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A limited series of synthetic tetrahydroisoquinoline alkaloids reduce inflammatory gene iNOS via inhibition of p-STAT-1 and suppress HMGB1 secretion in LPS-treated mice lung tissue

조회수 : 37 등록일 : 2017.11.16 00:00

저자 : Lee, DH (Lee, Duck Hyung)
출처 : INTERNATIONAL IMMUNOPHARMACOLOGY
출판일 : 2017.11.01


A limited series of synthetic tetrahydroisoquinoline alkaloids reduce inflammatory gene iNOS via inhibition of p-STAT-1 and suppress HMGB1 secretion in LPS-treated mice lung tissue


Ko, YS (Ko, Young Shin)1 ] Park, EJ (Park, Eun Jung)1,2 ] Kim, YM (Kim, Young Min)1 ] Kim, HJ (Kim, Hye Jung)1 ] Yun-Choi, H (Yun-Choi, HyeSook)3 ] Lee, DH (Lee, Duck Hyung)4 ] Chang, KC (Chang, Ki Churl)1,2 ]


[ 1 ] Gyeongsang Natl Univ, Inst Hlth Sci, Sch Med, Dept Pharmacol, Jinju 52527, South Korea
[ 2 ] Gyeongsang Natl Univ, Dept Convergence Med Sci Plus BK21, Jinju 52527, South Korea
[ 3 ] Seoul Natl Univ, Nat Prod Res Inst, Coll Pharm, Seoul 08826, South Korea
[ 4 ] Sogang Univ, Sch Nat Sci, Dept Chem, Seoul 04107, South Korea



Tetrahydroisoquinoline alkaloids (THIs) have shown to increase survival and beneficial effect on animal model of sepsis, partly due to heme oxygenase-1 (HO-1) induction. Here, we aimed to compare a limited series of synthesized THIs on HO-1 induction and inhibitory effect of iNOS and COX-2 expression in lipopolysaccharide (LPS)-activated RAW264.7 cells. To the end, most promising compound (THI-61) was tested whether this compound reduces iNOS protein expression and inflammatory markers (HMGB1, TNF-alpha) in LPS-treated mice lung tissue. The results indicated that N-carbonyl substituted THI seem to affect HO-1 induction depending on which functional group is attached to Cl position. All compounds that reduce LPS-activated NF-kappa B-luciferase activity showed to preferential inhibition of iNOS/NO but not COX-2/PGE(2) that was partly related to inhibition of STAT-1 phosphorylation. In particular, THI-61 induced translocation of Nrf2 from cytosol into the nucleus by an increased Nrf2-ARE binding activity, and reduced IL-113 production in LPS-activated RAW264.7 cells. The reduced expression of iNOS/NO by THI-61 was reversed by siHO-1RNA-transfection. In LPS-treated mice, THI61 significantly reduced iNOS protein in lung tissues, and HMGB1 and TNF-a levels in the BALF. We concluded that 1) lipophilic moiety of 1C substituent is much more important in N-carbonyl substituted THI for induction of HO-1, 2) newly synthesized THI-61 may be beneficial for treatment of lung injury.






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