title: Lipophilic modification enhances anti-colitic properties of rosmarinic acid by potentiating its HIF-prolyl hydroxylases inhibitory activity.
abstract: Inhibition of hypoxia inducible factor-prolyl hydroxylase-2 (HPH), leading to activation of hypoxia inducible factor (HIF)-1 is a potential therapeutic strategy for the treatment of colitis. Rosmarinic acid (RA), an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid is a naturally occurring polyphenolic compound with two catechols, a or inhibition of HPH. To improve accessibility of highly hydrophilic RA to HPH, an intracellular target, RA was chemically modified to decrease hydrophilicity. Of the less-hydrophilic derivatives, rosmarinic acid methyl ester (RAME) most potently inhibited HPH. Accordingly, RAME prevented hydroxylation of HIF-1α and consequently stabilized HIF-1α protein in cells. RAME inhibition of HPH and induction of HIF-1α were diminished by elevated doses of the required factors of HPH, 2-ketoglutarate and ascorbate. RAME induction of HIF-1α led to activation of an ulcer healing pathway, HIF-1-vascular endothelial growth factor (VEGF), in human colon carcinoma cells. RAME administered rectally ameliorated TNBS-induced rat colitis and substantially decreased the levels of pro-inflammatory mediators in the inflamed colonic tissue. In parallel with the cellular effects of RAME, RAME up-regulated HIF-1α and VEGF in the inflamed colonic tissue. Thus, lipophilic modification of RA improves its ability to inhibit HPH, leading to activation of the HIF-1-VEGF pathway. RAME, a lipophilic RA derivative, may exert anti-colitic effects via activation of the ulcer healing pathway.
authors.affiliation: College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Seongkeun
authors.initials: S
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Huijeong
authors.initials: H
authors.lastname: Park
authors.affiliation: College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Sungchae
authors.initials: S
authors.lastname: Hong
authors.affiliation: College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Soohwan
authors.initials: S
authors.lastname: Yum
authors.affiliation: College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Wooseong
authors.initials: W
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Pusan National University, Busan, Republic of Korea. Electronic address: jungy@pusan.ac.kr.
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Jung
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D003067:Coenzymes / Q000502:physiology; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053630:Depsides / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D004952:Esters; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D006900:Hydroxylation / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014302:Trinitrobenzenesulfonic Acid / Q000009:adverse effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000097123:Rosmarinic Acid
chemical_list: D001205:Ascorbic Acid; D002264:Carboxylic Acids; D002934:Cinnamates; D003067:Coenzymes; D053630:Depsides; D004791:Enzyme Inhibitors; D004952:Esters; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007656:Ketoglutaric Acids; D014302:Trinitrobenzenesulfonic Acid; D042461:Vascular Endothelial Growth Factor A; D000097123:Rosmarinic Acid
keywords: (+)-5,6-O-Isopropylidene-l-ascorbic acid; (PubChem CID: 54691418); 2-ketoglutarate (PubChem CID: 164533); Animal model; Cycloheximide (PubChem CID: 6197); Hypoxia inducible factor; Hypoxia inducible factor-prolyl hydroxylase; Lipophilic modification; MG132 (PubChem CID: 462382); Rosmarinic acid; Rosmarinic acid (PubChem CID: 5281792); Sodium ascorbate (PubChem CID: 23667548); TNBS-induced colitis; Trinitrobenzenesulfonic acid (PubChem CID : 11045)