Fig. 3: Vorinostat treatment of Rett tadpoles restores ciliary function, normalizes hypo- and hyperacetylated tubulin across tissues, and reduces GI tract inflammation. | Communications Medicine

Fig. 3: Vorinostat treatment of Rett tadpoles restores ciliary function, normalizes hypo- and hyperacetylated tubulin across tissues, and reduces GI tract inflammation.

From: AI-enabled drug prediction and gene network analysis reveal therapeutic use of vorinostat for Rett Syndrome in preclinical models

Fig. 3

a Olfactory cilia abnormalities due to MeCP2 knockdown were restored by treatment with vorinostat (magenta-yellow colormap of fluorescence intensity relative to z-position, cilia stained for tubulin using mouse anti-α acetylated tubulin and goat anti-mouse Alexa Fluor 594, scale bar = 10 µm), significantly restoring their b length (total number of cilium per condition: N = 43 Rett-Vor and N = 92 Rett-Vehicle, N = 89 Control-Vor, N = 69 Control-Vehicle). and c orientation (total number of multiciliated cells counted per condition: N = 60 Rett-Vor and N = 49 Rett-Vehicle, N = 50 Control-Vehicle). Functional rescue of cilia was also observed in both epithelial, d (N = 3 tadpoles per condition), and olfactory multiciliated cells, e in a microbead clearance assay (total number of tadpoles per condition: N = 4 Rett-Vor and N = 5 Rett-Vehicle, N = 5 Control-Vehicle). Despite the canonical HDACi activity of vorinostat, both hypoacetylated tubulin in the hindbrain (N = 10 Rett-Vor and N = 9 Rett-Vehicle, N = 9 Control-Vehicle tadpoles), f as well as hyperacetylated tubulin in the GI tract (distances from the adventitia epithelium: 26 in 1 µm increments), g was normalized. h Representative immunofluorescent cross-sectional views of the Xenopus gastrointestinal tract stained for ib4 and acetyl-\(\alpha\)-tubulin with Isolectin B4 FITC Conjugate and mouse anti-alpha acetylated tubulin and goat anti-mouse Alexa Fluor 594, respectively (scale bar = 20 µm; white lines delineate the lumen), and i plot showing that the % of ib4+ cells in the GI tract of tadpoles is increased in Rett tadpoles (N = 4 Rett-Vor and N = 5 Rett-Vehicle, N = 4 Control-Vehicle). Note that the Rett tadpole model has a higher % of ib4+ cells, which is indicative of inflammation and heightened pain response, and that this can be rescued by vorinostat treatment. Error bars indicate standard deviation.

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