Chemico-Biological Interactions最新文献_第10页

Synergistic inhibitory effects of enzalutamide and its phase I metabolite on UDP-glucuronosyltransferase 1A1 (UGT1A1) and risk prediction of drug-drug interactions 恩杂鲁胺及其I期代谢物对udp -葡萄糖醛酸糖基转移酶1A1 （UGT1A1）的协同抑制作用及药物-药物相互作用的风险预测

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-13 DOI: 10.1016/j.cbi.2025.111829

Tingting Zheng, Hang Yin, Hongna Shan, Lihuan Sun, Lili Jiang, Yong Liu

Enzalutamide (formerly called MDV3100), a second-generation androgen receptor inhibitor primarily used for treating castration-resistant prostate cancer (CRPC), has been shown to regulating UDP-glucuronosyltransferases (UGTs) expression, while its effects on the activity of UGT isoforms remain unclear. This study aimed to systemically investigate the effects of enzalutamide and its phase I metabolite on the UGT activities, and to assess the risk of drug-drug interactions (DDIs) resulting from UGT inhibition. Using high-performance liquid chromatography (HPLC) and enzyme kinetic studies, we evaluated the inhibitory effects of enzalutamide and its main phase I metabolite, N-desmethyl enzalutamide on 12 UGT isoforms and inhibition patterns. Our findings demonstrated that both enzalutamide and its metabolite exhibited potent inhibition against UGT1A1, with evidence of synergistic effects. Enzyme kinetic analysis revealed that both enzalutamide and its metabolite acted as competitive inhibitors of UGT1A1. In vitro-in vivo extrapolation (IVIVE) prediction indicated that concomitant use of enzalutamide with UGT1A1 substrates could induce clinically significant DDIs. Therefore, special caution should be warranted when administering enzalutamide alongside other drugs metabolized by UGT to mitigate potential DDIs.

Enzalutamide（以前称为MDV3100）是一种主要用于治疗去势抵抗性前列腺癌（CRPC）的第二代雄激素受体抑制剂，已被证明可调节udp -葡萄糖醛基转移酶（UGT）的表达，但其对UGT亚型活性的影响尚不清楚。本研究旨在系统研究恩杂鲁胺及其I期代谢物对UGT活性的影响，并评估UGT抑制引起的药物-药物相互作用（ddi）的风险。采用高效液相色谱（HPLC）和酶动力学研究，研究了enzalutamide及其主要I相代谢物n -去甲基enzalutamide对12种UGT亚型的抑制作用和抑制模式。我们的研究结果表明，enzalutamide及其代谢物对UGT1A1均表现出有效的抑制作用，并具有协同效应。酶动力学分析表明，enzalutamide及其代谢物都是UGT1A1的竞争性抑制剂。体外外推（IVIVE）预测表明，同时使用enzalutamide与UGT1A1底物可诱导临床显著的ddi。因此，当enzalutamide与其他由UGT代谢的药物一起使用以减轻潜在的ddi时，应特别小心。

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引用次数: 0

F–53B triggers ovarian granulosa cell senescence and ovarian dysfunction by triggering mitochondrial dysfunction F-53B通过触发线粒体功能障碍引发卵巢颗粒细胞衰老和卵巢功能障碍。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-13 DOI: 10.1016/j.cbi.2025.111791

Zhiyuan Wang , Yang Su , MengQin wang , Huiyi Xie , Xiaoli Chen , Wenwei Zheng , Yuanzhi Xie , Lili Feng , Xiuli Lian , Gaoxiong Wang , Na Lin

As a class of persistent organic pollutants, per-and polyfluoroalkyl substances (PFASs) are widely distributed in the global environment, posing potential threats to ecosystems and human health. 6:2 Chlorinated polyfluoroalkyl ether sulfonate (F–53B), a primary substitute for perfluorooctane sulfonic acid (PFOS), has been widely used and detected in human samples. However, current toxicological studies on F–53B mainly focus on organs such as the liver and intestines, while its effects on the female reproductive system—particularly ovarian function—remain incompletely understood. This work investigated the effects of F–53B on ovarian granulosa cells (COV434 and KGN cells) and ovarian function in mice, as well as its molecular mechanisms. In vitro results showed that F–53B exposure significantly promoted senescence of ovarian granulosa cells. Mechanistic studies revealed that F–53B induced senescence via the cGAS-STING-IRF3 signaling axis. Further analysis demonstrated that F–53B exacerbated senescence by inhibiting autophagy. In vivo studies showed that F–53B exposure caused ovarian dysfunction in mice, characterized by reduced follicular reserve, elevated serum follicle-stimulating hormone (FSH) levels, and decreased estradiol (E2) levels. Taken together, this work first reveals that F–53B induces senescence of ovarian granulosa cells through triggering innate immune signaling pathway, providing new experimental evidence for understanding the hazards of F–53B to female reproductive health. The findings not only provide critical data for the toxicity assessment of PFASs but also offer potential molecular targets for the prevention and intervention of premature ovarian failure.

全氟烷基和多氟烷基物质作为一类持久性有机污染物，广泛分布于全球环境中，对生态系统和人类健康构成潜在威胁。6:2氯化多氟烷基醚磺酸盐（F-53B）是全氟辛烷磺酸（PFOS）的主要替代品，已被广泛使用并在人体样本中检测到。然而，目前对F-53B的毒理学研究主要集中在肝脏和肠道等器官上，而其对女性生殖系统的影响——尤其是卵巢功能——仍然不完全清楚。本文研究了F-53B对小鼠卵巢颗粒细胞（COV434和KGN细胞）和卵巢功能的影响及其分子机制。体外实验结果显示，F-53B暴露可显著促进卵巢颗粒细胞的衰老。机制研究表明，F-53B通过cGAS-STING-IRF3信号轴诱导衰老。进一步分析表明，F-53B通过抑制自噬加速衰老。体内研究表明，F-53B暴露导致小鼠卵巢功能障碍，其特征是卵泡储备减少，血清促卵泡激素（FSH）水平升高，雌二醇（E2）水平降低。综上所述，本工作首次揭示了F-53B通过触发先天免疫信号通路诱导卵巢颗粒细胞衰老，为了解F-53B对女性生殖健康的危害提供了新的实验证据。这些发现不仅为PFASs的毒性评估提供了关键数据，也为卵巢早衰的预防和干预提供了潜在的分子靶点。

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引用次数: 0

Selective cytotoxicity of anhydroicaritin in ER-positive breast cancer via ESR1-mediated MAPK and apoptotic signaling 通过esr1介导的MAPK和凋亡信号传导对er阳性乳腺癌的选择性细胞毒性。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-11 DOI: 10.1016/j.cbi.2025.111825

Huiyan Ying , Jujia Zheng , Mingxiang Jiang , Wanlu Shi , Xiangwei Xu , Xiaofen Ni

Anhydroicaritin (AHI), a chemically characterized prenylated flavonoid, exhibits strong and selective cytotoxicity against estrogen receptor-positive (ER+) breast cancer cells. In this study, we aimed to elucidate its molecular and cellular toxicological mechanisms using an integrated strategy consisting of chemoinformatics, machine learning-based target prioritization, Mendelian randomization (MR) causal inference, and in vitro mechanistic assays. Network pharmacology analysis revealed that ESR1 (estrogen receptor 1) was ranked as the top hit hub gene and was further supported as a functional mediator of AHI action by machine learning models and MR analysis. Molecular docking and 100-ns molecular dynamics simulations demonstrated that AHI could form a stable and energetically preferred interaction with estrogen receptor 1 (ESR1). Subsequent mechanistic experiments in MCF-7 and ZR-75-1 cells revealed that AHI could attenuate the activity of MAPK signaling pathway and induce apoptosis by downregulating ESR1 mRNA expression through reducing ERα phosphorylation. Notably, AHI exhibited weak cytotoxicity against normal mammary epithelial cells, suggesting that it might exhibit selective toxicity toward malignant phenotypes. Our findings offered mechanistic evidence for the dual-level (post-translational and transcriptional) regulation of ESR1 signaling by AHI in ER+ breast cancer and suggested that AHI might be a subtype-specific chemotherapeutic lead compound.

Anhydroicaritin （AHI）是一种具有化学特征的烯酰化类黄酮，对雌激素受体阳性（ER+）乳腺癌细胞具有很强的选择性细胞毒性。在这项研究中，我们旨在通过化学信息学、基于机器学习的目标优先排序、孟德尔随机化（MR）因果推理和体外机制分析等综合策略来阐明其分子和细胞毒理学机制。网络药理学分析显示ESR1（雌激素受体1）被列为最受欢迎的枢纽基因，并通过机器学习模型和MR分析进一步支持其作为AHI作用的功能中介。分子对接和100-ns分子动力学模拟表明，AHI能够与雌激素受体1 （estrogen receptor 1, ESR1）形成稳定且能量优先的相互作用。随后在MCF-7和ZR-75-1细胞中进行的机制实验表明，AHI可通过降低ERα磷酸化，下调ESR1 mRNA表达，从而减弱MAPK信号通路的活性，诱导细胞凋亡。值得注意的是，AHI对正常乳腺上皮细胞表现出较弱的细胞毒性，这表明它可能对恶性表型表现出选择性毒性。我们的研究结果为AHI在ER+乳腺癌中双水平（翻译后和转录后）调控ESR1信号提供了机制证据，并提示AHI可能是一种亚型特异性化疗先导化合物。

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引用次数: 0

Subchronic exposure to T-2 toxin triggered neurobehavioral damage in developing juvenile rats was associated with oxidative stress and mitochondrial pathway-induced apoptosis of hippocampal neurons 亚慢性暴露于T-2毒素引发的幼年大鼠神经行为损伤与氧化应激和线粒体通路诱导的海马神经元凋亡有关。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-10 DOI: 10.1016/j.cbi.2025.111824

Junfeng Zhou , Fanshuang Meng , Qingwen Li , Hongyu Wang , Ning Zou

T-2 toxin represents a significant hazard to animal husbandry and human health. Studies have shown that T-2 toxins are able to induce neurotoxicity by disrupting the blood-brain barrier or by inducing neuronal dysfunction. And during the developmental period, a critical period for neurological development, the neurotoxic effects produced after exposure to T-2 toxins have not yet been fully elucidated. This study was concentrated on the neurotoxic impacts of T-2 toxin on hippocampus neurons using juvenile male Wistar rats as an experimental model. Through behavioral assessments, Hematoxylin–Eosin (HE) staining, Nissl staining, and transmission electron microscopy (TEM), we evaluated hippocampal pathological damage and its correlation with behavioral alterations. To elucidate the underlying mechanisms, we analyzed oxidative stress markers, including reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). We also detected mitochondrial membrane potential, hippocampus neuronal apoptosis, and associated protein and mRNA expression levels (Bax, Bcl-2, Caspase-3). These findings imply that (1) T-2 toxin exposure induced neurobehavioral deficits and hippocampus structural damage; (2) T-2 toxin triggered oxidative stress within the rat's hippocampus, characterized by suppressed SOD activity alongside upregulated ROS and MDA levels; and (3) T-2 toxin disrupted mitochondrial function, leading to increased neuronal apoptosis and altered expression of apoptosis-associated proteins and mRNA. These findings give an in-depth understanding of the molecular mechanisms by which T-2 toxin exerts neurotoxic effects. Offering a theoretical foundation for developing targeted therapeutic interventions.

T-2毒素对畜牧业和人类健康具有重大危害。研究表明，T-2毒素能够通过破坏血脑屏障或诱导神经元功能障碍来诱导神经毒性。而在神经发育的关键时期，暴露于T-2毒素后产生的神经毒性作用尚未完全阐明。本研究以幼年雄性Wistar大鼠为实验模型，研究T-2毒素对海马神经元的神经毒性作用。通过行为评估、苏木精-伊红（HE）染色、尼氏染色和透射电镜（TEM），我们评估了海马的病理损伤及其与行为改变的相关性。为了阐明潜在的机制，我们分析了氧化应激标志物，包括活性氧（ROS）、丙二醛（MDA）和超氧化物歧化酶（SOD）。我们还检测了线粒体膜电位、海马神经元凋亡以及相关蛋白和mRNA表达水平（Bax、Bcl-2、Caspase-3）。这些发现表明：(1)T-2毒素暴露导致神经行为缺陷和海马结构损伤；(2) T-2毒素引发大鼠海马内氧化应激，表现为SOD活性受到抑制，ROS和MDA水平升高；(3) T-2毒素破坏线粒体功能，导致神经元凋亡增加，凋亡相关蛋白和mRNA表达改变。这些发现为T-2毒素发挥神经毒性作用的分子机制提供了深入的了解。为发展有针对性的治疗干预提供理论基础。

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引用次数: 0

Cardiac glycosides toxicity: Mechanisms and mitigation strategies in recent studies 心脏糖苷毒性：近期研究的机制和缓解策略。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-10 DOI: 10.1016/j.cbi.2025.111817

Shuyun Xiao , Mengqi Tong , Jiayi Ren , Yidan Bai , Jian Xu , Kouharu Otsuki , Wei Li , Feng Feng , Jie Zhang

Cardiac glycosides, while renowned for their cardiotonic effects, present a significant challenge in drug development due to their narrow therapeutic window. Although their antitumor potential, exemplified by derivatives such as RX108 entering clinical trials, has renewed research interest, inherent cardiotoxicity remains a major safety concern. This review focuses on recent advances in understanding and mitigating cardiac glycoside toxicity. A central focus is placed on comprehensively summarizing the intricate molecular mechanisms underlying their cardiotoxicity, which extend beyond the canonical Na⁺/K⁺-ATPase inhibition. In addition, we examine their multi-organ toxicity profiles and corresponding clinical management strategies, with particular emphasis on digoxin-specific Fab antibodies. Another pivotal aspect of this review is a critical analysis of contemporary, rational structural modification strategies designed to decouple cardiotoxicity from therapeutic efficacy. By synthesizing these insights, this work aims to provide a foundational framework for overcoming the toxicity hurdles and advancing the repurposing of cardiac glycosides in precision oncology and other therapeutic areas.

心脏糖苷虽然以其强心作用而闻名，但由于其狭窄的治疗窗口，在药物开发中提出了重大挑战。虽然它们的抗肿瘤潜力，例如进入临床试验的RX108衍生物，重新引起了研究兴趣，但固有的心脏毒性仍然是一个主要的安全性问题。这篇综述的重点是了解和减轻心脏糖苷毒性的最新进展。中心重点放在全面总结其心脏毒性的复杂分子机制，这超出了典型的Na+/K+- atp酶抑制。此外，我们研究了它们的多器官毒性概况和相应的临床管理策略，特别强调地高辛特异性Fab抗体。本综述的另一个关键方面是对当代合理结构修饰策略的批判性分析，这些策略旨在将心脏毒性与治疗效果分离开来。通过综合这些见解，本工作旨在为克服毒性障碍和推进心脏糖苷在精确肿瘤学和其他治疗领域的再利用提供一个基础框架。

{"title":"Cardiac glycosides toxicity: Mechanisms and mitigation strategies in recent studies","authors":"Shuyun Xiao , Mengqi Tong , Jiayi Ren , Yidan Bai , Jian Xu , Kouharu Otsuki , Wei Li , Feng Feng , Jie Zhang","doi":"10.1016/j.cbi.2025.111817","DOIUrl":"10.1016/j.cbi.2025.111817","url":null,"abstract":"<div><div>Cardiac glycosides, while renowned for their cardiotonic effects, present a significant challenge in drug development due to their narrow therapeutic window. Although their antitumor potential, exemplified by derivatives such as RX108 entering clinical trials, has renewed research interest, inherent cardiotoxicity remains a major safety concern. This review focuses on recent advances in understanding and mitigating cardiac glycoside toxicity. A central focus is placed on comprehensively summarizing the intricate molecular mechanisms underlying their cardiotoxicity, which extend beyond the canonical Na<sup>+</sup>/K<sup>+</sup>-ATPase inhibition. In addition, we examine their multi-organ toxicity profiles and corresponding clinical management strategies, with particular emphasis on digoxin-specific Fab antibodies. Another pivotal aspect of this review is a critical analysis of contemporary, rational structural modification strategies designed to decouple cardiotoxicity from therapeutic efficacy. By synthesizing these insights, this work aims to provide a foundational framework for overcoming the toxicity hurdles and advancing the repurposing of cardiac glycosides in precision oncology and other therapeutic areas.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"423 ","pages":"Article 111817"},"PeriodicalIF":5.4,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145508518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GLS1 inhibitor CB-839 inhibits the malignant progression of 5-FU resistant hepatoma cells by regulating glutamine metabolism GLS1抑制剂CB-839通过调节谷氨酰胺代谢抑制5-FU耐药肝癌细胞的恶性进展。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-08 DOI: 10.1016/j.cbi.2025.111812

Hao Wang , Xiao-yan Wang , Jian-bo Ji , Zong-xue Zheng , Peng-fei Shang , Xiu-li Guo

Liver cancer, primary hepatocellular carcinoma (HCC), posing a significant threat to human health due to its high prevalence and limited treatment options. As a first-line chemotherapeutic agent for HCC, 5-fluorouracil (5-FU) has demonstrated significant efficacy in suppressing tumor cell proliferation through its cytotoxic mechanisms. Yet, prolonged 5-FU administration often induces chemo-resistant phenotypes in cancer cells, severely compromising the long-term efficacy of 5-FU-based treatment regimens and becoming a major barrier to successful HCC therapy. In this study, we investigated the mechanism underlying 5-FU resistance in Bel7402 hepatoma cells and found that it is closely related to metabolic reprogramming of glutamine. Notably, we demonstrated that CB-839, which is an inhibitor of glutamine metabolism's rate-limiting enzyme (glutaminase), has no notable anti-tumor activity alone but effectively enhances resistant HCC cells' sensitivity to 5-FU both in vitro and in vivo. The mechanism underlying this sensitization involves the disruption of cellular redox homeostasis. Specifically, the combination of CB-839 and 5-FU increases the accumulation of reactive oxygen species (ROS) and induces oxidative stress by consuming intracellular glutathione (GSH) reserves. Furthermore, this combination therapy elevates intracellular Fe²⁺levels and promotes lipid peroxidation, ultimately triggering ferroptosis. Collectively, these findings tentatively address certain aspects of the unclear mechanism underlying 5-FU resistance in HCC. Specifically, they may suggest targeting glutamine metabolism as a potential avenue for intervention and offer novel perspectives on understanding this resistance. Concurrently, these discoveries provide some support for optimizing chemotherapy regimens, with the aim of surmounting the current clinical challenges in reversing drug resistance.

肝癌，原发性肝细胞癌（HCC），由于其高患病率和有限的治疗选择，对人类健康构成重大威胁。5-氟尿嘧啶（5-FU）作为HCC的一线化疗药物，通过其细胞毒性机制抑制肿瘤细胞增殖的效果显著。然而，长时间的5-FU给药往往会在癌细胞中诱导化疗耐药表型，严重影响基于5-FU治疗方案的长期疗效，并成为成功治疗HCC的主要障碍。在本研究中，我们研究了Bel7402肝癌细胞5-FU耐药的机制，发现其与谷氨酰胺的代谢重编程密切相关。值得注意的是，我们证明了CB-839作为谷氨酰胺代谢限速酶（谷氨酰胺酶）的抑制剂，单独没有显著的抗肿瘤活性，但在体外和体内都有效地增强了耐药HCC细胞对5-FU的敏感性。这种致敏的机制涉及细胞氧化还原稳态的破坏。具体来说，CB-839和5-FU的结合增加了活性氧（ROS）的积累，并通过消耗细胞内谷胱甘肽（GSH）储备诱导氧化应激。此外，这种联合治疗提高细胞内Fe2+水平，促进脂质过氧化，最终引发铁下垂。总的来说，这些发现初步解决了HCC中5-FU耐药机制不明确的某些方面。具体来说，他们可能建议将谷氨酰胺代谢作为潜在的干预途径，并为理解这种耐药性提供新的视角。同时，这些发现为优化化疗方案提供了一些支持，旨在克服当前在逆转耐药方面的临床挑战。

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引用次数: 0

Corrigendum to “Insights into the diagnostic and prognostic value of paraoxonase 1-related variables and inflammatory markers in community-acquired pneumonia” [Chem. Biol. Interact. 418 (2025) 111606] 对社区获得性肺炎中对氧磷酶1相关变量和炎症标志物的诊断和预后价值的见解的更正[化学]。医学杂志。[互动]. 418 (2025)111606]

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-08 DOI: 10.1016/j.cbi.2025.111808

Frederic Ballester , Xavier Gabaldó-Barrios , Andrea Jiménez-Franco , Isabel Pujol , Simona Iftimie , Jordi Camps , Sandra Parra , Antoni Castro , Jorge Joven

引用次数: 0

Reflection about articaine: in vitro studies and clinical data - RE: Schwann cells exposed to articaine display distinct toxic pathways compared to lidocaine by Rodrigues da Silva et al. - Chem Biol Interact. 2025 Jan 25; 406: 111315 关于articaine的反思：体外研究和临床数据- RE：与Rodrigues da Silva等人相比，暴露于articaine的雪旺细胞显示出与利多卡因不同的毒性途径- Chem Biol interaction . 2025年1月25日；406: 111315。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-08 DOI: 10.1016/j.cbi.2025.111816

Filipe Polese Branco , Maria Cristina Leme Godoy dos Santos

引用次数: 0

Sex-specific aggressive and emotional behavior in myostatin-deficient mice: Ratio of acylated versus unacylated ghrelin is reduced, but not correlated with butyrylcholinesterase activity level, however parvalbumin expression is lost in the habenular complex 肌抑制素缺乏小鼠的性别特异性攻击和情绪行为：酰化与未酰化胃饥饿素的比例降低，但与丁基胆碱酯酶活性水平无关，然而小蛋白表达在habenular复合体中丢失。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-07 DOI: 10.1016/j.cbi.2025.111813

Barbara Vernus , Bénédicte Goustard , Béatrice Chabi , Christelle Bertrand-Gaday , Hillary Maillet , Meghan K. Cash , Pierre Delobel , Sylvain Cerda , Mélanie Macart , Anne Bonnieu , Sultan Darvesh , Arnaud Chatonnet

Myostatin plays crucial roles in negative regulation of muscle growth. Inactivation of the myostatin gene results in gross muscle hypertrophy. We observed that myostatin knock-out (myostatin-KO) mice are more aggressive than wild-type (WT) mice. Ghrelin is a hormone produced by cells of the gastrointestinal tract that activates cells in the brain and increases the drive to eat. The level of circulating ghrelin affects anxiety, stress, and aggression. Ghrelin controls expression of myostatin in disease-associated cachexia. Butyrylcholinesterase (BChE) is responsible for the deacylation of ghrelin. BChE knock-out mice show higher level of acylated ghrelin and are more aggressive than WT mice. De-acylation of ghrelin by BChE reduces aggression in mice. We hypothesized that the levels of expression of BChE, ghrelin and myostatin could explain the aggressive behavior of myostatin-myostatin-KO mice. Resident/intruder tests shows that male myostatin-KO mice are more aggressive than WT littermates. Female myostatin-KO mice show much higher spontaneous exercise than female WT and males of both genotypes. Behavioral tests (elevated plus maze and light/dark box) show that myostatin-KO mice present anxious behavior without any change in circulating corticosterone. Myostatin-KO mice have a lower acylated/unacylated ghrelin ratio. Female myostatin-KO mice show lower level of BChE activity compared with WT littermates. Comparison of staining for various neurotransmitter systems involved in behavior showed that the only region where there was a difference between WT and myostatin-KO mice was in the habenular complex which involved in regulation of behavior. Reduced ghrelin levels and loss of parvalbumin neurons of the habenular complex could partly explain the behavior of our model.

肌肉生长抑制素在肌肉生长负调控中起着至关重要的作用。肌肉生长抑制素基因失活导致肌肉肥大。我们观察到肌生长抑制素敲除（myostatin- ko）小鼠比野生型（WT）小鼠更具攻击性。胃饥饿素是一种由胃肠道细胞产生的激素，它能激活大脑细胞，增加食欲。胃饥饿素的循环水平影响焦虑、压力和攻击性。Ghrelin控制疾病相关恶病质中肌生长抑制素的表达。丁基胆碱酯酶（BChE）负责胃饥饿素的去酰化。BChE敲除小鼠显示出更高水平的酰化饥饿素，并且比WT小鼠更具攻击性。BChE对胃饥饿素的去酰化降低了小鼠的攻击性。我们假设BChE、胃饥饿素和肌肉生长抑制素的表达水平可以解释肌肉生长抑制素-肌肉生长抑制素- ko小鼠的攻击行为。驻地/入侵者试验显示雄性肌抑制素- ko小鼠比WT幼崽更具攻击性。雌性肌生成抑制素- ko小鼠比雌性WT和两种基因型的雄性小鼠表现出更高的自发运动。行为学测试（升高+迷宫和光/暗箱）显示肌生成他汀- ko小鼠表现出焦虑行为，而循环皮质酮没有任何变化。肌生长抑制素- ko小鼠的饥饿素酰化/未酰化比例较低。雌性肌生成抑制素- ko小鼠与WT窝鼠相比BChE活性水平较低。对参与行为的各种神经递质系统的染色比较表明，WT和myostatin-KO小鼠之间唯一存在差异的区域是参与行为调节的habenular complex。胃饥饿素水平的降低和小白蛋白神经元的缺失可以部分解释我们模型的行为。

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引用次数: 0

Genetic and functional dynamics of Butyrylcholinesterase in Alzheimer's disease: From mechanisms to clinical relevance 阿尔茨海默病中丁基胆碱酯酶的遗传和功能动力学：从机制到临床相关性

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-11-05 DOI: 10.1016/j.cbi.2025.111809

Uroš Prešern, Marko Goličnik, Aljoša Bavec

Butyrylcholinesterase (BChE), once regarded as a redundant cholinesterase, has emerged as an important modulator of Alzheimer's disease (AD). Unlike acetylcholinesterase (AChE), which declines during disease progression, BChE activity is preserved or elevated in the AD brain and becomes the predominant cholinesterase in advanced stages. Beyond its enzymatic role in acetylcholine hydrolysis, BChE is directly associated with amyloid plaques and tau pathology and has been implicated in neuroinflammatory processes. Genetic variants of the BCHE gene, most notably the K-variant, further contribute to inter-individual differences in AD susceptibility, disease onset, and therapeutic response, particularly in the context of APOE4. Evidence from biochemical, histological, and clinical studies indicates that BChE influences both the pathophysiology of AD and the effectiveness of cholinesterase inhibitor therapy, with rivastigmine providing unique benefits through dual AChE and BChE inhibition. Recent efforts to develop selective or multitarget BChE inhibitors underscore the enzyme's potential as a therapeutic target, while BChE-specific positron emission tomography tracers highlight its diagnostic promise by distinguishing AD-related amyloid plaques from those of normal aging. Despite these advances, uncertainties remain regarding the precise dynamics of BChE activity across disease stages, its contribution to plaque maturation and inflammation, and its influence on responses to novel anti-amyloid antibody therapies. Overall, BChE represents a multifaceted factor in AD pathogenesis, therapy, and biomarker development, warranting further genotype-stratified and mechanistic investigations to clarify its clinical utility.

丁酰胆碱酯酶（BChE）曾被认为是一种冗余胆碱酯酶，现已成为阿尔茨海默病（AD）的重要调节因子。与乙酰胆碱酯酶（AChE）在疾病进展过程中下降不同，BChE活性在AD大脑中保持或升高，并在晚期成为主要的胆碱酯酶。除了在乙酰胆碱水解中的酶促作用外，BChE还与淀粉样斑块和tau蛋白病理直接相关，并与神经炎症过程有关。BCHE基因的遗传变异，尤其是k变异，进一步导致AD易感性、疾病发病和治疗反应的个体差异，特别是在APOE4的背景下。来自生化、组织学和临床研究的证据表明，BChE影响AD的病理生理和胆碱酯酶抑制剂治疗的有效性，而利瓦斯汀通过AChE和BChE双重抑制提供独特的益处。最近开发选择性或多靶点BChE抑制剂的努力强调了该酶作为治疗靶点的潜力，而BChE特异性正电子发射断层扫描示踪剂通过区分ad相关淀粉样斑块和正常衰老的淀粉样斑块突出了其诊断前景。尽管取得了这些进展，但关于BChE活性在疾病阶段的精确动态，其对斑块成熟和炎症的贡献，以及其对新型抗淀粉样蛋白抗体治疗反应的影响，仍存在不确定性。总的来说，BChE代表了AD发病、治疗和生物标志物发展的多方面因素，需要进一步的基因型分层和机制研究来阐明其临床应用。

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引用次数: 0