Lactate, once disregarded as metabolic waste, is now recognized as a metabolite with important roles in oxidative metabolism and cardiovascular physiology. Cardiomyocytes readily oxidize lactate, allowing it to serve as an efficient myocardial energy substrate. On this basis, exogenous lactate administration has been explored in acute cardiac disease. Across animal models and clinical studies, lactate infusion consistently increased cardiac output and improved perfusion. The underlying mechanisms varied with dose and disease state, but involved reduced afterload, enhanced myocardial contractility, and context-dependent chronotropic effects. Mechanistic data support arterial vasorelaxation, venous contraction, and positive inotropy, with links to myocardial energetics and immunometabolic signaling. Overall, available evidence supports lactate as a potential metabolic and hemodynamic adjunct, while highlighting the need for further studies.
Extended periods of skeletal unloading cause rapid and severe bone loss, structural weakening, and increased fragility. Unlike postmenopausal osteoporosis, disuse bone atrophy is only partially responsive to pharmacological treatments, making it a critical and unresolved medical challenge in both space- and Earth-based medicine. Here, we investigate and assess the dose-response to P7C3 during the transition of bone-derived mesenchymal stem cells to osteoblasts and adipocytes, and its effect during human preosteoclast differentiation into mature osteoclasts in vitro. We further evaluate the in vivo protective properties of P7C3 against pathological bone atrophy induced by mechanical disuse. Data demonstrates that multifunctional P7C3 selectively promoted osteogenesis while inhibiting osteoclast maturation and activity. Proteomic analyses indicate osteogenic augmentation via ↑FSTL-1 and ↓IL-10Rβ, adipogenic inhibition via ↓ADIPOQ and ↑NAMPT, and osteoclastic inhibition via ↓OPN, ↑BMP-7 and ↑OPG. Enrichment analyses suggest the positive regulation of MAPK, JAK/STAT, and Wnt signaling pathways. Transcriptomic data reveal P7C3-induced cell-selective alterations in transcriptional programs within mitochondrial DNA, potentially promoting ATP generation through NADH activity, and regulating cellular energy metabolism. Hindlimb suspension (HLS) induced rapid pathologic bone loss in vivo, with an overarching drive towards adipogenesis (↑C4.A4, ↑FABP3, ↑ADIPOQ, and ↓Dcn) over osteogenesis (↑activin R2A, ↑LIFR and ↓STAT3) and augmented osteoclastic activity and cellular senescence, potentially via MAPK, JAK/STAT, and Wnt signaling. Despite HLS, P7C3 attenuated oxidative stress, RANKL, osteoclastic activity, bone marrow adiposity, cellular senescence, and pathological bone loss. P7C3 presents as an undiscovered and promising multi-target therapeutic strategy against disuse-induced bone atrophy for both space- and Earth-based applications.
Background Severe liver disease (SLD), including non-alcoholic fatty liver disease, alcoholic liver disease, viral hepatitis, and liver fibrosis/cirrhosis, is a systemic metabolic disorder that frequently coexists with diabetes. As one of the most common diabetic complications, diabetic retinopathy (DR) still has an unclear association with SLD. This study aimed to examine the relationship between hospitalization-defined SLD and subsequent hospitalization-defined DR, multimodal retinal imaging phenotypes, and shared plasma metabolic signatures that statistically accounted for part of the observed association. Methods We analyzed UK Biobank data from 499,852 participants. Time-dependent Cox models evaluated associations of SLD and its subtypes with incident DR. Multistate models assessed observed transitions from healthy state to diabetes and then to DR. Optical coherence tomography and color fundus photography parameters were analyzed to characterize retinal structural and vascular features cross-sectionally, and plasma metabolomic profiling was used to identify potential metabolic correlates shared by SLD and subsequent DR. Results During follow-up, 12,632 participants developed SLD. Incident SLD was associated with higher DR risk (HR, 2.38; 95% CI, 2.08–2.73). In multistate analyses, SLD was associated with increased observed rate of transition from diabetes to DR (HR, 1.18; 95% CI, 1.03–1.35). SLD was primarily associated with lower OCT-derived macular and neuroretinal thickness in the cross-sectional imaging subset. Exploratory mediation analyses identified a shared metabolic signature, predominantly characterized by apoB-containing lipoprotein composition and triglyceride-enriched remnant-related measures, that statistically accounted for part of the association between baseline SLD and subsequent DR. Conclusions Hospitalization-defined SLD and several of its subtypes were associated with a higher subsequent risk of hospitalization-defined DR and with a higher observed rate of transition from diabetes to DR. Cross-sectional retinal imaging analyses identified retinal structural and vascular imaging phenotypes associated with SLD. Circulating lipoprotein-related measures constituted a shared metabolic signature and statistically accounted for part of the observed association. These findings identify hospitalization-defined SLD as a marker of systemic disease burden associated with DR.
Background Obesity and its complications, including metabolic dysfunction-associated steatotic liver disease, remain significant global health challenges. Bariatric surgery has established clinical benefits, but the mechanisms driving metabolic improvements are not clearly defined. Methods We undertook a randomised, prospective, longitudinal (1-year) study in women living with obesity to determine the impact of a low-calorie diet followed by bariatric surgery (individuals randomised to sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB)) on metabolic phenotype, including MASLD. We combined repeated clinical assessments with state-of-the-art imaging, dynamic meal testing and a multi-omic analysis (proteomic, metabolomic) from tissue (multiple adipose depots, liver) and blood. A control group without obesity underwent identical phenotyping and molecular analysis with the exception of no low-calorie diet. Results Obesity was associated with metabolic, proteomic and hepatic dysregulation. Bariatric surgery normalized non-invasive assessments of liver phenotype and was associated with reductions in body fat, notably in android as opposed to gynoid fat mass. This was paralleled by proteomic changes in abdominal, but not gluteal, adipose tissue. Proteomic and metabolomic analyses highlighted putative roles for all-trans-retinol dehydrogenase, lumican and androgenic steroids in the regulation of metabolic phenotype. Clinical or molecular outcomes were not significantly different between SG and RYGB. Conclusions These data highlight the differential impact of bariatric surgery on adipose tissue depots, and this is likely to be crucial in delivering metabolic benefit. Furthermore, the specific pathways and targets that have been identified offer the potential for therapeutic intervention.
