Pharmacological research最新文献_第7页

Profiling the impact of anti-human CD20 monoclonal antibodies on lymphocyte B cell subsets and their precursors in the bone marrow and in lymphoid tissues in an immunocompromised mouse engrafted with human cells 分析抗人 CD20 单克隆抗体对骨髓中淋巴细胞 B 细胞亚群及其前体的影响，以及免疫功能低下小鼠淋巴组织中与人细胞接种的淋巴细胞 B 细胞亚群及其前体的影响。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-05 DOI: 10.1016/j.phrs.2024.107442

Annalisa Moregola , Fabrizia Bonacina , Giovanni Battista Vingiani , Roberta Frapolli , Renato Turrini , Giuseppe Danilo Norata

Ofatumumab (OFA) and ocrelizumab (OCRE) are two anti-CD20 monoclonal antibodies approved for the treatment of relapsing forms of multiple sclerosis due to their ability to deplete B lymphocytes. The aim of this study was to investigate the impact of these anti-hCD20 antibodies on B lymphocyte subsets in the circulation and in primary and secondary lymphoid organs in an immune system humanized mouse model (immunocompromised Rag2^−/−Il2rg^−/−CD47^−/−) engrafted with human CD34+ hematopoietic stem cells. Three months after humanization, mice, which present adaptive immune cells only of human origin, were treated with OFA (0.3 mg/Kg; day 1, 3 and 5), or OCRE (10 mg/kg; day 1) or saline. Seven days after the last injection a robust (>90 %) decrease of circulating human CD20+ B lymphocytes was observed in both OFA- and OCRE-treated mice. A partial replenishment of B lymphocytes was detectable in blood 36 days from the last injection in OFA-treated mice, while no B lymphocytes could be detected in OCRE-treated mice up to 65 days post injection. Bone marrow profiling showed that during hCD20+ B cell depletion and replenishment, OCRE-treated mice preserved only preB-I cells in the bone marrow, while the bone marrow of OFA-treated mice presented both preB-I as well as preB-II cells, with the latter subset being the one closest to differentiate into immature B cells. These data together with changes in B cell distribution in other tissues suggest that ofatumumab preserve BM niches, critical for B lymphocyte replenishment, limiting potential side effects of the treatment associated with the increased risk of infection.

Ofatumumab（OFA）和ocrelizumab（OCRE）是两种抗CD20单克隆抗体，因其能消耗B淋巴细胞而被批准用于治疗复发性多发性硬化症。本研究的目的是在免疫系统人源化小鼠模型（免疫受损的Rag2-/-Il2rg-/-CD47-/-）中，研究这些抗hCD20抗体对血液循环中的B淋巴细胞亚群以及原发性和继发性淋巴器官中的B淋巴细胞亚群的影响。人源化三个月后，小鼠接受 OFA（0.3 毫克/千克；第 1、3 和 5 天）或 OCRE（10 毫克/千克；第 1 天）或生理盐水治疗，这些小鼠体内只有源于人类的适应性免疫细胞。最后一次注射七天后，在接受 OFA 和 OCRE 治疗的小鼠中均观察到循环中的人类 CD20+ B 淋巴细胞大量减少（>90%）。经 OFA 处理的小鼠在最后一次注射后 36 天的血液中可检测到 B 淋巴细胞的部分补充，而经 OCRE 处理的小鼠在注射后 65 天仍检测不到 B 淋巴细胞。骨髓图谱显示，在 hCD20+ B 细胞耗竭和补充过程中，OCRE 处理的小鼠骨髓中只保留了前 B-I 细胞，而 OFA 处理的小鼠骨髓中既有前 B-I 细胞，也有前 B-II 细胞，后者是最接近分化为未成熟 B 细胞的亚群。这些数据以及 B 细胞在其他组织中分布的变化表明，ofatumumab 能保护 BM 龛位，这对 B 淋巴细胞的补充至关重要，从而限制了治疗可能产生的副作用，即增加感染风险。

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引用次数: 0

Cardiomyocyte-derived C-type natriuretic peptide diminishes myocardial ischaemic injury by promoting revascularisation and limiting fibrotic burden 心肌细胞源性 C 型钠尿肽可通过促进血管再通和限制纤维化负担来减轻心肌缺血损伤。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-05 DOI: 10.1016/j.phrs.2024.107447

Vanessa J. Lowe , Aisah A. Aubdool , Amie J. Moyes , Joshua P. Dignam , C. Perez-Ternero , Reshma S. Baliga , Nicola Smart , Adrian J. Hobbs

Background

C-type natriuretic peptide (CNP) is a significant player in the maintenance of cardiac and vascular homeostasis regulating local blood flow, platelet and leukocyte activation, heart structure and function, angiogenesis and metabolic balance. Since such processes are perturbed in myocardial infarction (MI), we explored the role of cardiomyocyte-derived CNP, and pharmacological administration of the peptide, in offsetting the pathological consequences of MI.

Methods

Wild type (WT) and cardiomyocyte-restricted CNP null (cmCNP^-/-) mice were subjected to left anterior descending coronary artery (LADCA) ligation and acute effects on infarct size and longer-term outcomes of cardiac repair explored. Heart structure and function were assessed by combined echocardiographic and molecular analyses. Pharmacological administration of CNP (0.2 mg/kg/day; s.c.) was utilized to assess therapeutic potential.

Results

Compared to WT littermates, cmCNP^-/- mice had a modestly increased infarct size following LADCA ligation but without significant deterioration of cardiac structural and functional indices. However, cmCNP^-/- animals exhibited overtly worse heart morphology and contractility 6 weeks following MI, with particularly deleterious reductions in left ventricular ejection fraction, dilatation, fibrosis and revascularization. This phenotype was largely recapitulated in animals with global deletion of natriuretic peptide receptor (NPR)-C (NPR-C^-/-). Pharmacological administration of CNP rescued the deleterious pathology in WT and cmCNP^-/-, but not NPR-C^-/-, animals.

Conclusions and implications

Cardiomyocytes synthesize and release CNP as an intrinsic protective mechanism in response to MI that reduces cardiac structural and functional deficits; these salutary actions are primarily NPR-C-dependent. Pharmacological targeting of CNP may represent a new therapeutic option for MI.

背景：C型钠尿肽（CNP）在维持心脏和血管稳态方面发挥着重要作用，可调节局部血流、血小板和白细胞活化、心脏结构和功能、血管生成和代谢平衡。由于心肌梗死（MI）时这些过程会受到干扰，我们探讨了心肌细胞衍生的 CNP 和药理施用该肽在抵消心肌梗死病理后果中的作用：方法：对野生型（WT）和心肌细胞限制性 CNP 空位（cmCNP-/-）小鼠进行冠状动脉左前降支（LADCA）结扎，并探讨其对梗死面积的急性影响和心脏修复的长期效果。心脏结构和功能通过超声心动图和分子分析进行综合评估。利用药理学方法给予 CNP（0.2 毫克/千克/天；静脉注射）来评估治疗潜力：结果：与WT同窝鼠相比，cmCNP-/-小鼠在结扎LADCA后梗死面积略有增加，但心脏结构和功能指标没有明显恶化。然而，cmCNP-/-动物在心肌梗死后6周表现出明显恶化的心脏形态和收缩力，尤其是左心室射血分数、扩张、纤维化和血管再通的有害减少。这种表型在全面缺失钠尿肽受体（NPR）-C（NPR-C-/-）的动物中基本重现。在 WT 和 cmCNP-/- 而非 NPR-C-/- 动物中，药理施用 CNP 可挽救有害病理：心肌细胞合成和释放 CNP 是对心肌缺血的内在保护机制，可减轻心脏结构和功能障碍；这些有益作用主要依赖于 NPR-C。以 CNP 为药理靶点可能是治疗心肌缺血的一种新方法。

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引用次数: 0

Antifungal properties of abnormal cannabinoid derivatives: Disruption of biofilm formation and gene expression in Candida species 异常大麻素衍生物的抗真菌特性：破坏念珠菌的生物膜形成和基因表达。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-04 DOI: 10.1016/j.phrs.2024.107441

Prince Ofori , Natalia Zemliana , Ilan Zaffran , Tatiana Etzion , Ronit Vogt Sionov , Doron Steinberg , Raphael Mechoulam , Natalya M. Kogan , Francesca Levi-Schaffer

Abnormal cannabinoids (including comp 3) are a class of synthetic lipid compounds with non-psychoactive properties and regioisomer configurations, but distinct from traditional cannabinoids since they do not interact with the established CB1 and CB2 receptors. Previous research showed the cardioprotective and anti-inflammatory potentials of comp 3 and more recently its antimicrobial effect on methicillin-resistant Staphylococcus aureus (MRSA). Given the escalating challenges posed by Candida infections and the rise of antifungal drug resistance, the exploration of novel therapeutic avenues is crucial. This study aimed to assess the anti-Candida properties of newly synthesized AbnCBD derivatives. AbnCBD derivatives were synthesized by acid catalysis-induced coupling and further derivatized. We evaluated the potential of the AbnCBD derivatives to inhibit the growth stages of various Candida species. By in vitro colorimetric assays and in vivo mice experiments, we have shown that AbnCBD derivatives induce differential inhibition of Candida growth. The AbnCBD derivatives, especially comp 3, comp 10, and comp 9 significantly reduced the growth of C. albicans, including FLC-resistant strains, and of C. tropicalis and C. parapsilosis but not of C auris compared to their controls (FLC and 0.5 % DMSO). Comp 3 also disrupted C. albicans biofilm formation and eradicated mature biofilms. Notably, other derivatives of AbnCBD disrupted the biofilm formation and maturation of C. albicans but did not affect yeast growth. In a murine model of VVC, comp 3 demonstrated significant fungal clearance and reduced C. albicans burden compared to vehicle and FLC controls. These findings highlight the potential of AbnCBDs as promising antifungal agents against Candida infections.

异常大麻素（包括化合物 3）是一类合成脂质化合物，具有非精神活性特性和雷公藤异构体结构，但与传统大麻素不同，因为它们不与已有的 CB1 和 CB2 受体相互作用。以前的研究表明，comp 3 具有保护心脏和抗炎的潜力，最近的研究还表明了它对耐甲氧西林金黄色葡萄球菌（MRSA）的抗菌作用。鉴于念珠菌感染带来的挑战不断升级以及抗真菌药物耐药性的增加，探索新的治疗途径至关重要。本研究旨在评估新合成的 AbnCBD 衍生物的抗念珠菌特性。AbnCBD 衍生物由酸催化偶联合成，并进一步衍生化。我们评估了 AbnCBD 衍生物抑制各种念珠菌生长阶段的潜力。通过体外比色实验和体内小鼠实验，我们发现 AbnCBD 衍生物对念珠菌的生长有不同程度的抑制作用。与对照组（FLC 和 0.5% DMSO）相比，AbnCBD 衍生物，尤其是化合物 3、化合物 10 和化合物 9 能显著降低白色念珠菌（包括 FLC 耐药菌株）、热带念珠菌和副丝状念珠菌的生长，但不能降低白色念珠菌的生长。化合物 3 还能破坏白僵菌生物膜的形成并根除成熟的生物膜。值得注意的是，AbnCBD 的其他衍生物会破坏白僵菌生物膜的形成和成熟，但不会影响酵母的生长。在小鼠 VVC 模型中，与药物和 FLC 对照组相比，化合物 3 能显著清除真菌并减少白僵菌的负担。这些发现凸显了 AbnCBD 作为抗念珠菌感染的抗真菌药物的潜力。

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引用次数: 0

β-amyloid’s neurotoxic mechanisms as defined by in vitro microelectrode arrays: a review 体外微电极阵列确定的β-淀粉样蛋白神经毒性机制：综述。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-04 DOI: 10.1016/j.phrs.2024.107436

Aoife O’Connell , Leo Quinlan , Andrea Kwakowsky

Alzheimer's disease is characterized by the aggregation of β-amyloid, a pathological feature believed to drive the neuronal loss and cognitive decline commonly seen in the disease. Given the growing prevalence of this progressive neurodegenerative disease, understanding the exact mechanisms underlying this process has become a top priority. Microelectrode arrays are commonly used for chronic, non-invasive recording of both spontaneous and evoked neuronal activity from diverse in vitro disease models and to evaluate therapeutic or toxic compounds. To date, microelectrode arrays have been used to investigate β-amyloids’ toxic effects, β-amyloids role in specific pathological features and to assess pharmacological approaches to treat Alzheimer’s disease. The versatility of microelectrode arrays means these studies use a variety of methods and investigate different disease models and brain regions. This review provides an overview of these studies, highlighting their disparities and presenting the status of the current literature. Despite methodological differences, the current literature indicates that β-amyloid has an inhibitory effect on synaptic plasticity and induces network connectivity disruptions. β-amyloid’s effect on spontaneous neuronal activity appears more complex. Overall, the literature corroborates the theory that β-amyloid induces neurotoxicity, having a progressive deleterious effect on neuronal signaling and plasticity. These studies also confirm that microelectrode arrays are valuable tools for investigating β-amyloid pathology from a functional perspective, helping to bridge the gap between cellular and network pathology and disease symptoms. The use of microelectrode arrays provides a functional insight into Alzheimer’s disease pathology which will aid in the development of novel therapeutic interventions.

阿尔茨海默病的特征是β-淀粉样蛋白的聚集，这种病理特征被认为是导致神经元丧失和认知能力下降的常见原因。鉴于这种进行性神经退行性疾病的发病率越来越高，了解这一过程的确切机制已成为当务之急。微电极阵列通常用于长期、无创地记录各种体外疾病模型的自发和诱发神经元活动，以及评估治疗或毒性化合物。迄今为止，微电极阵列已被用于研究β-淀粉样蛋白的毒性作用、β-淀粉样蛋白在特定病理特征中的作用以及评估治疗阿尔茨海默病的药理方法。微电极阵列的多功能性意味着这些研究可以使用多种方法，研究不同的疾病模型和脑区。本综述概述了这些研究，强调了它们之间的差异，并介绍了当前文献的现状。尽管在方法上存在差异，但目前的文献表明，β-淀粉样蛋白对突触可塑性有抑制作用，并诱发网络连接中断。β-淀粉样蛋白对自发性神经元活动的影响似乎更为复杂。总之，文献证实了 β 淀粉样蛋白诱导神经毒性的理论，它对神经元信号传导和可塑性具有渐进的有害影响。这些研究还证实，微电极阵列是从功能角度研究β-淀粉样蛋白病理学的重要工具，有助于弥合细胞和网络病理学与疾病症状之间的差距。微电极阵列的使用提供了对阿尔茨海默病病理的功能性洞察，这将有助于开发新型治疗干预措施。

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引用次数: 0

Identification of the TRPA1 cannabinoid-binding site TRPA1 大麻结合位点的鉴定

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-04 DOI: 10.1016/j.phrs.2024.107444

Tala Amawi , Alaa Nmarneh , Gilad Noy , Mariana Ghantous , Masha Y. Niv , Antonella Di Pizio , Avi Priel

Chronic pain accounts for nearly two-thirds of conditions eligible for medical cannabis licenses, yet the mechanisms underlying cannabis-induced analgesia remain poorly understood. The principal phytocannabinoids, the psychoactive Δ⁹-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD), exhibit comparable efficacy in pain management. Notably, THC functions as an agonist of cannabinoid receptor 1 (CB1), whereas CBD shows minimal activity on CB1 and CB2 receptors. Elucidating the molecular targets through which phytocannabinoids modulate the pain system is required for advancing our understanding of the pain pathway and optimizing medical cannabis therapies. Transient receptor potential ankyrin 1 (TRPA1), a pivotal chemosensor in the pain pathway, has been identified as a phytocannabinoid target. Unlike most TRPA1 activators, phytocannabinoid activation is not mediated through the electrophilic binding site, suggesting an alternative mechanism. Here, we identified the human TRPA1 channel cannabinoid-binding site (CBS) and demonstrated that mutations at residue Y840 abolished responses to both THC and CBD at saturating concentrations, indicating a shared primary binding site. Molecular modeling revealed distinct interactions of THC and CBD with the Y840 residue within the CBS. Additionally, CBD binds to the adjacent general anesthetic binding site at oversaturating concentrations. Our findings define the CBS of TRPA1 as overlapping with and adjacent to binding sites for other allosteric activators, suggesting that TRPA1 possesses a highly adaptable domain for binding non-electrophilic activators. This underscores its unique role as a chemosensor in the pain pathway. Furthermore, our results provide new insights into the molecular mechanisms of cannabinoid-induced analgesia and identify novel targets for pain management therapies.

慢性疼痛占符合医用大麻许可条件的病症的近三分之二，但人们对大麻诱导镇痛的机制仍然知之甚少。主要的植物大麻素，即具有精神活性的Δ9-四氢大麻酚（THC）和不具有精神活性的大麻二酚（CBD），在镇痛方面的功效相当。值得注意的是，四氢大麻酚是大麻素受体 1（CB1）的激动剂，而大麻二酚对 CB1 和 CB2 受体的活性很小。阐明植物大麻素调节疼痛系统的分子靶点对于加深我们对疼痛途径的了解和优化医用大麻疗法非常必要。瞬时受体电位炔诺酮 1（TRPA1）是疼痛通路中的一个关键化学传感器，已被确定为植物大麻素的靶点。与大多数 TRPA1 激活剂不同，植物大麻素的激活不是通过亲电结合位点介导的，这表明存在另一种机制。在这里，我们确定了人类 TRPA1 通道大麻素结合位点（CBS），并证明残基 Y840 的突变会在饱和浓度下取消对 THC 和 CBD 的反应，这表明存在一个共享的主要结合位点。分子建模揭示了 THC 和 CBD 与 CBS 中 Y840 残基的不同相互作用。此外，CBD 还能在过饱和浓度下与邻近的全身麻醉剂结合位点结合。我们的研究结果表明，TRPA1 的 CBS 与其他异位激活剂的结合位点重叠并相邻，这表明 TRPA1 拥有一个适应性很强的结构域，可以结合非亲电性激活剂。这凸显了它在疼痛通路中作为化学传感器的独特作用。此外，我们的研究结果还为大麻素诱导镇痛的分子机制提供了新的见解，并为疼痛控制疗法确定了新的靶点。

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引用次数: 0

Harnessing natural inhibitors of protein synthesis for cancer therapy: A comprehensive review 利用天然蛋白质合成抑制剂治疗癌症：全面回顾

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-04 DOI: 10.1016/j.phrs.2024.107449

Liqin Liu, Zhihui Li, Wenshuang Wu

Cancer treatment remains a formidable challenge in modern medicine, necessitating a nuanced understanding of its molecular underpinnings and the identification of novel therapeutic modalities. Among the intricate web of cellular pathways implicated in oncogenesis, protein synthesis has emerged as a fundamental process warranting meticulous investigation. This review elucidates the multifaceted role of protein synthesis pathways in tumor initiation and progression, highlighting the potential of targeting key nodes within these pathways as viable therapeutic strategies. Natural products have long served as a source of bioactive compounds with therapeutic potential owing to their structural diversity and evolutionary honing. Within this framework, we provide a thorough examination of natural inhibitors of protein synthesis as promising candidates for cancer therapy, drawing upon recent advancements and mechanistic insights. By synthesizing current evidence and elucidating key challenges and opportunities, this review aims to galvanize further research into the development of natural product-based anticancer therapeutics, thereby advancing the clinical armamentarium against malignancies.

癌症治疗仍然是现代医学的一项艰巨挑战，需要对其分子基础有细致入微的了解，并找出新的治疗方法。在与肿瘤发生有关的错综复杂的细胞通路中，蛋白质合成是一个值得深入研究的基本过程。这篇综述阐明了蛋白质合成途径在肿瘤发生和发展过程中的多方面作用，强调了靶向这些途径中的关键节点作为可行治疗策略的潜力。长期以来，天然产品一直是具有治疗潜力的生物活性化合物的来源，这得益于它们的结构多样性和进化磨练。在这一框架下，我们借鉴最新进展和机理见解，对作为癌症治疗候选药物的蛋白质合成天然抑制剂进行了深入研究。通过综合现有证据并阐明关键挑战和机遇，这篇综述旨在激励人们进一步研究开发基于天然产物的抗癌疗法，从而推进抗击恶性肿瘤的临床研究。

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引用次数: 0

β-asarone protects against age-related motor decline via activation of SKN-1/Nrf2 and subsequent induction of GST-4 β-asarone通过激活SKN-1/Nrf2和随后诱导GST-4防止与年龄相关的运动机能衰退

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-02 DOI: 10.1016/j.phrs.2024.107450

Ming Lei , Jiayu Wu , Yanheng Tan , Yang Shi , Wuyan Yang , Haijun Tu , Weihong Tan

Decelerating motor decline is important for promoting healthy aging in the elderly population. Acorus tatarinowii Schott is a traditional Chinese medicine that contains β-asarone as a pharmacologically active constituent. We found that β-asarone can decelerate motor decline in various age groups of Caenorhabditis elegans, while concurrently prolonging their lifespan and modulating synaptic transmission. To understand the mechanisms of its efficacy in motor improvement, we investigated and discovered that mitochondrial fragmentation, a marker for aging, is delayed after β-asarone treatment. Moreover, their efficacy is blocked by dysfunctional mitochondria. Corresponding to their role in regulating mitochondrial homeostasis, we found that SKN-1/Nrf2 and GST-4 are critical in the β-asarone treatment, and they appear to be activated via the insulin/IGF-1 signaling pathway. Well-developed intestinal microvilli are required for this process. Our study demonstrates the efficacy and mechanism of β-asarone treatment in age-related motor decline, contributing to the discovery of drugs for achieving healthy aging.

减缓运动机能衰退对促进老年人健康老龄化非常重要。唐菖蒲是一种传统中药，其药理活性成分为β-asarone。我们发现，β-asarone能减缓不同年龄组秀丽隐杆线虫的运动衰退，同时延长其寿命并调节突触传递。为了了解其改善运动能力的机制，我们研究发现，β-asarone 治疗后，衰老的标志物线粒体碎片会被延迟。此外，线粒体功能障碍也会阻碍其功效的发挥。与它们在调节线粒体平衡中的作用相对应，我们发现 SKN-1/Nrf2 和 GST-4 在 β-asarone 处理中起着关键作用，它们似乎是通过胰岛素/IGF-1 信号通路被激活的。这一过程需要发达的肠道微绒毛。我们的研究证明了β-asarone治疗老年性运动机能减退的疗效和机制，有助于发现实现健康老龄化的药物。

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引用次数: 0

Microglia-mediated neuron death requires TNF and is exacerbated by mutant Huntingtin 小胶质细胞介导的神经元死亡需要 TNF，突变型亨廷汀会加剧这种死亡。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-01 DOI: 10.1016/j.phrs.2024.107443

Alexander P. Young, Eileen M. Denovan-Wright

Microglia, the resident immune cells of the brain, regulate the balance of inflammation in the central nervous system under healthy and pathogenic conditions. Huntington’s disease (HD) is a chronic neurodegenerative disease characterized by activated microglia and elevated concentrations of pro-inflammatory cytokines within the brain. Chronic hyperactivation of microglia is associated with brain pathology and eventual neuron death. However, it is unclear which specific cytokines are required for neuron death and whether HD neurons may be hypersensitive to neuroinflammation. We assessed the profile of microglia-secreted proteins in response to LPS and IFNγ, and a conditioned media paradigm was used to examine the effects of these secreted proteins on cultured neuronal cells. STHdh^Q7/Q7 and STHdh^Q111/Q111 neuronal cells were used to model wild-type and HD neurons, respectively. We determined that STHdh^Q111/Q111 cells were hypersensitive to pro-inflammatory factors secreted by microglia, and that TNF was required to induce neuronal death. Microglia-mediated neuronal death could be effectively halted through the use of JAK-STAT or TNF inhibitors which supported the requirement for TNF as well as IFNγ in the process of secondary neurotoxicity. Further data derived from human HD patients as well as HD mice were suggestive of enhanced receptor density for TNF (TNFR1) and IFNγ (IFNGR) which could sensitize the HD brain to these cytokines. This highlights several potential mechanisms by which microglia may induce neuronal death and suggests that these mechanisms may be upregulated in the brain of HD patients.

小胶质细胞是大脑的常驻免疫细胞，在健康和致病条件下调节中枢神经系统的炎症平衡。亨廷顿舞蹈症（Huntington's disease，HD）是一种慢性神经退行性疾病，其特征是小胶质细胞活化和脑内促炎细胞因子浓度升高。小胶质细胞的长期过度激活与大脑病理学和神经元的最终死亡有关。然而，目前还不清楚神经元死亡需要哪些特定的细胞因子，也不清楚 HD 神经元是否会对神经炎症过敏。我们评估了小胶质细胞分泌的蛋白质对 LPS 和 IFNγ 的反应，并使用条件培养基范例来研究这些分泌的蛋白质对培养的神经元细胞的影响。我们用 STHdhQ7/Q7 和 STHdhQ111/Q111 神经元细胞分别模拟野生型和 HD 神经元。我们发现，STHdhQ111/Q111细胞对小胶质细胞分泌的促炎因子过敏，而TNF可诱导神经元死亡。使用 JAK-STAT 或 TNF 抑制剂可有效阻止小胶质细胞介导的神经元死亡，这证明在继发性神经毒性过程中需要 TNF 和 IFNγ。来自人类 HD 患者和 HD 小鼠的进一步数据表明，TNF（TNFR1）和 IFNγ（IFNGR）的受体密度增强，这可能使 HD 大脑对这些细胞因子敏感。这突显了小胶质细胞可能诱导神经元死亡的几种潜在机制，并表明这些机制可能在 HD 患者的大脑中上调。

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引用次数: 0

Influence of statin potency and liposolubility on Alzheimer’s disease patients: A population-based study 他汀类药物的效力和脂溶性对阿尔茨海默病患者的影响：一项基于人群的研究。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-01 DOI: 10.1016/j.phrs.2024.107446

Mar García-Zamora , Gemma García–Lluch , Lucrecia Moreno , Juan Pardo , Consuelo Cháfer – Pericás

Although Alzheimer’s disease (AD) cause is still unknown, there are several known risk factors, such as dyslipidemia. Statins are the most prescribed lipid-modifying therapies. Recent research has suggested a relationship between statins and AD, nevertheless, their ability to prevent AD is still unclear. Therefore, this cross-sectional study aimed to examine the relationship between statin use and anti-AD drug prescription. For that purpose, a database containing information on medications prescribed to patients aged 50 years or older (n = 233183) between 2018 and 2020 was used. Defined daily doses (DDDs) were calculated according to the ATC/DDD index 2023. Statistical analyses, with logistic regression and cumulative incidence, were carried out to assess statins and anti-AD drug consumption. As a result, a total of 47852 patients aged more than 70 years who were prescribed at least one antihypertensive, antidiabetic or lipid-modifying agent were included in the study. Of these, 45345 patients were classified within the cardiovascular risk group and 2483 were classified as patients with only hyperlipidemia. Patients using low-potency or hydrophilic statins had lower odds of anti-AD usage when compared to high-potency or lipophilic statins, respectively. Similarly, rosuvastatin and pitavastatin had lower odds of anti-AD medication intake when compared to atorvastatin. Finally, pitavastatin DDDs were prone to lower the odds of anti-AD medication usage when compared to rosuvastatin. In conclusion, a potential association between statins and the intake of AD medication has been observed. Specifically, low-potency (pitavastatin) and hydrophilic (rosuvastatin) statins were associated with less use of anti-AD medication.

虽然阿尔茨海默病（AD）的病因尚不清楚，但有几个已知的风险因素，如血脂异常。他汀类药物是最常用的调脂疗法。最近的研究表明，他汀类药物与阿兹海默症之间存在一定关系，但其预防阿兹海默症的能力仍不明确。因此，本横断面研究旨在探讨他汀类药物的使用与抗注意力缺失症药物处方之间的关系。为此，我们使用了一个数据库，其中包含2018年至2020年期间开给50岁或以上患者（n = 233183）的药物信息。根据ATC/DDD指数2023计算了定义日剂量（DDD）。采用逻辑回归和累积发生率进行统计分析，以评估他汀类药物和抗逆转录病毒药物的消耗量。结果，共有 47852 名 70 岁以上、至少服用一种降压药、抗糖尿病药或调脂药的患者被纳入研究。其中，45345 名患者被归类为心血管风险组，2483 名患者被归类为仅有高脂血症的患者。使用低效他汀类药物或亲水性他汀类药物的患者使用抗反式脂肪肝药物的几率分别低于使用高效他汀类药物或亲脂性他汀类药物的患者。同样，与阿托伐他汀相比，罗伐他汀和匹伐他汀的抗逆转录酶药物摄入几率较低。最后，与罗伐他汀相比，匹伐他汀DDD容易降低服用抗逆转录酶药物的几率。总之，我们观察到他汀类药物与摄入抗逆转录酶药物之间存在潜在联系。具体来说，低效（匹伐他汀）和亲水性（罗苏伐他汀）他汀类药物与较少使用抗逆转录酶药物有关。

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引用次数: 0

Revisiting the nature and pharmacodynamics of tacrolimus metabolites 重新审视他克莫司代谢物的性质和药效学作用

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-09-30 DOI: 10.1016/j.phrs.2024.107438

Rudy Mevizou , Hassan Aouad , François-Ludovic Sauvage , Hélène Arnion , Emilie Pinault , Jean-Sébastien Bernard , Gildas Bertho , Nicolas Giraud , Rodolphe Alves de Sousa , Adolfo Lopez-Noriega , Florent Di Meo , Mélanie Campana , Pierre Marquet

The toxicity of tacrolimus metabolites and their potential pharmacodynamic (PD) interactions with tacrolimus might respectively explain the surprising combination of higher toxicity and lower efficacy of tacrolimus despite normal blood concentrations, described in extensive metabolizers. To evaluate such interactions, we produced tacrolimus metabolites in vitro and characterized them by high resolution mass spectrometry (HRMS, for all) and nuclear magnetic resonance (NMR, for the most abundant, M-I). We quantified tacrolimus metabolites and checked their structure in patient whole blood and peripheral blood mononuclear cells (PBMC). We explored the interactions of M-I with tacrolimus in silico, in vitro and ex vivo. In vitro metabolization produced isoforms of tacrolimus and of its metabolites M-I and M-III, whose HRMS fragmentation suggested an open-ring structure. M-I and M-III open-ring isomers were also observed in patient blood. By contrast, NMR could not detect these open-ring forms. Transplant patients expressing CYP3A5 exhibited higher M-I/TAC ratios in blood and PBMC than non-expressers. Molecular Dynamics simulations showed that: all possible tacrolimus metabolites and isomers bind FKPB12; and the hypothetical open-ring structures induce looser binding between FKBP12 and calcineurins, leading to lower CN inhibition. In vitro, tacrolimus bound FKPB12 with more affinity than purified M-I, and the pool of tacrolimus metabolites and purified M-I had only weak inhibitory activity on IL2 secretion and not at all on NFAT nuclear translocation. M-I showed no competitive effect with tacrolimus on either test. Finally, M-I or the metabolite pool did not significantly interact with tacrolimus MLR suppression, thus eliminating a pharmacodynamic interaction.

他克莫司代谢物的毒性及其与他克莫司之间潜在的药效学（PD）相互作用，可能分别解释了在广泛代谢者中，尽管血药浓度正常，但他克莫司的毒性较高而疗效较低的惊人组合。为了评估这种相互作用，我们在体外产生了他克莫司代谢物，并通过高分辨质谱法（HRMS，针对所有代谢物）和核磁共振法（NMR，针对含量最高的代谢物 M-I）对其进行了表征。我们对患者全血和外周血单核细胞（PBMC）中的他克莫司代谢物进行了量化，并检查了它们的结构。我们探索了 M-I 与他克莫司在硅学、体外和体内的相互作用。体外代谢产生了他克莫司及其代谢物 M-I 和 M-III的异构体，它们的 HRMS 片段显示为开环结构。在患者血液中也观察到了开环异构体 M-I 和 M-III。相比之下，核磁共振无法检测到这些开环形式。表达 CYP3A5 的移植患者血液和 PBMC 中的 M-I/TAC 比率高于非表达者。分子动力学模拟显示：所有可能的他克莫司代谢物和异构体都能与 FKPB12 结合；假定的开环结构会导致 FKBP12 与钙神经元之间的结合更松散，从而导致较低的 CN 抑制作用。在体外，他克莫司与 FKPB12 结合的亲和力高于纯化的 M-I，而他克莫司代谢物池和纯化的 M-I 对 IL2 的分泌只有微弱的抑制活性，对 NFAT 核转位完全没有抑制作用。在这两项测试中，M-I 与他克莫司都没有竞争作用。最后，M-I 或代谢物池与他克莫司 MLR 抑制作用没有明显的相互作用，因此排除了药效学相互作用。

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引用次数: 0