title: Attenuation of TNF-α secretion by L-proline-based cyclic dipeptides produced by culture broth of Pseudomonas aeruginosa.
abstract: To identify small molecule inhibitors of TNF-α, bioassay- and LC-MS-guided chemical investigation on EtOAc extract of Pseudomonas aeruginosa ABS-36 culture broth (EEPA) was performed, which yielded four proline-based cyclic dipeptides, cyclo(Gly-l-Pro) (1), cyclo(l-Pro-l-Phe) (2), cyclo(trans-4-hydroxy-l-Pro-l-Phe) (3) and cyclo(trans-4-hydroxy-l-Pro-l-Leu) (4). Compounds 1 and 3 exhibited potent inhibition of TNF-α release with IC50 values of 4.5 and 14.2μg/mL, respectively, while EEPA showed IC50 of 38.8μg/mL under lipopolysaccharide treated RAW 264.7 cell ELISA assay. Also, marked attenuation of mRNA-expression of TNF-α was shown by all compounds. In vivo testing in rats of EEPA and chemically synthesized 4 validated significant TNF-α reduction with 51% (500mg/kg) and 79% (50mg/kg), respectively. In addition, all compounds exhibited significant diminution of IL-1β and IL-6 mRNA-expression levels and NO production. All samples displayed only weak toxicity to lipopolysaccharide-induced RAW 264.7 cells.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, Telangana State, India.
authors.forename: Rukaiyya
authors.initials: R
authors.lastname: Khan
authors.affiliation: Regional Agricultural Research Station, Professor Jayashankar Telangana State Agricultural University, Palem 509 215, Mahaboobnagar District, Telangana State, India.
authors.forename: Ameer
authors.initials: A
authors.lastname: Basha
authors.affiliation: Regional Agricultural Research Station, Professor Jayashankar Telangana State Agricultural University, Palem 509 215, Mahaboobnagar District, Telangana State, India.
authors.forename: Ragavendra
authors.initials: R
authors.lastname: Goverdhanam
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, Telangana State, India.
authors.forename: Poorna Chandra
authors.initials: PC
authors.lastname: Rao
authors.affiliation: Department of Chemistry and Materials Science, Tokyo Institute of Technology, O-okayama, Meguro, Tokyo 152-8551, Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Tanemura
authors.affiliation: Department of Chemistry and Materials Science, Tokyo Institute of Technology, O-okayama, Meguro, Tokyo 152-8551, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fujimoto
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, Telangana State, India. Electronic address: sajeli@hyderabad.bits-pilani.ac.in.
authors.forename: Ahil Sajeli
authors.initials: AS
authors.lastname: Begum
mesh_terms: D000818:Animals; D004151:Dipeptides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D011392:Proline / Q000737:chemistry; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism
chemical_list: D004151:Dipeptides; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D011392:Proline
keywords: Cyclic dipeptide; Interleukin-1β; Interleukin-6; Pseudomonas aeruginosa; TNF-α inhibitor