No abstract

Increasing evidence supports the hypothesis that inflammatory reactions serves an important function in the formation, progression and plaque rupture of atherosclerosis. Interleukin (IL)-1 primarily induces inflammation and is closely associated with the inflammatory environment and the formation of atherosclerosis. The present study aimed to establish an in vitro model for the evaluation of drug efficacy in the intervention of atherosclerosis from the inflammatory perspective, and to observe the anti-inflammatory effects of tanshinone IIA and andrographolide on atherosclerosis. The IL-1β-induced inflammation-activated endothelial cell (EC)-smooth muscle cell (SMC)-mononuclear cell (MC) co-culture model was established, based on the changes in a series of atherosclerosis-associated inflammatory markers secreted by ECs and SMCs. The expression of connexin in ECs, adhesion of MCs and changes in inflammatory signalling molecules were selected as evaluation indices for the inflammatory microenvironment of atherosclerosis. The use of this model revealed that tanshinone IIA exhibited significant efficacy against atherosclerosis and its inflammatory reactions. Inflammatory reactions were regarded as the primary mechanism underlying atherosclerosis. The established model simulated a series of relevant changes in the arterial wall under the inflammatory cytokines with oxidized low-density lipoprotein during the atherosclerotic process. The present study presented a reliable method for the identification of drugs with potential anti-inflammatory activity in atherosclerosis, for investigating the mechanisms of action, considering the improvement of the inflammatory state and the increase in plaque stability observed.

BackgroundThis study directly and dynamically investigated the effects of SL extract (i.e., a combination of Radix Salviae miltiorrhizae and Andrographis paniculata extract) on plaque progression in vivo by high resolution ultrasound biomicroscopy (UBM).MethodsAn atherosclerosis model was established by placing a perivascular collar on the right common carotid artery in apolipoprotein E-deficient (ApoE-/-) mice. Thickness, plaque area and local blood flow were observed by UBM, pathological changes were observed by histochemical staining, and lipid levels were measured by respective commercially available kits.ResultsCompared with the model group, the SL extract groups showed reduced wall thickness of the aortic arch (GC: P = 0.001, P = 0.002, and P < 0.001; LC: P < 0.001, P < 0.001, and P < 0.001; BC: P = 0.027, P = 0.017, and P = 0.003; respectively), which presented with retarded plaque progression of the cartoid artery with concordantly increased blood flow (P = 0.002 and P < 0.001) as visualized in vivo by UBM. Histological analysis confirmed the reduction of carotid atherosclerosis.ConclusionsThe SL extract inhibited the formation of atherosclerotic plaques in an ApoE-/- mice model by UBM analysis, and did so by effects that ameliorated local blood flow and improved blood lipid levels.

Metastasis is the leading lethal factor severely restraining the effectiveness of clinical treatment. TGF-beta is the key regulator for metastasis and influences paradoxically on cancer progression. The known TGF-beta blockers exert little selectivity on its functions, indiscriminately causing the anti-metastatic and pro-growth effects. Under such circumstances, specifically rebalancing the oncological function of TGF-beta provides a crucial oncotarget against metastasis. In our study, we established the screening platform targeting cell motility and identified a potential flavonoid, Chamaejasmenin B (ICJ), extracted from Stellera chamaejasme L. It suppressed the migration and invasion in breast cancer cells in vitro. Moreover, by dynamical quantification of breast cancer progression in small-animal imaging system, ICJ was proved to be a potent inhibitor of metastasis with minimal toxic side effects. Mechanism study further revealed that ICJ efficiently blocked TGF-beta induced EMT, disrupted the interaction between β3 integrin-TβRII complex and, consequently, resulted in the selective inhibition of FAK:Src:p38 pathway. Meanwhile, specific blockage of this pathway largely attenuated the anti-metastatic function of ICJ. Importantly, in contrast with the antagonistic effects on TGF-beta induced metastasis, ICJ obviously sensitized its cytostatic activity, suggesting that it was not a pan-blocker but a rebalancer for the functional output of TGF-beta. Collectively, by targeting TGF-beta Paradox, we experimentally provided a promising candidate for metastatic intervention.

No abstract