Yan Chun Li

Aging is a major driver of tissue senescence, but little is known about the development of age-unrelated tissue senescence. Here we show that nucleocytosolic acetyl-CoA deficiency in colon epithelial cells, caused by Acly ablation and bacterial depletion, triggers age-independent, p53-dependent colonic senescence leading to severe systemic inflammation. Acetate supplementation, acetate-producing bacterial transplantation, targeted depletion of senescent cells or treatment with lysine deacetylase inhibitors blocks colonic senescence and inflammatory injury. Spontaneous colonic senescence develops following simultaneous deletion of epithelial Acly and Acss2, confirming that microbe-derived acetate maintains the epithelial acetyl-CoA pool via ACSS2 to avert colonic senescence. Mechanistically, acetyl-CoA deficiency deprives a cohort of mitochondrial and nuclear proteins of acetylation, leading to increased oxidative stress and DNA repair stress that trigger cellular senescence. Among these proteins, ATP5F1A-K161 acetylation and H4-K5/8 acetylation are required to protect colonic epithelial cells from developing senescence. These observations unveil a previously unknown mechanism that governs colonic senescence.

Background: Emerging evidence suggests that the renin–angiotensin system plays an important role in the pathogenesis of inflammatory bowel disease, but few studies have directly assessed the therapeutic effect of renin inhibitors on colitis development. Method: Experimental colitis was induced in wild-type C57BL/6 mice and renin transgenic (RenTg) mice by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Following intrarectal TNBS instillation, the mice were treated with SPH3127 (sitokiren), a small-molecule renin inhibitor, twice a day by intraperitoneal injection or oral gavage. The therapeutic effect of SPH3127 was evaluated by assessing clinical symptoms, histological injuries, and colonic mucosal inflammatory parameters in these mice. Results: SPH3127 treatment by either delivery route markedly attenuated body weight loss, reduced clinical severity, alleviated colon mucosal ulceration in both C57BL/6 and RenTg mice, and prevented animal death in the case of RenTg mice. SPH3127 treatment blocked the local induction of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IFN-γ, IL-17) and promoted the production of anti-inflammatory cytokine IL-10 in the colon. Fluorescence-activated cell sorting analysis revealed that SPH3127 substantially diminished the accumulation of TH1 and TH17 cells in the colonic mucosa and confirmed that SPH3127-induced IL-10 production from mucosal CD25+ T cells in the mice. Conclusions: These results demonstrate that SPH3127 is able to effectively block colitis development in mouse experimental colitis models. Its anti-colitogenic activity is achieved at least in part by suppressing mucosal TH1 and TH17 activation while promoting IL-10 production from mucosal CD25+ T cells, thus forming an anti-inflammatory environment in the colonic mucosa.

Transcripts of Notch signaling components

Transcripts of Notch signaling components

Human AT1 and AT2 in colon cancers and adjacent mucosa

Westerns and IHC of Notch Signals

Colorectal cancer is a leading cause of cancer deaths. The renin-angiotensin system (RAS) is upregulated in colorectal cancer, and epidemiologic studies suggest RAS inhibitors reduce cancer risk. Because vitamin D (VD) receptor negatively regulates renin, we examined anticancer efficacy of VD and losartan (L), an angiotensin receptor blocker. Control Apc+/LoxP mice and tumor-forming Apc+/LoxP Cdx2P-Cre mice were randomized to unsupplemented Western diet (UN), or diets supplemented with VD, L, or VD+L, the latter to assess additive or synergistic effects. At 6 months, mice were killed. Plasma Ca2+, 25(OH)D3, 1α, 25(OH)2D3, renin, and angiotensin II (Ang II) were quantified. Colonic transcripts were assessed by qPCR and proteins by immunostaining and blotting. Cancer incidence and tumor burden were significantly lower in Cre+ VD and Cre+ L, but not in the Cre+ VD+L group. In Apc+/LoxP mice, VD increased plasma 1,25(OH)2D3 and colonic VDR. In Apc+/LoxP-Cdx2P-Cre mice, plasma renin and Ang II, and colonic tumor AT1, AT2, and Cyp27B1 were increased and VDR downregulated. L increased, whereas VD decreased plasma renin and Ang II in Cre+ mice. VD or L inhibited tumor development, while exerting differential effects on plasma VD metabolites and RAS components. We speculate that AT1 is critical for tumor development, whereas RAS suppression plays a key role in VD chemoprevention. When combined with L, VD no longer increases active VD and colonic VDR in Cre- mice nor suppresses renin and Ang II in Cre+ mice, likely contributing to lack of chemopreventive efficacy of the combination.