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.

2024-04-01·Nature Neuroscience

A phenotypic screening platform for identifying chemical modulators of astrocyte reactivity

Article

作者: Sas, Andrew R ; Segal, Benjamin M ; Allan, Kevin C ; Miller, Robert H ; Karl, Molly ; Cohn, Erin F ; Kerr, Alexis ; Jerome, Andrew D ; Kristell, James D ; Garrison, Eric ; Sturno, Annalise M ; Clayton, Benjamin L L ; Shick, H Elizabeth ; Tesar, Paul J ; Sepeda, Jesse A ; Maeno-Hikichi, Yuka ; Freundt, Eric C

Disease, injury and aging induce pathological reactive astrocyte states that contribute to neurodegeneration. Modulating reactive astrocytes therefore represent an attractive therapeutic strategy. Here we describe the development of an astrocyte phenotypic screening platform for identifying chemical modulators of astrocyte reactivity. Leveraging this platform for chemical screening, we identify histone deacetylase 3 (HDAC3) inhibitors as effective suppressors of pathological astrocyte reactivity. We demonstrate that HDAC3 inhibition reduces molecular and functional characteristics of reactive astrocytes in vitro. Transcriptional and chromatin mapping studies show that HDAC3 inhibition disarms pathological astrocyte gene expression and function while promoting the expression of genes associated with beneficial astrocytes. Administration of RGFP966, a small molecule HDAC3 inhibitor, blocks reactive astrocyte formation and promotes neuroprotection in vivo in mice. Collectively, these results establish a platform for discovering modulators of reactive astrocyte states, inform the mechanisms that control astrocyte reactivity and demonstrate the therapeutic benefits of modulating astrocyte reactivity for neurodegenerative diseases.

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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	-