BACKGROUND: Adult mammalian cardiomyocytes have limited proliferative capacity, but in specifically induced contexts they traverse through cell-cycle reentry, offering the potential for heart regeneration. Endogenous cardiomyocyte proliferation is preceded by cardiomyocyte dedifferentiation (CMDD), wherein adult cardiomyocytes revert to a less matured state that is distinct from the classical myocardial fetal stress gene response associated with heart failure. However, very little is known about CMDD as a defined cardiomyocyte cell state in transition. METHODS: Here, we leveraged 2 models of in vitro cultured adult mouse cardiomyocytes and in vivo adeno-associated virus serotype 9 cardiomyocyte–targeted delivery of reprogramming factors ( Oct4 , Sox2 , Klf4 , and Myc ) in adult mice to study CMDD. We profiled their transcriptomes using RNA sequencing, in combination with multiple published data sets, with the aim of identifying a common denominator for tracking CMDD. RESULTS: RNA sequencing and integrated analysis identified Asparagine Synthetase ( Asns ) as a unique molecular marker gene well correlated with CMDD, required for increased asparagine and also for distinct fluxes in other amino acids. Although Asns overexpression in Oct4 , Sox2 , Klf4 , and Myc cardiomyocytes augmented hallmarks of CMDD, Asns deficiency led to defective regeneration in the neonatal mouse myocardial infarction model, increased cell death of cultured adult cardiomyocytes, and reduced cell cycle in Oct4 , Sox2 , Klf4 , and Myc cardiomyocytes, at least in part through disrupting the mammalian target of rapamycin complex 1 pathway. CONCLUSIONS: We discovered a novel gene Asns as both a molecular marker and an essential mediator, marking a distinct threshold that appears in common for at least 4 models of CMDD, and revealing an Asns /mammalian target of rapamycin complex 1 axis dependency for dedifferentiating cardiomyocytes. Further study will be needed to extrapolate and assess its relevance to other cell state transitions as well as in heart regeneration.

Background/Objectives : Although systematic reviews and meta-analyses have examined immune-inflammatory indices in cardiovascular disease (CVD), the evidence remains scattered and inconsistent. This umbrella review aims to synthesize findings and evaluate the overall predictive value of these indices for clinical outcomes. Methods: We systematically searched PubMed, Cochrane Library, Web of Science, Embase, Scopus, and Medline for systematic reviews with meta-analyses assessing neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), platelet-to-lymphocyte ratio (PLR), and systemic inflammation response index (SIRI) in patients with CVD. Study quality and certainty of evidence were appraised using AMSTAR-2 and GRADE, respectively. Results: A total of 35 meta-analyses covering 106 unique outcomes were included, of which 87 showed significant associations. Elevated NLR and SII were consistently linked to higher risks of CVD mortality, major adverse cardiovascular events, myocardial infarction, heart failure, and stroke. PLR and SIRI were primarily associated with poor recovery from stroke and increased mortality in ST-elevation myocardial infarction. Specifically, the methodological quality of the included reviews was generally moderate to high according to AMSTAR-2, whereas none of the associations reached high certainty based on GRADE, with most rated as low or very low and about one-quarter as moderate certainty. Conclusions: The overall certainty of evidence remains limited according to GRADE, alongside methodological heterogeneity, population variability, and inconsistent thresholds that further restrict the direct applicability of these findings in clinical practice. Nevertheless, available evidence indicates that elevated immune-inflammatory indices are likely associated with worse clinical outcomes in patients with CVD. Future research should prioritize establishing standardized cutoffs, improving methodological consistency, and validating these indices across diverse populations to support their integration into clinical risk-stratification frameworks.

Bile acids are liver-derived signaling molecules that can be found in the brain, but their role there remains largely unknown. We found increased brain chenodeoxycholic acid (CDCA) in mice with absent 12α-hydroxylase (Cyp8b1), a bile acid synthesis enzyme. In these Cyp8b1^-/-, and in Wt mice administered CDCA, stroke infarct area was reduced. Elevated glutamate-induced excitotoxicity mediated by aberrant N-methyl-D-aspartate receptor (NMDAR) overactivation contributes to neuronal death in ischemic stroke. We found reduced glutamate-induced excitotoxicity in neurons from Cyp8b1^-/- and CDCA-treated Wt mice. CDCA decreased NMDAR-mediated excitatory post-synaptic currents by reducing over-activation of NMDAR subunit GluN2B in Wt brains. Synaptic NMDAR activity was also decreased in Cyp8b1^-/- brains. Expression and synaptic distribution of GluN2B were unaltered in Cyp8b1^-/- mice, suggesting CDCA may directly antagonize GluN2B-containing NMDARs. Supporting our findings, in a case-control cohort of acute ischemic stroke patients, we found lower circulatory CDCA. Together, our data suggest that CDCA, acting in the liver-brain axis, decreases GluN2B-containing NMDAR overactivation, contributing to neuroprotection in stroke.

Incorporating β-glucan-rich oat bran (OB) can attenuate postprandial glycemic response (PPGR) in solid foods, but its effect in liquid matrices is unclear. This study investigated the ability of differently processed low-dose-β-glucan-containing beverages to lower PPGR, and the mechanisms of action. Twenty participants consumed five malt beverages made from cocoa powder: intact OB (Intact), OB treated with enzymatic hydrolysis (EnzymA, EnzymB) or extrusion (Extr), or no OB (Ctrl). Four-hour postprandial incremental areas under the curve (iAUC) and peak incremental concentrations (iCmax) of glucose, insulin, glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), and paracetamol were evaluated. The molecular weight (MW) and extractability of the β-glucan in all the test products were also assessed. The three-hour glucose iAUC significantly decreased by −26%, −28%, −32%, and −38% in Intact, EnzymA, EnzymB, and Extr, respectively, and the insulin levels of the oat-containing products were also significantly lower compared to Ctrl. Intact and Extr elicited a lower insulin iCmax and GLP-1 3 h iAUC compared to Ctrl. However, the GIP and paracetamol levels were not changed. All the processed OBs improved β-glucan extractability and lowered the MW of β-glucan compared to Intact. In conclusion, low-dose oat β-glucan in a beverage significantly reduced PPGR, with effects maintained across different oat processing methods.

Eating late in the day is associated with circadian desynchrony, resulting in dysregulated metabolism and increased cardiometabolic disease risk. However, the underlying mechanisms remain unclear. Using targeted metabolomics of postprandial plasma samples from a secondary analysis of a randomised 2 × 2 crossover study in 36 healthy older Chinese adults, we have compared postprandial metabolic responses between high (HI) glycemic index (GI) or low-GI (LO) meals, consumed either at breakfast (BR) or at dinner (DI). 29 out of 234 plasma metabolites exhibited significant differences (p < 0.05) in postprandial AUC between BR and DI sessions, whereas only five metabolites were significantly different between HI and LO sessions. There were no significant interactions between intake timing and meal GI. Lower glutamine: glutamate ratio, lower lysine and higher trimethyllysine (TML) levels were found during DI compared with BR, along with greater postprandial reductions (δAUC) in creatine and ornithine levels during DI, indicating a worse metabolic state during the evening DI period. Greater reductions (δAUC) in postprandial creatine and ornithine were also observed during HI compared with LO (both p < 0.05). These metabolomic changes may indicate potential molecular signatures and/or pathways linking metabolic responses with cardiometabolic disease risk between different meal intake timings and/or meals with variable GI.

While dietary or supplementary antioxidants are thought to inhibit or delay oxidation of biological molecules, their utility in vivo has been marred by equivocal evidence. Consumption of polyphenol rich foods has been thought to alleviate postprandial oxidative stress and/or improve endothelial function. Although, previous studies suggested the utility of allantoin as a biomarker of oxidative stress, controlled dose response studies with dietary antioxidants to test this in humans have been limited. We therefore investigated the effects of 2 doses of polyphenol rich curry consumption on postprandial plasma concentrations of allantoin, allantoin to uric acid ratio, F2-isoprostanes using liquid chromatography-tandem mass spectrometry (LCMS-MS) and measured endothelial function using peripheral arterial tonometry (endoPAT). In a randomized controlled crossover trial in 17 non-smoking, healthy, Chinese men, aged 23.7 ± 2.4 years and BMI 23.1 ± 2.3 kg/m², the volunteers consumed 3 test meals in a random order, consisting of either non-curry Dose 0 Control (D0C, 0 g spices), or Dose 1 Curry (D1C, 6 g spices) or Dose 2 Curry (D2C, 12 g spices), after overnight fast. There were significant reductions in postprandial allantoin concentrations (p < 0.001) and allantoin to uric acid ratio (p < 0.001) at 2 h and 3 h following test meal consumption, indicating improvements in postprandial redox balance with increasing curry doses, although there were no differences between treatments on F2-isoprostane concentrations or on RHI (measured at 2 h only). Allantoin may have a utility as a biomarker of redox balance, in an acute setting. The study was registered at www.clinicaltrials.gov (Identifier No. NCT02599272).