A Bridged Phase 1, Randomized, Double-blind, Placebo-controlled Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of TBN in Healthy Subjects

The purpose of this study is to assess the safety, tolerability and pharmacokinetics (i.e. how study drug is taken up by the body) of TBN in healthy participants.

开始日期2024-12-15

申办/合作机构

广州喜鹊医药有限公司

CTR20232004 / Recruiting临床1期

单中心、开放、单次给药试验评价硝酮嗪片在肾功能不全和健康受试者中药代动力学特征

主要试验目的：评估不同程度肾功能不全受试者及健康受试者单次口服硝酮嗪片，对硝酮嗪及其主要代谢产物药代动力学特征的影响。次要试验目的：评估单次口服硝酮嗪片在不同程度肾功能不全受试者、健康青中年受试者和健康老年受试者中的安全性及耐受性。

开始日期2023-08-24

申办/合作机构

广州喜鹊医药有限公司

CTR20212371 / Completed临床1期

注射用硝酮嗪在健康受试者中的安全性、耐受性及药代动力学研究

1. 评价健康受试者对单次或多次给予高剂量注射用硝酮嗪的安全性和耐受性； 2. 评价单次或多次给予高剂量注射用硝酮嗪后，硝酮嗪及其主要代谢产物在健康受试者体内的药代动力学特征。

开始日期2021-09-23

申办/合作机构

广州喜鹊医药有限公司

100 项与 Nrf2 x mTORC1 x AMPK 相关的临床结果

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100 项与 Nrf2 x mTORC1 x AMPK 相关的转化医学

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0 项与 Nrf2 x mTORC1 x AMPK 相关的专利（医药）

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项与 Nrf2 x mTORC1 x AMPK 相关的文献（医药）

2025-01-01·Behavioural Brain Research

Emerging targets in amyotrophic lateral sclerosis (ALS): The promise of ATP-binding cassette (ABC) transporter modulation

Review

作者: Mannan, Ashi ; Mohan, Maneesh ; Nauriyal, Aayush ; Singh, Thakur Gurjeet

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative primarily affecting motor neurons, leading to disability and neuronal death, and ATP-Binding Cassette (ABC) transporter due to their role in drug efflux and modulation of various cellular pathways contributes to the pathogenesis of ALS. In this article, we extensively investigated various molecular and mechanistic pathways linking ALS transporter to the pathogenesis of ALS; this involves inflammatory pathways such as Mitogen-Activated Protein Kinase (MAPK), Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/Akt), Toll-Like Receptor (TLR), Glycogen Synthase Kinase 3β (GSK-3β), Nuclear Factor Kappa-B (NF-κB), and Cyclooxygenase (COX). Oxidative pathways such as Astrocytes, Glutamate, Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Sirtuin 1 (SIRT-1), Forkhead box protein O (FOXO), Extracellular signal-regulated kinase (ERK). Additionally, we delve into the role of autophagic pathways like TAR DNA-binding protein 43 (TDP-43), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and lastly, the apoptotic pathways. Furthermore, by understanding these intricate interactions, we aim to develop novel therapeutic strategies targeting ABC transporters, improving drug delivery, and ultimately offering a promising avenue for treating ALS.

2024-10-31·The FASEB Journal

Sestrin2 serves as a scaffold protein to maintain cardiac energy and metabolic homeostasis during pathological stress

Review

作者: Patterson, Cory ; Filho, Fernanda ; Nguyen, Jennie D. ; Adenawoola, Michael I. ; Wang, Hao ; Rouhi, Nadiyeh ; Li, Ji ; Slotabec, Lily ; Seale, Blaise

AbstractCardiovascular diseases (CVDs) are a leading cause of morbidity and mortality worldwide. Metabolic imbalances and pathological stress often contribute to increased mortality. Sestrin2 (Sesn2) is a stress‐inducible protein crucial in maintaining cardiac energy and metabolic homeostasis under pathological conditions. Sesn2 is upregulated in response to various stressors, including oxidative stress, hypoxia, and energy depletion, and mediates multiple cellular pathways to enhance antioxidant defenses, promote autophagy, and inhibit inflammation. This review explores the mechanisms through which Sesn2 regulates these pathways, focusing on the AMPK‐mTORC1, Sesn2‐Nrf2, and HIF1α‐Sesn2 pathways, among others. We can identify the potential therapeutic targets for treating CVDs and related metabolic disorders by comprehending these complex mechanisms. Sesn2's unique ability to respond thoroughly to metabolic challenges, oxidative stress, and inflammation makes it a promising prospect for enhancing cardiac health and resilience against pathological stress.

2024-09-01·Biochemical and Biophysical Research Communications

Tetramethylpyrazine nitrone delays the aging process of C. elegans by improving mitochondrial function through the AMPK/mTORC1 signaling pathway

Article

作者: Zhang, Zaijun ; Wang, Yuqiang ; Jing, Mei ; Yi, Peng ; Zhang, Ting ; Fei, Lili ; Sun, Yewei

Aging is characterized as the process of functional decline in an organism from adulthood, often marked by a progressive loss of cellular function and systemic deterioration of multiple tissues. Among the numerous molecular, cellular, and systemic hallmarks associated with aging, mitochondrial dysfunction is considered one of the pivotal factors that initiates the aging process. During aging, mitochondria undergo varying degrees of damage, resulting in impaired energy production and disruption of the homeostatic regulation of mitochondrial quality control systems, which in turn affects cellular energy metabolism and results in cellular dysfunction, accelerating the aging process. AMP-activated protein kinase (AMPK) and the mechanistic target of rapamycin complex 1 (mTORC1) are two central kinase complexes responsible for sensing intracellular nutrient levels, regulating metabolic homeostasis, modulating aging and play a crucial role in maintaining the homeostatic balance of mitochondria. Our previous studies found that the novel compound tetramethylpyrazine nitrone (TBN) can protect mitochondria via the AMPK/mTOR pathway in many animal models, extending healthy lifespan through the Nrf2 signaling pathway in nematodes. Building upon this foundation, we have posited a reasonable hypothesis, TBN can improve mitochondrial function to delay aging by regulating the AMPK/mTORC1 signaling pathway. This study focuses on the C. elegans, exploring the impact and underlying mechanisms of TBN on aging and mitochondrial function (especially the mitochondrial quality control system) during the aging process. The present studies demonstrated that TBN extends lifespan of wild-type nematodes and is associated with the AMPK/mTORC1 signaling pathway. TBN elevated ATP and NAD⁺ levels in aging nematodes while orchestrating mitochondrial biogenesis and mitophagy. Moreover, TBN was observed to significantly enhance normal activities during aging in C. elegans, such as mobility and pharyngeal pumping, concurrently impeding lipofuscin accumulation that were closely associated with AMPK and mTORC1. This study not only highlights the delayed effects of TBN on aging but also underscores its potential application in strategies aimed at improving mitochondrial function via the AMPK/mTOR pathway in C. elegans.

项与 Nrf2 x mTORC1 x AMPK 相关的新闻（医药）

2024-04-10

·E药经理人

喜鹊医药1类创新药物TBN可改善肌肉衰老与运动障碍 | 最新研究成果

广州2024年4月7日讯2024年3月，国际学术期刊《Biomedicine & Pharmacotherapy》刊登了喜鹊医药核心研发团队成员王玉强教授、张在军博士、孙业伟博士、张高小博士与暨南大学药学院、深圳市疾病预防控制中心深圳市现代毒理学重点实验室等多家机构成员合作研究的最新成果。该成果以《Tetramethylpyrazine Nitrone alleviates D-galactose-induced murine skeletal muscle aging and motor deficits by activating the AMPK signaling pathway》为题，详细揭示了喜鹊医药自主研发的1类创新药物硝酮嗪(TBN)在改善肌肉衰老、运动障碍及增强线粒体功能等方面的积极效果。研究团队采用D-半乳糖诱导的小鼠模型，深入研究了TBN对肌肉衰老和运动障碍的药效及作用机理。研究结果显示，TBN能够逆转包括p16、p21、鞘磷脂和端粒长度在内的多种衰老标志物水平，并增加腓肠肌组织重量，展示出改善肌肉衰老的显著药效。此外，通过对小鼠进行步态分析、爬杆测试和拉力测试等行为学评估，研究团队进一步发现了TBN在改善小鼠运动障碍方面的显著作用。同时，TBN对肌肉纤维化、炎症反应和线粒体功能的积极调节作用也在研究中得到了充分验证。TBN是中药川芎活性成分川芎嗪经化学结构修饰后得到的全新化学药物，由喜鹊医药创始人王玉强教授及其团队自主设计开发，具有多功能作用机理。TBN能够穿透血脑屏障，有效抑制钙离子超载、高效清除自由基、抑制炎症，并能够通过激活AMPK/PGC-1/Nrf2/HO-1信号通路显著增强线粒体功能，促进ATP的产生。此外，TBN还能通过抑制mTOR激活自噬通路，有效清除受损细胞组分和毒性蛋白。得益于新颖独特的作用机理，喜鹊医药TBN在包括本研究在内的多项与年龄及运动功能相关疾病的研究中展现出了很大的应用潜力，并在治疗缺血性脑卒中(AIS)、糖尿病肾病(DKD)和肌萎缩性侧索硬化症(ALS)等多项临床研究中取得了关键性进展，推进至临床II/III期阶段。特别值得一提的是，喜鹊医药近期完成的TBN治疗ALS的临床II期的试验结果显示，TBN治疗显著延缓ALS患者握力下降(P=0.037)，为患者运动功能带来了实质性的改善。推荐阅读：硝酮嗪能否解冻 ALS在人口老龄化趋势日益加剧的背景下，老年疾病的治疗与预防已成为社会关注的焦点，本项研究成果为解决肌肉衰老和运动障碍的治疗难题提供了新的视角和治疗策略，有望为相关患者带来福音。喜鹊医药将继续对TBN进行深入研究，挖掘其在改善衰老和运动障碍方面的潜力，为健康报喜。关于喜鹊医药广州喜鹊医药有限公司(简称喜鹊医药)是由国际知名药物化学家王玉强教授创办的临床阶段“First-in-Class”创新药物研究开发企业。秉持“求真务实，临床需求导向”的价值理念，基于小分子创新药物研究开发平台，喜鹊医药已经在心、脑血管及中枢神经系统疾病领域布局多条具有国际市场前景的药物管线，其中脑卒中(AIS)、糖尿病肾病(DKD)和肌萎缩侧索硬化(ALS)即将开展III期临床试验，另有II期临床项目7项，美国临床批件2项。喜鹊医药先后获得7项国家“新药创制”重大专项，获评广州市创业领军团队、广东省心脑血管与神经退行性疾病创新化学药物研发工程技术研究中心、第十届中国创新创业大赛生物医药组全国第二名等荣誉；喜鹊医药及其子公司已累计申请国内外专利90余项，已授权60余项，PCT专利20余项；与十余所高校、科研院所及百余家临床研究机构建立了合作关系。喜鹊医药已完成多轮融资，获得了包括仙瞳资本、康恩贝集团、中银粤财、科金控股等专业机构的持续支持。厚积薄发，喜鹊医药将持续为满足临床未满足需求而努力，为千万家庭之健康报喜。

临床2期