作者: Yue, Zejun ; Zheng, Nanbo ; Bai, Liang ; Wang, Rong ; Ren, Lingxuan ; Zhang, Yirong ; Liu, Enqi ; Wang, Weirong ; Zhao, Sihai ; Zhang, Wei ; Rong, XiaoYu ; Wen, Jiazeng

INTRODUCTIONKaempferol (KAE) is a flavonoid found in various plants. Recent studies showed that high dietary intake of KAE was associated with a lower risk of myocardial infarction; however, the cardioprotective mechanism of KAE remains unknown.OBJECTIVESTo determine the effect of KAE on cardiac injury in isoproterenol (ISO)-induced rats and cobalt chloride (CoCl₂)-treated cardiomyocytes, and the underlying mechanisms.METHODSMale rats were pretreated with different doses of KAE for 14 days, and then injected with ISO to induce myocardial ischemia injury. We also established a model of myocardial cell injury using rat H9c2 cardiomyocytes stimulated with CoCl₂.RESULTSWe found that KAE pretreatment significantly alleviated myocardial injury and improved cardiac function in ISO-injected rats. In addition, KAE reduced oxidative stress in rats with myocardial ischemia by decreasing malondialdehyde concentration and increasing superoxide dismutase activity, and protection of the myocardial mitochondrial structure. KAE also attenuated CoCl₂-induced injuryof H9c2 cardiomyocytes via suppression ofoxidative stress. With regard to the mechanism, we found that KAE down-regulated HDAC3 expression and up-regulated Nrf2 expression in ISO-induced rats and CoCl₂-stimulated cardiomyocytes. Incubation of cardiomyocytes with HDAC3-selective inhibitor RGFP966 augmented the protective effect of KAE and reduced oxidative stress. By contrast, HDAC3 overexpression by adenovirus attenuated the effect of KAE on oxidative stress compared with KAE treatment group. HDAC3 also regulated Nrf2 expression in the cardiomyocytes with RGFP966 or an adenovirus overexpressing HDAC3; but Nrf2 inhibition reduced the effect of KAE on ROS generation in CoCl₂-induced cardiomyocytes. Immunoprecipitation assay showed that HDAC3 interacted with Nrf2 in cardiomyocytes. Further studies found that KAE increased the acetylation level of Nrf2, while HDAC3 overexpression decreased the acetylation of Nrf2 compared with KAE treatment group.CONCLUSIONOur data show that KAE ameliorates cardiac injury by reducing oxidative stress via the HDAC3-mediated Nrf2 signaling pathway in cardiomyocytes.

2024-08-02·International journal of biological macromolecules

Biohybrid hydrogel inhibiting β-klotho/HDAC3 axis for hepatocellular carcinoma treatment.

Article

作者: Qiu, Junlan ; Zhu, Xinhua ; Ren, Haozhen ; Qiu, Mengdi ; Wen, Gaolin ; Xue, Lingling

Hepatocellular carcinoma (HCC), ranking as the fourth most prevalent cancer globally, has garnered significant attention due to its high invasiveness and mortality rates. However, drug therapies face challenges of inadequate efficacy and unclear mechanisms. Here, we propose a novel biohybrid hydrogel that targets β-klotho (KLB) for HCC treatment. As a dual-network hydrogel, this gel combines gelatin methacryloyl (GelMA) and polyvinyl alcohol (PVA) to ensure biocompatibility while enhancing controlled drug release. Notably, it exhibits good storage stability, high drug load capacity, and efficient water absorption. By introducing the HDAC3 inhibitor RGFP966, we can selectively inhibit the activation of KLB. This deactivation effectively blocks the FGF21-KLB signaling pathway and inhibits the progression of HCC. Importantly, we have successfully validated this unique phenomenon both in vivo and in vitro, providing substantial evidence for the efficacy of this hydrogel-based anti-tumor drug delivery system as a promising strategy for HCC treatment. This innovative research outcome brings new hope to the field of tumor therapy, providing a reliable theoretical foundation for future clinical applications.

2024-05-31·The FASEB Journal

Histone deacetylase‐3 regulates the expression of the amyloid precursor protein and its inhibition promotes neuroregenerative pathways in Alzheimer's disease models

Article

作者: Taylor, Ben ; Abelleira-Hervas, Laura ; Syed, Nelofer ; Sastre, Magdalena ; Di Giovanni, Simone ; Davis, Nicola ; Aleksynas, Robertas ; Karimian-Marnani, Najmeh ; Palmisano, Ilaria

AbstractHDAC3 inhibition has been shown to improve memory and reduce amyloid‐β (Aβ) in Alzheimer's disease (AD) models, but the underlying mechanisms are unclear. We investigated the molecular effects of HDAC3 inhibition on AD pathology, using in vitro and ex vivo models of AD, based on our finding that HDAC3 expression is increased in AD brains. For this purpose, N2a mouse neuroblastoma cells as well as organotypic brain cultures (OBCSs) of 5XFAD and wild‐type mice were incubated with various concentrations of the HDAC3 selective inhibitor RGFP966 (0.1–10 μM) for 24 h. Treatment with RGFP966 or HDAC3 knockdown in N2a cells was associated with an increase on amyloid precursor protein (APP) and mRNA expressions, without alterations in Aβ42 secretion. In vitro chromatin immunoprecipitation analysis revealed enriched HDAC3 binding at APP promoter regions. The increase in APP expression was also detected in OBCSs from 5XFAD mice incubated with 1 μM RGFP966, without changes in Aβ. In addition, HDAC3 inhibition resulted in a reduction of activated Iba‐1‐positive microglia and astrocytes in 5XFAD slices, which was not observed in OBCSs from wild‐type mice. mRNA sequencing analysis revealed that HDAC3 inhibition modulated neuronal regenerative pathways related to neurogenesis, differentiation, axonogenesis, and dendritic spine density in OBCSs. Our findings highlight the complexity and diversity of the effects of HDAC3 inhibition on AD models and suggest that HDAC3 may have multiple roles in the regulation of APP expression and processing, as well as in the modulation of neuroinflammatory and neuroprotective genes.

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适应症	最高研发状态	国家/地区	公司	日期
地中海贫血	临床前	英国	MRC Laboratory of Molecular Biology	2017-09-01
地中海贫血	临床前	澳大利亚	University of Melbourne	2017-09-01
地中海贫血	临床前	英国	University of Oxford	2017-09-01
阿尔茨海默症	临床前	美国	Rutgers State University of New Jersey	-