Licochalcone A attenuates abdominal aortic aneurysm induced by angiotensin II via regulating the miR-181b/SIRT1/HO-1 signaling

Licochalcone A (LA), a chalcone derived from liquorice, exhibits multiple biological activities, including anti-oxidation and anti-inflammation. This study aimed to investigate the role and underlying mechanism of LA in the abdominal aortic aneurysm (AAA). AAA model was established by continuous infusion of 1000 ng/kg/min of angiotensin II (AngII) in ApoE ^-/- mice for 4 weeks. At 7 days before AngII administration, 5 mg/kg/day or 10 mg/kg/day of LA was intraperitoneally administered to mice and continued for 4 weeks. The characteristics and quantification of AAAs were determined in situ. Real-time PCR or western blot was used to measure mRNA or protein levels of matrix metalloproteinase 2 and matrix metalloproteinase 9; pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6; apoptosis-related proteins Bax, Bcl-2, and active caspase-3; miR-181b; Sirtuin 1 (SIRT1); and heme oxygenase-1 (HO-1). Mouse-aorta-origin vascular smooth muscle (MOVAS) cells were used to confirm the involved pathways in vitro. We found LA administration dose-dependently reduced the incidence of AngII-induced AAA, aneurysm diameter enlargement, elastin degradation, matrix metalloproteinase production, pro-inflammatory cytokines and miR-181b expression, and vascular smooth muscle cell apoptosis. It elevated SIRT1 and HO-1 expression that was suppressed by AngII. AngII enhanced miR-181b but reduced SIRT1 and HO-1 expression in MOVAS cells. In AngII-stimulated MOVAS cells, downregulation of miR-181b significantly upregulated the expression of SIRT1 and HO-1, the effect of which was abrogated by SIRT1 siRNA. Collectively, LA could attenuate AngII-induced AAA by modulating the miR-181b/SIRT1/HO-1 signaling. LA might be a potential medical therapy for small AAA.     

MicroRNA-200c promotes osteogenic differentiation of human bone mesenchymal stem cells through activating the AKT/β-Catenin signaling pathway via downregulating Myd88

During the human bone formation, the event of osteogenic differentiation of human bone mesenchymal stem cells (hBMSCs) is vital, and recent evidence has emphasized the important role of microRNAs (miRNAs) in osteogenic differentiation of hBMSCs. This study aims to examine the potential effects of miR-200c in osteogenic differentiation of hBMSCs and understand their underlying mechanisms. HBMSCs were obtained via human bone marrow. During osteogenic induction and differentiation, cells were transfected with different plasmids with the intention of investigating the roles of miR-200c on osteogenic differentiation, calcium salt deposition, alkaline-phosphatase (ALP) activity, mineralized nodule formation, osteocalcin (OCN) content, and proliferation of osteoblasts. Following transfection, dual luciferase reporter gene assay was conducted so as to explore the correlation between miR-200c and Myd88. Moreover, the AKT/β-Catenin signaling pathway was blocked with an AKT/β-Catenin inhibitor, AKTi, to investigate its involvement. The hBMSCs were successfully isolated from human bone marrow. Myd88 was determined as a target gene of miR-200c. Gain and loss-of-function assays confirmed that overexpression of miR-200c, or silencing of Myd88 promoted osteogenic differentiation, increased calcium salt deposition, ALP activity, mineralized nodule formation, and enhanced the proliferation of osteoblasts following osteogenic differentiation of hBMSCs. Meanwhile, the downregulation of miR-200c has been shown to have the opposite effect. Furthermore, these findings showed that the miR-200c overexpression activated the AKT/β-Catenin signaling pathway by targeting Myd88. To sum up, the miR-200c upregulation induces osteogenic differentiation of hBMSCs by activating the AKT/β-Catenin signaling pathway via the inhibition of Myd88, providing a target for treatment of bone repair.     

Scutellarin exerts protective effects against atherosclerosis in rats by regulating the Hippo–FOXO3A and PI3K/AKT signaling pathways

Atherosclerosis (AS), a progressive disorder, is one of the tough challenges in the clinic. Scutellarin, an extract from Herba Erigerontis, is found to have oxygen-free radicals scavenging effects and antioxidant effects. In this study, we aimed to investigate the anti-AS effects of scutellarin is related to controlling the Hippo–FOXO3A and PI3K/AKT signal pathway. To establish an AS model, the rats in the scutellarin and model groups were intraperitoneally injected with vitamin D ₃ and then fed a high-fat diet for 12 weeks. In addition, in vitro angiotensin II-induced apoptosis of human aortic endothelial cells (HAECs) were used to establish models. Scutellarin significantly reduced blood lipid levels and increased antioxidase levels in both models. Additionally, scutellarin inhibited reactive oxygen species generation and apoptosis in HAECs. The impaired vascular barrier function was restored by using scutellarin in AS rats and in HAECs cells characterized by inhibiting mammalian sterile-20-like kinases 1 (Mst1) phosphorylation, Yes-associated protein (YAP) phosphorylation, forkhead box O3A (FOXO3A) phosphorylation at serine 207, nuclear translocation of FOXO3A, and upregulating protein expression of AKT and FOXO3A phosphorylation at serine 253. Scutellarin significantly reduced Bcl-2 interacting mediator of cell death (Bim), caspase-3, APO-1, CD95 (Fas), and Bax: Bcl-2-associated X (Bax) levels and activated Bcl-2: B-cell lymphoma-2 (Bcl-2). Scutellarin also significantly inhibited the expression of Mst1, YAP, FOXO3A at the messenger RNA level. When Mst1 was overexpressed or phosphoinositide 3-kinases suppressed, the effects of scutellarin were significantly blocked. In conclusion, the results of the present study suggest that scutellarin exerts protective effects against AS by inhibiting endothelial cell injury and apoptosis by regulating the Hippo–FOXO3A and PI3K/AKT signal pathways.     

AZGP1 is androgen responsive and involved in AR-induced prostate cancer cell proliferation and metastasis

Alpha-2-glycoprotein 1, zinc-binding (AZGP1), known as zinc-alpha-2-glycoprotein (ZAG), is a multifunctional secretory glycoprotein and relevant to cancer metastasis. Little is known regarding the underlying mechanisms of AZGP1 in prostate cancer (PCa). In the present study, we report that AZGP1 is an androgen-responsive gene, which is involved in AR-induced PCa cell proliferation and metastasis. In clinical specimens, the expression of AZGP1 in PCa tissues is markedly higher than that in adjacent normal tissues. In cultures, expression of AZGP1 is upregulated by the androgen-AR axis at both messenger RNA and protein levels. Furthermore, Chip-Seq assay identifies canonical androgen-responsive elements (AREs) at AZGP1 enhancer; and dual-luciferase reporter assays reveal that the AREs is highly responsive to androgen whereas mutations of the AREs abolish the reporter activity. In addition, AZGP1 promotes G1/S phase transition and cell cycle progress by increasing cyclin D1 levels in PCa cells. Functional studies demonstrate that knocking down endogenous AZGP1 expression in LNCaP and CWR22Rv1 cells largely weaken androgen/AR axis-induced cell migration and invasion. In vivo xenotransplantation tumor experiments also show that AZGP1 involves in androgen/AR axis-mediated PCa cell proliferation. Taken together, our study implicates for the first time that AZGP1 is an AR target gene and is involved in androgen/AR axis-mediated cell proliferation and metastasis in primary PCa.