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We have previously reported that fenofibrate displayed a potent antithrombotic effect by the inhibition of platelet aggregation. The present study was designed to investigate the effects of fenofibrate on the neointimal hyperplasia and its possible molecular mechanism. Neointimal hyperplasia was measured in balloon-inflated-induced vascular injury model of male Sprague-Dawley rats and cell proliferation was measured in primary cultured rat aortic vascular smooth muscle cells (VSMCs). Fenofibrate-treated group showed a significant reduction in neointimal formation (0.07±0.04mm(2)) from the control (0.13±0.04mm(2)). Fenofibrate significantly inhibited platelet-derived growth factor (PDGF)-BB-induced cell counting and [(3)H]-thymidine incorporation into DNA. Fenofibrate suppressed the PDGF-BB-inducible progression through G(0)/G(1) to S phase of cell cycle. Moreover, fenofibrate inhibited not only phosphorylation of retinoblastoma (Rb) protein and expression of cyclin D/E, CDK 2/4 and proliferating cell nuclear antigen (PCNA) proteins but also mitogen-activated protein kinase (MAPK) signaling pathways such as ERK 1/2, p38 and JNK phosphorylation. In conclusion, the present study demonstrates that fenofibrate significantly inhibits neointimal formation via G(0)/G(1) arrest of PDGF-BB-induced cell proliferation in association with the inhibition of MAPK, which resulted in the downregulation of expressions of cyclin D/E, CDK 2/4 and PCNA proteins, suggesting that fenofibrate may be useful for individuals with a high risk of thrombotic or cardiovascular diseases.

Obovatol is known to have various biological activities such as muscle relaxation, anti-gastric ulcer, anti-inflammatory, anti-allergic, and anti-bacterial activities. We examined the effects of JY0691, a newly synthesized obovatol derivative, on the viability and proliferation in rat aortic smooth muscle cells. We also determined the mechanism by which the compound induces cell cycle arrest of the cells. Treatment with JY0691 (0–3 μM) inhibited proliferation of the cells in a dose-dependent manner without any cytotoxic effect. JY0691 treatment did not decrease the levels of platelet-derived growth factor (PDGF) receptor and several protein kinases which had stimulated by exposing the cells to 25 ng/ml PDGF-BB. In contrast, the compound arrested the cell cycle progression in the G 0 /G 1 phase, which was related to the down-regulation of cell cycle regulatory factors such as cyclin D 1 /E, cyclin-dependent kinase (CDK)2/4, and proliferating cell nuclear antigen. Further, JY0691 induced cell cycle arrest in the G 1 phase through up-regulation of p21 cip1 , but not of p27 kip1 , where p53-mediated signaling was in part involved. Our current findings suggest that JY0691 contains anti-proliferative potential on aortic smooth muscle cells.

Abnormal proliferation of vascular smooth muscle cells (VSMCs) plays an essential functional role in the pathogenesis of vascular disorders, such as atherosclerosis, restenosis, and neointimal hyperplasia. In this study, we examined the effects of meso-dihydroguaiaretic acid (MDGA) on platelet-derived growth factor (PDGF)-BB-induced proliferation and the molecular basis of its underlying mechanism of action in rat aortic VSMCs. Incubation of resting VSMCs with MDGA for 24 h significantly diminished PDGF-BB-induced DNA synthesis in a dose-dependent manner. We also examined the effects of MDGA on PDGF-BB signal transduction. Pre-treatment of VSMCs with MDGA inhibited PDGF-BB-induced phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), p38, and C-Jun N-terminal kinase (JNK). MDGA also effectively inhibited phosphorylation of Akt, phospholipase C gamma 1 (PLCγ1), and PDGF receptor beta (PDGFRβ). These results indicate that MDGA may inhibit proliferation of VSMCs by suppressing autophosphorylation of PDGFRβ, and may be useful in the treatment of VSMC-associated vascular disease such as atherosclerosis, restenosis, and neointimal hyperplasia after angioplasty.

Mast cells are known to play a pivotal role in allergic diseases. Cross-linking of the high-affinity IgE receptor (FceRI) is known to be one of the major causes that lead to degranulation and allergic inflammation. An increase in intracellular calcium (Ca(2+)) concentration also triggers degranulation, bypassing receptor activation. Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is known to exhibit a variety of pharmacological activities including anti-allergic effects. However, the detailed molecular mechanisms involved in exhibiting anti-allergic effects by emodin were remained to be clarified. In the present investigation we report the regulatory function of emodin on the allergic signal mediators through Ca(2+) ionophore activation in mast cells. Emodin significantly inhibited A23187-induced tumor necrosis factor-α production and degranulation through the attenuation of protein kinase C, IκB kinase 2, and soluble N-ethylmaleimide-sensitive fusion factor attachment protein receptor complex formation, bypassing FceRI activation. Data from our study indicated that emodin acts by regulating multiple signaling pathways in inhibiting the allergic reactions in mast cells.

Indoledione derivatives have pronounced biological effects, i.e., cytotoxic activities against cancer cell lines and antifungal and antibacterial activities. The present study was designed to investigate the effects of YSK2821, a newly synthesized indoledione derivative, on platelet-derived growth factor (PDGF-BB)-induced vascular smooth muscle cell (VSMC) proliferation, as well as the molecular mechanisms of the anti-proliferative effects of YSK2821 in VSMCs. We found that YSK2821 caused the accumulation of cells in the G1 phase of the cell cycle and inhibited [3H]-thymidine incorporation. We demonstrated that YSK2821 remarkably decreased Akt kinase phosphorylation as the mechanism by which YSK2821 suppressed cell signal transduction events in VSMC proliferation. Furthermore, in terms of the effects of YSK2821 on cell cycle-related proteins, YSK2821 enhanced the expression of the cyclin-dependent protein kinase (CDK) inhibitor p27 and down-regulated CDK2 and cyclin E expression, but did not affect CDK4 and cyclin D1 expression. YSK2821 also inhibited the phosphorylation of Rb, a key regulator in the cell cycle. These results indicate that YSK2821, a newly synthesized indoledione derivative, may inhibit VSMC proliferation via a phosphatidylinositol (PI)-3 kinase-dependent pathway, and thus shed light on a novel role for YSK2821 as a potential preventive regulator of cardiovascular disease.