Background: The gut–vascular axis linking gut microbiota, intestinal barrier, and vascular endothelium is a key pathophysiological interface in chronic metabolic diseases. Dysbiosis and “leaky gut” enable bacterial products and gut-derived metabolites to enter the circulation, driving systemic inflammation and endothelial dysfunction. Single-target interventions show limited efficacy; combined gut-directed and endothelium-directed strategies remain underexplored. Methods: PubMed was searched from database inception to 31 August 2026 using a predefined search strategy combining terms for the gut–vascular axis, intestinal barrier, microbiota/metabolites, endothelial dysfunction, and combined interventions. Preclinical and clinical studies evaluating gut barrier integrity, microbiota modulation, or endothelial protection, alone or in combination, were included. No formal risk-of-bias scoring was performed; study design, sample size, endpoint type, follow-up, and limitations were appraised. Results: (1) The axis comprises three core components: gut barrier, endothelium, and microbial metabolites. (2) Pathological activation involves leaky-gut-driven endotoxemia, dysbiosis-induced metabolic inflammation, and immune crosstalk sustaining vascular inflammation. (3) Animal models demonstrate that combined interventions can reduce atherosclerotic plaque, improve endothelium-dependent relaxation, and lower systemic inflammation to a greater extent than some monotherapies; however, most studies have not directly compared combination therapy with both corresponding monotherapies or performed formal interaction testing, so true synergy remains unproven. (4) Limited clinical studies in metabolic syndrome and heart failure suggest improvements in surrogate endpoints, but large-scale randomised trials with hard cardiovascular endpoints are lacking. Conclusions: The gut–vascular axis is a promising therapeutic framework for cardiometabolic diseases, with a strong biological rationale. Combined gut- and endothelium-directed interventions offer a rational multi-target approach, but direct evidence that they provide superior clinical outcomes remains limited. Future research must prioritise hard-endpoint trials, standardised interventions and endpoints, long-term safety, reproducibility, multi-omics-based patient stratification, and next-generation microbiome therapies.
Allergic conjunctivitis (AC) is a common inflammatory ocular surface disease characterised by ocular itch, conjunctival redness, tearing, and frequent eye rubbing. Although the link between AC, eye rubbing and development of keratoconus is well established, the relationship between AC and lid wiper epitheliopathy (LWE) is less understood. Recent studies have identified a potential association between AC and LWE, suggesting that friction-induced damage to the lid wiper region may represent an under-recognised consequence of allergic conjunctivitis. This review synthesises current evidence linking allergic conjunctivitis, eye rubbing, ocular surface friction, and LWE, while highlighting emerging mechanistic insights from multi-omics research. LWE has potential as a novel clinical indicator of AC and may provide additional diagnostic value alongside other established biomarkers.
Background and Objectives: Re-amputation is an important adverse outcome of diabetic foot disease. This study compared age and preoperative inflammatory parameters between patients with and without subsequent re-amputation and examined their adjusted associations with re-amputation group membership. Materials and Methods: The records of 206 patients treated between 2013 and 2024 were reviewed retrospectively, with 103 patients included in each group. Laboratory parameters obtained before the index amputation were analyzed in both groups. Between-group comparisons were performed using the Mann–Whitney U test. Three exploratory binary logistic regression models included age and C-reactive protein (CRP), together with the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), or platelet-to-lymphocyte ratio (PLR). The regression and ROC analyses were based on 197 complete cases. Results: Patients in the re-amputation group were older and had higher WBC, neutrophil, monocyte, CRP, NLR, MLR, and PLR values and lower lymphocyte values. In the primary model, age (adjusted OR = 1.034, 95% CI: 1.010–1.058; p = 0.006) and CRP (adjusted OR = 1.006 per 1 mg/L, 95% CI: 1.003–1.010; p = 0.001) were independently associated with re-amputation group membership, whereas NLR was not (p = 0.834). Neither MLR (p = 0.176) nor PLR (p = 0.446) was independently associated in the alternative models. Individual-marker AUCs ranged from 0.604 to 0.647, indicating limited discrimination. Conclusions: Older age and higher pre-index-amputation CRP levels were independently associated with membership in the re-amputation group. Although NLR, MLR, and PLR differed between groups, these ratios were not independently associated after adjustment for age and CRP. The limited discriminatory performance and data-derived cutoff values require validation in larger, independent cohorts.
Background/Objectives: Metabolomics has the potential to enhance the definition of medication response phenotypes in early-phase clinical trials, yet global uptake and distribution are not well characterised. This study provides an international assessment of metabolomics integration in registered early-phase clinical trials. Methods: Data were obtained from the World Health Organization’s International Clinical Trials Registry Platform (ICTRP). Early-phase trials (phase 0–II) conducted from 2010 to 2025 were analysed, and metabolomics studies were identified using predefined keyword searches across trial records. Results: A total of 183,041 early-phase trials were identified, of which 640 (0.35%) incorporated metabolomics. Uptake has increased modestly over time but remains low overall and is concentrated predominantly in high-income countries. The United Kingdom demonstrated the highest proportional integration (1.3%), while the People’s Republic of China (n = 237) and the United States of America (n = 90) contributed the greatest absolute number of trials with metabolomics. Among the included metabolomic studies: 187 (29.2%) were phase 0, 229 (35.8%) were phase I trials, 183 (28.6%) were phase II, and 41 (6.4%) were combined phase I/II studies. Metabolomics was most commonly included as a secondary, rather than primary outcome (49.7% vs. 25.3%). Conclusions: Metabolomics remains underutilised in early-phase clinical trials. Addressing barriers to implementation will be critical to enable broader integration of metabolomics into early-phase clinical trials and to integrate a multi-omic approach to precision medicine.
Background: Chronic exposure to ultraviolet (UV) radiation, particularly UVB, is the primary driver of skin photoaging. Ferro-aging, a recently identified iron-triggered, lipid peroxidation-driven cellular senescence program distinct from acute ferroptotic cell death, has emerged as a critical contributor to age-related pathologies, yet its role in skin photoaging remains largely unexplored. Methods: In this study, we systematically evaluated the anti-photoaging efficacy of L-malate (LM), a naturally occurring organic acid, using both in vitro human skin cell models (HaCaT keratinocytes and HSFs) and an in vivo BALB/c nude mouse model of chronic UV irradiation. Results: Our results demonstrate that LM treatment significantly attenuated UVB-induced cellular senescence, DNA damage, and extracellular matrix remodeling in a dose-dependent manner. Mechanistically, LM may act by increasing the expression of malic enzymes (ME1 and ME2), thereby restoring intracellular NADPH levels and glutathione homeostasis. This metabolic restoration effectively blocks the ferro-aging cascade, as evidenced by suppressed ACSL4 upregulation, the maintenance of GPX4 protein levels, and reduced lipid peroxidation. Importantly, topical application of LM in UV-irradiated mice significantly ameliorated in vivo photoaging phenotypes and suppressed ferro-aging markers. Conclusions: In summary, our findings demonstrate that LM may inhibit ferro-aging through the ME1/ME2-NADPH antioxidant axis. This study reveals the possibility of ferro-aging as a potential novel therapeutic target in skin photoaging and suggests that LM is a promising naturally derived ferro-aging inhibitor with translational potential in anti-aging skincare.
