MHY1485

Chronic muscle fatigue is a condition characterized by debilitating muscle weakness and pain. Based on our recent finding to study the potential effect of mTOR on ATG13 inactivation in chronic muscle fatigue, we report that biweekly oral administration with MHY1485, a potent inducer of mTOR, develops chronic illness in mice resulting in severe muscle weakness. As a mechanism, we observed that MHY1485 feeding impaired ATG13-dependent autophagy, caused the infiltration of inflammatory M1 macrophages (Mφ), upregulated IL6 and RANTES by STAT3 activation, and augmented demyelination in muscle-serving nerve fibers. Interestingly, these mice displayed worsened muscle fatigue during 2-day post-treadmill exercise, suggesting the critical role of chronic mTOR activation in potential PEM pathogenesis. Interestingly, ATG13-repressor mice exhibited enhanced infiltration of M1Mφ cells, STAT3 activation, demyelination of nerve fibers, and PEM-like symptoms, suggesting the potential role of ATG13 impairment in post-exertional fatigue. HIGHLIGHTS: The potential role of mTOR activation in post-exertional fatigue is highlighted. As a molecular mechanism, mTOR activation augments autophagy impairment via ATG13 inactivation. Autophagy impairment induces IL-6 and RANTES via STAT3, demyelinates nerves in the muscle and spinal cord. ATG13 repressor mice (Tg-ATG13) displayed inflammatory demyelination and post-treadmill fatigue.

Breast cancer (BC) is one of the most prevalent malignant tumors among women, with estrogen receptor (ER)-positive patients constituting approximately 70 % of all cases. Endocrine therapy is currently a treatment option for patients with ER-positive BC; however, the development of resistance significantly limits the effectiveness of this treatment. Nano-curcumin (Nano-CUR) possesses anticancer properties and enhances bioavailability by improving the hydrophobic character of curcumin (CUR). However, the underlying mechanism by which Nano-CUR affects tamoxifen (TAM) resistance in ER-positive BC remains unknown. Here, we found that Nano-CUR promoted apoptosis and cell cycle arrest, inhibited cell proliferation and reduced the levels of cancer stem cells (CSCs)-related markers, including octamer-binding protein (OCT4), Nanog homeobox (NANOG) and sex-determining region Y-box 2 (SOX2) in TAM-resistant BC cells. Additionally, Nano-CUR demonstrated the ability to inhibit tumor malignant progression in TAM-treated BC mice. Mechanistically, Nano-CUR blocked the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in MCF-7/TAM and T47D/TAM cells. The activation of this pathway by its activators (PI3K activator 740Y-P, AKT activator SC-79, and mTOR activator MHY1485) effectively alleviated the anti-tumor effect induced by Nano-CUR in TAM-resistant BC cells. Collectively, these findings reveal that Nano-CUR contributes to the reduction of tumorigenesis and TAM resistance in ER-positive BC cells by inhibiting the PI3K/AKT/mTOR signaling pathway.