Betulinic acid hydroxamate prevents colonic inflammation and fibrosis in murine models of inflammatory bowel disease

M. E. Prados, A. Garcia-Martin, J. D. Unciti-Broceta, B. Palomares, J. A. Collado, Alberto MINASSI, M. A. Calzado, G. Appendino, E. Munoz

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

Abstract

Intestinal fibrosis is a common complication of inflammatory bowel disease (IBD) and is defined as an excessive accumulation of scar tissue in the intestinal wall. Intestinal fibrosis occurs in both forms of IBD: ulcerative colitis and Crohn’s disease. Small-molecule inhibitors targeting hypoxia-inducing factor (HIF) prolyl-hydroxylases are promising for the development of novel antifibrotic therapies in IBD. Herein, we evaluated the therapeutic efficacy of hydroxamate of betulinic acid (BHA), a hypoxia mimetic derivative of betulinic acid, against IBD in vitro and in vivo. We showed that BAH (5–20 μM) dose-dependently enhanced collagen gel contraction and activated the HIF pathway in NIH-3T3 fibroblasts; BAH treatment also prevented the loss of trans-epithelial electrical resistance induced by proinflammatory cytokines in Caco-2 cells. In two different murine models (TNBS- and DSS-induced IBD) that cause colon fibrosis, oral administration of BAH (20, 50 mg/kg·d, for 17 days) prevented colon inflammation and fibrosis, as detected using immunohistochemistry and qPCR assays. BAH-treated animals showed a significant reduction of fibrotic markers (Tnc, Col1a2, Col3a1, Timp-1, α-SMA) and inflammatory markers (F4/80+, CD3+, Il-1β, Ccl3) in colon tissue, as well as an improvement in epithelial barrier integrity and wound healing. BHA displayed promising oral bioavailability, no significant activity against a panel of 68 potential pharmacological targets and was devoid of genotoxicity and cardiotoxicity. Taken together, our results provide evidence that oral administration of BAH can alleviate colon inflammation and colitis-associated fibrosis, identifying the enhancement of colon barrier integrity as a possible mechanism of action, and providing a solid rationale for additional clinical studies.
Lingua originaleInglese
RivistaActa Pharmacologica Sinica
DOI
Stato di pubblicazionePubblicato - 1 gen 2020

Keywords

  • betulinic acid hydroxamate
  • colon inflammation
  • DSS
  • fibrosis
  • hypoxia-inducible factor
  • inflammatory bowel disease
  • prolyl hydroxylases
  • TNBS

Fingerprint

Entra nei temi di ricerca di 'Betulinic acid hydroxamate prevents colonic inflammation and fibrosis in murine models of inflammatory bowel disease'. Insieme formano una fingerprint unica.

Cita questo