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  • In cancer cells HIF upregulates

    2022-05-25

    In cancer cells, HIF-1α upregulates HK-II expression by binding to the hypoxia-responsive element in the HK-II promoter region to adapt to hypoxic conditions [20]. In the present study, we observed that mangiferin transiently increased HIF-1α expression in endothelial cells, suggesting another possible way for mangiferin to regulate cellular glucose metabolism. Because vessel endothelium is located in a microenvironment rich with oxygen supply, further study is necessary to know if HIF-1α induction could regulate HK-II in endothelial cells. Because VDAC is a component of the mPTP multiprotein complex, HK-II binds to the outer mitochondrial membrane with the connection of VDAC and is essential for the maintenance of the barrier of the inner mitochondrial membrane. Long-lasting mPTP opening induces the collapse of mitochondrial membrane potential, and thus impairs cellular energy efficiency by increasing ATP consumption in a futile effort to restore mitochondrial membrane potential. HK-II binding to mitochondria acts as a negative regulator for mPTP opening and confers profound protection against cell death [27]. Mangiferin prevented mPTP opening by preserving HK-II binding to mitochondria and thereby restored the collapse of the mitochondrial membrane potential, demonstrating the protection of mitochondrial functional integrity. Both Bax and Bcl-2 are the Bcl-2 family of proteins. In response to mitochondrial dysfunction, Bax translocates from the cytosol to mitochondria, where Bax binds to VDAC to form a VDAC-Bax channel for the release of cytochrome c [28]. However, the pro-apoptotic action of Bax could be prevented by Bcl-2 [28]. Mangiferin reduced the increased expression ratio of Bax to Bcl-2 in PA-stimulated endothelial cells, demonstrating the potential to protect cell survival. HK-II competes with Bax for binding to VDAC1 and mitochondrial HK-II structurally interferes with the ability of Bax to translocate from the (S)-Mephenytoin and bind to VDAC1 [29]. Bax binding to VDAC1 results in cytochrome c release and initiates apoptotic signaling by activation of caspase-3. Mangiferin increased mitochondrial HK-II and this action should contribute to preventing Bax binding to the outer mitochondria. As expected, mangiferin reduced cytochrome c release into the cytosol and resultantly inhibited cell apoptosis by blocking caspase-3 activation. In view of the regulation of mitochondrial HK-II by Akt activation, it is convinced that mangiferin protected endothelial cell survival via regulation of Akt/HK-II. The above-mentioned evidence provides the mechanism of mangiferin in protection of mitochondrial function. Short-term HFD feeding elevated the levels of FFAs in the blood without affecting other metabolic parameters, enabling us to observe the direct impact of FFAs on vessel function. Similar to the regulation in endothelial cells, oral administration of mangiferin increased Akt translocation to mitochondria and thereby preserved mitochondrial HK-II. As a result from mitochondrial protection, mangiferin reduced caspase-3 expression and protected vessel endothelial integrity by inhibiting ROS generation and enhancing NO production, well demonstrating its action in the protection of vessel function in vivo. In the present study, we confirmed that mitochondrial HK-II is essential for mitochondrial functional integrity in vessel endothelial cells. Mangiferin promoted HK-II binding to mitochondria via Akt activation and protected endothelial cells' survival by ameliorating mitochondrial dysregulation. The proposed mechanistic regulation was shown in Fig. 9. This finding also suggested that Akt activation and mitochondrial HK-II might be the therapeutical target for the protection of endothelial integrity.
    Conflict of interest
    Transparency document
    Acknowledgements This work was supported by the National Natural Science Foundation of China (grant numbers 31271466 and 81573698); Hebei Education Department Foundation (grant numbers ZD2014005 and QN2015181); Hebei Provincial Administration of Traditional Chinese Medicine (grant number 2014005); Hebei University of Chinese Medicine Natural Science Foundation for the Youth (grant number QNZ2014016); and Hebei Agriculture Department Foundation (grant number 2014553962).