Pharmacology & Therapeutics最新文献_第4页

Unveiling the silent threat: COVID-19 and myocardial injury 揭示无声的威胁：COVID-19和心肌损伤。

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-06-27 DOI: 10.1016/j.pharmthera.2025.108904

Ke Xu , Wu He , Bo Yu, James Jiqi Wang, Junfang Wu, Dao Wen Wang

Since COVID-19 firstly appeared in 2019 December, it has been defined as an infectious disease mainly performing lung symptoms, which contracted more attention. However, more and more findings indicate myocardial injury appears in considerable proportion of COVID-19 patients (30 % – 50 %) not only but also major cause leading to the death in patients, many of whom may be even without severe respiratory symptoms. Meanwhile myocarditis after injecting vaccines has been paid more attention to globally which always performs uncontrollable inflammation and lead to death. Now myocardial injury has been a main complication in patients with long COVID-19, which is worthy of attention. Furthermore, myocardial injury or myocarditis is detectable and treatable. In order to abstract attention to myocardial injury associated with COVID-19 and provide more evidence and experience for patients who still suffer myocardial injury from COVID-19 vaccines or long COVID-19, the review comprehensively summarized previous researches from pathogenesis, clinical symptoms, diagnosis and treatment and emphasized the crucial role of RASS inhibitors especially ARBs.

自2019年12月首次出现以来，新冠肺炎被定义为以肺部症状为主的传染病，受到了更多的关注。然而，越来越多的研究结果表明，相当比例的COVID-19患者（30 % - 50 %）出现心肌损伤，而且心肌损伤是导致患者死亡的主要原因，其中许多患者甚至可能没有严重的呼吸道症状。同时，注射疫苗后的心肌炎引起的不可控炎症和致人死亡已成为全球关注的焦点。目前心肌损伤已成为新冠肺炎长期患者的主要并发症，值得关注。此外，心肌损伤或心肌炎是可以检测和治疗的。为了抽除对COVID-19相关心肌损伤的关注，为COVID-19疫苗或长期COVID-19仍存在心肌损伤的患者提供更多的证据和经验，本文从发病机制、临床症状、诊断和治疗等方面全面总结了以往的研究，强调了RASS抑制剂特别是arb的关键作用。

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引用次数: 0

Antiviral drug repurposing: different approaches and the case of antifungal drugs 抗病毒药物的再利用：不同的方法和抗真菌药物的案例。

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-06-23 DOI: 10.1016/j.pharmthera.2025.108903

Sara Tuci , Beatrice Mercorelli , Arianna Loregian

In recent years, the emergence of new viruses and the re-emergence of old ones have posed a significant challenge to global Public Health. Viruses characterised by high morbidity and mortality rates have the potential to spread rapidly, causing large epidemic outbreaks and even pandemics. In this context, viral infections still lacking effective treatments represent a serious threat to human health. For this reason, sustained development and implementation of countermeasures are urgently needed against these infections, as they are for diseases for which the emergence of drug resistance is rapidly increasing. In this regard, compared to de novo drug discovery, drug repurposing could represent a highly efficient, faster, and more affordable strategy to develop new drugs. Here, we provide a comprehensive review of the different experimental and computational approaches used for drug repurposing and discuss their advantages and limitations in comparison with other drug discovery strategies. In addition, as an example of the successful application of drug repurposing, we present the case of approved antifungal drugs that could be repurposed to counteract viral infections.

近年来，新病毒的出现和旧病毒的重现给全球公共卫生带来了重大挑战。发病率和死亡率高的病毒有可能迅速传播，造成大规模流行病爆发，甚至大流行。在这种情况下，病毒感染仍然缺乏有效治疗，对人类健康构成严重威胁。因此，迫切需要持续制定和实施针对这些感染的对策，因为它们是针对正在迅速出现耐药性的疾病的对策。在这方面，与从头开始的药物发现相比，药物再利用可能是一种高效、更快、更经济的新药开发策略。在这里，我们全面回顾了用于药物再利用的不同实验和计算方法，并讨论了它们与其他药物发现策略相比的优点和局限性。此外，作为药物再利用成功应用的一个例子，我们提出了批准的抗真菌药物可以再利用来抵抗病毒感染的案例。

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引用次数: 0

Retinoid dynamics in vision: from visual cycle biology to retina disease treatments 视觉中的类维甲酸动力学：从视觉周期生物学到视网膜疾病治疗。

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-06-21 DOI: 10.1016/j.pharmthera.2025.108902

Jaclyn Swigris , Made Airanthi K. Widjaja-Adhi , Marcin Golczak

Light perception is a biological process that facilitates a profound interaction between the external world and the internal functions of living organisms. It begins with the absorption of photons with specialized visual pigments that contain vitamin A-derived chromophores. The light energy triggers the photoisomerization of the visual chromophore, initiating a cascade of signaling events that ultimately convert light into electrical signals interpreted as vision. However, the sustainability of vision relies on the continuous supply of the visual chromophore, which is maintained through light-dependent and light-independent processes. The importance of these processes is underscored by numerous blinding retinal diseases linked to impaired regeneration of the chromophore. Thus, research into the molecular mechanisms of visual chromophore biosynthesis has not only deepened our understanding of the organization of visual systems but also uncovered the etiologies of these debilitating diseases. In this review, we synthesize recent progress in understanding the mechanisms responsible for visual chromophore biosynthesis. We examine biological targets, therapeutic strategies, and drug discovery efforts aimed at restoring or bypassing metabolic blockades in visual chromophore regeneration, and assess the progress of clinical trials evaluating the effectiveness of therapies for degenerative retinal diseases.

光感知是一种生物过程，它促进了外部世界和生物体内部功能之间的深刻相互作用。它开始于用含有维生素a衍生的发色团的特殊视觉色素吸收光子。光能触发视觉发色团的光异构化，启动一系列信号事件，最终将光转化为被解释为视觉的电信号。然而，视觉的可持续性依赖于视觉发色团的持续供应，这是通过依赖光和不依赖光的过程来维持的。许多与发色团再生受损相关的致盲性视网膜疾病强调了这些过程的重要性。因此，对视觉发色团生物合成的分子机制的研究不仅加深了我们对视觉系统组织的理解，而且揭示了这些使人衰弱的疾病的病因。本文综述了近年来对视觉发色团生物合成机制的研究进展。我们研究了旨在恢复或绕过视觉发色团再生代谢阻断的生物学靶点、治疗策略和药物发现工作，并评估了评估退行性视网膜疾病治疗有效性的临床试验进展。

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引用次数: 0

Targeting myeloid cell immunometabolism to improve current non-small cell lung cancer therapies 靶向骨髓细胞免疫代谢改善当前非小细胞肺癌治疗。

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-06-04 DOI: 10.1016/j.pharmthera.2025.108893

Marah C. Runtsch , Stefano Angiari , Julia Kargl

Although recent advancements in immunotherapy have improved clinical outcomes, non-small cell lung cancer (NSCLC) is still the deadliest cancer type, as current treatments fail in many patients. This highlights a need for continued studies on this complex and multifaceted malignancy. The lung tumor microenvironment (TME) is marked by an infiltration of innate immune cells of the myeloid lineage, including macrophages and neutrophils, which affect patient outcomes. These cells induce inflammation and functional responses that can both promote and inhibit tumor growth and progression, with these functions being directly linked to their intracellular metabolism. The lung TME provides a milieu of signals, including cytokines and metabolites, that induce metabolic reprogramming in tumor-associated myeloid cells. Here, we review the present understanding of tumor-associated myeloid cell metabolism specifically in the context of NSCLC. Recent studies demonstrated that some metabolic pathways have the potential to be manipulated pharmacologically to eliminate or reprogram pathogenic, pro-tumor, and/or immunosuppressive myeloid cells to anti-tumor states for NSCLC therapies. Therefore, we highlight and propose potential metabolic targets in these myeloid cells, focusing on macrophages and neutrophils. These cells have direct roles in affecting subsequent responses of adaptive cells and their cellular metabolism must be further investigated to identify potential pharmacologic therapeutic targets. Targeting myeloid cell metabolism in the TME may be used in combination with the current regimen of immune checkpoint inhibition (ICI) and chemotherapy to improve outcomes for lung cancer patients.

尽管最近免疫治疗的进展改善了临床结果，但非小细胞肺癌（NSCLC）仍然是最致命的癌症类型，因为目前的治疗在许多患者中失败。这突出表明需要继续研究这种复杂和多方面的恶性肿瘤。肺肿瘤微环境（TME）的特征是骨髓系先天免疫细胞的浸润，包括巨噬细胞和中性粒细胞，这些细胞会影响患者的预后。这些细胞诱导炎症和功能反应，可以促进和抑制肿瘤的生长和进展，这些功能与其细胞内代谢直接相关。肺TME提供了一个信号环境，包括细胞因子和代谢物，诱导肿瘤相关骨髓细胞的代谢重编程。在这里，我们回顾了目前对肿瘤相关骨髓细胞代谢的理解，特别是在NSCLC的背景下。最近的研究表明，一些代谢途径有可能被药理学操纵，以消除或重新编程致病性、促肿瘤和/或免疫抑制的骨髓细胞，使其进入抗肿瘤状态，用于非小细胞肺癌治疗。因此，我们强调并提出了这些骨髓细胞的潜在代谢靶点，重点是巨噬细胞和中性粒细胞。这些细胞在影响适应性细胞的后续反应中具有直接作用，必须进一步研究它们的细胞代谢以确定潜在的药物治疗靶点。靶向TME中的髓细胞代谢可能与目前的免疫检查点抑制（ICI）和化疗方案联合使用，以改善肺癌患者的预后。

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引用次数: 0

Current and future therapeutics targeting mast cells in disease 目前和未来针对肥大细胞的疾病治疗方法。

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-05-30 DOI: 10.1016/j.pharmthera.2025.108892

William P.M. Worrall, Laurent L. Reber

Mast cells (MCs) are tissue resident immune cells which are best known for their detrimental role in allergy. Increasing evidence indicates that MCs are also central to the pathogenesis of chronic urticaria. Abnormal increase in MC burden, in most cases driven by gain-of-function mutations in the receptor KIT, can also lead to mastocytosis, a potentially severe malignant disease. Thus, MCs represent important therapeutic targets in all these diseases, and likely in a number of additional inflammatory conditions. In recent years, several monoclonal antibodies (mAbs) and small molecule inhibitors have been developed to directly target MCs or their mediators. Some of these therapeutics, including antagonists of the receptor MRGPRX2, tyrosine kinase inhibitors, anti-Siglec-6 and anti-KIT mAbs are now undergoing clinical evaluation. In this review, we describe the main mechanisms leading to MC activation, and their known functions in allergic diseases, chronic urticaria and mastocytosis. We then discuss recent preclinical and clinical data obtained with novel biologics aimed at targeting MCs in these diseases.

肥大细胞（MCs）是组织常驻免疫细胞，其在过敏中的有害作用最为人所知。越来越多的证据表明，MCs也是慢性荨麻疹发病机制的核心。在大多数情况下，由受体KIT的功能获得性突变驱动的MC负担异常增加也可导致肥大细胞增多症，这是一种潜在的严重恶性疾病。因此，MCs代表了所有这些疾病的重要治疗靶点，并且可能在许多其他炎症条件下。近年来，一些单克隆抗体（mab）和小分子抑制剂被开发出来直接靶向MCs或其介质。其中一些治疗方法，包括受体MRGPRX2拮抗剂、酪氨酸激酶抑制剂、抗siglec -6和抗kit单克隆抗体，目前正在进行临床评估。在这篇综述中，我们描述了导致MC激活的主要机制，以及它们在过敏性疾病、慢性荨麻疹和肥大细胞增多症中的已知功能。然后，我们讨论了针对这些疾病中MCs的新型生物制剂获得的最新临床前和临床数据。

引用次数: 0

Corrigendum to “Immunomodulation and targeted drug delivery with high intensity focused ultrasound (HIFU): Principles and mechanisms” [Volume 244, April 2023, 108393] “高强度聚焦超声（HIFU）的免疫调节和靶向药物递送：原理和机制”的勘误表[第244卷，2023年4月，108393]

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-05-30 DOI: 10.1016/j.pharmthera.2025.108890

Harshini Ashar, Happy Agarwal, Ashish Ranjan

引用次数: 0

Post-COVID pulmonary sequelae: Mechanisms and potential targets to reduce persistent fibrosis covid后肺后遗症：减少持续性纤维化的机制和潜在靶点

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-05-28 DOI: 10.1016/j.pharmthera.2025.108891

Emma C.A. Vreeman , Janesh Pillay , Janette K. Burgess

After the severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) pandemic, the emergence of long-term sequelae post-infection poses a new healthcare challenge. Following initial infection with SARS-CoV-2, approximately 1 in 10 people experience post-acute sequelae of COVID-19 (PASC), also known as long COVID. PASC can affect the entire body, with the airways and lungs being a primary target of the initial viral infection. Many post-COVID symptoms have been associated with fibrotic lung lesions and diminished respiratory function. The reversibility, persistence, or progression of post-COVID-19 pulmonary fibrosis is still a topic of debate. We aimed to compare current findings and examined similar viral infections from the past, to increase understanding of prevalence, persistence and possible pharmacological targets of post-COVID-19 pulmonary fibrosis.

Recent studies have documented PASC symptoms persisting up to 3 years post-recovery, and lung impairments present after 15 years after infection with the similar SARS-CoV virus in 2003. These findings suggest the potential for long-term pulmonary fibrosis following SARS-CoV-2 infection, highlighting the need for new anti-fibrotic treatments capable of reversing pulmonary fibrosis. Besides the approved anti-fibrotics, pirfenidone and nintedanib, other promising treatments include histone deacetylase inhibitors, angiotensin receptor blockers and mesenchymal stem cells. The pathophysiological mechanisms underlying post-COVID-19 pulmonary fibrosis are still incompletely understood, necessitating future research to clarify the development of persistent post-COVID-19 pulmonary fibrosis following SARS-CoV-2 infection. Given the widespread transmission of SARS-CoV-2, even a low prevalence of persistent post-COVID-19 pulmonary fibrosis would represent a significant public health concern for which therapeutic strategies are essential to identify.

严重急性呼吸综合征（SARS）冠状病毒2 （SARS- cov -2）大流行后，感染后长期后遗症的出现对卫生保健提出了新的挑战。在最初感染SARS-CoV-2后，大约十分之一的人会出现COVID-19急性后后遗症（PASC），也称为长COVID。PASC可以影响整个身体，呼吸道和肺部是最初病毒感染的主要目标。许多新冠肺炎后症状与肺纤维化病变和呼吸功能减弱有关。covid -19后肺纤维化的可逆性、持续性或进展仍然是一个有争议的话题。我们的目的是比较当前的研究结果，并检查过去类似的病毒感染，以增加对covid -19后肺纤维化的患病率、持久性和可能的药理学靶点的了解。最近的研究表明，PASC症状在康复后持续3 年，在2003年感染类似的sars冠状病毒后15 年出现肺损伤。这些发现表明，SARS-CoV-2感染后可能出现长期肺纤维化，强调需要能够逆转肺纤维化的新型抗纤维化治疗方法。除了批准的抗纤维化药物，吡非尼酮和尼达尼布，其他有希望的治疗方法包括组蛋白去乙酰化酶抑制剂，血管紧张素受体阻滞剂和间充质干细胞。covid -19后肺纤维化的病理生理机制尚不完全清楚，需要未来的研究来阐明SARS-CoV-2感染后持续性covid -19后肺纤维化的发展。鉴于SARS-CoV-2的广泛传播，即使是covid -19后持续肺纤维化的低患病率也将是一个重大的公共卫生问题，因此必须确定治疗策略。

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引用次数: 0

Recent advances in therapeutic targeting of the KRAS pathway in cancer KRAS通路靶向治疗肿瘤的研究进展。

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-05-28 DOI: 10.1016/j.pharmthera.2025.108889

Nadia Hitchen , Sarah Williams , Jayesh Desai

Recent advances in cancer therapy have significantly progressed through targeted inhibition of the rat sarcoma virus (RAS) signalling pathway, particularly focusing on Kirsten rat sarcoma virus (KRAS) mutations prevalent in cancers such as non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). Historically deemed “undruggable,” KRAS mutations, especially KRASG12C and KRASG12D, are now effectively targeted by specific inhibitors that have demonstrated promising clinical results. Agents such as Sotorasib, Adagrasib, and Divarasib exhibit notable efficacy against KRASG12C mutations, particularly in NSCLC, with combination strategies significantly improving outcomes, especially in CRC. With over 50 agents currently in development, targeting KRAS has become a rapidly expanding area of cancer therapeutics. However, substantial challenges remain, including optimizing clinical trial designs, particularly in early-phase trials, and integrating pharmacodynamic tools to refine dosing and treatment schedules, thus achieving an optimal balance between efficacy and patient tolerability. This review summarizes recent therapeutic advancements, highlighting the clinical development of KRAS-specific inhibitors, and emphasizes future strategies involving a combination of mutant-specific and broader mutant-independent approaches to overcome resistance, thereby offering promise for more durable cancer control and expanded patient eligibility.

通过靶向抑制大鼠肉瘤病毒（RAS）信号通路，特别是针对非小细胞肺癌（NSCLC）、结直肠癌（CRC）和胰腺导管腺癌（PDAC）等癌症中普遍存在的Kirsten大鼠肉瘤病毒（KRAS）突变，癌症治疗的最新进展取得了显著进展。KRAS突变，特别是KRASG12C和KRASG12D，在历史上被认为是“不可治疗的”，现在被特定的抑制剂有效地靶向，这些抑制剂已经显示出有希望的临床结果。Sotorasib、Adagrasib和Divarasib等药物对KRASG12C突变表现出显著的疗效，特别是在NSCLC中，联合策略显著改善了结果，特别是在CRC中。目前有超过50种药物正在开发中，靶向KRAS已成为癌症治疗的一个快速扩展的领域。然而，实质性的挑战仍然存在，包括优化临床试验设计，特别是在早期试验中，以及整合药效学工具来完善剂量和治疗计划，从而在疗效和患者耐受性之间实现最佳平衡。这篇综述总结了最近的治疗进展，重点介绍了kras特异性抑制剂的临床发展，并强调了未来的策略，包括结合突变特异性和更广泛的突变非依赖性方法来克服耐药性，从而为更持久的癌症控制和扩大患者的资格提供了希望。

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引用次数: 0

Alternative splicing in aging and aging-related diseases: From pathogenesis to therapy 衰老和衰老相关疾病的选择性剪接：从发病机制到治疗。

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-05-23 DOI: 10.1016/j.pharmthera.2025.108887

Mingrui Han , Peiru Han , Zihui Wang , Lingdong Kong , Qiang Xu , Qianqian Liu , Yang Sun

Aging is a complex biological process associated with nearly all diseases. Alternative splicing is increasingly recognized as an important contributor to aging and a key research pathway for extending human lifespan. In this review, we highlight the findings of alternative splicing in the hallmarks of aging including key processes such as genomic instability, telomere length, protein stability, autophagy processes, etc., as well as antagonistic hallmarks of aging such as various metabolic signals, energy metabolism, clearance of senescent cells, stem cell self-renewal, cell communication and inflammatory process, etc. We also discuss the roles of alternative splicing in age-related diseases, including neurodegenerative diseases, cardiovascular diseases, skeletal muscle-related diseases, metabolic disorders, cancer, sensory degeneration, and chronic inflammation, etc. These studies suggest that new anti-aging therapies could be developed by regulating key splicing proteins or specific splicing events.

衰老是一个复杂的生物学过程，几乎与所有疾病都有关。选择性剪接越来越被认为是衰老的重要因素，也是延长人类寿命的重要研究途径。在这篇综述中，我们重点介绍了选择性剪接在衰老标志中的发现，包括基因组不稳定性、端粒长度、蛋白质稳定性、自噬过程等关键过程，以及衰老的拮抗标志，如各种代谢信号、能量代谢、衰老细胞的清除、干细胞自我更新、细胞通讯和炎症过程等。我们还讨论了选择性剪接在年龄相关疾病中的作用，包括神经退行性疾病、心血管疾病、骨骼肌相关疾病、代谢紊乱、癌症、感觉变性和慢性炎症等。这些研究表明，可以通过调节关键剪接蛋白或特定剪接事件来开发新的抗衰老疗法。

引用次数: 0

N-methyl-D-aspartate receptors (NMDARs): a glutamate-activated cation channel with biased signaling and therapeutic potential in brain disorders n -甲基-d-天冬氨酸受体（NMDARs）：一种谷氨酸激活的阳离子通道，具有偏倚信号传导和治疗脑疾病的潜力。

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-05-22 DOI: 10.1016/j.pharmthera.2025.108888

Xuan Zhang , Wensheng Cai , Chao Wang , Jing Tian

N-methyl-D-aspartate receptors (NMDARs) are a class of calcium-permeable ion channel that are extensively distributed throughout the body, composed of various subunits. The presence of diverse ligands and subcellular localizations of the receptors confers biased signaling and distinct functional roles. Activation of the NMDARs induces calcium influx, which plays a pivotal role in neurotransmitter release, synaptic plasticity, and intracellular signaling. Differential localization of NMDARs at synaptic and extrasynaptic sites results in divergent physiological effects; excessive or insufficient activation of NMDARs disrupts calcium homeostasis, leading to neuronal damage and subsequent neurological dysfunction as well as related diseases. Therefore, it is crucial to develop drugs targeting NMDARs with high efficacy and low toxicity for treating brain disorders associated with NMDARs abnormalities. In this review, we summarize both mechanism research and clinical studies on NMDARs while discussing potential therapeutic targets aimed at modulating ion channel activity through regulating mechanisms, subunit rearrangement, membrane expression, and the specific targeting of synaptic versus extrasynaptic NMDARs. Our aim is to provide new insights for innovative drug development.

n -甲基-d-天冬氨酸受体（NMDARs）是一类广泛分布于全身的钙离子通道受体，由多种亚基组成。不同配体的存在和受体的亚细胞定位赋予了偏倚的信号和不同的功能作用。NMDARs的激活诱导钙内流，钙内流在神经递质释放、突触可塑性和细胞内信号传导中起关键作用。NMDARs在突触和突触外位置的不同定位导致不同的生理作用；NMDARs的过度或不足激活会破坏钙稳态，导致神经元损伤和随后的神经功能障碍以及相关疾病。因此，开发高效、低毒的靶向NMDAR药物治疗NMDAR异常相关疾病至关重要。在这篇综述中，我们总结了NMDARs的基础和临床研究，同时讨论了通过调节机制、亚基重排、膜表达以及突触与突触外NMDARs的特异性靶向来调节离子通道活性的潜在治疗靶点。我们的目标是为创新药物开发提供新的见解。

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引用次数: 0