Li Liu

Background: Childhood health adversity and socioeconomic disadvantage may shape late-life health, but evidence for incident disability and multimorbidity remains limited. Cross-cohort inference is complicated by non-equivalent measures of childhood experiences and differences in timing. We estimated cohort-specific prospective associations in the English Longitudinal Study of Ageing (ELSA) and the Survey of Health, Ageing and Retirement in Europe (SHARE). Methods: ELSA childhood-health/material-adversity indicators and health were assessed at wave 3. SHARE material/cultural disadvantage was assessed at wave 3 or wave 7, with health landmarks at waves 4 and 8; the two inception samples were analyzed separately. Outcomes were the first observed onset of difficulty in at least one of six activities of daily living (ADL-6) and the first observed onset of at least two of seven disease groups (MM-7). Complementary log–log person–period models incorporated interval duration, repeated observations, available survey-design information and baseline weights, and stabilized inverse-probability-of-censoring weights; death was a competing event. Highest exposure categories were compared with zero, without assuming measurement equivalence. Results: Combined survey/attrition-weighted models included 4,290/3,424 ELSA participants, 13,863/9,064 SHARE wave-3 participants, and 23,026/12,560 SHARE wave-7 participants for ADL-6/MM-7, respectively. In the mortality-ascertained ELSA wave 4–6 window, highest-versus-zero hazard ratios (HRs) were 1.43 (95% confidence interval [CI] 1.09–1.87) for ADL-6 and 1.35 (1.02–1.80) for MM-7. After excluding ADL-6 onset observed at wave 4, the lagged ELSA HR was 1.03 (0.70–1.52) through wave 6. Over waves 4–9, HRs were 1.47 (1.19–1.82) and 1.24 (0.98–1.57). SHARE wave-3 HRs were 1.36 (1.08–1.71) and 1.34 (1.09–1.64); wave-7 HRs were 1.60 (1.06–2.43) and 0.93 (0.68–1.27). Standardized competing-risk estimates showed a higher risk of ADL-6 in the primary ELSA analysis and both SHARE inception-sample analyses. MM-7 risk differences were positive in ELSA and SHARE wave 3, whereas the SHARE wave-7 contrast was imprecise and compatible with no association. Conclusion: The highest cohort-specific exposure category versus zero was associated with incident ADL disability in the primary ELSA and SHARE landmark analyses, but the ELSA association appeared strongest in the earliest interval and was not clearly sustained later. Associations with multimorbidity varied by observation window and SHARE inception sample. The findings neither establish measurement equivalence nor explain the observed cross-cohort heterogeneity.

Cardiac fibrosis is a critical pathological feature that drives pressure overload (PO)-induced heart failure (HF). This process involves a complex intercellular crosstalk between cardiac fibroblasts (CFs) and cardiomyocytes. Cardiomyocyte hypertrophy is a compensatory response to PO and undergoes metabolic reprogramming; however, the specific metabolite(s) transmitting the pro-fibrotic signals from hypertrophic cardiomyocytes to CFs remain largely unknown. In this study, we demonstrated that hypertrophic cardiomyocytes secreted elevated level of isoleucine metabolite ketoisoleucine (Ket), which activated CFs to exacerbate PO-induced cardiac fibrosis and dysfunction. Mechanistically, Ket docked with the membrane transporter MCT1, subsequently activating Smad2/3 signaling to upregulate EGR3 expression and its nuclear accumulation, where EGR3 directly bound to the promoter regions of Acta2 and Col3a1 , driving their transcription and promoting CF activation. Remarkably, inhibition of Ket secretion from hypertrophic cardiomyocytes attenuated their pro-fibrotic effects on CF activation, establishing this pathway as a key driver of PO-induced cardiac remodeling. We identify Ket as a metabolic mediator linking cardiomyocyte hypertrophy to cardiac fibrosis in PO conditions. Targeting the Ket-dependent cardiomyocyte-to-fibroblast signaling axis offers potential therapeutic targets for managing PO-induced HF by limiting pathological cardiac fibrosis.

Background: International Society on Thrombosis and Haemostasis (ISTH) overt disseminated intravascular coagulation (DIC) scoring is a standard bedside framework for infection-associated coagulopathy but does not capture anticoagulant-pathway markers. The study examined whether admission antithrombin III (AT-III) activity provided risk-enrichment information for septic shock among adults admitted with infection below the ISTH 2001 overt-DIC threshold. Methods: The study retrospectively analyzed 1,286 adults admitted with infection. AT-III activity was evaluated in the ISTH-complete and below-threshold subsets and compared with ISTH 2001 and 2025 SSC overt-DIC scores. Retrospective temporal adjudication compared first valid AT-III report availability with operational septic-shock onset. In a clinically indicated lactate-measured subset, the study assessed whether AT-III added discrimination beyond age, sex, and lactate. Firth-penalized regression evaluated the conditional association of AT-III with septic shock beyond age, sex, and raw ISTH components. Results: Among 1,027 ISTH-complete patients, 974 (94.8%) were below the ISTH 2001 overt-DIC threshold, including 44 of 60 septic-shock cases. In this subgroup, 43 of 44 shock cases had AT-III activity n = 518), AT-III increased AUC beyond age, sex, and lactate from 0.740 to 0.821; this increment persisted in the incident-shock analysis (0.680–0.792). In the primary Firth model, lower AT-III activity remained conditionally associated with shock (OR 3.10 per 1-SD decrease); the apparent and bootstrap-corrected AUCs were 0.900 and 0.888. Conclusion: Admission AT-III activity was associated with septic shock within the large ISTH below-threshold infection subgroup and provided high-sensitivity, low-positive-predictive-value enrichment information. Retrospectively reconstructed temporal ordering demonstrated a report-release-to-operational-onset interval in incident cases but does not establish prospective prediction, prospective workflow performance, or clinical benefit. AT-III should not be used as a standalone trigger for escalation decisions. Prospective, time-stamped validation is required.

Cardiovascular diseases remain the leading cause of mortality worldwide, with aging as a major risk factor. Endothelial cell (EC) dysfunction, driven by cellular senescence, is central to age‐related cardiomyopathy. Despite its clinical significance, the molecular mechanisms underlying endothelial senescence remain incompletely defined. In this study, we observed that the expression of the endothelial‐specific gene heat shock protein family A member 12B (HSPA12B) declines significantly with age. HSPA12B deficiency in mice accelerates age‐related EC senescence and cardiac dysfunction, whereas HSPA12B overexpression mitigates EC senescence, highlighting its protective role against vascular aging. Mechanistically, HSPA12B deficiency impairs X‐box binding protein 1 (XBP1) transcriptional activity and consequently reduces the expression of its downstream target genes suppressor/enhancer of lin‐12‐like (SEL1L) and HMG‐CoA reductase degradation protein‐1 (HRD1). This disruption compromises endoplasmic reticulum‐associated degradation (ERAD) of Stimulator of interferon genes (STING), resulting in persistent activation of the cyclic GMP‐AMP synthase (cGAS)‐STING pathway, a critical driver of EC senescence. In contrast, increased HSPA12B expression enhances XBP1 nuclear translocation and upregulates SEL1L and HRD1, thereby attenuating age‐related STING activation. Importantly, pharmacological inhibition of STING reversed the senescent phenotype caused by HSPA12B deficiency. Similarly, enhancing XBP1 activity restored SEL1L and HRD1 expression, reduced STING activation, and alleviated EC senescence. Conversely, SEL1L deficiency or HRD1 inhibition exacerbated STING activation and abolished the protective effects of HSPA12B. Collectively, these findings reveal a previously unrecognized role for HSPA12B in preserving endothelial homeostasis during aging by regulating XBP1‐mediated ER‐associated degradation of STING and highlight HSPA12B as a potential therapeutic target for age‐related cardiovascular dysfunction.

Myocardial ischemia/reperfusion (MI/R) injury is a major cause of adverse outcomes of revascularization following myocardial infarction. Anaerobic glycolysis during myocardial ischemia is well studied, but the role of aerobic glycolysis during the early phase of reperfusion is incompletely understood. Lactylation of Histone H3 (H3) is an epigenetic indicator of the glycolytic switch. Heat shock protein A12A (HSPA12A) is an atypic member of the HSP70 family. In the present study, we report that, during reperfusion following myocardial ischemia, HSPA12A was downregulated and aerobic glycolytic flux was decreased in cardiomyocytes. Notably, HSPA12A KO in mice exacerbated MI/R-induced aerobic glycolysis decrease, cardiomyocyte death, and cardiac dysfunction. Gain- and loss-of-function studies demonstrated that HSPA12A was required to support cardiomyocyte survival upon hypoxia/reoxygenation (H/R) challenge and that its protective effects were mediated by maintaining aerobic glycolytic homeostasis for H3 lactylation. Further analyses revealed that HSPA12A increased Smurf1-mediated Hif1α protein stability, thus increasing glycolytic gene expression to maintain appropriate aerobic glycolytic activity to sustain H3 lactylation during reperfusion and, ultimately, improving cardiomyocyte survival to attenuate MI/R injury.

Neonatal maternal separation (NMS) is an early-life stress (ELS) that can result in adult visceral hypersensitivity, which is usually manifested as chronic visceral pain. Although mast cells and corticotropin-releasing hormone (CRH) neurons are involved in stress response, whether there is an interaction between mast cells and CRH neurons in hypothalamic paraventricular nucleus (PVN) during the ELS-induced visceral hypersensitivity remains elusive. Herein, we established an NMS model by separating neonatal mice from their mothers, and observed that these mice presented visceral hypersensitivity in adulthood, as indicated by elevated abdominal withdrawal reflex and lowered visceral pain threshold. The NMS-induced adult visceral hypersensitivity was accompanied by activation of mast cells and CRH neurons in PVN. Also, NMS increased the histamine content (an inflammatory mediator mainly released by mast cells) and histamine H2 receptor (H2R) expression of CRH neurons in PVN. Remarkably, intra-PVN administration with mast cell stabilizer attenuated the NMS-induced CRH neuronal activation and adult visceral pain, while histamine administration showed the opposite effects. Moreover, intra-PVN injection with H2R antagonist alleviated the NMS-induced CRH neuronal activation, PKA and CREB phosphorylation, and importantly, adult visceral pain. Together, our findings revealed a role of an interaction between paraventricular mast cells and CRH neurons in NMS-induced adult visceral hypersensitivity, thereby providing a perspective for the management of visceral pain.

Rationale: Liver ischemia-reperfusion (LI/R) injury is characterized by two interconnected phases: local ischemia that causes hepatic cell damage to release damage-associated molecular pattern (DAMPs), and DAMPs that recruit immune cells to elicit inflammatory cascade for further injury of hepatocytes. High-mobility group box 1 (HMGB1) is a representative DAMP. Studies in macrophages demonstrated that HMGB1 is secreted after lactylation during sepsis. However, whether lactylation mediates HMGB1 secretion from hepatocytes after LI/R is known. Heat shock protein A12A (HSPA12A) is an atypical member of HSP70 family.

High levels of lactate are positively associated with the prognosis and mortality in patients with heart attack. Endothelial-to-mesenchymal transition (EndoMT) plays an important role in cardiac fibrosis. Here, we report that lactate exerts a previously unknown function that increases cardiac fibrosis and exacerbates cardiac dysfunction by promoting EndoMT following myocardial infarction (MI). Treatment of endothelial cells with lactate disrupts endothelial cell function and induces mesenchymal-like function following hypoxia by activating the TGF-β/Smad2 pathway. Mechanistically, lactate induces an association between CBP/p300 and Snail1, leading to lactylation of Snail1, a TGF-β transcription factor, through lactate transporter monocarboxylate transporter (MCT)–dependent signaling. Inhibiting Snail1 diminishes lactate-induced EndoMT and TGF-β/Smad2 activation after hypoxia/MI. The MCT inhibitor CHC mitigates lactate-induced EndoMT and Snail1 lactylation. Silence of MCT1 compromises lactate-promoted cardiac dysfunction and EndoMT after MI. We conclude that lactate acts as an important molecule that up-regulates cardiac EndoMT after MI via induction of Snail1 lactylation.

Circulating lactate levels are a critical biomarker for sepsis and are positively correlated with sepsis-associated mortality. We investigated whether lactate plays a biological role in causing endothelial barrier dysfunction in sepsis. We showed that lactate causes vascular permeability and worsens organ dysfunction in CLP sepsis. Mechanistically, lactate induces ERK-dependent activation of calpain1/2 for VE-cadherin proteolytic cleavage, leading to the enhanced endocytosis of VE-cadherin in endothelial cells. In addition, we found that ERK2 interacts with VE-cadherin and stabilizes VE-cadherin complex in resting endothelial cells. Lactate-induced ERK2 phosphorylation promotes ERK2 disassociation from VE-cadherin. In vivo suppression of lactate production or genetic depletion of lactate receptor GPR81 mitigates vascular permeability and multiple organ injury and improves survival outcome in polymicrobial sepsis. Our study reveals that metabolic cross-talk between glycolysis-derived lactate and the endothelium plays a critical role in the pathophysiology of sepsis.