Background Alzheimer's disease (AD) is a degenerative neurological disorder. Recent studies have indicated that histone deacetylases (HDACs) are among the most prominent epigenetic therapy targets and that HDAC inhibitors have therapeutic effects on AD. Here, we identified sodium valproate (VPA), a pan-HDAC inhibitor, and WT161, a novel HDAC6 selective inhibitor, as potential therapeutic agents for AD. Underlying molecular mechanisms were investigated. Methods A cellular model, N2a-APPswe, was established via lentiviral infection, and the APPswe/PSEN1dE9 transgenic mouse model was employed in the study. Western blotting, immunohistochemical staining, thioflavin-S staining, and ELISA were applied to detect protein expression in cells, tissues, or serum. RNA interference was utilized to knockdown the expression of specific genes in cells. The cognitive function of mice was assessed via the nest-building test, novel object recognition test, and Morris water maze test. Results Previous studies have focused mainly on the impact of HDAC inhibitors on histone deacetylase activity. Our study discovered that VPA and WT161 can downregulate the expression of multiple HDACs, such as HDAC1 and HDAC6, in both AD cell and mouse models. Moreover, they also affect the expression of APP and APP secretases (BACE1, PSEN1, ADAM10). RNA interference and subsequent vitamin C induction further confirmed that the expression of APP and APP secretases is indeed regulated by HDAC1 and HDAC6, with the JNK pathway being the intermediate link in this regulatory process. Through the above pathways, VPA and WT161 effectively reduced Aβ deposition in both AD cell and mouse models and significantly improved cognitive function in AD mice. Conclusions In general, we have discovered that the HDAC6-JNK-APP secretases cascade is an important pathway for VPA and WT161 to exert their therapeutic effects on AD. Investigations into the safety and efficacy of VPA and WT161 were also conducted, providing essential preclinical evidence for assessing these two epigenetic drugs for the treatment of AD.

Background Intestinal epithelial barrier dysfunction is a major pathological feature of inflammatory bowel disease (IBD). Stability and accuracy of intestinal epithelial cells (IECs) self-renew are the fundament of intestinal mucosal regeneration and repair. Fermentable dietary fibre and short-chain fatty acid (SCFA) play a role in cell proliferation, histone acetylation and immune responses. However, the results about SCFA modulating IECs proliferation are not coincided. There are several reason that SCFA can have an impact on IECs through immune cell in animal experiment and that also include animal gene background, SCFA concentration, cell types used in cell experiment l. So we adopted intestinal organoids to investigate the effect of butyrate on IECs self-renew to avoid the immune cell influence and signal type cell experiments limitation. Methods Six to 8 weeks wide-type mice and IL10−/− mice were used. Mouse intestinal crypt isolation and organoid culture were according to previously published methods (H. Clevers et al., Gastroenterology 2011). Re-suspended isolated ISCs were seeded onto 10 ml MatrigelTM (Corning 356237) in CellCarrier-96 Ultra Microplates per well (Perkinelmer 6055302). Sodium butyrate (SB) was administered at a final concentration (from 0 to 0.2mM) at Day1. Organoids’ cross-sectional area was measured and calculated, as well as all images were captured using an Operetta High-Content Imaging System and Harmony software 4.8. Results SB promoted intestinal organoids proliferation in a narrow effective concentration from 0.02 to 0.09 mM (Figure 1). The effective SB concentration applied to WT mice-derived organoids other than IL10−/− mice-derived organoids. SB can effectively and rapidly promote organoid proliferation (Figures 2 and 4). SB can continuously promote the proliferation of organoids-derived organoids (Figures 3 and 4). Conclusion There is a narrow effective SB concentrationpromotes WT mice-derived organoids other than IL10−/− mice-derived organoids. This result may be used to illustrate the phenomenon that IBD-associated microbiota and metabolites, butyrate, has different effects on IBD patient and IBD model mice.