Biochemical pharmacology最新文献_第6页

TBG096 stimulates hair regeneration through IGF-1R-mediated angiogenesis TBG096通过igf - 1r介导的血管生成刺激头发再生。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-29 DOI: 10.1016/j.bcp.2026.117764

Majid Manzoor , Danni Chen , Ting Jiang, Jiahui Lin, Jiayuan Zeng, Lan Xiang, Jianhua Qi

Current pharmacological treatments for alopecia mainly aim to prevent further hair loss. However, efforts to identify therapeutic agents capable of reactivating the hair cycle have limited success. Herein, we identify that TBG096, a novel natural product-derived molecule with anti-aging properties promotes hair growth. In particular, we investigated hair regeneration effects of topical and oral TBG096 treatments across various models, including female and male rats, naturally aged and dihydrotestosterone (DHT)-induced alopecia model mice. TBG096 facilitated the transition of hair follicles from the telogen to the anagen phase, enhancing hair growth rate in a dose-dependent manner. Mechanistically, TBG096 directly binds and activates insulin-like growth factor 1 receptor (IGF-1R) that in turn activates downstream phosphatidylinositol 3-kinase /protein Kinase B (PI3K/AKT) signaling pathway. IGF-1R/PI3K/AKT activation increased angiogenesis in the dermal papilla to promote hair follicle proliferation and differentiation. Conversely, inhibition of IGF-1R impaired TBG096 mediated angiogenesis and hair regrowth. In addition, TBG096 also reduced DHT levels, increased keratin 15 (k15) expression and regulated growth factors like IGF-1 and epidermal growth factor (EGF), suggesting a restoration of normal follicular function. This is the first study to comprehensively demonstrate that TBG096 effectively promotes hair regeneration independent of age, gender, or application method, making it a promising candidate for treating androgenic alopecia and age-related hair loss.

目前脱发的药物治疗主要是为了防止进一步脱发。然而，鉴别能够重新激活头发周期的治疗药物的努力收效甚微。在此，我们发现TBG096是一种具有抗衰老特性的新型天然产物衍生分子，可促进头发生长。特别地，我们研究了局部和口服TBG096治疗在各种模型中的毛发再生效果，包括雌性和雄性大鼠，自然衰老和双氢睾酮（DHT）诱导的脱发模型小鼠。TBG096促进毛囊从休止期向生长期过渡，以剂量依赖性方式提高头发生长速度。在机制上，TBG096直接结合并激活胰岛素样生长因子1受体（IGF-1R），进而激活下游磷脂酰肌醇3-激酶/蛋白激酶B （PI3K/AKT）信号通路。IGF-1R/PI3K/AKT激活可增加真皮乳头血管生成，促进毛囊增殖和分化。相反，抑制IGF-1R会损害tbg介导的血管生成和头发再生。此外，TBG096还能降低DHT水平，增加角蛋白15 （Keratin 15, k15）表达，调节生长因子如IGF-1和表皮生长因子（epidermal growth factor， EGF），提示恢复正常卵泡功能。这是第一个全面证明TBG096有效促进头发再生的研究，不受年龄、性别或使用方法的影响，使其成为治疗雄激素性脱发和年龄相关性脱发的有希望的候选药物。

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引用次数: 0

Ginsenoside Rf promotes testosterone synthesis through the cAMP/PKA/CREB signaling pathway to improve obesity-related male hypogonadism 人参皂苷Rf通过cAMP/PKA/CREB信号通路促进睾酮合成，改善肥胖相关男性性腺功能减退

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-28 DOI: 10.1016/j.bcp.2026.117758

Zhang runqi , Zheng xiaoxing , Chen yuqing , Qi xiangyu , Lu chenglin , Guan qingbo , Yu chunxiao

Obesity, as a major global public health issue, triggers various diseases, including male hypogonadism. Ginsenoside Rf, natural compounds extracted from ginseng, has unclear roles in obesity-related male hypogonadism. This study aims to investigate the effects of ginsenoside Rf on obesity-related male hypogonadism and to preliminarily explore its underlying mechanisms. Eight-week-old male mice were divided into normal diet (ND), high-fat diet (HFD), and HFD + Rf groups. After 12-week HFD feeding followed by 5-week intervention, Rf reduced HFD-induced body weight, testicular stromal lipid deposition, and fibrosis, while increasing testicular testosterone and upregulating synthesis-related proteins (Steroidogenic acute regulatory protein (Star), Scavenger receptor class B type 1 (Srb1), Cytochrome P450 family 11 subfamily a member 1 (Cyp11a1), Cytochrome P450 family 17 subfamily a member 1 (Cyp17a1)). Network pharmacology identified Star, Cyp11a1, and cyclic adenosine monophosphate (cAMP) signaling as potential targets/pathways. In palmitic acid (PA)-treated Leydig cells, Rf elevated Star, Cyp11a1, the phosphorylation levels of protein kinase A (p-Pka), and phosphorylation levels of Creb(p-Creb)/Creb (cAMP response element-binding protein) levels; these effects were reversed by PKA inhibitor H89. Ginsenoside Rf may promote testosterone synthesis via activating the cAMP/PKA/CREB pathway, highlighting its potential in treating obesity-related male hypogonadism.

肥胖，作为一个主要的全球公共卫生问题，引发各种疾病，包括男性性腺功能减退。人参皂苷Rf是一种从人参中提取的天然化合物，其在肥胖相关的男性性腺功能减退中的作用尚不清楚。本研究旨在探讨人参皂苷Rf对肥胖相关男性性腺功能减退的影响，并初步探讨其作用机制。将8周龄雄性小鼠分为正常饮食（ND）组、高脂饮食（HFD）组和高脂饮食+ Rf组。饲喂HFD 12周后再进行干预5周，Rf降低了HFD诱导的体重、睾丸间质脂沉积和纤维化，同时增加睾丸睾酮并上调合成相关蛋白（甾体急性调节蛋白（Star）、清道夫受体B类1型（Srb1）、细胞色素P450家族11亚家族1成员1 （Cyp11a1）、细胞色素P450家族17亚家族1成员1 (Cyp17a1)）。网络药理学鉴定了Star、Cyp11a1和环腺苷单磷酸（cAMP）信号作为潜在的靶点/途径。在棕榈酸（PA）处理的间质细胞中，Rf升高了Star、Cyp11a1、蛋白激酶A （p-Pka）的磷酸化水平和Creb(p-Creb)/Creb （cAMP反应元件结合蛋白）的磷酸化水平；这些作用被PKA抑制剂H89逆转。人参皂苷Rf可能通过激活cAMP/PKA/CREB通路促进睾酮合成，突出其治疗肥胖相关男性性腺功能减退的潜力。

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引用次数: 0

ICAP-1 alternative splicing regulates Talin tension polarization in NSCLC durotaxis ICAP-1选择性剪接调节非小细胞肺癌硬致性中的Talin张力极化

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-28 DOI: 10.1016/j.bcp.2026.117762

Yunfeng Hu , Wangxing Zhao , Ying Zhao , Lijun Zhang , Yuqing Shi , Shixiao Wan , HuanHuan Zhao , Jun Guo , Ying Song

The directional migration of cancer cells in response to tumor microenvironment stiffening is mediated through integrin-dependent mechanotransduction pathways, particularly involving integrin cytoplasmic domain-associated protein 1 (ICAP-1). In this study, we aimed to explore the role of Talin tension during directional migration of non-small cell lung cancer (NSCLC) cells, with a specific focus on the isoform-specific regulation by ICAP-1α and ICAP-1β. Our findings demonstrate that matrix stiffening triggers a significant shift in ICAP-1 isoform expression. ICAP-1α, but not ICAP-1β, reduces the aggressiveness and directionality of NSCLC cells on a cell-directed matrix (CDM) with a stiffness gradient. ICAP-1α exhibited an extensive subcellular distribution, which inhibits integrin activity and talin tension. Our results establish ICAP-1 as a critical mechanotransducer that relays signals from β1-integrin to Talin, and suggest that ICAP-1 alternative splicing could be harnessed as a potential therapeutic strategy for NSCLC.

肿瘤微环境强化时，癌细胞的定向迁移是通过整合素依赖的机械转导途径介导的，特别是涉及整合素细胞质结构域相关蛋白1 （ICAP-1）。在这项研究中，我们旨在探讨Talin张力在非小细胞肺癌（NSCLC）细胞定向迁移中的作用，并特别关注ICAP-1α和ICAP-1β的亚型特异性调控。我们的研究结果表明，基质硬化触发了ICAP-1异构体表达的显著变化。ICAP-1α，而不是ICAP-1β，降低了非小细胞肺癌细胞在细胞定向基质（CDM）上的侵袭性和方向性，具有刚度梯度。ICAP-1α表现出广泛的亚细胞分布，抑制整合素活性和talin张力。我们的研究结果表明，ICAP-1是将β1整合素信号传递给Talin的关键机械传感器，并表明ICAP-1选择性剪接可以作为非小细胞肺癌的潜在治疗策略。

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引用次数: 0

MICALL2 promotes angiogenesis of colorectal cancer by regulating the EGFR/PI3K/AKT/KLF5/VEGFA axis MICALL2通过调节EGFR/PI3K/AKT/KLF5/VEGFA轴促进结直肠癌血管生成

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-28 DOI: 10.1016/j.bcp.2026.117757

Shuzhen Hu , Fan Wang , Jiamei Xu , Ruixin Li , Hongzhe Liu , Tian Gao , Guoqun Ma , Yuhang Li , Yingxi Wang , Ying Liu , Yanhong Feng , Pushuai Wen , Jing Gao

Colorectal cancer (CRC) is a common malignancy with high incidence and mortality, and tumor angiogenesis plays a crucial role in its progression and metastasis. Although anti-angiogenic therapies are promising, their effectiveness is limited by side effects, drug resistance, and relapse, underscoring the urgent the need to explore novel mechanisms and targets underlying CRC angiogenesis. In this study, using single-cell RNA sequencing (scRNA-seq) and weighted gene co-expression network analysis (WGCNA), we found that MICALL2 is predominantly expressed in CRC epithelial cells and correlated with angiogenesis-related pathways, such as VEGFA/VEGFR2 signaling. This aligns with immunohistochemical results demonstrating a positive correlation between MICALL2 expression and microvessel density. Functionally, in vitro experiments showed that conditioned media from CRC cells overexpressing MICALL2 enhanced the viability, migration, and tube formation of human umbilical vein endothelial cells (HUVECs), whereas MICALL2 knockdown produced the opposite effects. In vivo, chick chorioallantoic membrane (CAM) assays and xenograft models confirmed the pro-angiogenic role of MICALL2. Mechanistically, MICALL2 stabilizes EGFR by inhibiting lysosomal degradation, leading to activation of the PI3K/AKT pathway, which in turn upregulates the transcription factor KLF5 and subsequent VEGFA expression. Pharmacological inhibition of PI3K via LY294002 reversed MICALL2-induced angiogenesis. Therefore, MICALL2 facilitates CRC angiogenesis through the EGFR/PI3K/AKT/KLF5/VEGFA axis and may serve as a promising target for anti-angiogenic therapy.

结直肠癌（Colorectal cancer， CRC）是一种发病率高、死亡率高的常见恶性肿瘤，肿瘤血管生成在其进展和转移中起着至关重要的作用。尽管抗血管生成疗法很有前景，但其有效性受到副作用、耐药性和复发的限制，因此迫切需要探索结直肠癌血管生成的新机制和靶点。本研究通过单细胞RNA测序（scRNA-seq）和加权基因共表达网络分析（WGCNA），我们发现MICALL2主要在CRC上皮细胞中表达，并与血管生成相关通路相关，如VEGFA/VEGFR2信号通路。这与免疫组织化学结果一致，表明MICALL2表达与微血管密度呈正相关。功能上，体外实验表明，CRC细胞的条件培养基过表达MICALL2增强了人脐静脉内皮细胞（HUVECs）的活力、迁移和管状形成，而MICALL2敲低则产生相反的效果。在体内，鸡绒毛尿囊膜（CAM）实验和异种移植模型证实了MICALL2的促血管生成作用。在机制上，MICALL2通过抑制溶酶体降解来稳定EGFR，从而激活PI3K/AKT通路，进而上调转录因子KLF5和随后的VEGFA表达。通过LY294002抑制PI3K逆转micall2诱导的血管生成。因此，MICALL2通过EGFR/PI3K/AKT/KLF5/VEGFA轴促进结直肠癌血管生成，可能成为抗血管生成治疗的一个有希望的靶点。

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引用次数: 0

Bioinspired material design for oral targeted delivery Systems: From structural bioinspiration to functional implementation 口服靶向递送系统的仿生材料设计：从结构仿生到功能实现。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-27 DOI: 10.1016/j.bcp.2026.117747

Minhui Xu , Tao Sun , Huangbang Liang , Guangfu Feng , Qiongfang Hu , Yuanchun Du , Jun Fang

Bioinspired materials (BMs) have emerged as a pivotal research focus in drug delivery, demonstrating significant potential for oral targeted delivery systems (OTDS) in recent years. By mimicking the structural features or functional mechanisms of biological systems, these materials significantly enhance delivery efficiency and optimize drug activity, offering a novel paradigm for the rational design of OTDS. Despite significant progress, existing evaluations primarily focus on single-disease applications or specific material types, leaving a systematic summary of the transition from structural design to functional manifestation in BMs notably lacking. Meanwhile, the advantages and limitations of different preparation methods and their influence on delivery performance remain underexplored. To address these gaps, this article provides a comprehensive analysis of the design strategies and functional mechanisms of BMs in OTDS, emphasizing two key dimensions: Structural emulation and biological emulation. Additionally, it critically evaluates the advantages and limitations of various preparation methods. By synthesizing experimental evidence from diverse disease models, with a focus on colitis and cancer as representative examples, this review systematically elucidates the pivotal role of BMs in improving oral drug targeting efficiency. Moreover, it proposes strategic approaches to optimize delivery systems and discusses critical challenges and future directions in the field. This work aims to facilitate the transition toward the rational design and clinical implementation of next-generation OTDS.

近年来，生物激发材料（BMs）已成为药物递送领域的关键研究热点，在口服靶向递送系统（OTDS）方面显示出巨大的潜力。这些材料通过模拟生物系统的结构特征或功能机制，显著提高了给药效率，优化了药物活性，为OTDS的合理设计提供了新的范式。尽管取得了重大进展，但现有的评估主要集中在单一疾病的应用或特定的材料类型上，对脑转移从结构设计到功能表现的转变缺乏系统的总结。同时，不同制备方法的优缺点及其对递送性能的影响还有待进一步研究。为了解决这些问题，本文全面分析了OTDS中脑转移的设计策略和功能机制，强调了两个关键维度：结构仿真和生物仿真。此外，它批判性地评估了各种制备方法的优点和局限性。本文通过综合不同疾病模型的实验证据，以结肠炎和癌症为代表，系统阐述脑转移瘤在提高口服药物靶向效率中的关键作用。此外，它还提出了优化交付系统的战略方法，并讨论了该领域的关键挑战和未来方向。这项工作旨在促进向下一代OTDS的合理设计和临床实施过渡。

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引用次数: 0

Identification of a novel chalcone derivative as ferroptosis inducer through targeting TrxR in prostate cancer 一种新的查尔酮衍生物通过靶向TrxR在前列腺癌中作为铁下垂诱导剂的鉴定。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-27 DOI: 10.1016/j.bcp.2026.117760

Jun Yan , Long Cheng , Qing-qing Ma , Qiao-xuan Zhang , Shu Gan , Hai-biao Lin , Li-qiao Han , Peng-wei Zhang , Fen Ouyang , Pei-feng Ke , Xian-zhang Huang

Prostate cancer (PCa) remains a major threat to male health. Due to the inevitable progression of incurable castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT), it is an urgent need to seek out new therapeutic strategies that not dependent on androgen receptor (AR) signaling pathway. Through high-throughput screening of our in-house compound library, compound CD-15, a chalcone derivative, demonstrated remarkable anti-proliferative activity on AR-negative PCa cells at subnanomolar concentrations and completely blocked tumor growth in both cell line-derived xenograft (CDX) mice model and a zebrafish patient-derived xenograft (zPDX) model. Notably, CD-15 displayed a more favorable safety profile than the clinically widely-used drug docetaxel. Leveraging drug affinity responsive target stability (DARTS) technology and virtual target screening, thioredoxin reductase (TrxR) was identified as the direct target of CD-15. Our study also found TrxR was over-expressed in the serum and tissues in PCa patients and TrxR1 knockdown partially attenuated the suppressive effect of CD-15 in vitro and in vivo. Moreover, several means including BIAM assay, molecular docking, LC-MS/MS and DARTS analysis confirmed that CD-15 covalently modified selenocysteine 498 (U) residues within the redox-active site of TrxR, leading to the enzyme inhibition. Mechanistically, CD-15 exerted a dual anti-PCa mechanism, which was capable of inducing ferroptosis in a TrxR-dependent manner. Altogether, CD-15 emerges as a promising candidate for the treatment of PCa and deserves further investigation.

前列腺癌（PCa）仍然是男性健康的主要威胁。由于无法治愈的去势抵抗性前列腺癌（CRPC）在雄激素剥夺治疗（ADT）后不可避免的发展，迫切需要寻求不依赖于雄激素受体（AR）信号通路的新治疗策略。通过对我们内部化合物文库的高通量筛选，化合物CD-15（查尔酮衍生物）在亚纳摩尔浓度下对ar阴性PCa细胞表现出显著的抗增殖活性，并在细胞系来源的异种移植（CDX）小鼠模型和斑马鱼患者来源的异种移植（zPDX）模型中完全阻断肿瘤生长。值得注意的是，CD-15显示出比临床广泛使用的药物多西他赛更有利的安全性。利用药物亲和响应性靶标稳定性（dart）技术和虚拟靶标筛选，确定了硫氧还蛋白还原酶（TrxR）为CD-15的直接靶标。我们的研究还发现，在PCa患者的血清和组织中TrxR过表达，TrxR1的敲低部分减弱了CD-15在体外和体内的抑制作用。此外，BIAM分析、分子对接、LC-MS/MS和DARTS分析等手段证实CD-15共价修饰TrxR氧化还原活性位点内的硒代半胱氨酸498 (U)残基，导致酶抑制。在机制上，CD-15具有双重抗pca机制，能够以trxr依赖的方式诱导铁下垂。总之，CD-15是治疗前列腺癌的一个有希望的候选药物，值得进一步研究。

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引用次数: 0

Unmasking the role of tumor microenvironment in the advanced stage of cancer treatment to mitigate risks during chemotherapy 揭示肿瘤微环境在晚期癌症治疗中减轻化疗风险的作用

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-27 DOI: 10.1016/j.bcp.2026.117754

Anchala Kumari, Niranjan Meher, Abhishek Dey, Saurav Awasthi, Shubhini A. Saraf, Nidhi Srivastava

The complexity of the tumor microenvironment in advanced-stage cancer critically diminishes the activity of chemotherapy, often reducing its efficacy to a point where the inherent risks become clinically unwarranted. This review “unmasks” the tumor microenvironment as a sophisticated barrier system driven primarily by hypoxia, i.e. severe oxygen deprivation. Hypoxia stabilizes master-regulators, including hypoxia-inducible factor-1α, which actively induce multidrug resistance. Specifically, hypoxia-inducible factor-1α orchestrates drug expulsion from the cancer cell via efflux pumps and enhances cellular repair of drug-induced DNA damage, functionally neutralizing cytotoxic agents. This resistance is compounded by tumor heterogeneity, which promotes the selection of aggressive, drug-evading subclones, and by hypoxia-induced degradation of the major histocompatibility complex class I, rendering cancer cells invisible to the immune system. Translational challenges, such as the mixed efficacy of hypoxia-activated prodrugs, highlight the urgent need for robust diagnostics to accurately verify tumor microenvironment conditions. To restore therapeutic efficacy and mitigate the risks of ineffective treatments, a paradigm shift is necessary: integrating tumor microenvironment-targeted agents (such as hypoxia-inducible factor-2α inhibitors) with adaptive dosing strategies guided by real-time molecular monitoring, including liquid biopsies and hypoxia-PET imaging. This integrated strategy is essential for achieving durable patient outcomes.

晚期癌症肿瘤微环境的复杂性严重降低了化疗的活性，往往降低其疗效，使其固有的风险在临床上变得毫无根据。这篇综述“揭示”了肿瘤微环境是一个复杂的屏障系统，主要由缺氧驱动，即严重缺氧。低氧稳定主调控因子，包括低氧诱导因子-1α，积极诱导多药耐药。具体来说，缺氧诱导因子-1α通过外排泵协调药物从癌细胞中排出，增强药物诱导的DNA损伤的细胞修复，在功能上中和细胞毒性药物。肿瘤的异质性促进了侵袭性、逃避药物的亚克隆的选择，并且缺氧诱导了主要组织相容性复合体I类的降解，使癌细胞对免疫系统不可见，从而加剧了这种耐药性。翻译方面的挑战，如缺氧激活前药的混合疗效，突出了迫切需要可靠的诊断来准确验证肿瘤微环境条件。为了恢复治疗效果并降低无效治疗的风险，有必要进行范式转变：将肿瘤微环境靶向药物（如缺氧诱导因子-2α抑制剂）与实时分子监测指导下的适应性给药策略结合起来，包括液体活检和缺氧pet成像。这一综合战略对于实现持久的患者预后至关重要。

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引用次数: 0

Obacunone mitigates cisplatin-induced ototoxicity by activating CRHBP-mediated autophagy 欧诺酮通过激活crhbp介导的自噬来减轻顺铂诱导的耳毒性。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-27 DOI: 10.1016/j.bcp.2026.117759

Shaoqin Cen , Zhenxing Hou , Yuan Zhang , Nan Wang , Zihe Zhao , Ao Li , Guoqiang Wan , Tianhong Zhang , Xia Gao

Cisplatin, a widely used antitumor agent, is limited in clinical application due to its ototoxicity. This study investigates the protective effects of obacunone, an active compound from Phellodendron bark, against cisplatin-induced hearing loss. Obacunone significantly improved the survival of cisplatin-treated House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, preserved the cochlear explant, and enhanced auditory function in mice upon cisplatin treatment. Mechanistically, obacunone inhibited cisplatin-induced apoptosis by activating autophagy. Transcriptome profiling revealed that the expression of corticotropin-releasing hormone-binding protein (CRHBP) was increased in the cisplatin and obacunone co-treated group compared to the cisplatin-only group. Overexpression of CRHBP significantly enhanced autophagy and inhibited apoptosis, mirroring the effects of obacunone. Our findings demonstrate that obacunone promotes autophagy by upregulating CRHBP, thereby reducing cisplatin-induced hair cell apoptosis. This study provides a novel therapeutic strategy using the natural product obacunone for preventing cisplatin-induced hearing loss and highlights the potential of CRHBP as a target for otoprotective interventions.

顺铂是一种广泛应用的抗肿瘤药物，但由于其耳毒性而限制了临床应用。本研究探讨了黄柏树皮活性化合物欧考诺酮对顺铂性听力损失的保护作用。欧诺酮显著提高顺铂治疗小鼠的House Ear Institute-Organ of Corti 1 （HEI-OC1）细胞的存活率，保存耳蜗外植体，并增强顺铂治疗小鼠的听觉功能。机制上，奥库农酮通过激活自噬抑制顺铂诱导的细胞凋亡。转录组分析显示，与单用顺铂组相比，顺铂和欧诺酮联合治疗组促肾上腺皮质激素释放激素结合蛋白（CRHBP）的表达增加。过表达CRHBP可显著增强细胞自噬，抑制细胞凋亡，与欧诺酮的作用类似。我们的研究结果表明，欧诺酮通过上调CRHBP促进自噬，从而减少顺铂诱导的毛细胞凋亡。本研究提供了一种新的治疗策略，利用天然产物欧诺酮预防顺铂性听力损失，并强调了CRHBP作为耳保护干预靶点的潜力。

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引用次数: 0

Hypoxia-inducible factor-1α in cardiovascular disease, mechanistic insights, pathophysiological roles, and therapeutic targeting strategies 缺氧诱导因子-1α在心血管疾病中的作用、机制、病理生理作用和治疗靶向策略

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-25 DOI: 10.1016/j.bcp.2026.117753

Md Ataur Rahman , Khandoker Asiqur Rahaman , Abdel Halim Harrath , Mohammed Al-Zharani , Maroua Jalouli

Hypoxia-inducible factor-1α (HIF-1α) is a critical mediator of hypoxic response at the transcriptional level and an emerging player in cardiovascular disease (CVD). Under normoxic conditions, HIF-1α undergoes prolyl hydroxylase (PHD)-mediated hydroxylation, which promotes its recognition by the von Hippel-Lindau (VHL) E3 ubiquitin ligase and subsequent proteasomal degradation. In contrast, hypoxic conditions inhibit this degradation pathway, leading to stabilization of HIF-1α, its nuclear translocation, heterodimerization with HIF-1β, and activation of transcriptional programs that regulate angiogenesis, glycolysis, erythropoiesis, and cell survival. In various cardiovascular disease, including ischemic heart disease, myocardial infarction, heart failure, and pulmonary hypertension, HIF-1α exhibits a dual nature: while transient activation elicits adaptive responses (angiogenesis, metabolic reprogramming), sustained or dysregulated activation underlies maladaptive remodeling, fibrosis, and arrhythmogenesis. Recent studies have highlighted the promise of pharmacological modulators of HIF-1α (prolyl hydroxylase inhibitors, small natural chemicals, gene therapy, nanoparticles) to restore oxygen homeostasis and enable cardiac repair. However, concerns of off-target effects and carcinogenesis have yet to be overcome. In this review, we provide an up-to-date overview of HIF-1α signaling in the context of cardiac disease, including downstream effectors, disease pathogenesis, and potential therapeutic strategies. Targeting HIF-1α presents a promising strategy for cardiovascular therapies and warrants appropriate manipulation depending on the disease stage and environment.

缺氧诱导因子-1α (HIF-1α)在转录水平上是缺氧反应的关键介质，也是心血管疾病（CVD）的新兴参与者。在常氧条件下，HIF-1α经历脯氨酸羟化酶（PHD）介导的羟基化，促进其被von Hippel-Lindau (VHL) E3泛素连接酶识别并随后进行蛋白酶体降解。相反，缺氧条件抑制了这种降解途径，导致HIF-1α的稳定，其核易位，与HIF-1β的异源二聚体化，以及调节血管生成、糖酵解、红细胞生成和细胞存活的转录程序的激活。在各种心血管疾病中，包括缺血性心脏病、心肌梗死、心力衰竭和肺动脉高压，HIF-1α表现出双重性质：短暂激活引发适应性反应（血管生成、代谢重编程），持续或失调的激活可能导致适应性不良重塑、纤维化和心律失常。最近的研究强调了HIF-1α的药理学调节剂（脯氨酸羟化酶抑制剂、小天然化学物质、基因治疗、纳米颗粒）在恢复氧稳态和心脏修复方面的前景。然而，对脱靶效应和致癌性的担忧尚未克服。在这篇综述中，我们提供了心脏疾病背景下HIF-1α信号的最新综述，包括下游效应物、疾病发病机制和潜在的治疗策略。靶向HIF-1α是一种很有前途的心血管治疗策略，需要根据疾病分期和环境进行适当的操作。

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引用次数: 0

Diacerein protects against Ovariectomy-Induced bone loss via reversal of NRF2 epigenetic suppression 通过逆转NRF2表观遗传抑制，二乙酰黄素可预防卵巢切除术诱导的骨质流失。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-24 DOI: 10.1016/j.bcp.2026.117748

Liang Qiao , Tao Shen , Yu Ben , Jian Dong , Bin Liu , Xiang Chen , Qing Jiang

Osteoporosis (OP) is a prevalent degenerative musculoskeletal disorder in middle-aged and elderly populations, characterized by reduced bone mineral density and an increased risk of fragility fractures. Its pathogenesis is closely linked to oxidative stress imbalance; however, effective long-term therapeutic options remain limited. Here, we report that diacerein, a clinically used drug for osteoarthritis, significantly ameliorates OVX (ovariectomy)-induced bone loss and abnormal bone metabolism. Mechanistically, we demonstrate that diacerein activates the transcription and activity of NRF2 (nuclear factor erythroid 2–related factor 2), a central regulator of the antioxidant response, leading to the restoration of cytoprotective protein expression and thereby exerting protective effects against osteoporosis. The beneficial effects of diacerein on bone protection were largely abolished in Nfe2l2 knockout mice, further underscoring the essential role of NRF2. Further investigation revealed that diacerein is metabolized in vivo into rhein, which exerts potent epigenetic activity. The upregulation of NRF2 appears to be primarily mediated through rhein’s inhibition of DNA methyltransferases (DNMTs) 1 and 3a. In summary, our study suggests that diacerein, a drug with a well-established safety profile and suitability for long-term use, represents a promising therapeutic candidate for the treatment of osteoporosis.

骨质疏松症（OP）是一种在中老年人群中普遍存在的退行性肌肉骨骼疾病，其特征是骨密度降低和脆性骨折的风险增加。其发病机制与氧化应激失衡密切相关；然而，有效的长期治疗选择仍然有限。在这里，我们报道了临床上用于治疗骨关节炎的药物地粘素，可以显著改善卵巢切除术引起的骨质流失和骨代谢异常。在机制上，我们证明了二乙酰胆碱激活NRF2（核因子-红细胞2相关因子2）的转录和活性，NRF2是抗氧化反应的中心调节因子，导致细胞保护蛋白表达的恢复，从而对骨质疏松症发挥保护作用。在Nfe2l2基因敲除小鼠中，二肾上腺素对骨骼保护的有益作用在很大程度上被消除，进一步强调了NRF2的重要作用。进一步的研究表明，二糖苷在体内代谢为大黄酸，并发挥强大的表观遗传活性。NRF2的上调似乎主要是通过大黄酸抑制DNA甲基转移酶（dnmt） 1和3a介导的。总之，我们的研究表明，糖尿苷，一种具有良好安全性和长期使用适用性的药物，代表了治疗骨质疏松症的有希望的治疗候选药物。

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引用次数: 0