Medicine in Drug Discovery最新文献_第2页

Predictive intervention medicine: a ML/AI/big data-driven pathway toward better healthcare system in the future 预测干预医学：机器学习/人工智能/大数据驱动的未来更好的医疗保健系统

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-12-01 DOI: 10.1016/j.medidd.2025.100225

Jiayu Liao , Rui Zeng , Yiran Tao , Xing Wen , Liqiang Hu , Yueqiu Liu , Guizhi Du , Fan Zhang , Yulan Deng , Zhaoyuan Tang , Lunxu Liu , Jingqiu Cheng , Wei Zhang

The current healthcare system mainly focusses on disease treatments. However, at current time, many diseases either lacks reversible approaches and need life-time medicines, such as diabetes, or need high medical costs, such as cancers. The recent rapid developments in Big Data, Machine Learning(ML), and Artificial Intelligence(AI), it is possible to develop disease predictive models for early or pre-diseases, and then followed with effective interventions. The data used in this process can include multidimensional data, such as medical exam data, biochemical data, multiomics data, environmental data and geographic data as well as imaging data. The interventive approaches can vary too, such as life-style changes, nutrition modification, immune modulation and herb supplements. If these overall processes are well monitored and controlled, similar to current drug discovery/development process, it can form a new type of medical science-predictive interventive medicine. A major difference between the traditional preventive medicine and the predictive interventive medicine is that the predicted disease risk is associated with individual, not the population, in the latter case. The effective implementation of the predictive interventive medicine can bring multiple benefits to improve the current healthcare system. First, it can prevent and/or slow down disease progression of individuals; Second, the reduction of diseases of individuals can improve personal life quality and reduce burdens for the family; Third, most of interventive approaches are less expensive than therapeutics, therefore, can reduce financial pressure of medical cares for both individuals and governments. We therefore propose that the predictive interventive medicine can be an effective strategy for better healthcare in the future.

目前的医疗体系主要侧重于疾病治疗。然而，目前，许多疾病要么缺乏可逆的方法，需要终身用药，如糖尿病，要么需要高昂的医疗费用，如癌症。随着大数据、机器学习（ML）和人工智能（AI）的快速发展，开发疾病早期或疾病前期的预测模型，然后进行有效的干预成为可能。该过程中使用的数据可以包括多维数据，如医学检查数据、生化数据、多组学数据、环境数据和地理数据以及成像数据。干预方法也各不相同，如改变生活方式、调整营养、调节免疫和补充草药。如果这些整体过程得到很好的监测和控制，类似于目前的药物发现/开发过程，它可以形成一种新型的医学科学-预测介入医学。传统预防医学与预测性干预医学的一个主要区别是，后者预测的疾病风险与个人有关，而不是与人群有关。预测介入医学的有效实施可以为改善当前的医疗体系带来多重效益。首先，它可以预防和/或减缓个体的疾病进展；第二，减少个人疾病可以提高个人生活质量，减轻家庭负担；第三，大多数干预方法比治疗方法更便宜，因此可以减轻个人和政府的医疗保健财政压力。因此，我们建议预测介入医学可以成为未来更好的医疗保健的有效策略。

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引用次数: 0

Association of mitragynine levels with lipid profiles in regular kratom (Mitragyna speciosa) users 米特ragyna（米特ragyna speciosa）常规服用者脂质谱与米特ragynine水平的关系

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-11-29 DOI: 10.1016/j.medidd.2025.100241

Slamet Wahyono , Mery Budiarti , Lusi Kristiana , Aris Yulianto , Weny Lestari , Rohmat Mujahid , Agung Eru Wibowo , Lola Ayu Istifiani , Zulvikar Syambani Ulhaq

Kratom (Mitragyna speciosa) is widely consumed in Southeast Asia for both medicinal and recreational purposes, yet its impact on human health remains unclear. This study examined sociodemographic factors, consumption patterns, serum mitragynine (MG) levels, and clinical chemistry parameters among 90 male participants from the Putussibau District, West Kalimantan, Indonesia. Participants were categorized into kratom users (n = 64) and non-users (n = 26). The majority of users indicated that they consumed kratom for health-related reasons, most commonly for 2–5 years, and nearly half reported daily intake exceeding 21 leaves. Serum MG concentrations were significantly higher among users than non-users, although no associations were observed with duration or intensity of consumption. Clinical chemistry analysis revealed that kratom users had lower levels of LDL, BUN, urea, and creatinine, alongside higher eGFR values, while no significant differences were detected in liver enzymes, glucose, HDL, triglycerides, or inflammatory markers. Notably, serum MG was negatively correlated with LDL and triglyceride levels. Stratified analysis indicated that long-term use was associated with favorable hepatic and lipid profiles, suggesting possible adaptive metabolic responses, whereas higher daily intake produced mild, subclinical elevations in liver and renal markers. Additionally, systemic inflammation, reflected by increased hsCRP and IL-6, was linked to self-reported anxiety, highlighting a potential peripheral mechanism connecting kratom use to central nervous system (CNS) effects. Overall, these findings suggest that regular kratom use may elicit adaptive physiological changes with minimal biochemical perturbation at moderate intake levels. Further longitudinal and mechanistic studies are warranted to clarify causal pathways and long-term health implications of kratom use.

Kratom （Mitragyna speciosa）在东南亚广泛用于医疗和娱乐目的，但其对人类健康的影响尚不清楚。本研究调查了来自印度尼西亚西加里曼丹Putussibau地区的90名男性参与者的社会人口学因素、消费模式、血清米特拉金（MG）水平和临床化学参数。参与者被分为kratom使用者（n = 64）和非使用者（n = 26）。大多数使用者表示，他们食用克拉托姆是出于与健康有关的原因，最常见的是持续2-5年，近一半的人报告每日摄入量超过21片。血清MG浓度在服用者中明显高于非服用者，尽管没有观察到与服用时间或强度的关联。临床化学分析显示，kratom使用者的LDL、BUN、尿素和肌酐水平较低，eGFR值较高，而肝酶、葡萄糖、高密度脂蛋白、甘油三酯或炎症标志物没有显著差异。值得注意的是，血清MG与LDL和甘油三酯水平负相关。分层分析表明，长期服用与良好的肝脏和脂质特征相关，表明可能的适应性代谢反应，而每日摄入量较高会导致肝脏和肾脏标志物轻度亚临床升高。此外，hsCRP和IL-6升高所反映的全身性炎症与自我报告的焦虑有关，强调了将克拉通使用与中枢神经系统（CNS）作用联系起来的潜在外周机制。总的来说，这些发现表明，在适度摄入水平下，定期使用克拉通可能会引起适应性生理变化，而生化干扰最小。进一步的纵向和机制研究是必要的，以澄清因果途径和长期健康影响的克拉通使用。

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引用次数: 0

Fluoxetine promotes lysosome biogenesis via regulation of a RIOK2-TFEB axis 氟西汀通过调控RIOK2-TFEB轴促进溶酶体的生物发生

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-11-11 DOI: 10.1016/j.medidd.2025.100239

Lingxi Lin , Lihua Zhou , Rong Cang , Bing Han , Yang Li

Lysosomes are central to cellular proteostasis and metabolic homeostasis, and their dysfunction contributes to neurodegenerative and metabolic disorders. The transcription factor TFEB coordinates lysosomal biogenesis and autophagy through phosphorylation-dependent regulation. Based on our previous finding that the dopamine transporter inhibitor LH2-051 activates TFEB and enhances lysosomal biogenesis, we asked whether other neurotransmitter transporter inhibitors exert similar effects. Here, we identify fluoxetine, a selective serotonin reuptake inhibitor (SSRI), as a new modulator of the TFEB–lysosome axis. Fluoxetine promotes TFEB nuclear translocation and lysosomal gene expression independently of mTORC1, GSK3β, CDK9, or serotonergic signaling. Mechanistically, fluoxetine induces dephosphorylation of TFEB at Ser74 and Ser151 by inhibiting the atypical kinase RIOK2, revealing a previously unrecognized RIOK2–TFEB regulatory pathway. Fluoxetine-induced activation of TFEB enhances lysosome-dependent degradation of lipid droplets and pathogenic protein aggregates (Aβ, α-synuclein, and polyQ). These findings uncover a serotonin-independent biological action of fluoxetine and suggest that neurotransmitter transporter inhibitors may constitute a pharmacological class that can systemically enhance lysosomal function in neurodegenerative disease.

溶酶体是细胞蛋白平衡和代谢稳态的核心，其功能障碍导致神经退行性和代谢紊乱。转录因子TFEB通过磷酸化依赖性调节来协调溶酶体的生物发生和自噬。基于我们之前的发现，多巴胺转运蛋白抑制剂LH2-051激活TFEB并增强溶酶体的生物发生，我们想知道其他神经递质转运蛋白抑制剂是否也有类似的作用。在这里，我们发现氟西汀，一种选择性5 -羟色胺再摄取抑制剂（SSRI），作为tfeb -溶酶体轴的一种新的调节剂。氟西汀促进TFEB核易位和溶酶体基因表达，独立于mTORC1、GSK3β、CDK9或血清素能信号。在机制上，氟西汀通过抑制非典型激酶RIOK2诱导TFEB在Ser74和Ser151位点的去磷酸化，揭示了先前未被识别的RIOK2 - TFEB调控途径。氟西汀诱导的TFEB激活增强了溶酶体依赖的脂滴和致病蛋白聚集体（Aβ、α-突触核蛋白和polyQ）的降解。这些发现揭示了氟西汀不依赖于血清素的生物学作用，并提示神经递质转运抑制剂可能构成一个药理学类别，可以系统地增强神经退行性疾病的溶酶体功能。

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引用次数: 0

Repurposing oncology drugs for Alzheimer’s: multi-omic convergence targeting cell-cycle, proteostasis, immunometabolism, and senescence 重新利用肿瘤药物治疗阿尔茨海默病：针对细胞周期、蛋白质平衡、免疫代谢和衰老的多组学趋同

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-10-31 DOI: 10.1016/j.medidd.2025.100237

S.T. Gopukumar , Dyumn Dwivedi , K. Gowri , M. Karpakavalli , Chandralekha Nair , Dewang Singh , Uddalak Das

Alzheimer’s disease (AD), the predominant dementia etiology, imposes a $1.5 trillion global burden in 2025, exacerbated by inexorable failures in amyloid-tau-centric monotherapies amid < 1 % trial success rates. This review synthesizes cross-disciplinary pathobiology underpinning oncology drug repurposing for AD, leveraging inverse epidemiological antagonism and convergent hallmarks: aberrant neuronal cell-cycle re-entry, proteostasis, mTORC1 hyperactivation impairing lysosomal flux, kynurenine pathway-driven immunometabolic decoupling, PARP1-mediated NAD + parthanatos, maladaptive neuroinflammation, and senescence-associated secretory phenotype (SASP)-amplified gliosis. Computational nomination pipelines—transcriptomic signature reversal, network proximity in multi-omic knowledge graphs, and ligand-based docking—prioritize pleiotropic oncology agents: c-Abl/Src TKIs enhancing autophagic Aβ/tau clearance; multikinase modulators resolving mast cell-microglial dyshomeostasis; rapalogs restoring proteostasis; IDO1 antagonists normalizing astrocytic lactate shuttling; PARPi mitigating genomic instability; HDACi reinstating synaptic epigenomes; and senolytics purging senescent glia. Phase I/II trials evince biomarker modulation with geriatric-adapted dosing, yet underscore translational hurdles: BBB penetration, off-target liabilities, and polypharmacy in APOE ε4-enriched cohorts. A precision roadmap advocates orthogonal combinations, delivery-first PBPK modeling, and biomarker-anchored adaptive platforms to recalibrate AD’s networked trajectory toward disease-modifying efficacy.

阿尔茨海默病（AD）是主要的痴呆症病因，到2025年将给全球带来1.5万亿美元的负担，而以淀粉样蛋白为中心的单一疗法在1%的试验成功率中不可避免地失败，加剧了这一负担。这篇综述综合了支持肿瘤药物重新用于AD的跨学科病理生物学，利用逆流行病学拮抗和趋同特征：异常的神经元细胞周期再进入、蛋白质停滞、mTORC1过度激活损害溶酶体通量、犬尿氨酸途径驱动的免疫代谢解耦合、parp1介导的NAD + parthanatos、适应性不良的神经炎症和衰老相关分泌表型（SASP）扩增的胶质细胞增生。计算提名管道——转录组特征逆转、多组学知识图中的网络接近性和基于配体的对接——优先考虑多效肿瘤药物：c-Abl/Src TKIs增强自噬的Aβ/tau清除；多激酶调节剂解决肥大细胞-小胶质细胞失衡问题Rapalogs恢复蛋白质平衡；IDO1拮抗剂使星形细胞乳酸穿梭正常化；PARPi减轻基因组不稳定性；hdac恢复突触表观基因组；以及清除衰老神经胶质的抗衰老药物。I/II期试验证明了生物标志物调节与老年适应剂量，但强调了转化障碍：血脑屏障渗透，脱靶负荷和APOE ε4富集队列的多药。精确路线图提倡正交组合、交付优先的PBPK建模和生物标志物锚定的自适应平台，以重新校准AD的网络轨迹，以达到疾病改善疗效。

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引用次数: 0

Antioxidant and biocompatible CuO-starch/PVA nanoscaffolds via ultrasonic green synthesis using Turbinaria conoides (brown marine macroalgae) 超声波绿色合成具有抗氧化和生物相容性的cuo -淀粉/PVA纳米支架

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-10-28 DOI: 10.1016/j.medidd.2025.100238

Pooja Shree Sugumar , R Sivaramakrishnan , Gopalakrishnan Velliyur Kanniappan , Vijayalakshmi Pandurangan , Selvaraj Jayaraman , Vinoth Kumar Dhayalan , Monica Mironescu , Ion Dan Mironescu , Chella Perumal Palanisamy

This study reports, sustainable and biogenic synthesis of copper oxide nanoparticles (CuO NPs) using ultrasonic-assisted Turbinaria conoides aqueous extract and their incorporation into starch/polyvinyl alcohol (PVA) electrospun nanoscaffolds for biomedical applications. The biosynthesized CuO NPs exhibited characteristic surface plasmon resonance (SPR) at 270–300 nm and a monoclinic crystalline structure, as confirmed by UV–Vis spectroscopy and XRD analysis. FTIR spectra revealed successful CuO NPs-polymer interactions, while SEM imaging showed uniform nanofibers with well-dispersed CuO NPs. The nanocomposite scaffolds demonstrated enhanced thermal stability, with decomposition onset at 326.78 °C, and excellent biocompatibility (cell viability ≥ 100 % in MTT assays). The CuO-loaded scaffolds exhibited higher antioxidant activity (IC₅₀ ∼ 18 µg/mL) compared to bare NPs (IC₅₀ ∼ 28 µg/mL). Although zeta potential measurements indicated moderate colloidal stability (−11.39 mV), the overall results highlight the potential of these nanocomposite scaffolds for tissue engineering and therapeutic applications, particularly in wound healing and oxidative stress management. This green synthesis approach offers a sustainable platform for developing functional biomaterials.

本研究报道了利用超声辅助下的conoides水萃取物可持续合成氧化铜纳米粒子（CuO NPs），并将其加入淀粉/聚乙烯醇（PVA）静电纺丝纳米支架中用于生物医学应用。通过紫外可见光谱和x射线衍射分析证实，生物合成的CuO纳米粒子在270 ~ 300 nm处表现出特征性的表面等离子体共振（SPR）和单斜晶型结构。FTIR光谱显示CuO NPs与聚合物相互作用成功，而SEM成像显示CuO NPs分布良好，纳米纤维均匀。纳米复合材料支架表现出增强的热稳定性，在326.78°C时开始分解，并且具有良好的生物相容性（MTT试验中细胞存活率≥100%）。与裸NPs （IC50 ~ 28µg/mL）相比，负载cuo的支架具有更高的抗氧化活性（IC50 ~ 18µg/mL）。虽然zeta电位测量显示胶体稳定性适中（- 11.39 mV），但总体结果强调了这些纳米复合支架在组织工程和治疗应用方面的潜力，特别是在伤口愈合和氧化应激管理方面。这种绿色合成方法为开发功能性生物材料提供了一个可持续的平台。

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引用次数: 0

Shortcomings in the development of anti‑SARS-CoV-2 drugs: prioritizing medicinal chemistry efforts toward RdRp, 3CLpro, and PLpro inhibitors 抗SARS-CoV-2药物开发的不足：优先考虑RdRp、3CLpro和PLpro抑制剂的药物化学工作

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-10-26 DOI: 10.1016/j.medidd.2025.100236

Mehdi Valipour

引用次数: 0

Green Remedies: Pharmacological potential of phytonutrients for combatting air pollution-related respiratory diseases 绿色疗法：植物营养素对抗空气污染相关呼吸系统疾病的药理学潜力

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-10-24 DOI: 10.1016/j.medidd.2025.100235

Shobna L. Thuraisingam , Irene Heijink , Bey-Hing Goh , Yoon-Yen Yow

Millions of people die from air pollution each year, posing a worldwide threat to health. Hazardous gases such as nitrogen dioxide (NO₂) and particulate matter (PM) with aerodynamic dimensions of 10 µm (PM₁₀), 2.5 µm (PM_2.5) and 0.1 µm (PM_0.1) are examples of air pollutants which can travel deep into the airways and alveolar regions of the lungs. Inhalation of PM and other gaseous pollutants induces oxidative stress and damage in the airway epithelium, resulting in activation of pro-inflammatory responses and attraction of immune cells. This review discusses the prevalence and consequences of air pollutants on respiratory illnesses, emphasizing the necessity for effective treatments. It also spotlights promising natural products and their derived compounds, which have demonstrated favourable pharmacological properties in managing oxidative stress and inflammation, crucial contributors to respiratory diseases, based on a thorough analysis of existing literature. Among these, marine algae have emerged as a particularly rich source of bioactive compounds including sulfated polysaccharides, phlorotannins, carotenoids, and sterols that exhibit potent antioxidant, anti-inflammatory, and immunomodulatory effects. These algae-derived phytonutrients interact with key molecular targets and signalling pathways involved in airway inflammation, oxidative stress, immune responses, and airway remodelling.

Understanding the mechanism of PM induced lung pathology provides insights into the potential efficacy of natural products, especially marine algae, in managing respiratory conditions. The review also addresses challenges and limitations associated with the use of phytochemical compounds derived from natural products, including standardization, safety, and clinical translation. Through a deep understanding of their phytochemical makeup and underlying mechanisms, researchers and healthcare practitioners can investigate innovative therapeutic approaches and develop targeted interventions to improve respiratory health.

每年有数百万人死于空气污染，对全球健康构成威胁。空气动力学尺寸分别为10 μ m （PM10）、2.5 μ m （PM2.5）和0.1 μ m （PM0.1）的二氧化氮（NO2）和颗粒物（PM）等有害气体是可深入气道和肺部肺泡区域的空气污染物的例子。吸入PM和其他气态污染物可诱导气道上皮氧化应激和损伤，从而激活促炎反应和吸引免疫细胞。本文讨论了空气污染物对呼吸系统疾病的影响，强调了有效治疗的必要性。根据对现有文献的全面分析，它还重点介绍了有前途的天然产品及其衍生化合物，这些产品在控制氧化应激和炎症方面显示出有利的药理特性，而氧化应激和炎症是呼吸系统疾病的关键因素。其中，海洋藻类已成为生物活性化合物的特别丰富来源，包括硫酸盐多糖、绿单宁、类胡萝卜素和甾醇，它们具有强大的抗氧化、抗炎和免疫调节作用。这些藻类衍生的植物营养素与气道炎症、氧化应激、免疫反应和气道重塑中的关键分子靶点和信号通路相互作用。了解PM诱导的肺部病理机制，可以深入了解天然产物，特别是海藻在控制呼吸系统疾病方面的潜在功效。本综述还讨论了与使用源自天然产物的植物化学化合物相关的挑战和限制，包括标准化、安全性和临床翻译。通过深入了解它们的植物化学组成和潜在机制，研究人员和医疗从业者可以研究创新的治疗方法，并制定有针对性的干预措施，以改善呼吸系统健康。

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引用次数: 0

Molecular strategies in BRAF targeting: advances in patents, structure activity relationship and future prospects BRAF靶向的分子策略：专利进展、构效关系及未来展望

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-10-10 DOI: 10.1016/j.medidd.2025.100234

Purabi Saha , Jugnu Goyal , Shammy Jindal , Vikramdeep Monga , Kamya Goyal

BRAF, a serine or threonine protein kinase, plays a crucial role in the MAPK/ERK signaling pathway and is implicated in various malignancies, including melanoma, colorectal, lung, thyroid, and hematologic cancers. The V600E mutation is the most prevalent BRAF alteration, leading to constitutive kinase activation and uncontrolled cell proliferation. This review comprehensively discusses molecular strategies targeting BRAF, including structure–activity relationships (SARs), recent advancements in small-molecule inhibitors, and their clinical implications. FDA-approved some BRAF inhibitors, such as Encorafenib, Vemurafenib and Dabrafenib have significantly improved patient outcomes, particularly in melanoma. However, resistance mechanisms, including reactivation of MAPK signaling and alternate oncogenic pathways, pose therapeutic challenges. The development of next-generation inhibitors, combination therapies targeting MEK and ERK, and novel small molecules are promising approaches to overcoming resistance. This review further highlights recent patents, clinical trial data, and future prospects in BRAF-targeted therapies. Understanding the intricate signaling mechanisms and resistance pathways will aid in designing effective treatment strategies for BRAF-mutated cancers.

BRAF是一种丝氨酸或苏氨酸蛋白激酶，在MAPK/ERK信号通路中起着至关重要的作用，并与各种恶性肿瘤有关，包括黑色素瘤、结直肠癌、肺癌、甲状腺癌和血液癌。V600E突变是最常见的BRAF改变，导致组成型激酶激活和不受控制的细胞增殖。这篇综述全面讨论了靶向BRAF的分子策略，包括结构-活性关系（SARs）、小分子抑制剂的最新进展及其临床意义。fda批准的一些BRAF抑制剂，如Encorafenib、Vemurafenib和Dabrafenib，显著改善了患者的预后，特别是在黑色素瘤中。然而，耐药机制，包括MAPK信号的再激活和替代的致癌途径，给治疗带来了挑战。下一代抑制剂的开发、针对MEK和ERK的联合治疗以及新型小分子是克服耐药性的有希望的方法。这篇综述进一步强调了braf靶向治疗的最新专利、临床试验数据和未来前景。了解复杂的信号机制和耐药途径将有助于设计针对braf突变癌症的有效治疗策略。

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引用次数: 0

Determine interaction affinity changes of the SUMO E1 activating enzymes during SUMO activation using qFRET technology 使用qFRET技术测定SUMO E1激活酶在SUMO激活过程中的相互作用亲和力变化

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-10-05 DOI: 10.1016/j.medidd.2025.100233

Ling Jiang , Yiran Tao , Xin Wen , Jiayu Liao

The heterodimeric E1 complex, Aos1-Uba2, catalyzes the first adenylation activation of the SUMO1 peptide in the SUMOylation cascade. The reaction affinity and dynamics of the Aos1-Uba2 heterodimer during the first step activation have yet to be determined. The K_d for the Aos1-Uba2 interaction provides a unique perspective for the activation step of the ubiquitin-like protein conjugation cascade. Here, we report for the first time the determination of the Aos1 and Uba2 interaction dissociation constant (K_d) and kinetics using the qFRET assay. We also used the SPR method to verify the interaction K_d between Aos1 and Uba2. We also determined the kinetics changes of Aos1-Uba2 when SUMOs and ATP were added to the reaction in real time. The results showed that forming a thioester bond between SUMO1 and Uba2 increases the FRET signal, indicating that the E1 heterodimer is more stable and bound to each other in SUMO and ATP. These results suggest that the qFRET method can be used to determine protein interaction affinity changes and track real-time changes in protein conformation and dynamics changes during biochemical reactions.

异二聚体E1复合物Aos1-Uba2在SUMO1级联反应中催化SUMO1肽的第一个腺苷化激活。在第一步活化过程中，Aos1-Uba2异源二聚体的反应亲和力和动力学尚未确定。Aos1-Uba2相互作用的Kd为泛素样蛋白偶联级联的激活步骤提供了一个独特的视角。在这里，我们首次报道了使用qFRET测定Aos1和Uba2相互作用解离常数（Kd）和动力学。我们还使用SPR方法验证了Aos1与Uba2之间的相互作用Kd。我们还实时测定了在反应中加入sumo和ATP时Aos1-Uba2的动力学变化。结果表明，在SUMO1和Uba2之间形成硫酯键增加了FRET信号，表明E1异二聚体在SUMO和ATP中更稳定且相互结合。这些结果表明，qFRET方法可以用于确定蛋白质相互作用的亲和力变化，并实时跟踪生化反应过程中蛋白质构象的变化和动力学变化。

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引用次数: 0

Anle138b improves insulin resistance in mice and its possible signal pathways Anle138b改善小鼠胰岛素抵抗及其可能的信号通路

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-09-29 DOI: 10.1016/j.medidd.2025.100232

Shiwaner Chen , Qiuyun Ren , Jieling Chen , Xiaona Liu , Rongni Huang , Bing Huang , Naili Wei , Jie Wu

Insulin resistance (IR), a hallmark of metabolic syndrome, is characterized by diminished tissue sensitivity to insulin, leading to hyperglycemia, hyperinsulinemia, and strong associations with metabolic disorders, such as hypertension, obesity, and type 2 diabetes mellitus (T2DM). In this study, we investigated the therapeutic potential of anle138b, a highly active small-molecule compound derived from 3,5-diphenylpyridine (DPP), in treating IR. Using a C57BL/6J mouse model with stable metabolic dysfunction, induced by a high-fat diet, we demonstrate that anle138b treatment improved key metabolic parameters compared to controls. Specifically, anle138b reduced fasting blood glucose, serum triglycerides, total cholesterol, and fasting insulin levels, and improved HOMA-IR (homeostasis model assessment of IR) scores. Additionally, anle138b enhanced glucose tolerance and lowered elevated organ indices, including liver index and epididymal fat index. Histopathological analysis revealed morphological recovery of pancreatic acinar cells and hepatic cord architecture, along with reduced ectopic fat deposition. Mechanistically, qPCR and western blot analyses showed that anle138b downregulated the mRNA and protein expression of both SREBP-1c and ADRA2A in the pancreas, liver, and skeletal muscle. These findings suggest that anle138b ameliorates IR by modulating SREBP-1c- and ADRA2A-mediated signaling pathways. Given the growing need for novel hypoglycemic and lipid-lowering agents, anle138b represents a promising therapeutic candidate for metabolic disorders, offering a potential strategy to combat diabetes and IR.

胰岛素抵抗（IR）是代谢综合征的一个标志，其特征是组织对胰岛素的敏感性降低，导致高血糖、高胰岛素血症，并与代谢紊乱（如高血压、肥胖和2型糖尿病（T2DM））密切相关。在这项研究中，我们研究了anle138b，一种从3,5-二苯基吡啶（DPP）中衍生的高活性小分子化合物，在治疗IR中的治疗潜力。通过高脂饮食诱导的C57BL/6J小鼠稳定代谢功能障碍模型，我们证明与对照组相比，anle138b治疗改善了关键代谢参数。具体来说，anle138b降低了空腹血糖、血清甘油三酯、总胆固醇和空腹胰岛素水平，并改善了HOMA-IR（稳态模型评估IR）评分。此外，anle138b提高了葡萄糖耐量，降低了肝脏指数和附睾脂肪指数等器官指数。组织病理学分析显示胰腺腺泡细胞和肝索结构形态恢复，同时异位脂肪沉积减少。机制上，qPCR和western blot分析显示，anle138b下调了SREBP-1c和ADRA2A在胰腺、肝脏和骨骼肌中的mRNA和蛋白表达。这些发现表明anle138b通过调节SREBP-1c-和adra2a介导的信号通路来改善IR。鉴于对新型降糖药和降脂药的需求日益增长，anle138b代表了代谢紊乱的有希望的治疗候选药物，为对抗糖尿病和IR提供了潜在的策略。

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引用次数: 0