An Interventional, Randomised, Double-blind, Parallel-group, Placebo-controlled, Flexible-dose, Adaptive Study of the Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease

The primary objective of the FALCON study is to evaluate the efficacy of KL1333 on selected disease manifestations of primary mitochondrial disease (PMD) following 48 weeks of treatment. This objective involves evaluating the efficacy of KL1333 versus placebo on fatigue symptoms and impacts on daily living as well as on functional lower extremity strength and endurance. Additionally, the study evaluates the safety and tolerability of KL1333.

开始日期2022-12-13

申办/合作机构

Abliva AB

NCT04643249 / Completed临床1期

A Phase I, Open-label, Fixed-sequence, Crossover, Drug-drug Interaction Study to Investigate the Inhibition Potential of KL1333 on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in Healthy Subjects

开始日期2020-11-10

申办/合作机构

Abliva AB

100 项与 NQO1 x NAD+ 相关的临床结果

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100 项与 NQO1 x NAD+ 相关的转化医学

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0 项与 NQO1 x NAD+ 相关的专利（医药）

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项与 NQO1 x NAD+ 相关的文献（医药）

2024-08-12·Biomacromolecules

Enzyme-Triggered Degradation of Supramolecularly Cross-Linked Polymersomes of Azobenzene-Based Polyurethane: Cell-Selective Anticancer Drug Release

Article

作者: De, Priyadarsi ; Bag, Sagar ; Molla, Mijanur Rahaman ; Mondal, Arun ; Kolay, Soumya ; Das, Madhuchhanda ; Sengupta, Arunima

Enzyme-responsive self-assembled nanostructures for drug delivery applications have gained a lot of attention, as enzymes exhibit dysregulation in many disease-associated microenvironments. Azoreductase enzyme levels are strongly elevated in many tumor tissues; hence, here, we exploited the altered enzyme activity of the azoreductase enzyme and designed a main-chain azobenzene-based amphiphilic polyurethane, which self-assembles into a vesicular nanostructure and is programmed to disassemble in response to a specific enzyme, azoreductase, with the help of the nicotinamide adenine dinucleotide phosphate (NADPH) coenzyme in the hypoxic environment of solid tumors. The vesicular nanostructure sequesters, stabilizes the hydrophobic anticancer drug, and releases the drug in a controlled fashion in response to enzyme-triggered degradation of azo-bonds and disruption of vesicular assembly. The biological evaluation revealed tumor extracellular matrix pH-induced surface charge modulation, selective activated cellular uptake to azoreductase overexpressed lung cancer cells (A549), and the release of the anticancer drug followed by cell death. In contrast, the benign nature of the drug-loaded vesicular nanostructure toward normal cells (H9c2) suggested excellent cell specificity. We envision that the main-chain azobenzene-based polyurethane discussed in this manuscript could be considered as a possible selective chemotherapeutic cargo against the azoreductase overexpressed cancer cells while shielding the normal cells from off-target toxicity.

2024-07-01·Phytomedicine

Shenling Baizhu powder alleviates non-alcoholic fatty liver disease by modulating autophagy and energy metabolism in high-fat diet-induced rats

Article

作者: Pi, Dajin ; Song, Qingliang ; Pan, Maoxing ; Deng, Yuanjun ; Yan, Haizhen ; Pan, Jinyue ; Liang, Zheng ; Qiu, Yebei ; Zhen, Jianwei ; Fan, Wen ; Li, Yuanyou ; Zhang, Yupei ; Zheng, Chuiyang ; Yang, Qinhe

BACKGROUNDNon-alcoholic fatty liver disease (NAFLD) has emerged as a burgeoning health problem worldwide, but no specific drug has been approved for its treatment. Shenling Baizhu powder (SL) is extensively used to treat NAFLD in Chinese clinical practice. However, the therapeutic components and pharmacological mechanisms of SL against NAFLD have not been thoroughly investigated.PURPOSEThis study aimed to investigate the pharmacological impact and molecular mechanism of SL on NAFLD.METHODSFirst, we established an animal model of NAFLD by high-fat diet (HFD) feeding, and evaluated the therapeutic efficacy of SL on NAFLD by physiological, biochemical, pathological, and body composition analysis. Next, the effect of SL on autophagic flow in NAFLD rats was evaluated by ultrastructure, immunofluorescence staining, and western blotting. Moreover, an integrated strategy of targeted energy metabolomics and network pharmacology was performed to characterize autophagy-related genes and explore the synergistic effects of SL active compounds. UPLC-MS/MS, molecular docking combined with in vivo and in vitro experiments were conducted to verify the key compounds and genes. Finally, a network was established among SL-herb-compound-genes-energy metabolites-NAFLD, which explains the complicated regulating mechanism of SL on NAFLD.RESULTSWe discovered that SL decreased hepatic lipid accumulation, hepatic steatosis, and insulin resistance, and improved systemic metabolic disorders and pathological abnormalities. Subsequently, an integrated strategy of targeted energy metabolomics and network pharmacology identified quercetin, ellagic acid, kaempferol, formononetin, stigmasterol, isorhamnetin and luteolin as key compounds; catalase (CAT), AKT serine/threonine kinase 1 (AKT), nitric oxide synthase 3 (eNOS), NAD(P)H quinone dehydrogenase 1 (NQO1), heme oxygenase 1 (HO-1) and hypoxia-inducible factor 1 subunit alpha (HIF-1α) were identified as key genes; while nicotinamide adenine dinucleotide phosphate (NADP) and succinate emerged as key energy metabolites. Mechanistically, we revealed that SL may exert its anti-NAFLD effect by inducing autophagy activation and forming a comprehensive regulatory network involving key compounds, key genes, and key energy metabolites, ultimately alleviating oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction.CONCLUSIONOur study demonstrated the therapeutic effect of SL in NAFLD models, and establishes a basis for the development of potential products from SL plant materials for the treatment of NAFLD.

2024-01-01·Chinese Journal of Natural Medicines

Discovery of proqodine A derivatives with antitumor activity targeting NAD(P)H: quinone oxidoreductase 1 and nicotinamide phosphoribosyltransferase

Article

作者: Xue, Jiayu ; Zhang, Bo ; Zhu, Ya ; Song, Jiangzhou ; Zou, Guiqing ; Ao, Lanjia ; Xu, Xiaowei ; Zhao, Zhou ; Hao, Haiping ; Sun, Huiyong

NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavin protease highly expressed in various cancer cells. NQO1 catalyzes a futile redox cycle in substrates, leading to substantial reactive oxygen species (ROS) production. This ROS generation results in extensive DNA damage and elevated poly (ADP-ribose) polymerase 1 (PARP1)-mediated consumption of nicotinamide adenine dinucleotide (NAD⁺), ultimately causing cell death. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD⁺ salvage synthesis pathway, emerges as a critical target in cancer therapy. The concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD⁺ depletion. In this study, we designed, synthesized, and assessed a novel series of proqodine A derivatives targeting both NQO1 and NAMPT. Among these, compound T8 demonstrated potent antitumor properties. Specifically, T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and NAMPT. This discovery offers a promising new molecular entity for advancing anticancer research.