Curcumol alleviates cardiac remodeling via the AKT/NF-κB pathway.

Cardiac remodeling is the final stage of almost all cardiovascular diseases, leading to heart failure and arrhythmias. However, the pathogenesis of cardiac remodeling is not fully understood, and specific treatment schemes are currently unavailable. Curcumol is a bioactive sesquiterpenoid that has anti-inflammatory, anti-apoptotic, and anti-fibrotic properties. This study aimed to investigate the protective effect of curcumol on cardiac remodeling and elucidate its relevant underlying mechanism. Curcumol significantly attenuated cardiac dysfunction, myocardial fibrosis, and hypertrophy in the animal model of isoproterenol (ISO)-induced cardiac remodeling. Curcumol also alleviated cardiac electrical remodeling, thereby reducing the risk of ventricular fibrillation (VF) after heart failure. Inflammation and apoptosis are critical pathological processes involved in cardiac remodeling. Curcumol inhibited the inflammation and apoptosis induced by ISO and TGF-ß1 in mouse myocardium and neonatal rat cardiomyocytes (NRCMs). Furthermore, the protective effects of curcumol were found to be mediated through the inhibition of the protein kinase B (AKT)/nuclear factor-kappa B (NF-κB) pathway. The administration of an AKT agonist reversed the anti-fibrotic, anti-inflammatory, and anti-apoptotic effects of curcumol and restored the inhibition of NF-κB nuclear translocation in TGF-ß1-induced NRCMs. Our study suggests that curcumol is a potential therapeutic agent for the treatment of cardiac remodeling.

BRD4770 inhibits vascular smooth muscle cell proliferation via SUV39H2, but not EHMT2 to protect against neointima formation.

The behavior of vascular smooth muscle cells (VSMCs) contributes to the formation of neointima. We previously found that EHMT2 suppressed autophagy activation in VSMCs. BRD4770, an inhibitor of EHMT2/G9a, plays a critical role in several kinds of cancers. However, whether and how BRD4770 regulates the behavior of VSMCs remain unknown. In this study, we evaluate the cellular effect of BRD4770 on VSMCs by series of experiments in vivo and ex vivo. We demonstrated that BRD4770 inhibited VSMCs' growth by blockage in G2/M phase in VSMCs. Moreover, our results demonstrated that the inhibition of proliferation was independent on autophagy or EHMT2 suppression which we previous reported. Mechanistically, BRD4770 exhibited an off-target effect from EHMT2 and our further study reveal that the proliferation inhibitory effect by BRD4770 was associated with suppressing on SUV39H2/KTM1B. In vivo, BRD4770 was also verified to rescue VIH. Thus, BRD4770 function as a crucial negative regulator of VSMC proliferation via SUV39H2 and G2/M cell cycle arrest and BRD4770 could be a molecule for the therapy of vascular restenosis.

Fucoxanthin alleviated atherosclerosis by regulating PI3K/AKT and TLR4/NFκB mediated pyroptosis in endothelial cells.

Fucoxanthin, a type of natural xanthophyll carotenoid, is mainly present in seaweeds and various microalgae. This compound has been proved to possess multiple functions including antioxidation, anti-inflammation and anti-tumor. Atherosclerosis is widely deemed as a chronic inflammation disease, and as the basis of vascular obstructive disease. However, there is rare research about fucoxanthin's effects on atherosclerosis. In this study, we demonstrated that the plaque area of mice treated with fucoxanthin was significantly reduced compared to the group that did not receive fucoxanthin. In addition, Bioinformatics analysis showed that PI3K/AKT signaling might be involved in the protective effect of fucoxanthin, and this hypothesis was then verified in vitro endothelial cell experiments. Besides, our further results showed that endothelial cell mortality measured by TUNEL and flow cytometry was significantly increased in the oxidized low-density lipoprotein (ox-LDL) treatment group while significantly decreased in the fucoxanthin treatment group. In addition, the pyroptosis protein expression level in the fucoxanthin group was significantly lower than that in the ox-LDL group, which indicated that fucoxanthin improved the pyroptosis level of endothelial cells. Furthermore, it was revealed that TLR4/NFκB signaling were also participated in the protection of fucoxanthin on endothelial pyroptosis. Moreover, the protection of fucoxanthin on endothelial cell pyroptosis was abrogated when PI3K/AKT was inhibited or TLR4 was overexpressed, which further suggested the anti-pyroptosis effect of fucoxanthin was mediated through regulations of PI3K/AKT and TLR4/NFκB signaling.

Effect of novel bioresorbable scaffold composed of poly-L-lactic acid and amorphous calcium phosphate nanoparticles on inflammation and calcification of surrounding tissues after implantation.

To study the effect of novel bioresorbable scaffold composed of poly-L-lactic acid (PLLA) and amorphous calcium phosphate (ACP) nanoparticles on inflammation and calcification of surrounding tissues after implantation. Ninety six PLLA/ACP scaffolds and 96 PLLA scaffolds were randomly implanted in the back muscle tissue of 48 SD rats. At the 1st, 2nd, 4th, and 12th weeks after implantation, the calcium, phosphorus, and alkaline phosphatase levels in the blood serum and the contents of calcium and alkaline phosphatase in the tissue surrounding the scaffolds were measured. Hematoxylin-eosin staining was performed to count the inflammatory cells. Von kossa staining was performed to observe calcification of the surrounding tissue around the scaffold. NF-κB staining was performed by immunohistochemistry to calculate the positive expression index of inflammatory cells. Western blot was used to detect the expression of IL-6 and BMP-2 in the tissues surrounding the scaffolds. At the 1st, 2nd, 4th, and 12th weeks after scaffold implantation, there were no significant difference in the serum concentration of calcium, phosphorus, alkaline phosphatase and in the tissue homogenate concentration of alkaline phosphatase between the two groups (P > 0.05). The level of calcium in tissue homogenates was lower in the PLLA/ACP group than in the PLLA group at 12-week (P < 0.05). The hematoxylin-eosin staining results showed that the inflammatory cell count in the PLLA/ACP group was lower than the PLLA group at 4-week and 12-week (P < 0.05). The results of NF-kB positive expression index showed that the PLLA group was significantly more than the PLLA/ACP group at 4-week and 12-week (P < 0.01). Western blot results showed that IL-6 expression levels in the PLLA/ACP group scaffolds were significantly lower than those in the control group at the 2-week, 4-week and 12-week (P < 0.05). The expression of BMP-2 in the PLLA group was significantly lower than that in the control group at 4-week and 12-week (P < 0.05). The PLLA/ACP composite material has good histocompatibility. The integration of nanoscale ACPs reduces the inflammatory response induced by acidic metabolites of PLLA material and may inhibit tissue calcification by reducing the amount of calcification factors in the body.

Hepatocyte growth factor regulates the TGF-ß1-induced proliferation, differentiation and secretory function of cardiac fibroblasts.

Cardiac fibroblast (CF) proliferation and transformation into myofibroblasts play important roles in cardiac fibrosis during pathological myocardial remodeling. In this study, we demonstrate that hepatocyte growth factor (HGF), an antifibrotic factor in the process of pulmonary, renal and liver fibrosis, is a negative regulator of cardiac fibroblast transformation in response to transforming growth factor­ß1 (TGF­ß1). HGF expression levels were significantly reduced in the CFs following treatment with 5 ng/ml TGF­ß1 for 48 h. The overexpression of HGF suppressed the proliferation, transformation and the secretory function of the CFs following treatment with TGF­ß1, as indicated by the attenuated expression levels of α-smooth muscle actin (α­SMA) and collagen I and III, whereas the knockdown of HGF had the opposite effect. Mechanistically, we identified that the phosphorylation of c­Met, Akt and total protein of TGIF was significantly inhibited by the knockdown of HGF, but was significantly enhanced by HGF overexpression. Collectively, these results indicate that HGF activates the c­Met­Akt­TGIF signaling pathway, inhibiting CF proliferation and transformation in response to TGF­ß1 stimulation.