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Background: Hyperoside (quercetin-3-O-β-D-galactopyranoside) is a flavonol glycoside compound derived from plants in the Hypericum and Crataegus genera that reportedly exhibits an array of anti-inflammatory, antioxidant, and antitumor properties such that it has been used to treat various diseases. Whether it can serve as an effective treatment for chronic myeloid leukemia (CML) cells, however, has yet to be established. The present study was thus devised to assess the therapeutic effects of hyperoside on CML cells and to clarify the underlying mechanism of action., Methods: Cellular viability, proliferative activity, migration, and apoptotic death were respectively analyzed through CCK-8, EDU, transwell, and flow cytometry assays. RNA-seq and bioinformatics approaches were further employed to evaluate the mechanisms through which hyperoside influences CML cells, while analyses of reactive oxygen species (ROS) and free iron were detected with commercial kits. Transmission electron microscopy was used to assess mitochondrial morphology. Molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) approaches were also used to explore the ability of hyperoside to target NRF2., Results: From a mechanistic perspective, hyperoside was able to inhibit SLC7A11/GPX4 signaling in a manner that was abrogated by the ferroptosis inhibitor ferrostatin-1. NRF2 was also closely associated with the inactivation of the SLC7A11/GPX4 axis mediated by hyperoside such that overexpressing NRF2 ablated the benefits associated with hyperoside treatment., Conclusions: The present analyses indicate that hyperoside can target the NRF2/SLC7A11/GPX4 axis to induce ferroptotic CML cell death., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Vascular calcification is a complication that is frequently encountered in patients affected by atherosclerosis, diabetes, and chronic kidney disease (CKD), and that is characterized by the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). At present, there remains a pressing lack of any effective therapies that can treat this condition. The sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin (DAPA) has shown beneficial effects in cardiovascular disease. The role of this inhibitor in the context of vascular calcification, however, remains largely uncharacterized. Our findings revealed that DAPA treatment was sufficient to alleviate in vitro and in vivo osteogenic transdifferentiation and vascular calcification. Interestingly, our study demonstrated that DAPA exerts its anti-calcification effects on VSMCs by directly targeting SGLT2, with the overexpression of SGLT2 being sufficient to attenuate these beneficial effects. DAPA was also able to limit the glucose levels and NAD + /NADH ratio in calcified VSMCs, upregulating sirtuin 1 (SIRT1) in a caloric restriction (CR)-dependent manner. The SIRT1-specific siRNA and the SIRT1 inhibitor EX527 attenuated the anti-calcification effects of DAPA treatment. DAPA was also to drive SIRT1-mediated deacetylation and consequent degradation of hypoxia-inducible factor-1α (HIF-1α). The use of cobalt chloride and proteasome inhibitor MG132 to preserve HIF-1α stability mitigated the anti-calcification activity of DAPA. These analyses revealed that the DAPA/SGLT2/SIRT1 axis may therefore represent a viable novel approach to treating vascular calcification, offering new insights into how SGLT2 inhibitors may help prevent and treat vascular calcification., (© 2024. The Author(s).)

Mounting evidence suggests that intraplaque angiogenesis is associated with the progression of atherosclerotic plaques and the development of intraplaque hemorrhage. The specificity of intraplaque immune cell infiltration may be associated with abnormalities in the structure and function of the nascent capillaries. Here, we analyzed expression levels of angiogenesis-associated genes in early and advanced carotid atheromatous plaque tissues as well as in stable and intraplaque hemorrhage plaques. Expression profiles of advanced arterial plaques based on angiogenesis-associated genes were classified into subtypes by performing a consensus clustering analysis. The correlation between the immune microenvironment of plaques and expression of angiogenesis-associated genes was also explored using the single sample gene set enrichment analysis method and the CIBERSORT algorithm. We identified hub angiogenesis-associated genes showing similar expression patterns throughout plaque adverse progression, and constructed a prediction model using the random forest algorithm. Receiver operating curves were constructed to evaluate efficacy in identification of intraplaque hemorrhage in a plaque. Our results suggest that heterogeneity of angiogenesis-related genes may promote the malignant development of plaques and cause plaque rupture. In conclusion, we propose a model based on expression of angiogenesis-related genes to predict the risk of plaque rupture., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)