Inhibiting neuronal ferroptosis is essential for mitigating neural damage and enhancing recovery in central nervous system (CNS) disorders, including intracerebral hemorrhagic stroke (ICH). Lactate accumulation correlates with ICH severity, yet the role of lactate-derived histone lactylation, a novel epigenetic modification, in ferroptosis and its mechanisms is not fully understood. In this study, we aimed to investigate the role of histone lactylation on neuronal ferroptosis in ICH models, both in vitro and in vivo. We discovered elevated lactate and histone lactylation post-ICH in mice, with a significant increase in H3K14la during the early stages of ferroptosis in hemin-challenged primary cortical neurons. Pharmacological or genetic inhibition of H3K14la by targeting lactate dehydrogenase (LDH) enzyme activity effectively suppressed neuronal ferroptosis. We further identified p300/CBP and class I histone deacetylases (HDACs) as the key modifiers of H3K14la in this process. Through chromatin immunoprecipitation-sequencing and RNA-sequencing (RNA-seq) in hemin-treated neurons, we pinpointed the Ca²⁺-ATPase PMCA2 encoding gene as a direct downstream target of H3K14la. H3K14la/PMCA2 promoted ferroptosis by elevating intracellular calcium levels. In line with our in vitro findings, inhibiting H3K14la/PMCA2 reduced neuronal degeneration and improved functional outcomes in an ICH mouse model induced by intracranial injection of collagenase into the striatum. Taken together, our findings elucidate the role of histone lactylation and PMCA2 in neuronal ferroptosis and implicate that targeting histone lactylation could be a promising therapeutic strategy for ICH and related CNS diseases.

The diagnosis and management of aortic dissection (AD), a critical cardiovascular disease (CVD), remains significant challenges in clinical practice. PIWI-interacting RNAs (piRNAs), a newly discovered class of non-coding small RNAs, play key regulatory role in various CVDs. However, the mechanism of their action in AD remains unclear. Through sequencing of aortic clinical samples from AD patients, we identified piRNA-0228 (piR-0228) as the most significantly downregulated piRNA in AD patients compared with healthy populations. Overexpression and knockdown of piR-0228 in mouse monocyte macrophage leukemia cells (RAW264.7) and aortic vascular smooth muscle cells (VSMCs) revealed that piR-0228 regulates key cytopathic processes, primarily involving inflammatory response and necrosis, driven by stimulator of interferon genes (STING) pathway. Bioinformatics analysis and validation demonstrated that receptor-interacting protein kinase 1 (RIPK1) was a direct target gene of piR-0228, confirmed by both in vivo and in vitro studies. Finally, in an AD animal model, we observed that piR-0228 agomir significantly reduced mortality, morbidity, inflammation and vascular remodeling, demonstrating the effective therapy of piR-0228 agomir in reversing the disease's pathological progression. Therefore, our findings establish piR-0228 as a promising therapeutic target for AD and provide valuable insights for the future development of clinical treatment strategies for this condition.

Drug-induced liver injury (DILI), which results from pharmaceuticals or their metabolites, is intricately associated with oxidative stress and is the most common liver disease. Biothiols play pivotal roles in maintaining redox homeostasis, cellular signalling, and cell growth. Moreover, alterations in biothiols levels are closely correlated with various health complications triggered by oxidative stress, including cardiovascular disorders, neurodegenerative diseases, and cancer. Consequently, developing strategies for the rapid and accurate detection of biothiols has garnered significant attention in clinical diagnostics.

Based on our previous work, we have rationally constructed a novel activatable red-emitting fluorescent probe featuring α, β-unsaturated acrylate as a recognition unit for the detection of biological thiols for the first time. Upon reaction with biothiols, the probe exhibits significant fluorescence enhancement at 625 nm. Furthermore, the excellent selectivity, sensitivity, and low cytotoxicity of FR-10C establish it as a potent tool for biothiols detection in complex biological systems. Moreover, zebrafish experiments and the DILI mouse model were employed to evaluate the potential of FR-10C to detect biothiols in living organisms, which proved its sensitive detection ability of changes in biothiols level in dynamic biological environments.

The successful design of this probe has unveiled a promising avenue for advancing thiol-activatable fluorescent probes which highlights the potential of the α, β-unsaturated acrylate unit as a novel and specific recognition moiety for thiols.

Type 2 myocardial infarction (T2MI) occurs due to an imbalance between coronary blood supply and myocardial oxygen demand, leading to ischemia without the rupture of an atherosclerotic plaque, distinguishing it from Type 1 myocardial infarction (T1MI). Although T2MI is frequently diagnosed in clinical practice and associated with a poor prognosis, there is limited understanding of the sex differences in this condition, despite women representing a higher proportion of T2MI cases compared to T1MI. This review explores the definitions, epidemiological aspects, and clinical scenarios that reveal significant differences in T2MI between men and women that contribute to disparities in outcomes. It examines the unique roles that sex and gender play in the development, presentation, and diagnosis of T2MI, emphasizing the need for greater awareness of these factors. Understanding how these differences contribute to this condition is essential for developing patient-tailored approaches to managing this often-undervalued disease and improving outcomes.

Resistant hypertension (RH) remains a major cardiovascular challenge despite optimal pharmacological treatment. Intermittent fasting (IF) has demonstrated beneficial effects in various diseases, but its impact on RH and the underlying mechanisms remain unclear. In this study, we explored the effects of a 2-week IF regimen (16-hour fasting/8-hour eating) on RH patients and spontaneously hypertensive rats (SHRs) resistant to antihypertensive drugs. We found that IF significantly reduced blood pressure in RH patients, accompanied by a shift in the gut microbiota, including increased abundance of Akkermansia muciniphila and Adlercreutzia equolifaciens. These microbiota alterations were correlated with a decrease in lipopolysaccharide (LPS) and trimethylamine-N-oxide (TMAO) levels, and an increase in short-chain fatty acids (SCFAs). Furthermore, fecal microbiota transplantation (FMT) from drug-resistant SHRs successfully transferred both hypertension and impaired drug efficacy to recipient rats. Supplementation with Akkermansia muciniphila and Adlercreutzia equolifaciens significantly lowered blood pressure in SHR rats resistant to antihypertensive drugs. In RH patients, oral supplementation with Akkermansia muciniphila reduced blood pressure and normalized LPS, TMAO, and SCFA levels. Our findings provide both clinical and mechanistic evidence supporting IF and A. muciniphila supplementation as promising non-pharmacological approaches for managing resistant hypertension.

Cardiovascular diseases (CVDs) remain the leading cause of global mortality, accounting for 32 % of deaths worldwide in 2021. The increasing prevalence of CVDs highlights the urgent need for novel diagnostic and therapeutic approaches. Circular RNAs (circRNAs), a class of single-stranded RNA molecules produced via back-splicing, have gained attention as potential biomarkers and therapeutic targets due to their distinctive features. Unlike linear RNAs, circRNAs lack 5' caps and 3' poly(A) tails, making them highly resistant to exonuclease degradation and granting them an extended half-life of 19-24 h. Their stability, tissue- and disease-specific expression, evolutionary conservation, and responsiveness to pathological stimuli enable them to regulate key biological processes such as apoptosis, metabolism, and inflammation. Growing evidence links circRNAs to CVD pathogenesis: in cardiomyopathies, circHIPK3 and circFndc3b contribute to hypertrophy and diastolic dysfunction through miR-30a sponging and SERCA2a inhibition; in atherosclerosis, circANRIL exhibits protective effects by modulating ribosomal RNA synthesis and vascular smooth muscle cell proliferation; after myocardial infarction, circZNF609 reduces inflammation while circFndc3b helps prevent apoptosis; and in hypertension, downregulation of hsa-circ-0005870 serves as a specific biomarker. This review further explores circRNAs' diagnostic potential in biofluids, such as serum circHIPK3 for myocardial injury, and their therapeutic applications through silencing with antisense oligonucleotides or delivery of protective mimetics. Despite promising advances, challenges remain, including achieving tissue-specific delivery and addressing the complex pleiotropic effects of circRNAs. Successfully integrating circRNA-based tools into clinical practice could transform CVD management by enabling earlier detection and more personalized treatment strategies.

Amyloidoses are a group of diseases characterized by the pathological deposition of non-degradable misfolded protein fibrils, including those associated with plasma cell neoplasias, chronic inflammatory conditions, and age-related disorders, among others. Precise identification of the fibril-forming and thereby amyloidosis type defining protein is crucial for prognosis and correct therapeutic intervention. While immunohistochemistry (IHC) is widely used for amyloid typing, it requires extensive interpretation expertise and can be limited by inconclusive staining results. Thus, mass spectrometry (MS), if available, has been proposed as the preferred method for amyloid typing by international specialized centers (USA, UK) using primarily spectral counts for quantification. Here, we introduce an alternative method of relative quantification to further enhance the accuracy and reliability of proteomic amyloid typing. We analyzed 62 formalin-fixed, paraffin-embedded (FFPE) tissue samples, primarily endomyocardial biopsies, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and employed internal normalization of iBAQ values of amyloid-related proteins relative to serum amyloid P component (APCS) for amyloidosis typing. The APCS method demonstrated robust performance across multiple LC-MS/MS platforms and achieved complete concordance with clear cut IHC typed amyloidosis cases. More importantly, it resolved unclear amyloid cases with inconclusive staining results. Additionally, for samples without a distinct fibril-forming protein identified in the standard procedure, de novo sequencing uncovered immunoglobulin light chain components, enabling the diagnosis of rare AL-amyloidosis subtypes. Finally, we established machine learning approach (XGBoost) achieving 94% accuracy by using ∼160 amyloid-related proteins as input variables. In summary, the iBAQ APCS normalization method extended by de novo sequencing allows robust, accurate, and reliable diagnostic amyloid typing, and can be complemented by an AI-based classification. Careful reviewing of each histological sample and the clinical context, nevertheless, remains indispensable for accurate interpretation.

This study employed a network toxicology strategy to elucidate the toxic mechanisms of polyethylene terephthalate microplastics (PET-MPs) on atherosclerosis (AS). AS is a chronic inflammatory vascular disease that may be aggravated by PET-MPs. By integrating network toxicology, molecular docking, and transcriptome analysis, tumor necrosis factor (TNF), chemokine receptor 4 (CXCR4), CX3C chemokine receptor 1 (CX3CR1), and protein tyrosine phosphatase receptor type C (PTPRC) were identified as core interaction genes between PET and AS. Through bio-enrichment analysis, we discovered that the toxicity of PET is primarily associated with the cascade reaction of vascular inflammation and abnormal macrophage activation. Molecular docking experiments confirmed a strong binding affinity between PET and these targets (<-5.0 kcal/mol). In vitro results showed that PET significantly increased the mRNA levels of TNF-α, CXCR4, CX3CR1, and PTPRC, triggering an inflammatory response and causing chemokine receptor dysfunction. In an AS mouse model, increased aortic plaque area and aortic valve collagen deposition were observed, along with elevated expression of core target genes' mRNA, even without direct exposure to PET-MPs, exhibiting effects consistent with those seen in vitro. Collectively, these studies suggest that PET can induce inflammatory responses and disrupt immune system balance by regulating the expression levels of TNF, CXCR4, CX3CR1, and PTPRC, thus promoting the progression of atherosclerotic diseases. This paper provides the first comprehensive investigation into the impact and mechanisms of microplastics on AS, demonstrating how PET contributes to its development and establishing a basis for identifying new therapeutic targets for cardiovascular diseases linked to microplastics.

Understanding the distribution and variation in NMR-based inflammatory markers is crucial to the evaluation of their clinical utility in disease prognosis and diagnosis. We applied high-resolution ¹H NMR spectroscopy of blood plasma and serum to measure the acute phase reactive glycoprotein signals (GlycA and GlycB) and the subregions of the lipoprotein-based Supramolecular Phospholipid Composite signals (SPC₁, SPC₂, and SPC₃) in a large multicohort population study. A total of 5702 samples were studied to determine the signal variations in a range of chronic and acute inflammatory conditions. We found that while GlycA and GlycB were increased in inflammation, the SPC regions behaved independently of Glyc signals, with SPC₂ and SPC₃ being reduced in chronic inflammation in comparison to healthy controls (p-value SPC₂ = 2.9 × 10^-10, p-value SPC₃ = 2.2 × 10^-3) and SPC₁ (p-value = 0.29) being unchanged. SPC₁ was decreased in acute inflammation, indicating a link to the immune response (p-value = 2.5 × 10^-11). These findings confirm the independent biological relevance of all three SPC subregions and contraindicate the use of aggregate SPC values as general inflammatory markers.

Previous studies evaluating the influence of inter-hospital transfer on mortality in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI) reported conflicting results. The multicenter BRIGHT-4 trial demonstrated that bivalirudin plus a post-PCI high-dose infusion (1.75 mg/kg/h) reduced the 30-day primary endpoint of all-cause mortality or Bleeding Academic Research Consortium (BARC) types 3-5 bleeding compared with heparin monotherapy in STEMI patients. This study aimed to assess the impact of inter-hospital transfer on clinical outcomes and the effectiveness of bivalirudin versus heparin in STEMI patients undergoing PCI.

In BRIGHT-4, 2,121 (35.7%) patients were transferred to a tertiary hospital for primary PCI while 3,817 (64.3%) were directly admitted to an interventional facility. The primary outcome was the composite of all-cause death or BARC types 3-5 bleeding occurring within 30 days. The secondary outcomes included stent thrombosis. Adjustments were made for baseline covariates and randomized treatments. Transferred patients had a longer median time from symptom onset to wire crossing the infarct-related artery (6.00 versus 3.93 hrs, P < 0.0001). At 30 days, there were no significant between-group differences in the rates of the primary outcome (4.2% versus 3.4%, adjusted hazard ratio [HR] 0.99, 95% confidence intervals [CI] 0.73, 1.33, P = 0.94) or its components. Bivalirudin with a high-dose post-PCI infusion was associated with consistent reductions of the primary outcome in the transfer (3.5% versus 4.8%, adjusted HR 0.66, 95%CI 0.42, 1.05) and direct admission (2.8% versus 4.1%, adjusted HR 0.62, 95% CI 0.43, 0.89) group compared with heparin monotherapy (Pinteraction = 0.78), as well as individually for stent thrombosis. The main limitations of this study are that it is a post hoc analysis, and the long-term prognostic impact of transfer on STEMI patients requires further investigation.

In this post hoc analysis, 30-day clinical outcomes for STEMI patients transferred for PCI were not significantly worse than direct admission patients. Bivalirudin with a post-PCI high-dose infusion for 2-4 hrs was associated with lower rates of 30-day all-cause mortality, major bleeding and stent thrombosis, consistently observed in transfer and direct admission patients.

BRIGHT-4 trial NCT03822975 http://www.clinicaltrials.gov.