Browsing UMB Open Access Articles by Author "Ma, H."
Bazedoxifene Attenuates Abdominal Aortic Aneurysm Formation via Downregulation of Interleukin-6/Glycoprotein 130/Signal Transducer and Activator of Transcription 3 Signaling Pathway in Apolipoprotein E-Knockout MiceYan, D.; Ma, H.; Lin, J. (Frontiers Media S.A., 2020)Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease characterized by aortic dilatation and predominantly affects an elderly population. Accumulating evidence suggests that Interleukin-6 (IL-6) and the signal transducer and activator of transcription 3 (STAT3) play an important role in formation of AAAs. However, it remains unclear whether Bazedoxifene (BAZ) could suppress the activation of IL-6/GP130/STAT3 in vascular cells and the formation of AAA. Here we explored the effect of BAZ on AngII-stimulated AAA formation. ApoE–/– mice infused with AngII for 28 days using osmotic minipumps were treated with placebo or 5mg/kg BAZ. In our results most of the AngII-induced mice developed AAA with exacerbated inflammation, degradation of elastin fibers, STAT3 phosphorylation, and increased expression of matrix metalloproteinases (MMPs). These effects were markedly attenuated by BAZ. Furthermore, BAZ suppressed the stimuli-induced (IL-6 or AngII) expression of P-STAT3, MMP2 and MMP9 in vascular smooth muscle cells (VSMCs). BAZ inhibited wound healing, colony formation and suppressed STAT3 nuclear translocation in vitro. In conclusion, these results indicated that BAZ downregulated IL-6/GP130/STAT3 signaling and interfered with AAA formation induced by AngII in ApoE-/- mice, which indicates a novel potential strategy for the prevention and therapy of AAA. Copyright 2020 The Authors
Bazedoxifene exhibits growth suppressive activity by targeting interleukin-6/glycoprotein 130/signal transducer and activator of transcription 3 signaling in hepatocellular carcinomaMa, H.; Yan, D.; Wang, Y. (Blackwell Publishing Ltd, 2019)The interleukin (IL)-6/glycoprotein (GP)130/signal transducer and activator of transcription (STAT)3 pathway is emerging as a target for the treatment of hepatocellular carcinoma. IL-6 binds to IL-6R, forming a binary complex, which further combines with GP130 to transduce extracellular signaling by activating STAT3. Therefore, blocking the interaction between IL-6 and GP130 may inhibit the IL-6/GP130/STAT3 signaling pathway and its biological effects. It has been reported that bazedoxifene acetate (BAZ), a selective estrogen receptor modulator approved by the US Food and Drug Administration, could inhibit IL-6/GP130 protein-protein interactions. Western blot, immunofluorescence staining, wound healing and colony formation assays were used to detect the effect of BAZ on liver cancer cells. Cell viability was evaluated by MTT assay. Apoptosis of cells was determined using the Annexin V-FITC detection kit. Mouse xenograft tumor models were utilized to evaluate the effect of BAZ in vivo. Our data showed that BAZ inhibited STAT3 phosphorylation (P-STAT3) and expression of STAT3 downstream genes, inducing apoptosis in liver cancer cells. BAZ inhibited P-STAT3 induced by IL-6, but not by leukemia inhibitory factor. BAZ inhibited P-STAT1 and P-STAT6 less significantly as elicited by interferon-α, interferon-γ and IL-4. In addition, pretreatment of BAZ impeded the translocation of STAT3 to nuclei induced by IL-6. BAZ inhibited cell viability, wound healing and colony formation in vitro. Furthermore, tumor growth in HEPG2 mouse xenografts were significantly inhibited by daily intragastric gavage of BAZ. Our results suggest that BAZ inhibited the growth of hepatocellular carcinoma in vitro and in vivo, indicating another potential strategy for HCC prevention and therapy. ©2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
Inhibition of Interleukin-6/glycoprotein 130 signalling by Bazedoxifene ameliorates cardiac remodelling in pressure overload miceShi, W.; Ma, H.; Lin, J. (Blackwell Publishing Inc., 2020)The role of IL-6 signalling in hypertensive heart disease and its sequelae is controversial. Our group demonstrated that Bazedoxifene suppressed IL-6/gp130 signalling in cancer cells but its effect on myocardial pathology induced by pressure overload is still unknown. We explored whether Bazedoxifene could confer benefits in wild-type C57BL/6J mice suffering from transverse aortic constriction (TAC) and the potential mechanisms in H9c2 myoblasts. Mice were randomized into three groups (Sham, TAC, TAC+Bazedoxifene, n = 10). Morphological and histological observations suggested TAC aggravated myocardial remodelling while long-term intake of Bazedoxifene (5 mg/kg, intragastric) attenuated pressure overload-induced pathology. Echocardiographic results indicated Bazedoxifene rescued cardiac function in part. We found Bazedoxifene decreased the mRNA expression of IL-6, MMP2, Col1A1, Col3A1 and periostin in murine hearts after 8-week surgery. By Western blot detection, we found Bazedoxifene exhibited an inhibition of STAT3 activation in mice three hours and 8 weeks after TAC. Acute TAC stress (3 hours) led to down-regulated ratio of LC3-Ⅱ/LC3-Ⅰ, while in mice after long-term (8 weeks) TAC this ratio becomes higher than that in Sham mice. Bazedoxifene inverted the autophagic alteration induced by TAC at both two time-points. In H9c2 myoblasts, Bazedoxifene suppressed the IL-6-induced STAT3 activation. Moreover, IL-6 reduced the ratio of LC3-Ⅱ/LC3-Ⅰ, promoted P62 expression but Bazedoxifene reversed both changes in H9c2 cells. Our data suggested Bazedoxifene inhibited IL-6/gp130 signalling and protected against cardiac remodelling together with function deterioration in TAC mice. Copyright 2020 The Authors.