Dehydrocorydaline (DHC), an active component of Corydalis yanhusuo (Y.H. Chou & Chun C. Hsu) W.T. Wang ex Z.Y. Su & C.Y. Wu (Papaveraceae), exhibits protective and pain-relieving effects on coronary heart disease, but the underlying mechanism still remains unknown. Network pharmacology and experimental validation both in vivo and in vitro were applied to assess whether DHC can treat myocardial ischemia-reperfusion injury (MIRI) by regulating the forkhead box O (FoxO) signalling pathway to inhibit apoptosis. DHC and MIRI targets were retrieved from various databases. Molecular docking and microscale thermophoresis (MST) determined potential binding affinity. An in vivo mouse model of MIRI was established by ligating the left anterior descending coronary artery. C57BL/6N mice were divided into sham, MIRI, and DHC (intraperitoneal injection of 5 mg/kg DHC) groups. Haematoxylin and eosin, Masson, and immunohistochemical stainings verified DHC treatment effects and the involved signalling pathways. In vitro, H9c2 cells were incubated with DHC and underwent hypoxia/reoxygenation. TUNEL, JC-1, and reactive oxygen species stainings and western blots were used to explore the protective effects of DHC and the underlying mechanisms. Venny analysis identified 120 common targets from 121 DHC and 23,354 MIRI targets. DHC exhibited high affinity for CCND1, CDK2, and MDM2 (<-7 kcal/mol). In vivo, DHC attenuated decreases in left ventricular ejection fraction and fractional shortening, reduced infarct sizes, and decreased cTnI and lactate dehydrogenase levels. In vitro, DHC alleviated apoptosis and oxidative stress in the hypoxia/reoxygenation model by attenuating ΔΨm disruption; reducing the production of reactive oxygen species; upregulating Bax and CCND1 via the FoxO signalling pathway, as well as cleaved-caspase 8; downregulating the apoptosis-associated proteins Bcl-2, Bid, cleaved-caspase 3, and cleaved-caspase 9; and promoting the phosphorylation of FOXO1A and MDM2. By upregulating the FoxO signaling pathway to inhibit apoptosis, DHC exerts a cardioprotective effect, which could serve as a potential therapeutic option for MIRI.

Panax notoginseng saponin (PNS) has shown potent activities in treating patients with atherosclerosis (AS), whereas its immunometabolic mechanism remained unknown. To elucidate the characteristics of metabolomics of AS plaque and identify immunometabolic mechanisms of PNS in treating AS. PNS components were characterized using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MSE). Spatial Metabolomics was performed to reveal characteristics of plaque from atherosclerosis patients. Then we verified different glycolysis and sphingolipid metabolites between chronic coronary disease (CCD) patients and health control (HC). In vivo and in vitro experiments were performed to study the relationship among hypoxia-inducible factor-1 α (Hif-1α), glycolysis, and macrophage polarization, as well as the protective role and underlying mechanism of PNS in AS. Among 8058 metabolites, 117 metabolites were greatly downregulated and 355 metabolites were remarkably upregulated in the plaque area. Sphingolipid metabolism ranked the top according to KEGG analysis, among which sphingosine-1-phosphate (S1P) and specifically sphingomyelin (SPH) were significantly reduced in CCD patients. Overexpression of Hif-1α could induce macrophage M1 polarization, enhance glycolysis, promote excessive UDP-glucose ceramide glucosyltransferase (UGCG) production, and reduce S1P, resulting in a proinflammatory response. Chemical characterization of PNS verified the presence of the principal saponins (R1, Rg1, Rb1, Rd, Re), which subsequently was shown to act as a novel Hif-1α inhibitor, exerting its anti-atherosclerotic effects through multiple pathways, specifically, downregulating key glycolytic regulators (PFKFB3, GLUT1, HK2) and suppressing downstream glycolysis; promoting the expression of MRC1/iNOS to inhibit M1 macrophage polarization; upregulating S1P to modulate sphingolipid metabolism, thereby alleviating AS. These findings emphasize the anti-AS effects of PNS through a novel immunometabolic mechanism, particularly its role as a Hif-1α inhibitor that disrupts such pathways driving AS progression.

1. Aortic stenosis is one of the most common valvular heart diseases in elderly populations, with a prevalence of moderate-to-severe disease reaching over 3% in individuals aged ≥75 years [1,2]. Ch...

The prevention and management of degenerative heart disease remain challenging and could potentially be significantly improved by understanding of ageing biomarker dynamics. In this study, we constructed the calcific aortic valve mouse model at different age points, measured valve function degeneration along with valve calcification, and investigated the nonlinear dynamics using sequencing data and deep learning models. In C57BL/6 N mouse model, the older mice had higher levels of peak transvalvular jet velocity in terms of valve function. Regarding valve calcification, collagen and elastic fiber calcification in the middle layer increased significantly at 48-week-old (p < 0.001), and the calcification spread to the inner endothelial cells at 72-week-old (p < 0.0001). RNA sequencing illustrated that 30 genes, including Acadsb, L2hgdh, and Cpped1, showed increased expression with age. Among them, four genes, namely Hipk2, 9430069I07Rik, Peli3, and Slc22a12, increased more than threefold in aortic tissues in 72-week-old mice compared to 6-week-old mice. Moreover, a large proportion of genes changed in a nonlinear pattern (6,325 out of 12,160, 52%). In conclusion, both linear and nonlinear gero-markers were found in the calcific aortic valve mouse modeling, which highlighted specific periods of significant wave with accelerated ageing (48-week-old in mice).

Endothelial-to-mesenchymal transition (EndMT) is an endothelial plasticity program that contributes to vascular remodeling, inflammation, extracellular matrix remodeling, calcification, and plaque instability in atherosclerosis. Recent lineage-tracing, single-cell RNA sequencing, and spatial transcriptomic studies have revealed that EndMT is not a uniform or irreversible process, but rather a spectrum of partial, intermediate, and advanced endothelial transition states with stage- and region-specific effects. During atherosclerosis, EndMT may participate in lesion initiation, plaque progression, fibrous cap remodeling, and advanced plaque vulnerability. Mechanistically, EndMT is regulated by interconnected metabolic, signaling, transcriptional, epigenetic, and biomechanical pathways, including TGF-β/SMAD, FGF/FGFR1, BMP, Notch, Wnt/β-catenin, KLF2/KLF4, glycolysis–lactate–lactylation, fatty acid oxidation, HDACs, non-coding RNAs, and extracellular vesicle-mediated communication. Therapeutically, EndMT-targeted strategies should aim to prevent or reverse early maladaptive EndMT while selectively restraining sustained inflammatory, osteogenic, fibroblast-like, or matrix-degrading EndMT states. However, clinical translation remains limited by marker nonspecificity, vascular-bed heterogeneity, disease-stage dependence, inadequate modeling of human plaque rupture, and the lack of validated biomarkers. Future integration of lineage tracing, single-cell and spatial multi-omics, human-relevant models, plaque-risk stratification, and targeted delivery systems may enable precise modulation of EndMT to slow atherosclerosis progression and improve plaque stability.