Hui Huang

Aims: Vascular endothelial senescence is a critical contributor to the development of cardiovascular disease and energy production deficiency plays a pivotal role in cellular senescence. Long noncoding RNAs (lncRNAs) are increasingly recognized as key regulators in biological aging processes. However, their involvement in energy metabolism and its relationship with endothelial senescence remains poorly understood. Methods and results: LncRNA microarray analysis was performed to profile lncRNAs using young and aged human aortas, and we identified a novel lncRNA, Aging Associated Transcript (lncAAT), which was predominantly localized in the nucleus of vascular endothelial cells and exhibited age-dependent increase. Endothelial-specific knockout of lncAAT in mice delayed vascular aging, enhanced endothelial-mediated vasodilation, and improved angiogenesis in a hindlimb-ischemia model. RNA-sequencing showed that lncAAT knockdown upregulated genes associated with energy metabolism including glycolysis and oxidative phosphorylation. LncAAT overexpression mediated fall in energy production led to endothelial senescence in vivo and in vitro. Mechanistically, lncRNA pulldown in combination with liquid chromatography–tandem mass spectrometry analysis found that AAT interacted with pyruvate kinase isozyme type M2 (PKM2) located at the nucleus. The lncAAT-PKM2 complex competitively blocked the interaction between PKM2 and STAT3, impairing energy metabolism gene transcription and ultimately leading to endothelial senescence. Conclusion: Our current findings firstly reveal the essential role of lncAAT in promoting vascular endothelial senescence through defective energy metabolism. Inhibition of lncAAT expression presents a promising therapeutic strategy for alleviating vascular aging and reducing the burden of cardiovascular diseases in humans.

Background: Chronic kidney disease affects more than 10% of the global population and is associated with elevated Parkinson’s disease risk, substantially compromising patients’ quality of life. However, the precise pathophysiological mechanisms underlying this association remain unclear. This review aims to synthesize current evidence and explore the potential pathophysiological mechanisms linking chronic kidney disease to the pathogenesis of Parkinson’s disease. Main Body: Hyperhomocysteinemia, characterized by elevated homocysteine levels, is a common metabolic disturbance in both chronic kidney disease and Parkinson’s disease. In CKD, impaired renal clearance and metabolic dysfunction lead to homocysteine accumulation. This review examines the hypothesis that hyperhomocysteinemia serves as a key biochemical mediator, linking the two diseases by driving neurodegenerative processes central to Parkinson’s disease pathogenesis, including oxidative stress, chronic neuroinflammation, and neuronal apoptosis, which culminate in dopaminergic neurodegeneration. Conclusions: This review delineates the pathogenic pathways linking CKD to Parkinson’s disease through hyperhomocysteinemia, positioning it as a plausible and actionable intermediary. Addressing hyperhomocysteinemia has emerged as a rational strategy with the potential to elucidate disease mechanisms and mitigate Parkinson’s disease risk in the vulnerable chronic kidney disease population.

Aortic arch calcification (AoAC) is an established independent predictor of coronary heart disease and broader cardiovascular outcomes. We have developed a

Osteoarthritis (OA) is driven by a vicious cycle of inflammation and reactive oxygen species (ROS). While cobalt‐based metal‐organic framework (MOF) nanozymes are potent catalase (CAT) mimics, their therapeutic efficacy is crippled by an inherently weak superoxide dismutase (SOD)‐like activity that prevents full‐chain ROS scavenging. Here, we resolve this imbalance through an innovative “pre‐embedding/activation” strategy. This approach involves pre‐embedding Zn ²⁺ into a cobalt‐based framework to create a stable yet activatable precursor. The subsequent dopamine (DA)‐driven “activation” then remodels the latent Zn/Co‐N coordination sites, unlocking an efficient SOD‐to‐CAT catalytic relay by synergistically amplifying the SOD‐like activity for seamless elimination of the entire ROS cascade. This powerful scavenging capability restores mitochondrial function and reprograms macrophages toward an anti‐inflammatory M2 phenotype by inhibiting the ROS‐mediated S100A8/NF‐κB signaling axis and its destructive positive feedback loop. The resulting immunomodulation translates to profound therapeutic outcomes in a rat OA model, where it simultaneously promotes chondrocyte anabolism to achieve significant cartilage repair while suppressing peripheral nerve sensitization to provide sustained pain relief. Our work thus establishes nanoscale interfacial reconstruction as a powerful and rational platform for engineering sophisticated catalytic relays within nanozymes for advanced biomedical applications.

Atrial fibrillation (AF) is a common arrhythmia associated with increased risks of stroke and heart failure. Early differentiation between paroxysmal and p

Osteoporosis represents a major health challenge in aging populations, yet its diagnosis largely depends on dual-energy X-ray absorptiometry (DXA), which i

BACKGROUND: As an iron-dependent form of regulated cell death caused by lipid peroxidation, ferroptosis has been implicated in ischemic injury, but the underlying mechanisms in acute myocardial infarction (AMI) remain poorly defined. ALDH2 (acetaldehyde dehydrogenase 2) catalyzes detoxification of lipid aldehydes derived from lipid peroxidation and acetaldehydes from alcohol consumption. The Glu504Lys polymorphism of ALDH2 (rs671, ALDH2*2), affecting ≈40% of East Asians, is associated with increased risk of myocardial infarction (MI). This study aims to investigate the role of ALDH2*2 and ferroptosis in AMI. METHODS: A Chinese cohort of 177 patients with acute heart failure with ALDH2 wild type and ALDH2*2 was enrolled. The MI mouse model of left anterior descending coronary artery ligation was conducted on wild-type and ALDH2*2 mice and mice with cardiomyocyte-specific knockdown of eIF3E (eukaryotic translation initiation factor 3 subunit E) by adeno-associated virus. The lipid peroxidation products were measured by mass spectrometry–based lipidomics and metabolomics in human plasma, mouse serum samples, mouse heart tissues, and primary cardiac myocytes. RESULTS: Human ALDH2*2 carriers exhibit more severe heart failure after AMI with features of ferroptosis in plasma, as seen through lipidomic analysis, characterized by increased bioactive lipids and decreased antioxidants, such as coenzyme Q10 and BH4 (tetrahydrobiopterin). Similar features were observed in MI mouse models of ALDH2*2, whereas ferroptosis inhibition by Fer-1 significantly improved heart function and reversed ferroptosis markers. Importantly, ALDH2*2 significantly decreased ALDH2 protein levels, whereas ferroptosis-related markers, including TFRC (transferrin receptor) and ACSL4 (acyl-coenzyme A synthetase long-chain family member 4) were notably upregulated in the infarct heart tissues. Mechanistically, ALDH2 physically interacts with the eIF3 complex via the eIF3E factor, which prevents eIF3E-eIF4G1 (eukaryotic initiation factor 4G)-mRNA assembly. The ALDH2*2 variant causes ALDH2 deficiency, disrupting its interaction with the eIF3 complex by releasing the bound eIF3E to assemble an eIF3E-eIF4G1-mRNA ternary complex, thereby driving selective translation of mRNAs (eg, TFRC, ACSL4, and UAP1) containing the GAGGACR (R represents A/G) motif to promote ferroptosis. Consistently, cardiomyocyte-specific eIF3E knockdown restored ALDH2*2 cardiac function by attenuating ferroptosis in MI. CONCLUSIONS: ALDH2*2 aggravates acute heart failure after MI by promoting the selective translation of mRNAs containing the GAGGACR motif, thereby driving cardiomyocyte ferroptosis. Targeting ferroptosis represents a potential therapeutic option for mitigating MI injury, especially for ALDH2*2 carriers.

Vascular calcification is highly associated with cardiovascular morbidity and mortality among patients with chronic kidney disease (CKD). Despite its clinical severity, no effective therapies exist to halt its progression. Sirtuin 6 (SIRT6) has recently emerged as a promising therapeutic target for vascular calcification. Our prior work demonstrated that SIRT6 activation inhibits vascular calcification by attenuating the osteogenic trans differentiation of vascular smooth muscle cells (VSMCs). While the natural compound cyanidin can activate SIRT6, its clinical translation is hampered by poor bioavailability and the absence of targeted delivery systems. To address this, we developed a dual targeting nanoplatform (TROC) based on Ti₃C₂ nanosheets co‐assembled with osteocalcin (OCN) and RANKL antibodies for the targeted delivery of cyanidin. Leveraging data from the Framingham Heart Study offspring cohort and in vitro VSMC models, we first established dietary anthocyanins as an independent protective factor against aortic calcification. We then demonstrated that TROC exhibits excellent stability and dose‐dependently reduces calcium deposition in VSMCs. Furthermore, in vivo fluorescence and computed tomography (CT) multimodal imaging confirmed the selective accumulation of TROC at calcification sites and its efficacy in alleviating vascular calcification. This novel drug delivery system represents a promising strategy for advancing the clinical treatment of Vascular calcification.

Vascular calcification (VC) is a critical vascular pathological event, contributing to the rise in both the prevalence and fatality of cardiovascular diseases. However, the lack of effective therapeutic strategies for VC is attributed primarily to the incomplete understanding of its underlying molecular mechanisms. In this study, we discovered that long interspersed nuclear element 1 (LINE1) was significantly upregulated in the calcified arteries of both human individuals and mouse models. Mechanistically, silencing LINE1 expression or inhibiting its activity with adding nucleoside reverse transcriptase inhibitors (NRTIs, a class of validated LINE1 inhibitors) effectively prevented the osteogenic reprogramming of vascular smooth muscle cells (VSMCs). Moreover, NRTIs treatment substantially mitigated VC in chronic kidney disease (CKD)-induced and vitamin D₃-overloaded VC mouse models. RNA sequencing analysis revealed that LINE1 depletion (via small interfering RNA) or NRTIs intervention downregulated the cGAS-STING signaling pathway and its associated inflammatory genes in VSMCs. Functional validation revealed that stimulation of the cGAS‒STING pathway exacerbated VC, whereas its pharmacological inhibition alleviated VC. Notably, we identified LINE1-derived cDNA as a direct activator of the cGAS‒STING pathway, demonstrating that LINE1 inhibition suppresses VC by blocking cGAS‒STING activation and subsequent inflammatory responses. Clinically, a cross-sectional study involving 1,785 participants revealed that patients receiving NRTIs therapy presented a significantly lower incidence of VC and reduced calcification scores. Multivariate logistic regression analysis further confirmed that NRTIs use is an independent protective factor against VC incidence and progression. Collectively, these findings establish LINE1 as promising therapeutic targets for VC and highlight NRTIs as potential candidates for developing novel strategies against VC.

Aims Atrial fibrillation (AF) is a common arrhythmia associated with increased risks of stroke and heart failure. Early differentiation between paroxysmal and persistent AF at first diagnosis is critical for guiding treatment decisions. This study aimed to develop an interpretable machine learning model based on structured electronic health records (EHR) to distinguish AF subtypes and identify key contributing factors. Methods and results In this multicenter, retrospective cohort study, data were collected from three tertiary hospitals in China between January 2013 and January 2023. A total of 11,986 patients with suspected AF were screened, of whom 4155 patients with first-diagnosed AF were included (paroxysmal: 2565 [61.3%]; persistent: 1620 [38.7%]). Structured EHR variables including clinical demographics, serological indicators, and echocardiographic parameters were extracted. Variable selection was performed using Spearman correlation and least absolute shrinkage and selection operator regression. Three machine learning algorithms were trained and externally validated. The CatBoost model achieved the best performance, with an area under the receiver operating characteristic curve of 0.876 (95% CI: 0.871–0.880) and accuracy of 0.808 (95% CI: 0.803–0.816). Sensitivity and specificity ranged from 0.802 to 0.811. Shapley additive explanations (SHAP) were used to interpret model outputs and identify variables most associated with AF subtype classification. Conclusion This multicenter study demonstrates that interpretable machine learning models based on structured EHR data can accurately distinguish paroxysmal from persistent AF at first diagnosis. The proposed model may facilitate early subtype-specific risk stratification and personalized treatment, potentially improve outcomes and reduce disparities in AF care across different medical conditions.