Pharmacological research最新文献_第10页

Blood proteomics and multimodal risk profiling of human volunteers after incision injury: A translational study for advancing personalized pain management after surgery 人类志愿者切口损伤后血液蛋白质组学和多模式风险分析：一项促进手术后个性化疼痛管理的转化研究。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-01 DOI: 10.1016/j.phrs.2025.107580

Daniel Segelcke , Julia R. Sondermann , Christin Kappert , Bruno Pradier , Dennis Görlich , Manfred Fobker , Jan Vollert , Peter K. Zahn , Manuela Schmidt , Esther M. Pogatzki-Zahn

A significant number of patients develop chronic pain after surgery, but prediction of those who are at risk is currently not possible. Thus, prognostic prediction models that include bio-psycho-social and physiological factors in line with the complex nature of chronic pain would be urgently required. Here, we performed a translational study in male volunteers before and after an experimental incision injury. We determined multi-modal features ranging from pain characteristics and psychological questionnaires to blood plasma proteomics. Outcome measures included pain intensity ratings and the extent of the area of hyperalgesia to mechanical stimuli surrounding the incision, as a proxy of central sensitization. A multi-step logistic regression analysis was performed to predict outcome measures based on feature combinations using data-driven cross-validation and prognostic model development. Phenotype-based stratification resulted in the identification of low and high responders for both outcome measures. Regression analysis revealed prognostic proteomic, specific psychophysical, and psychological features. A combinatorial set of distinct features enabled us to predict outcome measures with increased accuracy compared to using single features. Remarkably, in high responders, protein network analysis suggested a protein signature characteristic of low-grade inflammation. Alongside, in silico drug repurposing highlighted potential treatment options employing antidiabetic and anti-inflammatory drugs. Taken together, we present here an integrated pipeline that harnesses bio-psycho-physiological data for prognostic prediction in a translational approach. This pipeline opens new avenues for clinical application with the goal of stratifying patients and identifying potential new targets, as well as mechanistic correlates, for postsurgical pain.

相当多的患者在手术后会出现慢性疼痛，但目前还不可能预测那些有风险的患者。因此，迫切需要包括生物心理、社会和生理因素的预后预测模型，以符合慢性疼痛的复杂性。在这里，我们在实验性切口损伤之前对男性志愿者进行了一项转化研究。我们确定了从疼痛特征、心理问卷到血液蛋白质组学的多模态因素。切口后的结果测量是疼痛强度评分和切口周围机械刺激的痛觉过敏区域的程度，作为中枢致敏的代表。采用多步逻辑回归分析，利用数据驱动的交叉验证和预后模型开发来预测基于特征组合的结果测量。基于表型的分层导致对两种结果测量的低反应和高反应的识别。回归分析显示预后的蛋白质组学、特定的心理生理和心理参数。与使用单一特征相比，不同参数的组合集使我们能够以更高的准确性预测结果措施。值得注意的是，在高应答者中，蛋白质网络分析显示了低级别炎症的蛋白质特征。此外，计算机药物再利用强调了使用抗糖尿病和抗炎药物的潜在治疗选择。综上所述，我们在这里提出了一个综合管道，利用生物心理生理数据在翻译方法中进行预后预测。该管道为临床应用开辟了新的途径，目的是对患者进行分层，确定潜在的新靶点以及术后疼痛的机制相关。德国临床试验注册中心：（drks-id: drks00016641）。

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引用次数: 0

GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study CRP对他汀类药物反应的GWAS进一步支持APOE在他汀类药物反应中的作用：GIST联合研究。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-01 DOI: 10.1016/j.phrs.2024.107575

Emma F. Magavern , Harshal Deshmukh , Geraldine Asselin , Elizabeth Theusch , Stella Trompet , Xiaohui Li , Raymond Noordam , Y.-D. Ida Chen , Teresa E. Seeman , Kent D. Taylor , Wendy S. Post , Jean-Claude Tardif , Dirk S. Paul , Emelia J. Benjamin , Nancy L. Heard-Costa , Ramachandran S. Vasan , Jerome I. Rotter , Ronald M. Krauss , J.Wouter Jukema , Paul M. Ridker , Helen R. Warren

Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response.

CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts.

Our GWAS identified two genome-wide significant (P < 5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer’s and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P < 0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered.

The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer’s, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment.

他汀类药物是心血管疾病一级和二级预防的一线治疗药物。临床研究表明，他汀类药物可以独立于降脂机制来降低c反应蛋白（CRP），这是一种炎症标志物。我们的目的是阐明与CRP他汀类药物反应相关的遗传位点。CRP -他汀类药物反应是在治疗结束和治疗开始测量之间log-CRP的变化。使用1000个基因组输入数据进行CRP反应的队列水平全基因组关联研究（GWAS），检测了约1000万个常见遗传变异。GWAS荟萃分析结合了来自7个队列和临床试验的结果，总计14070名GIST联盟中接受他汀类药物治疗的欧洲血统个体。次要分析包括他汀类药物与安慰剂的相互作用分析，以及非洲血统队列的查找。我们的GWAS鉴定了两个全基因组显著的(P

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引用次数: 0

How spinal GABAergic circuits modulate cerebral processing of postsurgical pain 脊髓gaba能回路如何调节大脑对术后疼痛的处理。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-01 DOI: 10.1016/j.phrs.2025.107609

Bruno Pradier , Daniel Segelcke , Nathalie Just , Mirjam Augustin , Nina Nagelmann , Cornelius Faber , Esther Pogatzki-Zahn

Post-surgical pain affects millions each year, hindering recovery and quality of life. Surgical procedures cause tissue damage and inflammation, leading to peripheral and central sensitization, resulting in pain at rest or mechanical and heat hyperalgesia. In a rat model for post-surgical pain, spinal GABAergic transmission via GABA_A receptors reduces mechanical hypersensitivity but has no effect on pain at rest. While fMRI studies show consistent brain activity changes during mechanical stimulation in post-surgical pain, central processing of pain at rest and the role of spinal GABAergic circuits on surgical pain processing is currently unclear. The aim of this study was to evaluate the influence of an acute surgical incision injury, a proxy for post-surgical pain, on the cerebral processing of pain at rest and mechanical hypersensitivity, and to assess the influence of spinal GABA_A-circuits on this processing. In rats, a unilateral incision affected sensorimotor and thalamo-limbic subnetworks at rest and following mechanical stimulation, indicating changes in neural processing relevant to pain at rest and mechanical hypersensitivity in post-surgical pain. Enhancing spinal GABAergic tone increased functional connectivity (FC) in parts of these subnetworks during mechanical stimulation, but not at rest, highlighting spino-cerebral interactions in pain regulation relevant for mechanical hypersensitivity and potentially the transisition to chronic pain after surgery but likely not for pain at rest. These findings underscore the complex and interconnected nature of brain networks in post-surgical pain processing, and provide insights into potential spinal targets for pharmacological intervention to alleviate post-surgical pain and prevent it's chronification.

术后疼痛每年影响数百万人，影响康复和生活质量。外科手术引起组织损伤和炎症，导致外周和中枢致敏，导致休息时疼痛或对机械刺激的痛觉过敏等。在术后疼痛大鼠模型中，通过GABAA受体的脊髓gaba能传递减少了机械超敏反应，但对静止疼痛没有影响。虽然fMRI研究显示，在术后疼痛的机械刺激过程中，大脑活动发生了一致的变化，但休息时疼痛的中枢处理和脊髓gaba能回路在手术疼痛处理中的作用目前尚不清楚。本研究的目的是评估急性手术切口（术后疼痛的代表）对静息疼痛和机械超敏反应的大脑处理的影响，并评估脊髓gabaa回路对这一处理的影响。在大鼠中，单侧切口损伤影响休息时和机械刺激后的感觉运动和丘脑边缘亚网络，表明与休息时疼痛和术后疼痛的机械超敏反应相关的神经加工发生了变化。增强脊髓gaba能张力在机械刺激时增加了这些子网络部分的功能连接（FC），但在静止状态下没有，突出了术后疼痛调节中的脊髓-大脑相互作用，这些相互作用与机械超敏反应和术后慢性疼痛的潜在发展有关，但可能与静止疼痛无关。这些发现强调了术后疼痛处理中大脑网络的复杂性和相互关联性，并为减轻术后疼痛和预防其慢性化的药物干预提供了潜在的脊柱靶点。

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引用次数: 0

Blocking ANGPTL3 and CD47 impact on atherosclerosis-correspondence 阻断ANGPTL3和CD47对动脉粥样硬化相关性的影响。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-01 DOI: 10.1016/j.phrs.2025.107601

Han-Yong Hou, Yan-Shiang Chen, Su-Boon Yong, Chin-Yuan Yii, Yu-Tsun Su

引用次数: 0

High-fat diet and neuroinflammation: The role of mitochondria

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-01 DOI: 10.1016/j.phrs.2025.107615

Mingxue Song , Yao Bai , Fuyong Song

In recent years, increasing evidence has supported that high-fat diet (HFD) can induce the chronic, low-grade neuroinflammation in the brain, which is closely associated with the impairment of cognitive function. As the key organelles responsible for energy metabolism in the cell, mitochondria are believed to involved in the pathogenesis of a variety of neurological disorders. This review summarizes the current progress in the field of the relationship between HFD exposure and neurodegenerative diseases, and outline the major routines of HFD induced neuroinflammation and its pathological significance in the pathogenesis of neurodegenerative diseases. Furthermore, the article highlights the pivotal role of mitochondrial dysfunction in driving the neuroinflammation in the setting of HFD. Danger-associated molecular patterns (DAMPs) from damaged mitochondria can activate innate immune signaling pathways, while mitochondrial dysfunction itself can lead to metabolic remodeling of inflammatory cells, thus inducing neuroinflammation. More importantly, mitochondrial damage, neuroinflammation, and insulin resistance caused by HFD form a mutually reinforcing vicious cycle, ultimately leading to the death of neurons and promoting the progression of neurodegenerative diseases. Thus, in-depth elucidation of the role and underlying mechanisms of mitochondrial dysfunction in HFD-induced metabolic disorders may not only expand our understanding of the mechanistic linkages between HFD and etiology of neurodegenerative diseases, but also help develop the specific strategies for the prevention and treatment of neurodegenerative diseases.

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引用次数: 0

Optical imaging guidance in oncologic surgery and interventional oncology 肿瘤外科和介入肿瘤学的光学成像指导。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-01 DOI: 10.1016/j.phrs.2025.107612

Yiming Liu , Karim Valji , Wayne Monsky , Chuansheng Zheng , Xiaoming Yang

Over recent decades, optical imaging (OI) has become an integral part of medical imaging, offering significant advantages over other modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI). OI is distinguished by its real-time imaging capability, cost-effectiveness, portability, absence of ionizing radiation, and high patient acceptability. The introduction of advanced optical dyes (including FDA-approved agents like indocyanine green, Cytalux, and Gleolan) has greatly enhanced its clinical utility. OI has shown clear benefits in the management of patients with cancer, originally by open surgery and now extending to minimally invasive, image-guided interventional procedures. This review highlights recent developments in OI for oncology, emphasizing its benefits for clinicians in guiding surgical and interventional procedures.

近几十年来，光学成像（OI）已成为医学成像的一个组成部分，与计算机断层扫描（CT）和磁共振成像（MRI）等其他方式相比，光学成像（OI）具有显著的优势。成骨不全的特点是其实时成像能力、成本效益、便携性、无电离辐射和患者接受度高。引进先进的光学染料（包括fda批准的药物，如吲哚菁绿、Cytalux和Gleolan）大大提高了其临床应用。OI在癌症患者的治疗中显示出明显的益处，最初是通过开放手术，现在扩展到微创、图像引导的介入手术。本文综述了肿瘤成骨不全的最新进展，强调了其对临床医生指导外科和介入手术的益处。

引用次数: 0

Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-01 DOI: 10.1016/j.phrs.2025.107637

Yaojun Ren , Min Xue , Xinhui Hui , Xiuyu Liu , Muhammad Asad Farooq , Yiran Chen , Yuzhou Ji , Yixin Duan , Iqra Ajmal , Jie Yao , Wenzheng Jiang

Gastric cancer remains a significant global health burden, characterized by regional variations in incidence and poor survival prospects in advanced stages. Natural killer (NK) cells play a crucial role in the body’s anti-cancer defense, and chimeric antigen receptor (CAR)–NK cell therapy is gaining attention as a cutting-edge and promising treatment method. This study aims to tackle the challenge of TGF-β-mediated tumor immune evasion within the immunosuppressive tumor microenvironment by designing a novel chimeric cytokine receptor TRII/21 R, which consists of extracellular domains of TGF-β receptor II (TRII) and transmembrane and intracellular domains of IL-21 receptor (21 R) and can convert the immunosuppressive signal from TGF-β in the tumor microenvironment (TME) into an NK cell activation signal through the IL-21R-STAT3 pathway. We successfully constructed NKG2D-CAR-NK cells expressing TRII/21 R and demonstrated strong anti-tumor activity against cancer cells both in vitro and in vivo. The co-expression of TRII/21 R in CAR-NK cells enhanced the cytotoxicity, promoted proliferation and survival capabilities, and reduced the expression of exhaustion markers. In the xenograft mouse model, TRII/21R-CAR-NK cells significantly inhibited tumor growth and improved the survival rate of tumor-bearing mice compared to the mice receiving control CAR-NK cells. Additionally, TRII/21 R co-expression enhanced NK cells' infiltration, activation, and persistence within the tumor, indicating a robust anti-tumor response mediated by the JAK-STAT3 signaling pathway. This study underscores the therapeutic potential of TRII/21R-modified CAR-NK cells as a breakthrough strategy for combating cancer.

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引用次数: 0

Intercellular communication is crucial in the regulation of healthy aging via exosomes 细胞间通讯是通过外泌体调节健康衰老的关键。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-01 DOI: 10.1016/j.phrs.2025.107591

Huifang Sun , Tengyuan Xia , Shuting Ma , Tao Lv, Yuhong Li

The hallmarks of aging encompass a variety of molecular categories (genomic, telomeric, and epigenetic), organelles (proteostasis, autophagy, and mitochondria), cellular components (including stem cells), systems (such as intercellular communication and chronic inflammation), and environmental factors (dysbiosis and nutrient sensing). These hallmarks play a crucial role in the aging process. Despite their intricate interconnections, the relationships among the hallmarks of aging remain unclear. Although the boundaries between these hallmarks may be indistinct, they exhibit interdependence, with the influence of one hallmark extending to others. Building on this foundation, we investigated the interrelations among the various hallmarks of aging and provided a systematic overview of their logical relationships, proposing that cellular communication plays a crucial role in the aging process. Exosomes function as a primary mode of cellular communication and significantly impact the aging process. Therefore, we propose utilizing exosomes as valuable tools for understanding the mechanisms of aging and addressing age-related concerns. Exosomes may represent a novel approach for the treatment and diagnosis of aging-related conditions in animals. Furthermore, our research reveals that exocytosis in young nematodes slows the aging process, while exocytosis in aged nematodes has the opposite effect, accelerating aging. In conclusion, exosomes act as intercellular messengers that influence the maintenance of a healthy aging process and link the hallmarks of aging with indicators of well-being.

衰老的标志包括各种分子类别（基因组、端粒和表观遗传）、细胞器（蛋白质平衡、自噬和线粒体）、细胞成分（包括干细胞）、系统（如细胞间通讯和慢性炎症）和环境因素（生态失调和营养感知）。这些特征在衰老过程中起着至关重要的作用。尽管它们之间有着错综复杂的相互联系，但衰老特征之间的关系仍不清楚。虽然这些标志之间的界限可能是模糊的，但它们表现出相互依存，一个标志的影响延伸到其他标志。在此基础上，我们研究了衰老的各种特征之间的相互关系，并系统地概述了它们之间的逻辑关系，提出细胞通信在衰老过程中起着至关重要的作用。外泌体作为细胞通讯的主要模式，显著影响衰老过程。因此，我们建议利用外泌体作为理解衰老机制和解决年龄相关问题的有价值的工具。外泌体可能代表了一种治疗和诊断动物衰老相关疾病的新方法。此外，我们的研究表明，年轻线虫的胞吐作用减缓了衰老过程，而老年线虫的胞吐作用则相反，加速了衰老。总之，外泌体作为细胞间信使，影响健康衰老过程的维持，并将衰老的标志与健康指标联系起来。

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引用次数: 0

Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery 靶向G蛋白偶联受体的隐变构位点作为偏倚药物发现的新策略。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-01 DOI: 10.1016/j.phrs.2024.107574

Xin Qiao , Xiaolong Li , Mingyang Zhang , Ning Liu , Yanmei Wu , Shaoyong Lu , Ting Chen

G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors and are highly effective targets for therapeutic drugs. GPCRs couple different downstream effectors, including G proteins (such as Gi/o, Gs, G12, and Gq) and β-arrestins (such as β-arrestin 1 and β-arrestin 2) to mediate diverse cellular and physiological responses. Biased signaling allows for the specific activation of certain pathways from the full range of receptors’ signaling capabilities. Targeting more variable allosteric sites, which are spatially different from the highly conserved orthosteric sites, represents a novel approach in biased GPCR drug discovery, leading to innovative strategies for targeting GPCRs. Notably, the emergence of cryptic allosteric sites on GPCRs has expanded the repertoire of available drug targets and improved receptor subtype selectivity. Here, we conduct a summary of recent progress in the structural determination of cryptic allosteric sites on GPCRs and elucidate the biased signaling mechanisms induced by allosteric modulators. Additionally, we discuss means to identify cryptic allosteric sites and design biased allosteric modulators based on cryptic allosteric sites through structure-based drug design, which is an advanced pharmacotherapeutic approach for treating GPCR-associated diseases.

G蛋白偶联受体（gpcr）是最大的膜受体家族，是治疗药物的高效靶点。gpcr偶联不同的下游效应物，包括G蛋白（如Gi/o、Gs、G12和Gq）和β-阻滞蛋白（如β-阻滞蛋白1和β-阻滞蛋白2），介导多种细胞和生理反应。偏置信号允许特定的激活某些途径，从全方位的受体的信号能力。靶向更多可变的变构位点，这些变构位点在空间上与高度保守的正构位点不同，代表了偏置GPCR药物发现的新方法，导致了靶向GPCR的创新策略。值得注意的是，GPCRs上隐变容位点的出现扩大了可用药物靶点的范围，提高了受体亚型的选择性。在这里，我们总结了gpcr上隐变构位点的结构测定的最新进展，并阐明了变构调节剂诱导的偏态信号传导机制。此外，我们讨论了通过基于结构的药物设计来识别隐变构位点和设计基于隐变构位点的偏化变构调节剂的方法，这是治疗gpcr相关疾病的一种先进的药物治疗方法。

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引用次数: 0

Natural products targeting RAS by multiple mechanisms and its therapeutic potential in cancer: An update since 2020 多种机制靶向RAS的天然产物及其在癌症中的治疗潜力：自2020年以来的更新。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-02-01 DOI: 10.1016/j.phrs.2025.107577

Yanqing Liu , Jie Chen , Xiang Li , Yu Fan , Cheng Peng , Xiaochun Ye , Yingshuang Wang , Xin Xie

RAS proteins, as pivotal signal transduction molecules, are frequently mutated and hyperactivated in various human cancers, closely associated with tumor cell proliferation, survival, and metastasis. Despite extensive research on RAS targeted therapies, developing effective RAS inhibitors remains a significant challenge. Natural products, endowed with unique chemical structures and diverse biological activities through long-term natural selection, have emerged as a vital resource for discovering novel RAS-targeted therapeutic drugs. This review focuses on the latest advancements in targeting RAS with natural products and categorizes these natural products based on their mechanisms of action. Additionally, we discuss the challenges faced by these natural products during clinical translation, including issues related to pharmacokinetics. Strategies such as combination therapy, structural optimization, and drug delivery systems are anticipated to enhance efficacy and overcome these challenges.

RAS 蛋白作为关键的信号转导分子，在各种人类癌症中经常发生突变和过度激活，与肿瘤细胞的增殖、存活和转移密切相关。尽管对 RAS 靶向疗法进行了广泛研究，但开发有效的 RAS 抑制剂仍是一项重大挑战。天然产物经过长期的自然选择，具有独特的化学结构和多样的生物活性，已成为发现新型 RAS 靶向治疗药物的重要资源。本综述重点介绍利用天然产物靶向 RAS 的最新进展，并根据作用机制对这些天然产物进行分类。此外，我们还讨论了这些天然产物在临床转化过程中面临的挑战，包括与药代动力学相关的问题。联合疗法、结构优化和给药系统等策略有望提高疗效并克服这些挑战。通过多种机制靶向 RAS 的天然产品。

引用次数: 0