title: Palmitoylethanolamide Modulates Inflammation-Associated Vascular Endothelial Growth Factor (VEGF) Signaling via the Akt/mTOR Pathway in a Selective Peroxisome Proliferator-Activated Receptor Alpha (PPAR-α)-Dependent Manner.
abstract: OBJECTIVE
  Angiogenesis is emerging as a pivotal process in chronic inflammatory pathologies, promoting immune infiltration and prompting carcinogenesis. Ulcerative Colitis (UC) and Crohn's Disease (CD) represent paradigmatic examples of intestinal chronic inflammatory conditions in which the process of neovascularization correlates with the severity and progression of the diseases. Molecules able to target the angiogenesis have thus the potential to synergistically affect the disease course. Beyond its anti-inflammatory effect, palmitoylethanolamide (PEA) is able to reduce angiogenesis in several chronic inflammatory conditions, but no data about its anti-angiogenic activity in colitis have been produced, yet.
  
  
  METHODS
  The effects of PEA on inflammation-associated angiogenesis in mice with dextran sulphate sodium (DSS)-induced colitis and in patients with UC were assessed. The release of Vascular Endothelial Growth Factor (VEGF), the hemoglobin tissue content, the expression of CD31 and of phosphatidylinositol 3-kinase/Akt/mammalian-target-of-rapamycin (mTOR) signaling axis were all evaluated in the presence of different concentrations of PEA and concomitant administration of PPAR-α and -γ antagonists.
  
  
  RESULTS
  Our results demonstrated that PEA, in a selective peroxisome proliferator activated receptor (PPAR)-α dependent mechanism, inhibits colitis-associated angiogenesis, decreasing VEGF release and new vessels formation. Furthermore, we demonstrated that the mTOR/Akt axis regulates, at least partly, the angiogenic process in IBD and that PEA directly affects this pathway.
  
  
  CONCLUSIONS
  Our results suggest that PEA may improve inflammation-driven angiogenesis in colonic mucosa, thus reducing the mucosal damage and potentially affecting disease progression and the shift towards the carcinogenesis.
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sarnelli
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: D'Alessandro
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Iuvone
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', La Sapienza University of Rome, Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Capoccia
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', La Sapienza University of Rome, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gigli
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Pesce
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', La Sapienza University of Rome, Rome, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Seguella
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', La Sapienza University of Rome, Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Nobile
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Aprea
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Maione
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
authors.forename: Giovanni Domenico
authors.initials: GD
authors.lastname: de Palma
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Cuomo
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', La Sapienza University of Rome, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Steardo
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', La Sapienza University of Rome, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Esposito
mesh_terms: D000328:Adult; D000577:Amides; D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000378:metabolism; D016264:Dextran Sulfate / Q000009:adverse effects*; D004195:Disease Models, Animal; D004983:Ethanolamines / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D047493:PPAR alpha / Q000378:metabolism*; D010169:Palmitic Acids / Q000008:administration & dosage* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D000577:Amides; D004983:Ethanolamines; D047493:PPAR alpha; D010169:Palmitic Acids; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C005958:palmidrol; D016264:Dextran Sulfate; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases