Biochemical pharmacology最新文献_第10页

Metabolic activation of lumisterol to biologically active metabolites and their mechanism of action lumisterol对生物活性代谢物的代谢活化及其作用机制。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-17 DOI: 10.1016/j.bcp.2026.117711

Andrzej T. Slominski , Tae-Kang Kim , Zorica Janjetovic , Senthilkumar Ravichandran , Yuwei Song , Ewa Podgorska , Radomir M. Slominski , Franz Ewendt , Yuhua Song , Justyna Szpotan , Alisa A. Mobley , Cynthia J. Schwartz , Vyshnavi Rallapalle , Arup K. Indra , David K. Crossman , Michael B. Fessler , Anton M. Jetten , Michael F. Holick , Robert C. Tuckey

Lumisterol₃ (L₃) is produced photochemically from 7-dehydrocholesterol (7-DHC) in response to high doses of ultraviolet B (UVB). We previously demonstrated that it can be hydroxylated to mono- and dihydroxy-lumisterols by CYP11A1 and CYP27A1. In the present study, we demonstrate the presence of CYP27A1-derived 25(OH)L₃, (25R)-27(OH)L₃ and (25S)-27(OH)L₃ in the epidermis and human serum. Human immortalized epidermal keratinocytes and human colonic Caco-2 and murine hepatoma (Hepa 1–6) metabolized L₃ to these biologically active hydroxyderivatives. These metabolites stimulated keratinocyte differentiation and inhibited keratinocyte proliferation. We also demonstrate that L₃ and L₃-hydroxymetabolites protect human epidermal melanocytes against UVB irradiation by inhibiting reactive oxygen species production and DNA damage. Addition of 20S(OH)L₃ to murine dermal fibroblasts induced significant changes in their gene expression profiles that were different from those induced by structurally related 20S(OH)cholesterol, 20S(OH)7-DHC and 20S(OH)D₃. The L₃ hydroxymetabolites interacted with the aryl hydrocarbon receptor (AhR) and the peroxisome proliferator-activated receptor γ (PPARγ), as demonstrated in functional assays and molecular modeling. These findings indicate that these hydroxylumisterols can regulate biological functions of epidermal cells by acting on AhR and PPARγ. Thus, L₃ generated in the skin by UVB radiation can act as a pro-hormone that is metabolized intracellularly by CYP11A1 and CYP27A1 into biologically active metabolites. These metabolites can regulate skin functions, and possibly have other biological functions after they enter the systemic circulation. These findings open previously unexpected, exciting new areas of research on the physiological role of lumisterols through their action on defined nuclear receptors.

Lumisterol3 （L3）是由7-脱氢胆固醇（7-DHC）在高剂量紫外线B （UVB）下光化学反应产生的。我们之前已经证明它可以被CYP11A1和CYP27A1羟基化成单羟基和二羟基lumisterol。在本研究中，我们证实了cyp27a1衍生的25(OH)L3、(25R)-27(OH)L3和(25S)-27(OH)L3存在于表皮和人血清中。人永生化表皮角质形成细胞和人结肠Caco-2和小鼠肝癌（Hepa 1-6）将L3代谢为这些具有生物活性的羟基衍生物。这些代谢物刺激角质细胞分化，抑制角质细胞增殖。我们还证明L3和L3-羟基代谢物通过抑制活性氧的产生和DNA损伤来保护人类表皮黑色素细胞免受UVB照射。小鼠真皮成纤维细胞添加20S(OH)L3后，其基因表达谱发生了显著变化，与结构相关的20S（OH）胆固醇、20S(OH)7-DHC和20S(OH)D3诱导的基因表达谱不同。L3羟基代谢物与芳烃受体（AhR）和过氧化物酶体增殖激活受体γ (PPARγ)相互作用，在功能分析和分子模型中得到证实。这些结果表明，这些羟基茴香醇可能通过作用于AhR和PPARγ来调节表皮细胞的生物学功能。因此，UVB辐射在皮肤中产生的L3可以作为促激素，在细胞内被CYP11A1和CYP27A1代谢为具有生物活性的代谢物。这些代谢物可以调节皮肤功能，进入体循环后可能具有其他生物学功能。这些发现打开了以前意想不到的、令人兴奋的新研究领域，通过对特定核受体的作用来研究lumisterol的生理作用。

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引用次数: 0

Repurposing dronedarone for colorectal cancer therapeutic via suppression of the AKT/ERK signaling pathways 通过抑制AKT/ERK信号通路，将drone - edarone用于结直肠癌治疗。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-16 DOI: 10.1016/j.bcp.2026.117715

Tong Gong , Yan Jin , Hongmei Zhu , Zeying Cheng , Hong Fang , Ning Xu , Fanting Zhao , Yingqian Liu , Peng Chen

Colorectal cancer (CRC) remains one of the most prevalent and challenging cancers and advanced CRCs are resistant to targeted therapy, chemotherapy and immunotherapy. Therefore, it is urgent to develop new treatment strategies or therapeutic agents for CRC to improve clinical efficacy. Within the landscape of emerging therapeutic modalities, drug repurposing offers a particularly promising avenue for enhancing clinical outcomes. Herein, we revealed the functional repurposing of dronedarone, an FDA (the US Food and Drug Administration)-approved class III antiarrhythmic agent, demonstrating its potent anti-proliferative effects against CRC cells. Through rational drug structure modification, we synthesized thirteen dronedarone derivatives, among which derivative D4 demonstrated superior antiproliferative potency and lower toxicity both in vitro and in vivo. Mechanically, dronedarone and D4 induced mitochondrial dysfunction and suppressed both AKT (protein kinase B) and ERK (extracellular regulated protein kinase) signaling pathways simultaneously leading to CRC cells apoptosis. Collectively, our study sheds light on repurposing non-oncology drug dronedarone and its derivatives with their molecular mechanisms for CRC treatment.

结直肠癌（CRC）仍然是最普遍和最具挑战性的癌症之一，晚期结直肠癌对靶向治疗、化疗和免疫治疗具有耐药性。因此，迫切需要开发新的治疗策略或药物来提高结直肠癌的临床疗效。在新兴的治疗模式中，药物再利用为提高临床结果提供了一个特别有希望的途径。在此，我们揭示了dronedarone的功能改造，FDA（美国食品和药物管理局）批准的III类抗心律失常药物，显示其对CRC细胞的有效抗增殖作用。通过合理的药物结构修饰，我们合成了13个drone - edarone衍生物，其中衍生物D4在体外和体内均表现出较强的抗增殖能力和较低的毒性。机械上，dronedarone和D4诱导线粒体功能障碍，同时抑制AKT（蛋白激酶B）和ERK（细胞外调节蛋白激酶）信号通路，导致结直肠癌细胞凋亡。总的来说，我们的研究揭示了非肿瘤药物drone - edarone及其衍生物在CRC治疗中的分子机制。

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引用次数: 0

Arachidonic acid analog AACOCF3 suppresses cPLA2-negative NSCLC cell proliferation by targeting SSRP1 to activate the IFNα/β pathway 花生四烯酸类似物AACOCF3通过靶向SSRP1激活IFNα/β通路抑制cpla2阴性NSCLC细胞增殖。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117708

Hongbo Wang , Zihao Wen , Yupeng Jia , Xinyu Tong , Weifang Wang , Ze Wang , Hongkai Jin , Xiaoya Gao , Xinyuan Tao , Hao Cheng , Tingting Li , Shinan Li , Tingting Chen , Kunfang Li , Bo Li

AACOCF3, a cell-permeable arachidonic acid analogue, is widely established as a selective inhibitor of cytosolic phospholipase A2 (cPLA2, PLA2G4A) in studies of metabolic disorders. Although its primary mechanism involves cPLA2 inhibition, emerging evidence indicates that AACOCF3 may target additional protein entities, exemplified by calcium-independent phospholipase A2 (iPLA2, PLA2G6) and fatty acid amide hydrolase (FAAH). Notably, cPLA2 displays a markedly heterogeneous expression profile in non-small cell lung cancer (NSCLC). Our findings establish that AACOCF3 exerts more potent growth inhibition in cPLA2-negative NSCLC cells, with IC50 values of 15.13 μM for H1975 and 15.84 μM for PC9 cells, in contrast to the cPLA2-positive A549 cells (IC50 = 56.23 μM). Mechanistically, AACOCF3 upregulates IFN-α/β signaling-associated genes (e.g., IFNB1, ISG15) specifically in cPLA2-negative NSCLC cells. This aligns with TCGA-LUAD data revealing that PLA2G4A-low tumors predominantly engage immune-activation pathways rather than metabolic programs when compared to PLA2G4A-high counterparts. Through integrated molecular docking and surface plasmon resonance (SPR) analysis, we identified structure-specific recognition protein 1 (SSRP1) as a direct molecular target of AACOCF3 in cPLA2-negative NSCLC, with SPR binding studies confirming a stable interaction (Kd = 25.9 μM). Ectopic SSRP1 expression abrogated AACOCF3-induced phenotypic alterations, concurrently suppressing IFN-α/β signaling. Collectively, these results provide evidence that AACOCF3 exerts its anti-proliferative effect by targeting SSRP1, which leads to the activation of the IFNα/β pathway, thereby underscoring its therapeutic promise for the cPLA2-negative patient subpopulation.

AACOCF3是一种具有细胞渗透性的花生四烯酸类似物，在代谢紊乱的研究中被广泛认为是胞质磷脂酶A2 （cPLA2, PLA2G4A）的选择性抑制剂。尽管其主要机制涉及cPLA2抑制，但新出现的证据表明，AACOCF3可能靶向其他蛋白质实体，例如钙非依赖性磷脂酶A2 （iPLA2, PLA2G6）和脂肪酸酰胺水解酶（FAAH）。值得注意的是，cPLA2在非小细胞肺癌（NSCLC）中表现出明显的异质性表达谱。研究结果表明，与cpla2阳性的A549细胞（IC50 = 56.23 μM）相比，AACOCF3在cpla2阴性的NSCLC细胞中具有更强的生长抑制作用，H1975细胞的IC50值为15.13 μM， PC9细胞的IC50值为15.84 μM。在机制上，AACOCF3在cpla2阴性的NSCLC细胞中特异性上调IFN-α/β信号相关基因（如IFNB1， ISG15）。这与TCGA-LUAD数据一致，表明与pla2g4a高水平的肿瘤相比，pla2g4a低水平的肿瘤主要参与免疫激活途径而不是代谢程序。通过综合分子对接和表面等离子体共振（SPR）分析，我们确定了结构特异性识别蛋白1 （SSRP1）是AACOCF3在cpla2阴性NSCLC中的直接分子靶点，SPR结合研究证实了稳定的相互作用（Kd = 25.9 μM）。异位SSRP1表达消除了aacocf3诱导的表型改变，同时抑制了IFN-α/β信号传导。总之，这些结果证明AACOCF3通过靶向SSRP1发挥其抗增殖作用，从而导致IFNα/β通路的激活，从而强调了其治疗cpla2阴性患者亚群的前景。

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引用次数: 0

Onecut2, negatively regulated by methyltransferase METTL3, inhibits polycystic ovary syndrome by transcriptionally modulating SIRT3 expression Onecut2受甲基转移酶METTL3负调控，通过转录调节SIRT3表达抑制多囊卵巢综合征。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117712

Mingxing Sui, Shuying Wu, Qingqing Song, Siyao Chen, Yingli Lu

Polycystic ovary syndrome (PCOS) is characterized by a constellation of symptoms, including menstrual cycle irregularities, hyperandrogenism, and polycystic ovarian morphology. Despite extensive research efforts, a thorough understanding of the underlying pathophysiology and effective treatment options for PCOS remain elusive. In this study, ovarian tissues from dehydroepiandrosterone (DHEA)-induced PCOS mice and control mice underwent mRNA sequencing. Through a comprehensive bioinformatics analysis, we systematically examined the sequencing data, and one cut homeobox 2 (Onecut2), a significantly downregulated gene in PCOS mice, was identified and selected as the primary research target. Our findings determined that the overexpression of Onecut2 efficiently alleviated pathological changes and reduced mitochondrial dysfunction in DHEA-induced PCOS mice. Additionally, Onecut2 was found to be expressed at a low level in human ovarian granulosa KGN cells treated with dihydrotestosterone (DHT). Gain-of-function and loss-of-function experiments uncovered that Onecut2 played a role in inhibiting apoptosis and mitochondrial damage in DHT-treated KGN cells. Dual-luciferase reporter assays demonstrated that Onecut2 overexpression activated the transcriptional activity of the sirtuin 3 (SIRT3) promoter, thereby controlling the function of granulosa cells. Mechanistic investigation revealed that the mRNA stability of Onecut2 was regulated by methyltransferase-like 3 (METTL3) via m6A modification. Collectively, this study demonstrates that Onecut2 exerts an inhibitory role in PCOS progression by transcriptionally regulating SIRT3 expression and that this regulation is influenced by METTL3-mediated m6A methylation.

多囊卵巢综合征（PCOS）以一系列症状为特征，包括月经周期不规则、雄激素过多和多囊卵巢形态。尽管进行了广泛的研究，但对多囊卵巢综合征的潜在病理生理和有效治疗方案的透彻理解仍然难以捉摸。在本研究中，对脱氢表雄酮（DHEA）诱导的PCOS小鼠和对照小鼠的卵巢组织进行mRNA测序。通过全面的生物信息学分析，我们系统地检查了测序数据，确定并选择了PCOS小鼠中显著下调的一个剪切同源盒2 （Onecut2）基因作为主要研究目标。我们的研究结果表明，Onecut2的过表达有效地缓解了dhea诱导的PCOS小鼠的病理变化，并减少了线粒体功能障碍。此外，Onecut2被发现在双氢睾酮（DHT）处理的人卵巢颗粒KGN细胞中低水平表达。功能获得和功能丧失实验发现，Onecut2在dht处理的KGN细胞中发挥抑制凋亡和线粒体损伤的作用。双荧光素酶报告基因分析表明，Onecut2过表达激活sirtuin 3 （SIRT3）启动子的转录活性，从而控制颗粒细胞的功能。机制研究表明，Onecut2的mRNA稳定性受甲基转移酶样3 （METTL3）通过m6A修饰调控。综上所述，本研究表明Onecut2通过转录调节SIRT3表达在PCOS进展中发挥抑制作用，而这种调节受mettl3介导的m6A甲基化的影响。

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引用次数: 0

Corrigendum to “Almonertinib inhibits liver cancer progression by triggering autophagy-dependent ferroptosis through inhibition of the PI3K/Akt1/mTOR pathway”. [Biochem. Pharmacol. 245 (2026) 117628] “Almonertinib通过抑制PI3K/Akt1/mTOR通路触发自噬依赖性铁下垂来抑制肝癌进展”的更正。(生物化学。药理学杂志。245 (2026)117628 [j]

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117690

Lulu Liang , Xueshuang Wang , Baier Sun , Yipeng Sun , Jing Chen , Jiebang Jiang , Li Meng , Sisi He , Rongpeng Li , Fei Wang

引用次数: 0

Mertk-driven tunneling nanotube formation in macrophages preserves mitochondrial homeostasis during kidney Ischemia-Reperfusion Attack 巨噬细胞中mertk驱动的隧道纳米管形成在肾缺血再灌注攻击期间保持线粒体稳态。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117713

Jun Zeng , Ruoqing Li , Liyin Chai , Ying Zhang , Li Gong , Xiaolin Yuan , Qiufang Bai , Shuping Xiao , Jialian Wang , Sha Xiang , Haili Sun , Zhengyang Liu , Xingqing Chen , Ning Li , Bailin Niu , Mei Mei , Bingbing Shen

Renal ischemia–reperfusion (I/R) injury is a critical pathological process in organ transplantation and acute kidney injury (AKI), involving oxidative stress, inflammation, and mitochondrial dysfunction. Macrophage-expressed Mertk, a key regulator of tissue homeostasis, remains understudied in renal I/R injury. Mertk knockout (Mertk-KO) mice and their wild-type (WT) littermates were subjected to renal I/R injury. Mertk deficiency exacerbated renal tubular injury, inflammation, and oxidative stress in I/R-induced AKI. ATP production decreased, and mitochondrial morphology was disrupted in RTECs from Mertk-KO mice compared to WT mice. In vitro studies demonstrated that knockdown of Mertk in kidney-resident macrophages (KRMs) aggravated renal tubular epithelial cells (RTECs) injury, proliferation inhibition, apoptosis, and mitochondrial dysfunction under hypoxia-reoxygenation (H/R) conditions. Conversely, Mertk overexpression in KRMs attenuated these detrimental effects. Notably, Mertk overexpression facilitated tunneling nanotubes (TNTs) formation and promoted intercellular mitochondrial trafficking between KRMs and RTECs, maintaining mitochondrial homeostasis in RTECs. LAT-A treatment inhibited TNTs formation and abrogated the protective effects of Mertk overexpression. This study established Mertk as a critical mediator of KRMs-RTECs crosstalk through TNTs-dependent mitochondrial homeostasis regulation, providing mechanistic insights into AKI progression. Mertk-expressed KRMs-mediated mitochondrial transfer through TNT formation, providing a potential therapeutic target for AKI.

肾缺血再灌注（I/R）损伤是器官移植和急性肾损伤（AKI）的重要病理过程，涉及氧化应激、炎症和线粒体功能障碍。巨噬细胞表达的Mertk是组织稳态的关键调节因子，在肾I/R损伤中的研究尚不充分。Mertk敲除（Mertk- ko）小鼠及其野生型（WT）仔鼠遭受肾I/R损伤。在I/ r诱导的AKI中，Mertk缺乏加重了肾小管损伤、炎症和氧化应激。与WT小鼠相比，Mertk-KO小鼠RTECs中ATP的产生减少，线粒体形态被破坏。体外研究表明，在缺氧-再氧（H/R）条件下，肾内巨噬细胞（KRMs）中Mertk的敲低会加重肾小管上皮细胞（RTECs）损伤、增殖抑制、凋亡和线粒体功能障碍。相反，KRMs中Mertk的过表达减轻了这些有害影响。值得注意的是，Mertk过表达促进了隧道纳米管（TNTs）的形成，促进了KRMs和rtec之间的细胞间线粒体运输，维持了rtec中的线粒体稳态。lata处理抑制了TNTs的形成，并消除了Mertk过表达的保护作用。本研究证实Mertk是通过依赖tnts的线粒体稳态调节介导KRMs-RTECs串扰的关键介质，为AKI进展提供了机制上的深入了解。mertk表达的krms通过TNT形成介导的线粒体转移，为AKI提供了潜在的治疗靶点。

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引用次数: 0

LIFR antagonism reverses epithelial pro-CAF programs in pancreatic ductal adenocarcinoma LIFR拮抗剂逆转胰腺导管腺癌上皮前caf程序。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117707

Cristina Di Giorgio , Maria Rosaria Sette , Benedetta Sensini , Eleonora Giannelli , Ginevra Lachi , Silvia Marchianò , Francesca Paniconi , Carmen Massa , Ginevra Urbani , Rosa De Gregorio , Valentina Sepe , Maria Chiara Monti , Federica Moraca , Bruno Catalanotti , Fabio Cartaginese , Eleonora Distrutti , Angela Zampella , Michele Biagioli , Stefano Fiorucci

Extracellular matrix remodelling that occurs in pancreatic ductal adenocarcinoma (PDAC) is considered a promoting factor of cancer growth, immune evasion and therapeutic resistance. Cancer-associated fibroblasts (CAFs) that constitute the dominant stromal population, arise primarily from activated pancreatic stellate cells and display remarkable functional heterogeneity, encompassing inflammatory iCAFs and contractile myCAFs. Although epithelial-stromal communication is central to PDAC biology, the upstream mechanisms that prime tumour cells toward CAF-Activating cells remain incompletely defined. The leukaemia inhibitory factor (LIF), a pleiotropic cytokine of the IL-6 family, is highly expressed in PDAC and has been implicated in tumour progression. However, the role of LIF and LIF receptor (LIFR):gp130 complex in promoting CAF activation is poorly defined. Here, we combined human PDAC transcriptomics, immunofluorescence and epithelial-stromal co-culture assays to define LIF-driven pro-CAF programs and evaluate their pharmacological reversibility. In PDAC cancer cells, MIAPaCa-2 cells, LIF induced a coordinated transcriptional network encompassing inflammatory mediators, paracrine fibroblast-activating signals and ECM/mechanotransductive modules, while repressing stromal-inhibitory genes. These signatures were recapitulated in PDAC tissues, where LIF expression directly correlated with CAF markers and with stromal remodelling genes. On this background, we have developed a novel steroidal LIFR antagonist, LRI310, and evaluate its effects on LIF:LIFR axis. Exposure of PDCA cell lines to LRI310 suppresses STAT3 activation and counteracts effects of LIF on proliferation and CAF-inducing transcriptional programs. Collectively, these findings identify LIF as an important epithelial driver of CAF-oriented transcriptional programs in PDAC and support the development of LIFR antagonism as a promising strategy to modulate the desmoplastic microenvironment.

发生在胰腺导管腺癌（PDAC）的细胞外基质重构被认为是促进肿瘤生长、免疫逃避和治疗抵抗的因素。癌相关成纤维细胞（CAFs）构成了主要的基质群体，主要来自活化的胰腺星状细胞，并显示出显著的功能异质性，包括炎症性icaf和收缩性myCAFs。尽管上皮间质通讯是PDAC生物学的核心，但将肿瘤细胞引向cafa激活细胞的上游机制仍未完全确定。白血病抑制因子（LIF）是IL-6家族的一种多效性细胞因子，在PDAC中高度表达，并与肿瘤进展有关。然而，LIF和LIF受体（LIFR）：gp130复合物在促进CAF激活中的作用尚不明确。在这里，我们结合了人类PDAC转录组学，免疫荧光和上皮-基质共培养分析来定义lifd驱动的前caf程序并评估其药理学可逆性。在PDAC癌细胞、MIAPaCa-2细胞中，LIF诱导了一个协调的转录网络，包括炎症介质、旁分泌成纤维细胞激活信号和ECM/机械转导模块，同时抑制基质抑制基因。这些特征在PDAC组织中重现，其中LIF表达与CAF标记物和基质重塑基因直接相关。在此背景下，我们开发了一种新的甾体LIFR拮抗剂LRI310，并评估了其对LIFR轴的作用。暴露于LRI310的PDCA细胞系可抑制STAT3的激活，并抵消LIF对增殖和ca诱导转录程序的影响。总的来说，这些发现确定了LIFR是PDAC中ca导向转录程序的重要上皮驱动因素，并支持LIFR拮抗剂作为调节结缔组织微环境的有前途的策略的发展。

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引用次数: 0

The myocardial ischemic cascade network and multi-target synergistic interventions: From molecular mechanisms to therapeutic innovations 心肌缺血级联网络和多靶点协同干预：从分子机制到治疗创新

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117704

Lei Qi , Jia Yi , Yuntian Shen , Haiyan Jiang , Xinlei Yao , Bingqian Chen , Hualin Sun

Myocardial ischemic injury involves a multi-layered pathological cascade driven by interconnected energy metabolism disorders, calcium overload, oxidative stress, mitochondrial dysfunction, and inflammatory responses. Ischemia-hypoxia impairs mitochondrial oxidative phosphorylation, causing ATP depletion, acidosis, and calcium overload. Reperfusion exacerbates injury through ROS burst, mPTP opening, and NLRP3 inflammasome activation, leading to pro-inflammatory cytokine release. Sustained endoplasmic reticulum stress promotes apoptosis via the PERK/CHOP pathway, forming a vicious cycle with oxidative stress and inflammation. These processes collectively trigger diverse programmed cell death modalities—apoptosis, pyroptosis, ferroptosis, necroptosis, and cuproptosis—while microcirculatory disturbances cause the “no-reflow” phenomenon, culminating in irreversible damage. Therapeutic strategies are shifting from revascularization to multi-target interventions. Reperfusion injury is mitigated by ischemic conditioning (IPoC, RIC) via RISK/SAFE pathways and ALDH2-SIRT3 axis activation. Cell death is targeted using ferroptosis inhibitors (e.g., Liproxstatin-1), NLRP3/caspase-1 blockers, and autophagy regulators (e.g., Astragaloside IV). Mitochondrial/metabolic therapies include mitochondrial-targeted drugs (e.g., CsA@PLGA-PEG-SS31), metabolic modulators (Trimetazidine), and neuroendocrine agents (ARNI, SGLT2 inhibitors). Regenerative approaches employ stem cells/exosomes, gene therapy, and tissue engineering via paracrine signaling. Precision medicine integrates multi-omics and AI for risk stratification, while biomimetic nanocarriers enhance drug delivery. Future therapies should co-target the “energy-death-inflammation” network to advance myocardial ischemia treatment toward systemic repair and improved clinical outcomes.

心肌缺血损伤涉及一个多层次的病理级联反应，由相互关联的能量代谢紊乱、钙超载、氧化应激、线粒体功能障碍和炎症反应驱动。缺血-缺氧损害线粒体氧化磷酸化，引起ATP耗竭、酸中毒和钙超载。再灌注通过ROS爆发、mPTP开放和NLRP3炎性体激活加剧损伤，导致促炎细胞因子释放。持续的内质网应激通过PERK/CHOP途径促进细胞凋亡，与氧化应激和炎症形成恶性循环。这些过程共同引发不同的程序性细胞死亡模式——凋亡、焦亡、铁亡、坏死亡和铜亡——而微循环紊乱导致“无回流”现象，最终导致不可逆的损伤。治疗策略正从血运重建术转向多靶点干预。缺血调节（IPoC， RIC）通过RISK/SAFE通路和ALDH2-SIRT3轴激活减轻再灌注损伤。细胞死亡的目标是使用铁凋亡抑制剂（如利普司他汀-1）、NLRP3/caspase-1阻滞剂和自噬调节剂（如黄芪甲苷IV）。线粒体/代谢治疗包括线粒体靶向药物（例如CsA@PLGA-PEG-SS31）、代谢调节剂（曲美他嗪）和神经内分泌药物（ARNI、SGLT2抑制剂）。再生方法采用干细胞/外泌体、基因治疗和通过旁分泌信号传导的组织工程。精准医学结合多组学和人工智能进行风险分层，仿生纳米载体增强药物传递。未来的治疗应共同靶向“能量-死亡-炎症”网络，以推进心肌缺血治疗走向全身修复和改善临床结果。

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引用次数: 0

Inhibition of Ca2+-activated chloride channels by the NSAID meclofenamate for anti-diarrhea 非甾体抗炎药甲氯芬酯抗腹泻对Ca2+激活的氯离子通道的抑制作用。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117710

Qinqin Li , Huan Shi , Ping Zhou , Xiangyu Li , Yani Liu , KeWei Wang

Dysfunctional calcium-activated chloride channels (CaCCs) are implicated in many pathological phenotypes and diseases. The CaCC ANO1/TMEM16A robustly expressed in epithelial cells plays an essential role in regulation of Cl^- secretion and intestinal motility. In this study, we investigated the effects of a nonsteroidal anti-inflammatory drug (NSAID) meclofenamate on ANO1 channel and dextran sulfate sodium (DSS)-induced diarrhea in mice. Meclofenamate inhibits CaCC ANO1 channel in a concentration-dependent manner with an IC₅₀ of 16.2 ± 2.7 μM. Meclofenamate also reduces single-channel open probability without altering the channel conductance. Molecular docking and site-directed mutagenesis demonstrate that residues R515, R535 and E654 are important for meclofenamate-mediated ANO1 inhibition. Selectivity evaluation demonstrates that meclofenamate also inhibits other CaCCs, including ANO2, ANO6 and Bestrophin-1 with IC₅₀ values ranging from approximately 10 to 20 μM. Further in vivo experiments show that meclofenamate dose-dependently reduces intestinal peristalsis and diarrhea induced by DSS in mice. Altogether, our findings reveal a novel role of meclofenamate in inhibiting CaCC currents and alleviating DSS-induced acute diarrhea, thus holding repurposing potential for therapy of diarrhea or gastrointestinal dysfunction.

功能失调的钙活化氯离子通道（CaCCs）与许多病理表型和疾病有关。在上皮细胞中强烈表达的cac ANO1/TMEM16A在调节Cl-分泌和肠蠕动中起重要作用。在这项研究中，我们研究了非甾体抗炎药（NSAID）甲氯芬酯对ANO1通道和葡聚糖硫酸钠（DSS）诱导的小鼠腹泻的影响。甲氯芬酯抑制CaCC ANO1通道呈浓度依赖性，IC50为16.2 ± 2.7 μM。在不改变通道电导的情况下，甲氯芬酯也能降低单通道打开概率。分子对接和定点诱变表明，残基R515、R535和E654对甲氯芬酸介导的ANO1抑制很重要。选择性评价表明，甲氯芬酯还能抑制其他CaCCs，包括ANO2、ANO6和Bestrophin-1， IC50值约为10 ~ 20 μM。进一步的体内实验表明，甲氯芬酯能剂量依赖性地减少DSS引起的小鼠肠道蠕动和腹泻。总之，我们的研究结果揭示了甲氯芬酯在抑制CaCC电流和减轻dss诱导的急性腹泻方面的新作用，从而具有治疗腹泻或胃肠道功能障碍的潜力。

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引用次数: 0

DNMT1 knockdown mitigates sepsis-induced myocardial dysfunction by preventing TFAM-mediated mitochondrial DNA cytosolic escape and subsequent cGAS-STING to regulate macrophage M2 polarization DNMT1敲低可通过阻止tfam介导的线粒体DNA胞质逃逸和随后的cGAS-STING调节巨噬细胞M2极化，减轻败血症诱导的心肌功能障碍。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117709

Min Li , Yang Liu , Kuo Qu , Yu Zhang , Hailing Yang

Sepsis-induced myocardial dysfunction (SIMD) is a prevalent complication of sepsis and correlates with high mortality. The study investigated the effect of inhibiting DNA methyltransferase 1 (DNMT1) on SIMD and its potential mechanism. In this study, an SIMD mouse model was established using lipopolysaccharide (LPS). Two weeks before modeling, mice were intraperitoneally injected with the DNMT1 inhibitor decitabine or Vehicle. Pretreatment with the DNMT1 inhibitor decitabine in SIMD mice improved survival, cardiac function, and reduced cardiomyocyte apoptosis. In LPS-stimulated RAW264.7 macrophages, DNMT1 knockdown promoted M2 polarization while suppressing M1 polarization, and reduced apoptosis in cardiomyocytes cultured with conditioned media. Mechanistically, DNMT1 depletion upregulated mitochondrial transcription factor A (TFAM) by reducing DNA methylation modification, which alleviated mitochondrial dysfunction and limited mitochondrial DNA (mtDNA) release into the cytosol. This subsequently inactivated the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. TFAM downregulation reversed the improvement in mitochondrial function achieved by DNMT1 knockdown, while cGAS upregulation averted DNMT1 knockdown-inhibited mtDNA cytosolic escape-mediated cGAS-STING. In vivo validation confirmed this mechanism. Collectively, DNMT1 regulates mitochondrial dysfunction and cytosolic mtDNA release by modulating TFAM promoter DNA methylation, thereby activating the cGAS-STING pathway, further influencing macrophage polarization and cardiomyocyte apoptosis, and ultimately exacerbating SIMD.

脓毒症引起的心肌功能障碍（SIMD）是脓毒症的常见并发症，与高死亡率相关。本研究探讨了抑制DNA甲基转移酶1 （DNMT1）对SIMD的影响及其潜在机制。本研究采用脂多糖（LPS）建立SIMD小鼠模型。造模前2周，小鼠腹腔注射DNMT1抑制剂地西他滨或Vehicle。DNMT1抑制剂地西他滨预处理SIMD小鼠可改善生存、心功能并减少心肌细胞凋亡。在lps刺激的RAW264.7巨噬细胞中，DNMT1敲低促进M2极化，抑制M1极化，减少条件培养基培养的心肌细胞凋亡。从机制上说，DNMT1缺失通过减少DNA甲基化修饰来上调线粒体转录因子A (TFAM)，从而减轻线粒体功能障碍，限制线粒体DNA （mtDNA）释放到细胞质中。这随后使干扰素基因环GMP-AMP合成酶刺激因子（cGAS-STING）通路失活。TFAM下调逆转了DNMT1敲低实现的线粒体功能改善，而cGAS上调避免了DNMT1敲低抑制mtDNA胞质逃逸介导的cGAS- sting。体内验证证实了这一机制。综上所述，DNMT1通过调节TFAM启动子DNA甲基化调节线粒体功能障碍和胞质mtDNA释放，从而激活cGAS-STING通路，进而影响巨噬细胞极化和心肌细胞凋亡，最终加重SIMD。

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