title: Propionyl-L-Carnitine is Efficacious in Ulcerative Colitis Through its Action on the Immune Function and Microvasculature.
abstract: OBJECTIVE
  Microvascular endothelial dysfunction characterizes ulcerative colitis (UC), the most widespread form of inflammatory bowel disease. Intestinal mucosal microvessels in UC display aberrant expression of cell adhesion molecules (CAMs) and increased inflammatory cell recruitment. Propionyl-L-carnitine (PLC), an ester of L-carnitine required for the mitochondrial transport of fatty acids, ameliorates propionyl-CoA bioavailability and reduces oxidative stress in ischemic tissues. The present study aimed to document the efficacy of anti-oxidative stress properties of PLC in counteracting intestinal microvascular endothelial dysfunction and inflammation.
  
  
  METHODS
  To evaluate the efficacy in vivo, we analyzed the effects in intestinal biopsies of patients with mild-to-moderate UC receiving oral PLC co-treatment and in rat TNBS-induced colitis; in addition, we investigated antioxidant PLC action in TNF-α-stimulated human intestinal microvascular endothelial cells (HIMECs) in vitro.
  
  
  RESULTS
  Four-week PLC co-treatment reduced intestinal mucosal polymorph infiltration and CD4(+) lymphocytes, ICAM-1(+) and iNOS(+) microvessels compared with placebo-treated patients with UC. Oral and intrarectal administration of PLC but not L-carnitine or propionate reduced intestinal damage and microvascular dysfunction in rat TNBS-induced acute and reactivated colitis. In cultured TNF-α-stimulated HIMECs, PLC restored β-oxidation and counteracted NADPH oxidase 4-generated oxidative stress-induced CAM expression and leukocyte adhesion. Inhibition of β-oxidation by L-aminocarnitine increased reactive oxygen species production and PLC beneficial effects on endothelial dysfunction and leukocyte adhesion. Finally, PLC reduced iNOS activity and nitric oxide accumulation in rat TNBS-induced colitis and in HIMEC cultures.
  
  
  CONCLUSIONS
  Our results show that the beneficial antioxidant effect of PLC targeting intestinal microvasculature restores endothelial β-oxidation and function, and reduces mucosal inflammation in UC patients.
authors.affiliation: Anatomic Pathology, Tor Vergata University, Rome, Italy.
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Scioli
authors.affiliation: Sigma-Tau, Pomezia, Rome, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Stasi
authors.affiliation: Anatomic Pathology, Tor Vergata University, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Passeri
authors.affiliation: Anatomic Pathology, Tor Vergata University, Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Doldo
authors.affiliation: Anatomic Pathology, Tor Vergata University, Rome, Italy.
authors.forename: Gaetana
authors.initials: G
authors.lastname: Costanza
authors.affiliation: Sigma-Tau, Pomezia, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Camerini
authors.affiliation: Anatomic Pathology, Luigi Sacco Hospital, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fociani
authors.affiliation: Experimental Medicine and Biochemical Sciences, Tor Vergata University of Rome, Rome, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Arcuri
authors.affiliation: Sigma-Tau, Pomezia, Rome, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Lombardo
authors.affiliation: Sigma-Tau, Pomezia, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pace
authors.affiliation: Sigma-Tau, Pomezia, Rome, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Borsini
authors.affiliation: Anatomic Pathology, Tor Vergata University, Rome, Italy.
authors.forename: Augusto
authors.initials: A
authors.lastname: Orlandi