Inhibitory effects of OD 78 [3-(4-bromo-phenoxy)-4,5-dihydroxybenzoic acid-methyl ester] on the proliferation and migration of TNF-α-induced rat aortic smooth muscle cells

Abstract

The proliferation and migration of vascular smooth muscle cells (VSMCs) play important roles in the formation and progression of intimal thickening in early-phase atherosclerosis and in restenosis after vascular injury. Tumor necrosis factor-α (TNF-α) is released from macrophages in atherosclerotic lesions and from neointimal vascular smooth muscle cells after balloon-injury. Obovatol, a major biphenolic component isolated from the Magnolia obovata leaf, is known to have anti-inflammatory and antitumor activities. The goal of this study was to examine the cardioprotective effects of the obovatol derivative OD 78 on the TNF-α-induced proliferation and migration of rat aortic smooth muscle cells (RASMCs). The antiproliferative effects of OD 78 on RASMCs were examined by cell counting and [(3)H]-thymidine incorporation assays. Treatment of cells with 1-4 μM OD 78 inhibited the proliferation and DNA synthesis of TNF-α-stimulated RASMCs in a concentration-dependent manner, without cytotoxicity. Treatment with OD 78 inhibited TNF-α-mediated p38 phosphorylation, but did not change the activation of extracellular signal-regulated kinase or c-Jun N-terminal kinase. Furthermore, treatment with OD 78 decreased TNF-α-induced levels of cyclin E, cyclin D1, CDK2, proliferating cell nuclear antigen, and phosphorylated retinoblastoma protein, but not the CDK4 expression level. Also, OD 78 inhibits the migration of TNF-α-induced RASMC in transwells. OD 78 treatment strongly decreased matrix metalloproteinase-9 (MMP-9) expression in a dose-dependent manner, but the MMP-2 expression was unchanged. These results show that OD 78 may be developed as a potential antiproliferative agent for the treatment of angioplasty restenosis and atherosclerosis.

Forming of Demethoxycurcumin Nanocrystallite-Chitosan Nanocarrier for Controlled Low Dose Cellular Release for Inhibition of the Migration of Vascular Smooth Muscle Cells

“…Therefore, inhibition of VSMC proliferation and migration has becoming a crucial concern in medical and pharmaceutical communities over the years. Earlier studies have shown that pretreatment with antioxidants can significantly reduce balloon injury-induced neointima formation. , Until now, a number of therapeutic antiproliferative, antioxidant, and anti-inflammatory drugs have been reported to exert inhibitory efficacy toward the VSMCs, − although an optimal dosing has barely been quantitatively determined both in vitro and in vivo , especially under a sustained elution manner. One major hurdle is the poor bioavailability of those selected drugs as a result of poor physiological solubility, which has been addressed to considerably attenuate therapeutic efficacy of drugs.…”

JJK694, a Synthesized Obovatol Derivative, Inhibits Platelet Activation by Suppressing Cyclooxygenase and Lipoxygenase Activities

“…33,34) We identified recently an anti-platelet effect of obovatol, which appeared to be mainly mediated by inhibition of PLC 2 phosphorylation. 18) However, the inhibitory effect of obovatol derivatives on platelet aggregation and the mechanisms are not understood. Hence, we are investigating the antiplatelet effect of JJK694, an obovatol derivative, on washed rabbit platelets.…”

“…Tel: +82-43-261-2821; Fax: +82-43-268-2732; E-mail: ypyun@chungbuk.ac.kr Abbreviations: AA, arachidonic acid; TXA 2 , thromboxane A 2 ; PGD 2 , prostaglandin; COX, cyclooxygenase; LOX, lipoxygenase; PLC, phospholipase C; 12-HETE, 12-hydroxy-5,8,10,14-eicosatetraenoic acid; JY0695, 5-allyl-3-(4-allylphenoxy)-1,2-phenylene diacetate; U46619, 9,11-dideoxy-9,11-methanoepoxy prostaglandin F 2 ; BSA, bovine serum albumin; Fura 2/AM, fura 2 acetoxymethyl ester; OPT, o-phthalaldehyse; DMSO, dimethyl sulfoxide; ACD, anticoagulant citrate dextrose; TCA, trichloroacetic acid; PRP, platelet-rich plasma biological activities, including anti-proliferative, [18][19][20] neurotrophic, 21) anti-fibrillogenic, 22) anti-platelet, 23,24) anti-fungal, 25) and anti-inflammatory activities. 26) Park et al found that obovatol inhibited platelet activation in vitro and thrombus formation in vivo.…”

“…26) Park et al found that obovatol inhibited platelet activation in vitro and thrombus formation in vivo. 18) Hence, the present study focused on the development of obovatol derivatives as anti-platelet agents. Recently, we prepared a synthetic obovatol derivative and named it JJK694 (Fig.…”