Biochemical pharmacology最新文献_第6页

Corrigendum to “Arenobufagin, a bufadienolide compound from toad venom, inhibits VEGF-mediated angiogenesis through suppression of VEGFR-2 signaling pathway” [Biochem. Pharmacol. 83(9) (2012) 1251-1260] “蟾毒素，一种来自蟾蜍毒液的蟾毒二烯内酯化合物，通过抑制VEGFR-2信号通路抑制vegf介导的血管生成”[生物化学]的更正。药理学杂志，83(9)(2012)1251-1260。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-12-22 DOI: 10.1016/j.bcp.2025.117626

Manmei Li , Shuai Wu , Zhong Liu , Wei Zhang , Jing Xu , Ying Wang , Junshan Liu , Dongmei Zhang , Haiyan Tian , Yaolan Li , Wencai Ye

引用次数: 0

Inflammatory protein signatures associated with high rivaroxaban exposure 与利伐沙班高暴露相关的炎症蛋白特征。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-12-21 DOI: 10.1016/j.bcp.2025.117663

Catherine Feliu , Jean Escal , Cyril Leven , Sophie Hodin , Vanessa Rigaud , Philippe Gonzalo , Francis Coutureau , Karine Lacut , Jeremy Thereaux , Xavier Delavenne

Direct oral anticoagulants, including rivaroxaban, are widely prescribed for the prevention and treatment of thromboembolic disorders. Despite generally predictable pharmacokinetics (PK), real-world data reveal striking interindividual variability in exposure, raising concerns for both efficacy and bleeding risk. Known genetic and clinical determinants explain only part of this variability, underscoring the need to identify additional contributors. This study aimed to explore systemic protein signatures associated with rivaroxaban exposure intensity. Plasma samples were obtained from 64 participants in a phase I clinical study (NCT04180436) including healthy controls, obese patients, and post-bariatric surgery patients. Rivaroxaban PK was assessed after 20 mg once-daily dosing, and patients were stratified into high and low exposure groups. Untargeted plasma proteomic analysis was performed by liquid chromatography coupled with high-resolution mass spectrometry, followed by univariate and multivariate statistical analyses. Targeted C-reactive protein (CRP) quantification and multiplex cytokine assays were used to validate findings. Differential abundance and multivariate modeling identified inflammation and vascular related proteins associated with high rivaroxaban exposure. Notably, CRP and lipoprotein(a) (LPA) were consistently elevated in high exposure groups. Targeted CRP quantification confirmed these results, even in cases of mild to moderate inflammation. Cytokine analyses revealed a pro-inflammatory profile, characterized by increased interferon gamma and reduced Tumor Necrosis Factor alpha in high exposure patients. Protein–protein interaction networks highlighted CRP, LPA, albumin, and Apolipoprotein B as central hubs, while functional enrichment revealed pathways related to acute inflammation, oxidative stress, and vascular regulation. These findings suggest that systemic inflammation may contribute to rivaroxaban overexposure, with CRP emerging as a promising biomarker to support more personalized anticoagulant strategies.

直接口服抗凝剂，包括利伐沙班，被广泛用于预防和治疗血栓栓塞性疾病。尽管通常可预测的药代动力学（PK），现实世界的数据显示惊人的个体间差异暴露，提高了对疗效和出血风险的关注。已知的遗传和临床决定因素只能解释这种变异性的一部分，强调需要确定其他因素。本研究旨在探索与利伐沙班暴露强度相关的全身蛋白质特征。血浆样本来自一项I期临床研究（NCT04180436）的64名参与者，包括健康对照组、肥胖患者和减肥手术后患者。每日一次给药20mg后评估利伐沙班PK，并将患者分为高暴露组和低暴露组。采用液相色谱联用高分辨率质谱进行非靶向血浆蛋白质组学分析，然后进行单因素和多因素统计分析。靶向c反应蛋白（CRP）定量和多重细胞因子测定用于验证结果。差异丰度和多变量模型确定了与利伐沙班高暴露相关的炎症和血管相关蛋白。值得注意的是，高暴露组CRP和脂蛋白(a) （LPA）持续升高。即使在轻度至中度炎症的情况下，靶向CRP定量也证实了这些结果。细胞因子分析揭示了促炎特征，在高暴露患者中表现为干扰素γ增加和肿瘤坏死因子α减少。蛋白相互作用网络突出了CRP、LPA、白蛋白和载脂蛋白B作为中心枢纽，而功能富集揭示了与急性炎症、氧化应激和血管调节相关的途径。这些发现表明，全身性炎症可能导致利伐沙班过度暴露，而CRP正在成为一种有希望的生物标志物，以支持更个性化的抗凝策略。

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引用次数: 0

Ginsenoside compound K exerts osteoprotective effects by suppressing osteoclastogenesis and promoting preosteoclast PDGF-BB-induced angiogenesis via targeting CSF1R. 人参皂苷化合物K通过靶向CSF1R抑制破骨细胞生成，促进破骨前细胞pdgf - bb诱导的血管生成，发挥骨保护作用。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-12-21 DOI: 10.1016/j.bcp.2025.117661

Shuai Chen, Bizhi Tan, Shangbin Cui, Mingbin Zhan, Yibo Wang, Fangli Huang, Tingxuan Wang, Zemin Ling, Yuan Zhang, Junnan Hu, Wei Guo, Hao Hu, Xuenong Zou

We previously found that oral administration of Panax notoginseng saponins (PNS) alleviated bone loss in ovariectomy(OVX)-induced osteoporotic mice. However, the specific active component responsible for this effect and its underlying mechanism remained unclear. Ginsenoside compound K (CK), one of the main active components of PNS, may serve as a promising therapeutic agent for osteoporosis. This study demonstrated that CK inhibited osteoclastogenesis and promoted type H vessel formation to alleviate bone loss in OVX mice. In vitro, CK concentration-dependently inhibited RANKL-induced osteoclastogenesis. In addition, high concentration CK inhibited the migration and tubule formation of HUVECs. However, treating HUVECs with CK + RANKL-stimulated RAW264.7 conditional medium showed enhancement of migration and tubule formation ability, which was blocked by adding PDGF-BB neutralising-antibody. Proteomics and network pharmacological analysis revealed CK may directly target CSF1R and inhibit osteoclast differentiation via PI3K/AKT/NFκB pathway,which subsequently conformed by drug affinity responsive target stability, cellular thermal shift, surface plasmon resonance and western blot assays. Furthermore, adding macrophage colony-stimulating factor (M-CSF) mitigated the inhibitory effect of CK on osteoclast differentiation and PI3K/AKT/NFκB pathway activation. Taken together, we demonstrated that CK exerts osteoprotective effects by targeting CSF1R to inhibit PI3K/AKT/NFκB pathway, thereby suppressing osteoclastogenesis and promoting preosteoclast PDGF-BB-induced angiogenesis.

我们之前发现口服三七皂苷（PNS）可减轻卵巢切除术（OVX）诱导的骨质疏松小鼠的骨质流失。然而，导致这种效果的具体活性成分及其潜在机制尚不清楚。人参皂苷化合物K （CK）是PNS的主要活性成分之一，有望成为治疗骨质疏松症的一种有前景的药物。本研究表明，CK抑制破骨细胞生成，促进H型血管形成，减轻OVX小鼠骨质流失。在体外，CK浓度依赖性地抑制rankl诱导的破骨细胞生成。此外，高浓度CK抑制HUVECs的迁移和小管形成。然而，用CK + rankl刺激的RAW264.7条件培养基处理HUVECs，显示出迁移和小管形成能力的增强，通过添加PDGF-BB中和抗体来阻断。蛋白质组学和网络药理学分析表明，CK可能通过PI3K/AKT/NFκB途径直接靶向CSF1R，抑制破骨细胞分化，随后的药物亲和力响应靶标稳定性、细胞热位移、表面等离子体共振和western blot检测证实了这一结论。此外，加入巨噬细胞集落刺激因子（M-CSF）可减轻CK对破骨细胞分化和PI3K/AKT/NFκB通路激活的抑制作用。综上所述，我们证明CK通过靶向CSF1R抑制PI3K/AKT/NFκB通路发挥骨保护作用，从而抑制破骨细胞生成，促进破骨细胞前pdgf - bb诱导的血管生成。

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引用次数: 0

Eicosanoids and Inflammation: A delicate balance of Pro-Inflammatory and Pro-Resolving mediators 类二十烷酸和炎症：促炎和促解介质的微妙平衡。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-12-20 DOI: 10.1016/j.bcp.2025.117662

Woo Hyun Park

Inflammation represents a fundamental biological process essential for host defense and tissue integrity. However, its dysregulation, frequently characterized by a failure of active resolution, underpins a vast array of chronic pathologies. Central to this intricate process is the superfamily of eicosanoids, which are potent bioactive lipid mediators derived from 20-carbon polyunsaturated fatty acids (PUFAs). Historically, specific eicosanoids, such as prostaglandins (PGs) and leukotrienes (LTs), were regarded primarily as pro-inflammatory agents purported to be responsible for mediating vasodilation, leukocyte trafficking, nociception, and pyrexia. Consequently, therapeutic interventions like non-steroidal anti-inflammatory drugs (NSAIDs) concentrated on inhibiting their production via cyclooxygenase (COX). A significant paradigm shift posited that resolution is not passive decay but an active process orchestrated by specialized pro-resolving mediators (SPMs), including lipoxins, resolvins, protectins, and maresins. While pharmacological reports suggested these mediators direct inflammatory cessation via specific receptors, recent independent investigations have raised salient questions regarding their endogenous biosynthesis, receptor validation, and detection. This review details established biosynthetic mechanisms (COX, LOX, CYP) and contrasts classical pro-inflammatory signaling with proposed SPM actions. Crucially, a balanced perspective on the extant scientific debate is furnished, addressing the empirical challenges in reproducing SPM receptor activation—and the novel alternative mechanisms now being proposed—as well as the analytical hurdles impending their quantification. Finally, an examination is conducted regarding how a defined imbalance in these opposing mediator pathways contributes to the pathophysiology of diverse conditions, followed by a discussion of emerging therapeutic strategies that have evolved from solely inflammation-inhibition to the active promotion of its resolution.

炎症是宿主防御和组织完整性的基本生物学过程。然而，它的失调，经常以主动解决的失败为特征，支持了大量的慢性疾病。这个复杂过程的核心是类二十烷超家族，它是来自20碳多不饱和脂肪酸（PUFAs）的有效生物活性脂质介质。历史上，特定的类二十烷，如前列腺素（pg）和白三烯（lt），主要被认为是促炎剂，据称负责介导血管舒张、白细胞运输、伤害感觉和发热。因此，非甾体抗炎药（NSAIDs）等治疗干预措施主要通过环氧化酶（COX）抑制它们的产生。一个重要的范式转变假设溶解不是被动的衰变，而是一个由专门的促溶解介质（SPMs）精心策划的主动过程，包括脂毒素、溶解蛋白、保护蛋白和蛋白。虽然药理学报告表明这些介质通过特定受体直接停止炎症，但最近的独立研究提出了关于其内源性生物合成、受体验证和检测的突出问题。这篇综述详细介绍了已建立的生物合成机制（COX， LOX， CYP），并对比了经典的促炎信号和SPM的作用。至关重要的是，对现有的科学辩论提供了一个平衡的观点，解决了重现SPM受体激活的经验挑战，以及现在提出的新的替代机制，以及即将量化的分析障碍。最后，对这些对立介质通路中定义的不平衡如何促进不同条件的病理生理进行了检查，随后讨论了新兴的治疗策略，这些策略已经从单纯的炎症抑制发展到积极促进其解决。

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引用次数: 0

MEK inhibitor induces cardiac complications by preventing ZMYND8-mediated ubiquitination and proteasomal degradation of HMGB1 MEK抑制剂通过阻止zmynd8介导的泛素化和HMGB1蛋白酶体降解诱导心脏并发症。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-12-19 DOI: 10.1016/j.bcp.2025.117660

Huangxi Fu , Feng Jiang , Anqi Xu , Taicheng Zhou , Ning Liu , Xueqin Chen , Zizheng Gao , Wentong Wu , Hao Yan , Xiaochun Yang , Bo Yang , Qiaojun He , Peihua Luo , Zhifei Xu

The cardiac complications caused by drugs, including cardiac dysfunction and heart failure, significantly limit the wide clinical application of drugs and lead to morbidity and mortality. High mobility group box 1 (HMGB1) plays an extensive role in drug-induced cardiotoxicity. However, the cardiotoxic mechanisms for most small-molecule kinase inhibitors (SMKIs) remains unknown. Here, we identify that accumulated HMGB1 is associated with the cardiac complications caused by a series of FDA-approved SMKIs, among which trametinib-induced cardiomyocyte death was most significantly reversed by HMGB1 knockout. Moreover, cardiomyocyte-specific Hmgb1 deletion in mice could improve cardiac muscle contraction, calcium regulation and cardiomyocyte apoptosis in autophagy- or inflammation-independent manner. We further show that trametinib leads to the aberrant accumulation of HMGB1 by increasing its stability via inhibiting zinc finger protein Zinc Finger MYND-Type Containing 8 (ZMYND8)-mediated ubiquitination and proteasomal degradation of HMGB1, identifying ZMYND8 as a novel negative regulator of HMGB1 stability in cardiomyocyte and a potential novel regulator of cardiac function. Glycyrrhizic acid, an HMGB1 inhibitor used in clinic, prevents trametinib-induced cardiac complications. These findings reveal the mechanism and propose an effective intervention strategy for trametinib-induced cardiac complications, which would contribute to the safe application of trametinib, cardiac safety evaluation of drugs or candidate compounds and novel drug development.

药物引起的心脏并发症，包括心功能障碍和心力衰竭，极大地限制了药物的广泛临床应用，并导致发病率和死亡率。高迁移率组框1 （HMGB1）在药物性心脏毒性中发挥着广泛的作用。然而，大多数小分子激酶抑制剂（SMKIs）的心脏毒性机制尚不清楚。在这里，我们发现积累的HMGB1与一系列fda批准的SMKIs引起的心脏并发症有关，其中敲除trametinib诱导的心肌细胞死亡最显著地逆转了HMGB1。此外，小鼠心肌细胞特异性Hmgb1缺失可以通过自噬或炎症不依赖的方式改善心肌收缩、钙调节和心肌细胞凋亡。我们进一步发现，曲美替尼通过抑制锌指蛋白锌指MYND-Type Containing 8 （ZMYND8）介导的泛素化和蛋白酶体降解来增加HMGB1的稳定性，从而导致HMGB1的异常积累，从而确定ZMYND8是心肌细胞中HMGB1稳定性的一种新的负调节因子，也是一种潜在的心功能的新型调节因子。甘草酸是临床使用的HMGB1抑制剂，可预防曲美替尼引起的心脏并发症。这些发现揭示了曲美替尼诱发心脏并发症的机制，并提出了有效的干预策略，为曲美替尼的安全应用、药物或候选化合物的心脏安全性评价以及新药开发提供了依据。

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引用次数: 0

Senolytic elimination of therapy-induced senescent cells by ABT-263 improves chemotherapeutic efficacy in esophageal squamous cell carcinoma ABT-263对治疗诱导的衰老细胞的溶解性消除提高了食管鳞状细胞癌的化疗疗效。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-12-19 DOI: 10.1016/j.bcp.2025.117659

Dan Zhang , Ju Zhu , Rui Zou , Han Zhang , Bao-Ping Yu , Pan Li , Yang Luo , Zheng Jiang , Yu Hou , Jian-Wei Zhang

Esophageal squamous cell carcinoma (ESCC) is routinely treated with platinum-based chemotherapy but almost inevitably relapses. Our previous study demonstrated that cisplatin (CDDP) induced ESCC cell senescence, and senescent cells promoted the aggressive behaviors of neighboring cancer cells through the senescence-associated secretory phenotype (SASP). Notably, the use of ‘senolytic’ drugs that selectively remove senescent cells by inducing apoptosis has been proven to improve therapeutic efficacy, but their potential application in ESCC therapy has not yet been studied. In this study, we observed that therapy-induced ESCC cell senescence was associated with poor prognosis of ESCC patients. We found that anti-apoptotic BCL-2 family member BCL-XL mediated the survival of CDDP-induced senescent ESCC cells, and senolytic drug ABT-263 (navitoclax, an inhibitor of BCL-2 and BCL-XL) selectively eliminated senescent cells by triggering apoptosis, thereby attenuating SASP-driven ESCC cell proliferation and migration in vitro and improving CDDP efficacy in a mouse model of ESCC. Mechanistically, the enhanced interaction between BCL-XL and pro-apoptotic effector protein BAX conferred apoptosis resistance in senescent ESCC cells, and ABT-263 treatment disrupted this interaction to activate apoptosis. Overall, our data indicate that CDDP-induced senescent ESCC cells could be eliminated using senolytic drugs that target BCL-XL, and thus senolytic therapy could be a potential effective strategy for improving chemotherapeutic efficacy in ESCC.

食管鳞状细胞癌（ESCC）的常规治疗是铂基化疗，但几乎不可避免地复发。我们前期研究表明，顺铂（CDDP）诱导ESCC细胞衰老，衰老细胞通过衰老相关分泌表型（senescence associated secretory phenotype， SASP）促进邻近癌细胞的侵袭行为。值得注意的是，通过诱导凋亡选择性去除衰老细胞的“抗衰老”药物已被证明可以提高治疗效果，但其在ESCC治疗中的潜在应用尚未得到研究。在本研究中，我们观察到治疗诱导的ESCC细胞衰老与ESCC患者预后不良相关。我们发现抗凋亡BCL-2家族成员BCL-XL介导CDDP诱导的衰老ESCC细胞的存活，而抗衰老药物ABT-263 （navitoclax， BCL-2和BCL-XL的抑制剂）通过触发凋亡选择性地消除衰老细胞，从而在体外减弱sasp驱动的ESCC细胞的增殖和迁移，提高CDDP在ESCC小鼠模型中的疗效。在机制上，BCL-XL和促凋亡效应蛋白BAX之间的相互作用增强了衰老ESCC细胞的凋亡抗性，而ABT-263的处理破坏了这种相互作用，激活了细胞凋亡。总之，我们的数据表明，cddp诱导的衰老ESCC细胞可以通过靶向BCL-XL的抗衰老药物消除，因此抗衰老治疗可能是提高ESCC化疗疗效的潜在有效策略。

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引用次数: 0

IL-18 potentiates platelet activation and thrombosis through IL-18Rα-dependent MAPKs and PI3K/Akt signaling IL-18通过il - 18r α依赖的MAPKs和PI3K/Akt信号通路增强血小板活化和血栓形成。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-12-18 DOI: 10.1016/j.bcp.2025.117656

Maieryemu Waresi , Huili Zhou , Can Jiao , Jingjing Hu , Mengsha Shi , Xuanhan Lin , Tianxin Ye , Chaoyang Huang , Wei Zhang , Xiaogang Guo , Haoxuan Zhong

Arterial thrombosis is a leading cause of global cardiovascular mortality. Clinical evidence indicates that elevated IL-18 levels independently predict cardiovascular events, yet its direct role in thrombosis is poorly understood. Hence, targeting IL-18 could be a novel therapeutic strategy. This study investigated the mechanism of IL-18 in platelet activation and evaluated the antithrombotic efficacy of interleukin-18 binding protein (IL-18BP). Through in vitro and in vivo models, including Il18r1^-/- mice, we demonstrated that IL-18 enhances platelet activation and thrombus formation via its receptor interleukin-18 receptor alpha (IL-18Rα). This action was mediated through the potentiation of MAPKs and PI3K/Akt signaling. Strikingly, IL-18BP exhibited superior antiplatelet effects in both mouse models and human subjects, including those with coronary artery disease (CAD). Our findings reveal that IL-18 is a key promoter of thrombosis and identify IL-18BP as a highly effective, targeted therapy for cardiovascular disease.

动脉血栓形成是全球心血管疾病死亡的主要原因。临床证据表明，IL-18水平升高可独立预测心血管事件，但其在血栓形成中的直接作用尚不清楚。因此，靶向IL-18可能是一种新的治疗策略。本研究探讨了IL-18在血小板活化中的作用机制，并评价了白细胞介素-18结合蛋白（IL-18BP）的抗血栓作用。通过体外和体内模型，包括Il18r1-/-小鼠，我们证明了IL-18通过其受体白介素-18受体α (IL-18Rα)增强血小板活化和血栓形成。这种作用是通过MAPKs和PI3K/Akt信号的增强介导的。引人注目的是，IL-18BP在小鼠模型和人类受试者（包括冠状动脉疾病（CAD）患者）中均表现出优越的抗血小板作用。我们的研究结果表明，IL-18是血栓形成的关键启动子，并确定IL-18BP是一种高效的靶向治疗心血管疾病的药物。

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引用次数: 0

Septin 2: A direct target of Ginsenoside Rg1 mediating its neuroprotective effects Septin 2：人参皂苷Rg1介导其神经保护作用的直接靶点。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-12-18 DOI: 10.1016/j.bcp.2025.117655

Jun Li , Jie-Chun Zhou , Wei-Ping Wen , Yu Zhou , Hui-Lin Li , Shu-Jie He , Yu-Ting Liu , Zhi-You Yang , Xiu-Hong Piao , Shu-Mei Wang , Jie Yu , Yue-Wei Ge

Ginsenoside Rg1 (Rg1), a representative saponin of ginseng, is evidenced with a remarkable neuroprotective effect; however, its direct target in neural cells has not been addressed. The present study investigated the reconstructing effect on the damaged neurite network of Rg1, and its direct target responsible for this bio-effect. The results showed that Rg1 can alleviate the Aβ_25-35-induced neuronal damage and synaptic atrophy in primary neurons and PC12 cell models, respectively. Furthermore, the Septin 2, involved in cell division and cytoskeleton organization, was identified as a protein specifically binding to Rg1. In addition, the overexpression and knockdown of Septin 2 in PC12 cells supported its role in mediating the neural protective effect of Rg1. These findings uncover Septin 2 as a key target of Rg1 in neural cells, which also provides insight into the intervention mechanism of ginseng in neurological disorders.

人参皂苷Rg1 （Rg1）是人参中具有代表性的皂苷，具有显著的神经保护作用；然而，其在神经细胞中的直接靶点尚未得到解决。本研究探讨了Rg1对受损神经突网络的重建作用及其产生这种生物效应的直接靶点。结果表明，Rg1可减轻原代神经元和PC12细胞模型中a β25-35诱导的神经元损伤和突触萎缩。此外，参与细胞分裂和细胞骨架组织的Septin 2被鉴定为特异性结合Rg1的蛋白。此外，PC12细胞中Septin 2的过表达和敲低支持其介导Rg1的神经保护作用。这些发现揭示了Septin 2是Rg1在神经细胞中的关键靶点，这也为人参对神经系统疾病的干预机制提供了新的思路。缩写：Rg1，人参皂苷Rg1；AD，阿尔茨海默病；β淀粉样β蛋白;神经原纤维缠结；药物亲和反应靶稳定性；细胞热移测定；IP-MS，免疫沉淀-质谱联用；PDL poly-D-lysine;HS，马血清；胎牛血清；重组人β-神经生长因子；WB, Western blot；IF：免疫荧光染色；等温滴定量热法；q-PCR、RNA提取和实时荧光定量PCR；gDNA，基因组DNA；SEC：排色色谱法；DAPI 4’,6-Diamidino-2-Phenylindole;GppNp, Guanosine-5”——(β,γ)酰亚胺的三磷酸腺苷。

引用次数: 0

Activation of IL-17/CEBPB/PFKFB3 triggers energy metabolic switching and goblet cell differentiation in ulcerative colitis IL-17/CEBPB/PFKFB3的激活触发溃疡性结肠炎的能量代谢转换和杯状细胞分化。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-12-17 DOI: 10.1016/j.bcp.2025.117654

Hui Zhao , Zhiliang Hu

Goblet cell depletion, frequently reported as a symptom of ulcerative colitis (UC), may reflect a combination of increased mucus release, decreased mucus storage, and altered goblet cell differentiation. Here, we studied the underlying mechanisms of CCAAT/enhancer-binding protein beta (CEBPB), which is enriched in interleukin (IL)-17 signaling, in goblet cell differentiation during UC. The IL-17/CEBPB/6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) signaling axis in vivo was elicited through an IL-17A-neutralizing antibody and adeno-associated viruses targeting goblet cells. Goblet cells were used to assess the effects of IL-17/CEBPB/PFKFB3 signaling on goblet cell differentiation. IL-17 signaling activated CEBPB-mediated PFKFB3 transcription in goblet cells of dextran sodium sulfate-induced mice and drove a switch in the mode of energy metabolism from oxidative phosphorylation to aerobic glycolysis in goblet cells. The abnormal glycolytic activity of goblet cells was detrimental to cell differentiation and maturation, leading to decreased mucin secretion and weakened intestinal barrier capacity of the goblet cells, which led to the progression of UC. Overall, these results indicate that IL-17 pro-inflammatory signaling activates CEBPB/PFKFB3 expression to drive aerobic glycolysis in goblet cells, leading to goblet cell dysfunction and UC progression.

杯状细胞耗竭常被报道为溃疡性结肠炎（UC）的一种症状，可能反映了粘液释放增加、粘液储存减少和杯状细胞分化改变的共同作用。在这里，我们研究了CCAAT/增强子结合蛋白β (CEBPB)在UC过程中杯状细胞分化中的潜在机制，CEBPB富含白细胞介素(IL)-17信号。通过IL- 17a中和抗体和针对杯状细胞的腺相关病毒，在体内诱导出白细胞介素(IL)-17/CEBPB/6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶3 （PFKFB3）信号轴。利用杯状细胞研究IL-17/CEBPB/PFKFB3信号通路对杯状细胞分化的影响。IL-17信号激活了葡聚糖硫酸钠诱导小鼠杯状细胞中cebpb介导的PFKFB3转录，并驱动了杯状细胞中能量代谢模式从氧化磷酸化到有氧糖酵解的转换。杯状细胞糖酵解活性异常，不利于细胞分化和成熟，导致杯状细胞黏液分泌减少，肠道屏障能力减弱，从而导致UC的进展。总的来说，这些结果表明IL-17促炎信号激活CEBPB/PFKFB3表达，驱动杯状细胞的有氧糖酵解，导致杯状细胞功能障碍和UC进展。

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引用次数: 0

TRPV1 mediates oxidative stress and autophagy pathways to regulate airway MUC5AC secretion TRPV1通过氧化应激和自噬途径调节气道MUC5AC分泌。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-12-17 DOI: 10.1016/j.bcp.2025.117658

Xiaochun Huang , Hailan Wang , Jintao Gan , Danli Zhu , Yuheng Dai , Xiaobin Wang , Li Liu , Yulin Liu , Jing Jia

Airway mucus hypersecretion is a prevalent chronic inflammatory disorder characterized by elevated mucin5AC (MUC5AC) expression, which exacerbates airflow limitation and increases susceptibility to lung infections. Transient receptor potential vanilloid 1 (TRPV1) channels, widely distributed across the airways, play a pivotal role in lung inflammation and tissue damage; however, the specific mechanism by which TRPV1 modulates airway MUC5AC expression remains unclear. To address this gap, we established an in vivo model of airway mucus hypersecretion in C57BL/6 mice via intratracheal administration of Pseudomonas aeruginosa (PA), followed by measurement of MUC5AC and TRPV1 expression levels. TRPV1 knockout mice were generated to assess lung inflammation, airway mucus secretion, and changes in MUC5AC and autophagy-related proteins following PA exposure. In vitro, an airway mucus hypersecretion model was created using Pyocyanin-treated NCI-H292 cells to measure intracellular TRPV1 and MUC5AC levels and investigate interactions between TRPV1, MUC5AC, oxidative stress, and autophagy. Both in vivo and in vitro models demonstrated that TRPV1 inhibition significantly reduced MUC5AC secretion, concurrent with decreased reactive oxygen species (ROS) production, mitigated oxidative stress, and attenuated autophagy. Further analysis revealed that the ROS scavenger N-acetylcysteine effectively decreased intracellular autophagy, while the autophagy inhibitor 3-Methyladenine significantly reduced MUC5AC secretion. Collectively, these findings indicate that TRPV1 inhibition reduces airway MUC5AC secretion through modulation of oxidative stress and autophagy pathways, suggesting TRPV1 as a promising therapeutic target for airway mucus hypersecretion diseases.

气道粘液高分泌是一种常见的慢性炎性疾病，其特征是mucin5AC （MUC5AC）表达升高，加剧气流限制，增加对肺部感染的易感性。瞬时受体电位香草样蛋白1 （TRPV1）通道广泛分布于气道，在肺部炎症和组织损伤中起关键作用；然而，TRPV1调节气道MUC5AC表达的具体机制尚不清楚。为了解决这一空白，我们通过气管内给药铜绿假单胞菌（Pseudomonas aeruginosa， PA）建立了C57BL/6小鼠气道粘液高分泌的体内模型，并测量了MUC5AC和TRPV1的表达水平。产生TRPV1敲除小鼠，以评估PA暴露后肺部炎症、气道粘液分泌以及MUC5AC和自噬相关蛋白的变化。体外，采用pyocyanin处理的NCI-H292细胞建立气道粘液高分泌模型，测定细胞内TRPV1和MUC5AC水平，探讨TRPV1、MUC5AC与氧化应激和自噬之间的相互作用。体内和体外模型均表明，TRPV1抑制显著减少MUC5AC分泌，同时减少活性氧（ROS）的产生，减轻氧化应激，减弱自噬。进一步分析发现，ROS清除剂n -乙酰半胱氨酸可有效降低细胞内自噬，而自噬抑制剂3-甲基腺苷可显著降低MUC5AC的分泌。综上所述，这些发现表明TRPV1抑制通过调节氧化应激和自噬途径减少气道MUC5AC的分泌，提示TRPV1是气道粘液高分泌性疾病的一个有希望的治疗靶点。

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引用次数: 0