （NGR1）是一种从三七中提取的关键皂苷。在神经退行性疾病，如中风和阿尔茨海默病（AD）的实验模型中得到了广泛的研究。基于严格的文献筛选和动物研究的荟萃分析，我们证实NGR1显著减少脑缺血再灌注模型中的梗死体积，并改善AD小鼠的逃避潜伏期。从机制上讲，NGR1通过减轻氧化应激、抑制神经炎症、抑制细胞凋亡和保存神经血管单位来提供神经保护。通过网络药理学、反向虚拟筛选、分子对接等手段，初步确定了潜在靶点和信号通路，为后续研究提供理论基础。然而，由于口服生物利用度差以及血脑和血脊髓屏障的渗透性有限，NGR1的临床转化仍然有限。为了解决这些挑战，我们总结了递送策略，包括纳米颗粒载体、鼻内给药和渗透性增强剂，以促进NGR1进入中枢神经系统。我们还讨论了其他可能的方法，如结构改造和定向输送，分析了各自的优势和局限性。总的来说，这些发现突出了NGR1作为预防和治疗神经退行性疾病的有希望的候选者。

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引用次数: 0

Epigenetic Regulation in calcific aortic valve disease: Mechanisms and therapeutic potential 钙化主动脉瓣疾病的表观遗传调控：机制和治疗潜力

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-17 DOI: 10.1016/j.phrs.2025.108073

Hanshen Luo, Yuehang Yang, Chiyang Xie, Chuli Shi, Siyuan Liu, Jiawei Shi

Calcific aortic valve disease (CAVD) is a progressive cardiovascular disorder pathologically defined by valvular sclerosis, fibrosis, and ectopic mineralization, which constitutes a substantial and growing public health burden. Currently, surgical intervention represents the sole effective treatment, underscoring a critical unmet need for novel pharmacological strategies that can halt disease progression or provide early therapeutic intervention. Extensive research has established that the pathogenesis of CAVD is driven by a complex interplay of multiple mechanisms including inflammatory responses, oxidative stress, and metabolic dysregulation which are intricately modulated by epigenetic regulation, post-transcriptional modifications, and protein post-translational modifications. In recent years, the field of epigenetics has garnered considerable attention, particularly for its pivotal role in the pathogenesis of oncological and cardiovascular diseases and the subsequent development of targeted therapeutic strategies. Consequently, numerous investigations have been dedicated to elucidating the involvement of epigenetic mechanisms in CAVD, encompassing DNA methylation, histone modifications (including methylation and acetylation), and RNA methylation, with a pronounced emphasis on the regulatory functions of non-coding RNAs. This review synthesizes recent advances in our understanding of epigenetic mechanisms underlying CAVD, with a specific focus on the role of RNA N6-methyladenosine (m6A) methylation, and highlights the pivotal significance of epigenetic modulation in critical biological processes and CAVD pathogenesis. Collectively, these findings offer valuable mechanistic insights and may illuminate novel paths toward the clinical translation of epigenetically targeted therapies for CAVD.

钙化性主动脉瓣病（CAVD）是一种进行性心血管疾病，病理定义为瓣膜硬化、纤维化和异位矿化，构成了巨大且日益增长的公共卫生负担。目前，手术干预是唯一有效的治疗方法，强调了对能够阻止疾病进展或提供早期治疗干预的新型药理策略的关键未满足需求。大量研究表明，CAVD的发病机制是由多种机制的复杂相互作用驱动的，包括炎症反应、氧化应激和代谢失调，这些机制由表观遗传调控、转录后修饰和蛋白质翻译后修饰复杂地调节。近年来，表观遗传学领域获得了相当大的关注，特别是其在肿瘤和心血管疾病的发病机制以及随后的靶向治疗策略发展中的关键作用。因此，许多研究都致力于阐明CAVD的表观遗传机制，包括DNA甲基化，组蛋白修饰（包括甲基化和乙酰化）和RNA甲基化，并强调非编码RNA的调节功能。本文综述了近年来我们对CAVD的表观遗传机制的理解，特别关注RNA n6 -甲基腺苷（m6A）甲基化的作用，并强调了表观遗传调控在CAVD的关键生物学过程和发病机制中的关键意义。总的来说，这些发现提供了有价值的机制见解，并可能为CAVD的表观遗传靶向治疗的临床翻译照亮新的途径。

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引用次数: 0

Mast cells in digestive diseases: New insights to keep them under control 消化系统疾病中的肥大细胞：控制肥大细胞的新见解。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-14 DOI: 10.1016/j.phrs.2025.108069

Hayriye Akel Bilgic, Marie Bek, Mirelle Kleuskens, Frank Redegeld

The gut mucosa serves as an essential interface between the internal and external environment, providing a continuous barrier against possible harmful luminal content. The regulation of this protective function is controlled by immune-mediated and non-immune mechanisms, wherein mast cells (MCs) play a key role. These versatile immune cells are strategically located in the lining of the gastrointestinal (GI) tract, where they help maintain the integrity of the intestinal barrier, regulate blood flow, control the entry of immune cells into tissues, and participate in various physiological processes, such as wound healing and intestinal peristalsis. However, excessive MC activation may disturb the gut balance, which could cause a "leaky gut", where increased permeability of the intestinal lining allows substances to pass into the bloodstream, causing various health problems. Studies have confirmed an increased presence of MCs in the intestinal lining of individuals with compromised barriers, as seen in conditions like gastrointestinal diseases (GIDs). Hence, precise regulation of MC activity is essential for maintaining intestinal health and limiting disease progression. In this review, we aim to offer a comprehensive and current overview of the role of MCs in GIDs by delving into their origins, functions, and interactions in the GI environment. We explore the "leaky gut" concept, examining how MCs influence the intestinal barrier and its association with GIDs. Additionally, we describe the latest advancements in MC research, including targeted therapies and potential future directions.

肠道黏膜是内外环境之间的重要接口，为可能有害的肠道内容物提供了持续的屏障。这种保护功能的调节由免疫介导和非免疫机制控制，其中肥大细胞（MCs）起关键作用。这些多功能免疫细胞战略性地位于胃肠道的内壁，在那里它们帮助维持肠道屏障的完整性，调节血液流动，控制免疫细胞进入组织，并参与各种生理过程，如伤口愈合和肠道蠕动。然而，过度的MC激活可能会扰乱肠道平衡，从而导致“漏肠”，即肠道内膜通透性增加，使物质进入血液，导致各种健康问题。研究证实，屏障受损的个体肠道内壁中MCs的存在增加，如胃肠道疾病（gid）等疾病。因此，精确调节MC活性对于维持肠道健康和限制疾病进展至关重要。在这篇综述中，我们旨在通过深入研究MCs的起源、功能和在GI环境中的相互作用，对MCs在GI中的作用进行全面和最新的概述。我们探讨了“漏肠”的概念，研究了MCs如何影响肠屏障及其与gid的关联。此外，我们描述了MC研究的最新进展，包括靶向治疗和潜在的未来方向。

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引用次数: 0

Rapid 64Cu radiolabeling and in vivo evaluation of DSPE–NODAGA liposomes in a murine mammary tumor model DSPE-NODAGA脂质体在小鼠乳腺肿瘤模型中的快速64Cu放射性标记及体内评价

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-12 DOI: 10.1016/j.phrs.2025.108065

Elena Markova , Mathias Kranz , Morten Karlsen , Camilla Wolowczyk , Angel Moldes-Anaya , Nataša Škalko-Basnet , Rune Sundset , Alexandros Marios Sofias , Rodrigo Berzaghi , Montserrat Martin-Armas , Sjoerd Hak

Understanding the in vivo behavior of nanomedicines is critical for optimizing their therapeutic efficacy and facilitating personalized treatment strategies. In the quest to develop positron emission tomography (PET) methodology for liposome biodistribution studies, we systematically compared three liposome radiolabeling strategies - remote loading of ⁶⁴Cu into liposomes containing the hydrophilic chelator NOTA, membrane labeling using ATSM, and surface labeling with DSPE-NODAGA (phospholipid DSPE conjugated with chelator NODAGA) - to identify an effective method for liposome radiolabeling with ⁶⁴Cu. Our results demonstrated that DSPE-NODAGA incorporated in PEGylated liposomes allows for achieving 100 % radiochemical yield of ⁶⁴Cu at room temperature within just 5 min. Stability studies confirmed liposome integrity and minimal transchelation or dissociation in serum over 24 h, highlighting its suitability for in vivo applications. PET/MR imaging in healthy and tumor-bearing mice revealed prolonged circulation of ⁶⁴Cu-labeled PEGylated liposomes (PL-NODAGA) and significant tumor accumulation, validating DSPE-NODAGA’s potential for real-time tracking of liposome delivery. These findings establish the incorporation of DSPE-NODAGA as a robust and adaptable platform for PET-based monitoring of lipidic nanomedicine.

了解纳米药物的体内行为对于优化其治疗效果和促进个性化治疗策略至关重要。为了开发用于脂质体生物分布研究的正电子发射断层扫描（PET）方法，我们系统地比较了三种脂质体放射性标记策略——将64Cu远程装载到含有亲水性螯合剂NOTA的脂质体中，使用ATSM进行膜标记，以及使用DSPE-NODAGA（磷脂DSPE与螯合剂NODAGA偶联）进行表面标记——以确定一种有效的64Cu脂质体放射性标记方法。我们的研究结果表明，加入聚乙二醇脂质体的DSPE-NODAGA可以在室温下仅5分钟内实现100%的64Cu放射化学产率。稳定性研究证实脂质体的完整性和最小的转移或解离在血清中超过24小时，强调其适合体内应用。健康小鼠和肿瘤小鼠的PET/MR成像显示64cu标记的聚乙二醇脂质体（PL-NODAGA）循环延长和显著的肿瘤堆积，验证了DSPE-NODAGA在实时跟踪脂质体递送方面的潜力。这些发现建立了DSPE-NODAGA作为基于pet的脂质纳米药物监测的强大且适应性强的平台。

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引用次数: 0

Antibody-drug conjugates: A new twist to overcome EGFR-TKIs resistance in non-small cell lung cancer 抗体-药物结合物：在非小细胞肺癌中克服EGFR-TKIs耐药性的新方法

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-12 DOI: 10.1016/j.phrs.2025.108066

Shengqian Deng , Chengtao Sun , Dewen Liu , Yusha Zhang , Jizhou Zhang , Xiaojuan Li , Xu Jia , Guoyin Kai

Non-small cell lung cancer (NSCLC) accounts for 80–90 % of all lung cancer cases and is characterized by high incidence and mortality rates. The epidermal growth factor receptor (EGFR), one of the most frequently mutated genes in NSCLC, has become a key target for treatment through the development of EGFR-tyrosine kinase inhibitors (EGFR-TKIs). While EGFR-TKIs have shown significant therapeutic effects, clinical observations indicate that most patients eventually develop drug resistance. Antibody-drug conjugates (ADCs) represent a potent strategy to overcome EGFR-TKIs resistance by precisely delivering cytotoxic payloads to tumor cells via targets such as EGFR itself or other relevant molecules. In this review, we provide a comprehensive overview of EGFR-TKIs, including their structure, clinical applications, and mechanisms of resistance. We examine the role of ADCs in EGFR-mutated NSCLC, focusing on current targets such as MET, HER2, TROP2, and EGFR, as well as emerging targets under investigation. It is worth mentioning that the development of bispecific ADCs represents a novel frontier in overcoming resistance. We also discuss other novel therapeutic approaches to overcome EGFR-TKIs resistance, including protein degradation–targeting chimeras, poly (ADP-ribose) polymerase inhibitors, aurora kinase inhibitors, and metabolic reprogramming strategies. Finally, we summarize the main challenges associated with ADCs-based therapies and highlight future directions for optimizing treatment in EGFR-TKI-resistant NSCLC.

非小细胞肺癌（NSCLC）占所有肺癌病例的80-90%，其特点是发病率和死亡率高。表皮生长因子受体（EGFR）是NSCLC中最常见的突变基因之一，通过开发EGFR-酪氨酸激酶抑制剂（EGFR- tkis）已成为治疗的关键靶点。虽然EGFR-TKIs已显示出显著的治疗效果，但临床观察表明，大多数患者最终会产生耐药性。抗体-药物偶联物（adc）是一种克服EGFR- tkis耐药性的有效策略，它通过靶细胞（如EGFR本身或其他相关分子）将细胞毒性有效载荷精确地递送到肿瘤细胞。本文就EGFR-TKIs的结构、临床应用及耐药机制等方面进行综述。我们研究了adc在EGFR突变的非小细胞肺癌中的作用，重点关注当前的靶标，如MET、HER2、TROP2和EGFR，以及正在研究的新靶标。值得一提的是，双特异性adc的发展代表了克服耐药性的新前沿。我们还讨论了其他克服EGFR-TKIs耐药的新治疗方法，包括蛋白降解靶向嵌合体、聚（adp -核糖）聚合酶抑制剂、极光激酶抑制剂和代谢重编程策略。最后，我们总结了与基于adcs的治疗相关的主要挑战，并强调了优化egfr - tki耐药NSCLC治疗的未来方向。

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引用次数: 0

VEGF-B: A multifaceted modulator with emerging therapeutic applications VEGF-B：一种具有新兴治疗应用的多方面调节剂

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-11 DOI: 10.1016/j.phrs.2025.108064

Chunsik Lee , Myung-Jin Kim , Eunyoung Jung , Jianing Zhang , Vivek Hamse Kameshwar , Nayoung Oh , Anil Kumar , Han-Woong Lee , Xuri Li , Yonghwan Kim

Long overshadowed by VEGF-A, vascular endothelial growth factor B (VEGF-B) has emerged as a critical regulator of vascular, metabolic, and immune cross-talk. Unlike the potent angiogenic factor VEGF-A, VEGF-B does not induce vascular leakage but modulates tissue-specific functions, including fatty acid transport, neuronal survival, and immunometabolism, through its receptors VEGFR1 and NRP1. Its roles are often paradoxical, suppressing angiogenesis in some cancers while promoting metastasis and immune evasion in others, highlighting its profoundly context-dependent nature of action. Recent discoveries, such as the identification of FGFR1 as a key receptor and the essential role of VEGF-B in T cell survival, have revitalized interest in its therapeutic potential. However, clinical translation remains challenging, as exemplified by the recent failure of the anti-VEGF-B antibody CSL346 in diabetic kidney disease, underscoring our incomplete understanding of VEGF-B biology. This review integrates cutting-edge insights into the diverse functions of VEGF-B, proposes a mechanistic framework for its complex signaling networks, and outlines a roadmap for developing precision therapies for metabolic, cardiovascular, neurodegenerative, and oncological diseases. We address the critical translational challenges to maximize the therapeutic benefits while preserving the crucial homeostatic functions of VEGF-B.

长期被VEGF-A掩盖，血管内皮生长因子B （VEGF-B）已成为血管、代谢和免疫串扰的关键调节因子。与有效的血管生成因子VEGF-A不同，VEGF-B不会诱导血管渗漏，而是通过其受体VEGFR1和NRP1调节组织特异性功能，包括脂肪酸运输、神经元存活和免疫代谢。它的作用往往是矛盾的，在一些癌症中抑制血管生成，而在另一些癌症中促进转移和免疫逃避，这突出了它的作用具有深刻的环境依赖性。最近的发现，如FGFR1作为关键受体的鉴定和VEGF-B在T细胞存活中的重要作用，重新激发了人们对其治疗潜力的兴趣。然而，临床转化仍然具有挑战性，正如最近抗VEGF-B抗体CSL346在糖尿病肾病中的失败所证明的那样，强调了我们对VEGF-B生物学的不完整理解。本综述整合了对VEGF-B多种功能的前沿见解，提出了其复杂信号网络的机制框架，并概述了开发代谢、心血管、神经退行性和肿瘤疾病的精确治疗的路线图。我们解决了关键的翻译挑战，以最大限度地提高治疗效益，同时保持VEGF-B的关键稳态功能。

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引用次数: 0

Evaluation of in vitro antiviral activity against different SARS-CoV-2 variants of a protease PROTAC degrader 一种蛋白酶PROTAC降解物对不同SARS-CoV-2变体的体外抗病毒活性评价

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-09 DOI: 10.1016/j.phrs.2025.108063

Mirko G. Liturri, A. Bergna, A. Lai, C. Della Ventura, A. Gabrieli, I. Seravalli, S. Ciofi-Baffoni, E. Lenci, A. Trabocchi, S. Rusconi

引用次数: 0

Pharmacological profile and therapeutic evaluation of ROC-101, a potent and selective ROCK inhibitor, in arterial hypertension and pulmonary fibrosis ROC-101是一种有效的选择性ROCK抑制剂，在动脉高血压和肺纤维化中的药理分析和治疗评价。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-08 DOI: 10.1016/j.phrs.2025.108062

Rigen Mo , Sarah Lucas , Xiao-Jiang Feng , Adrian Hackett , Ed Skucas , Kevin G. Liu , Ji-In Kim , Pegah Kolahi , Jack Gaffney , Jillian J. Spinney , Rachel S. Knipe , Jeegar P. Patel , M. Kathryn Steiner , Serra Elliott , William Marshall , James Hui , Shawn N. Grant , Masha V. Poyurovsky

Rho-associated coiled-coil kinases (ROCK1 and ROCK2) are important therapeutic targets in fibrosis. ROCK transduces profibrotic biomechanical (substrate stiffness) and biochemical (transforming growth factor-β, lysophosphatidic acid, connective tissue growth factor) stimuli from circulation and the extracellular matrix to cells. Herein, we present a novel selective inhibitor of ROCK1 and ROCK2 (pan-ROCK), ROC-101 (previously known as KD045), and demonstrate its activity as an antifibrotic agent. ROC-101 strongly inhibited ROCK in biochemical and cellular assays and exhibited optimal drug-like pharmacokinetics and physicochemical properties. ROC-101 was well tolerated following oral administration and had desirable selectivity against non-ROCK kinases and other high liability targets. ROC-101 treatment disrupted profibrotic gene expression in fibroblasts and reduced markers of vascular leakage in vivo. ROC-101 was efficacious in three different rodent models of pulmonary parenchymal, vascular, and airway diseases: 1) ROC-101 treatment reduced airway hypersensitivity to methacholine in an ovalbumin-induced asthma model and had blood pressure–lowering effects consistent with the role of ROCK in smooth muscle contractility and confirming in vivo target engagement; 2) ROC-101 showed efficacy in attenuating pulmonary arterial hypertension in the semaxanib/hypoxia-induced disease model; and 3) in the bleomycin-induced lung fibrosis model, ROC-101 demonstrated disease-modifying activity in the fibrotic lung, lowering collagen deposition, improving histology, reducing immune cell infiltration, and decreasing ROCK target phosphorylation. These in vivo and functional assessments support the development of ROC-101 as a potential therapeutic modality in pulmonary fibrosis and pulmonary hypertension.

rho相关的卷曲卷曲激酶（ROCK1和ROCK2）是纤维化的重要治疗靶点。ROCK将促纤维化的生物力学（底物刚度）和生化（转化生长因子-β、溶血磷脂酸、结缔组织生长因子）刺激从循环和细胞外基质传导到细胞。在此，我们提出了一种新的ROCK1和ROCK2（泛rock）选择性抑制剂，ROC-101（以前称为KD045），并证明其作为抗纤维化剂的活性。ROC-101在生化和细胞实验中对ROCK有明显抑制作用，并表现出最佳的药物样药代动力学和理化性质。口服给药后，ROC-101耐受性良好，对非rock激酶和其他高负荷靶标具有理想的选择性。ROC-101治疗破坏了成纤维细胞中纤维化基因的表达，减少了体内血管渗漏的标志物。ROC-101在三种不同的肺实质、血管和气道疾病模型中均有效：1)在卵清蛋白诱导的哮喘模型中，ROC-101治疗可降低气道对甲胆碱的超敏反应，并具有降低血压的作用，这与ROCK在平滑肌收缩中的作用一致，证实了体内靶点参与；2) ROC-101在semaxanib/缺氧诱导的疾病模型中具有降低肺动脉高压的疗效；3)在博来霉素诱导的肺纤维化模型中，ROC-101在纤维化肺中表现出疾病改善活性，降低胶原沉积，改善组织学，减少免疫细胞浸润，降低ROCK靶点磷酸化。这些体内和功能评估支持ROC-101作为肺纤维化和肺动脉高压的潜在治疗方式的发展。

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