Search Results (29,863)

Leukocyte recruitment from blood into tissues involves sequential adhesive steps, including rolling and integrin-dependent arrest. VLA-4 can support firm adhesion and, in some settings, rolling interactions, whereas CD44–hyaluronan interactions have also been implicated in leukocyte rolling. Here, we used adhesion assays and parallel-plate flow chamber experiments to analyze CD44–hyaluronan-dependent monocyte interactions on ECV304 monolayers and to compare them with α4-integrin-sensitive adhesion on endothelial monolayers. WEHI 78/24 monocytoid cells interacted with ECV304 monolayers in a CD44- and hyaluronan-dependent manner, whereas adhesion to HMEC-1 and bEnd.3 monolayers was sensitive to α4-integrin blockade. Blocking CD44, adding soluble hyaluronan, or treating ECV304 monolayers with hyaluronidase reduced adhesion and rolling. Mixed primary human monocyte preparations also showed CD44-dependent adhesion and rolling on ECV304 monolayers. ECV304 cells are interpreted here not as endothelial cells, but as T24-derived, hyaluronidase-sensitive cellular monolayers useful for functional analysis of CD44–hyaluronan-dependent interactions. These findings support a substrate-dependent functional hierarchy in which CD44–hyaluronan-dependent monocyte rolling becomes detectable when α4-integrin-dependent adhesion is not dominant, while emphasizing the cell-model-based nature of the assay. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly associated with the development of cardiovascular disease (CVD); however, the mechanisms responsible are currently unknown. We have developed a model of MASLD due to the loss of hepatocyte peroxisome proliferator-activated receptor α (PPARα^HEPKO). We found that plasma beta-hydroxybutyrate (BHOB) levels were significantly reduced in PPARα^HEPKO mice and aimed to investigate the therapeutic potential of restoring BHOB levels in the development of CVD in these mice. Thirty-week-old PPARα^HEPKO and control PPARα^FL/FL mice were randomized to receive 1,3 butanediol (1,3-BDO), a precursor of BHOB, in drinking water for 6 weeks. 1,3-BDO treatment resulted in a significant increase in plasma BHOB levels, a significant decrease in mean arterial blood pressure, improvement in systolic and diastolic function, a decrease in vascular stiffness, and improved exercise performance in PPARα^HEPKO mice. 1,3-BDO treatment did not alleviate hepatic steatosis in PPARα^HEPKO mice; however, it improved plasma cholesterol levels and decreased cardiac lipid accumulation, fibrosis, and apoptosis. 1,3-BDO treatment also resulted in a significant increase in cardiac AMP-activated protein kinase (AMPK) levels. Increasing plasma BHOB levels reverses CVD in our mouse model of MASLD. A similar approach could be an effective strategy for preventing the development of CVD in patients with human MASLD. Full article

Cutaneous tissue engineering has advanced from simple coverage substitutes to increasingly complex living constructs, yet the field remains constrained by a decisive problem: timely and durable perfusion. Many engineered skin substitutes can appear vascular in static culture or in small-animal models. However, they still fail when blood flow must be established quickly enough to rescue cells across clinically relevant tissue thickness. Rather than re-catalog platforms already summarized in recent reviews, this critical narrative review reframes the field around perfusion as the master functional endpoint rather than vessel density alone. We analyze the vascularization bottleneck as a sequence, internal network formation, host inosculation, flow initiation, and perfusion stability—and use that sequence to reassess biomaterial design, cell-based strategies, immunomodulation, decellularized matrices, bioprinting, microfluidics, and prevascularization. We intentionally distinguish implantable skin substitutes from perfused in vitro platforms such as skin-on-chip systems, arguing that these are linked but non-interchangeable application spaces with different success criteria. Building on this distinction, we propose a research agenda centered on functional benchmarking of perfusion, spatiotemporal coordination of scaffold dynamics, immune–mural–lymphatic–vascular crosstalk, scalable hierarchical vascular fabrication, and predictive human test platforms. The central argument is that translation will depend not on ever more isolated pro-angiogenic interventions but on integrated systems that survive the ischemic interval, connect rapidly, tolerate blood entry, maintain a workable inflow–outflow balance, and remodel into a stable, skin-specific microvasculature. Full article

Cardiac rehabilitation (CR) is strongly recommended in secondary cardiovascular prevention; indeed, in patients after cardiac surgery or with coronary artery disease or heart failure, this intervention is recommended to decrease mortality, morbidity, and disability, and to improve quality of life and cardiorespiratory fitness. Moreover, each step of the cardiovascular continuum denotes a potential risk factor for the progression of cognitive frailty; this interaction is highly prevalent, affecting approximately one-third of all patients in cardiology settings. For these reasons, CR should consider the patient’s cognitive domain; however, cognitive assessment is still rarely integrated into standard CR protocols. Therefore, this comprehensive review presents current evidence and recent updates on the interaction between CR and cognitive impairment, focusing on physiological mechanisms, core components, benefits, and strategies for implementing CR in patients with cognitive frailty to optimize recovery and prognosis. Full article

Background: The relationship between physical exercise and human longevity constitutes one of the most consequential intersections in contemporary preventive medicine. Although international guidelines recommend 150 min of moderate-intensity exercise weekly, growing evidence suggests that the architecture of optimal exercise is far more complex, encompassing dose, modality, timing across the lifespan, and the paradox risks imposed by extreme endurance. Methods: We included in this narrative review landmark cohort studies, randomized controlled trials, meta-analyses, and expert physiological frameworks published in high-impact cardiovascular, sports medicine, and longevity journals from 1966 to 2024. Results: Cardiorespiratory fitness (CRF), indexed by maximal oxygen uptake (VO₂ max), demonstrates the strongest and most linear dose–response relationship with all-cause mortality identified in preventive medicine, with every 1 metabolic equivalent of task (MET) increment associated with a 12–15% reduction in mortality risk. The optimal dose of vigorous-intensity exercise follows a J-shaped dose–response curve: 3–5 sessions per week generating 1–2.4 h of vigorous activity is associated with the lowest all-cause mortality risk in large prospective cohorts, whereas chronic extreme endurance exercise incurs measurable atrial remodeling, patchy myocardial fibrosis, and a 5.3-fold increase in the risk of atrial fibrillation. The importance of exercise types shifts profoundly across the lifespan, transitioning from aerobic capacity effort in the third decade to resistance training in the seventh decade and neuromuscular stability in the eighth. Based on our interpretation of the available evidence, we propose a structured, personalized four-step exercise pathway integrating CRF assessment, lifespan-adapted prescription, lifestyle co-interventions, and periodic reassessment. Conclusions: Among currently available lifestyle interventions, regular exercise is consistently associated with some of the largest and most reproducible reductions in all-cause and cardiovascular mortality observed in prospective cohort data, while remaining accessible and cost-effective. Full article

Background: Neovascular age-related macular degeneration (nAMD) remains a leading cause of irreversible central vision loss. Although anti-vascular endothelial growth factor (anti-VEGF) therapy has transformed management, pivotal trials enrolled exclusively treatment-naïve patients, leaving clinicians without pooled evidence to guide switching decisions in previously treated eyes. This systematic review and meta-analysis assessed real-world visual, anatomical, durability, and safety outcomes following switching to aflibercept 8 mg in previously treated nAMD. Methods: Following PRISMA 2020 guidelines, we searched PubMed, Embase, Web of Science, CENTRAL, Scopus, and Google Scholar through April 2026. Studies reporting switching to aflibercept 8 mg with change in best-corrected visual acuity (BCVA), central subfield thickness (CST), or treatment interval were included. Continuous outcomes were pooled using random-effects models with Hartung–Knapp–Sidik–Jonkman adjustment; proportions were estimated using generalized linear mixed models. Methodological quality was evaluated using the JBI Critical Appraisal Checklist for Case Series. Certainty of evidence was assessed using GRADE. The protocol was registered with PROSPERO (CRD420261371334). Results: Twenty-one studies met inclusion criteria. BCVA remained stable (WMD: −0.017 logMAR; 95% CI: −0.027 to −0.007; +0.83 ETDRS letters; I² = 0%). CST decreased significantly (WMD: −21.5 µm; 95% CI: −29.3 to −13.7; I² = 56.0%), and treatment intervals extended by +1.79 weeks (95% CI: +1.32 to +2.27; I² = 74.3%). Intraretinal and subretinal fluid each resolved in 37.5% of eyes. Intraocular inflammation was rare across 9959 treated eyes, though this pool was not restricted to switched eyes, with no confirmed retinal vasculitis. Sensitivity analyses confirmed robustness across all co-primary estimates. GRADE certainty was low for BCVA and very low for CST and treatment interval. Conclusions: Low-certainty evidence suggests that switching to aflibercept 8 mg preserves visual acuity, while very-low-certainty evidence suggests reductions in central subfield thickness and modest extension of treatment intervals. Intraocular inflammation was rare, though safety denominators included non-switch eyes. These findings provide preliminary pooled estimates to inform switch decisions in previously treated eyes. Full article

Background/Objectives: Patients with chronic kidney disease (CKD) have an increased risk of ischemic heart disease (IHD). Some discrepancies exist between cardiological and nephrological guidelines regarding the extent of diagnostic procedures in CKD patients who are candidates for kidney transplantation. The aim of this study was to assess the cardiac status of these patients after cardiological checkup. Methods: The present study included all kidney transplant candidates referred to the Regional Qualification Center between January 2021 and February 2024. We characterized the group of patients in whom IHD was diagnosed during the cardiological checkup. Results: Among 346 patients, IHD was newly identified in 44 (12.7%) subjects. These patients were significantly older [median 62.9 (51.9–65.4) vs. 47.2 (36.8–57.9) years; p < 0.001], had longer dialysis vintage [median 20 (12.5–42) vs. 14 (6–31) months; p < 0.05] and were more frequently diabetic (29.6 vs. 16.9%, p < 0.05) than the rest of the study cohort. Of note, they were also characterized by significantly more frequent manifestation of atherosclerosis lesions visualized using routine imaging methods (i.e., chest X-ray and abdominal aorta and iliac artery visualization). The stepwise logistic regression analysis revealed that age [OR 1.05 (1.02–1.09); p <0.01] and the ad hoc atherosclerotic score [OR 1.88 (1.27–2.77); p < 0.001] independently predicted the diagnosis of IHD during the cardiological qualification of potential kidney transplant candidates. Conclusions: During the cardiological examination, IHD was diagnosed in a substantial number of kidney transplant candidates. The presence of atherosclerotic lesions detected by routine noninvasive vascular system imaging methods may suggest the need for extending IHD diagnostics even in relatively young patients without clinical symptoms. Full article

L-citrulline is a non-protein amino acid with critical roles in perinatal and neonatal physiology through the intestinal–renal arginine–citrulline axis and nitric oxide (NO) production. During pregnancy, L-citrulline supports placental angiogenesis, vascular adaptation, and fetal growth through augmentation of arginine availability and endothelial NO production. In neonates, particularly preterm infants, developmental immaturity of citrulline and arginine synthesis contributes to hypoargininemia and may increase susceptibility to necrotizing enterocolitis, bronchopulmonary dysplasia with pulmonary hypertension, sepsis, and impaired intestinal function. Although L-citrulline has emerged as a promising modulator of NO bioavailability, prior reviews have largely focused on either adult cardiovascular disease or isolated neonatal applications, with limited integration of its mechanistic and translational relevance across the perinatal and neonatal continuum. Collectively, current evidence supports L-citrulline as a promising translational target in maternal–fetal and neonatal medicine because of its central role in vascular, inflammatory, and metabolic regulation. However, adequately powered clinical trials are needed to define optimal dosing, timing, patient selection, and long-term outcomes before routine clinical implementation can be recommended. This review provides a comprehensive evaluation of L-citrulline metabolism and its therapeutic potential from pregnancy through neonatal life, with emphasis on the intestinal–renal arginine–citrulline axis, endothelial function, and NO-mediated vascular regulation. We specifically examine the role of citrulline in key pathophysiologic mechanisms underlying maternal and neonatal disease, including endothelial dysfunction, impaired NO bioavailability, inflammation, oxidative stress, and abnormal placental vascular remodeling. Full article

In recent years, bisphenol F (BPF) and bisphenol S (BPS) have been used in several everyday products to replace bisphenol A (BPA), since exposure to BPA has been associated with the development of several pathologies. However, recent studies have also been associating exposure to BPA substitutes with the development of various pathologies, including cardiovascular diseases, and the safety of BPA substitutes for human health has been questioned. Thus, this study aimed to investigate and compare BPA, BPF and BPS effects on arterial tone and to explore the mechanisms involved. The results suggest that BPA, BPS and BPF exert non-genomic and endothelium-independent relaxant effects on arteries and smooth muscle cells from the umbilical cord. Regarding genomic effects, the results suggest that BPA, BPF, and BPS disrupted the primary mechanisms underlying HUA relaxation by interfering with the cGMP signaling pathway and modulating the Ca²⁺ channels activity. Moreover, these results suggest that BPF alters the vasorelaxant response more than BPA and BPS. Therefore, replacing BPA with its substitutes does not appear to be beneficial for human cardiovascular health. Thus, in the future, the vascular effects of these bisphenols should be further evaluated to clarify their modes of action and future implications for maternal-fetal health. Full article

Background: Obesity and metabolic syndrome (MS) often co-exist; however, these conditions can exist independently as metabolically healthy obesity (MHO) and as metabolic obesity (MO). Methods: We investigated the association between metabolic status and body weight and risk of obstructive angiographic coronary artery disease (CAD), long-term major adverse cardiovascular events (MACEs), and all-cause mortality in women with signs/symptoms of ischemic heart disease (IHD) enrolled in the original cohort of the Women’s Ischemia Syndrome Evaluation (WISE) study (1997–2001) followed for mortality for a median of 8.6 years (range: 0–11.3 years). Normal weight (NW) was defined as a body mass index (BMI) < 25 kg/m², overweight (OW) was defined as a BMI of 25–29 kg/m², obesity (O) was defined as ≥30 kg/m². MS was defined according to the NCEP ATP III Harmonized definition, metabolically healthy (MHO) was defined as obesity in the absence of MS, and MO was defined as MS in NW individuals. Results: 503 women were evaluated including 20.7% MH-NW, 14.7% MH-OW, 8.5% MHO, 6.2% MO, 21.9% MS-OW, 28.0% MS-O. Compared to MH-NW (reference), MHO was associated with a lower risk of MACEs (aHR 0.50; 95% CI 0.29, 0.85, p = 0.011) and mortality (aHR 0.50; 95% CI 0.27, 0.95, p = 0.035). MO was associated with higher odds of obstructive CAD (aOR 2.10; 95% CI 1.33, 3.33, p = 0.002) and a higher risk of MACEs (aHR 1.67, 95% CI 1.07, 2.59, p = 0.023). Conclusions: In women with suspected IHD, compared with MH-NW, MHO was associated with a lower risk of MACEs and mortality, whereas MO had higher odds of obstructive CAD and a greater MACE risk. These findings challenge simplistic BMI-based risk paradigms and emphasize the benefits of using metabolic status assessment over weight alone. Full article

Background/Objectives: Despite advances in the TNM staging system, prognostic heterogeneity persists in early-stage non-small cell lung cancer (NSCLC). Lymphatic invasion (LI) is a known marker of aggression, but its independent significance in the critical, low-risk Stage I, N0 subgroup—typically ineligible for adjuvant therapy—remains poorly defined. We hypothesized that LI acts as a powerful, yet hidden, risk factor in this highly favourable cohort. Methods: This retrospective cohort study included 988 consecutive patients who underwent curative anatomical resection for NSCLC. All patients underwent complete resection with pathologically confirmed negative surgical margins (R0 resection). Cases were staged according to the 9th Edition of the TNM Classification of Malignant Tumours (TNM-9) and grouped as LI-positive or LI-negative. A critical subgroup analysis focused on 347 truly low-risk patients (TNM Stage I, N0, no vascular or pleural invasion). Overall survival (OS) was evaluated using the Kaplan–Meier method and multivariable Cox proportional hazards models. Results: In the entire cohort (n = 988), LI was present in 40.9% of cases. LI positivity was an independent predictor of worse OS in multivariable analysis (HR: 1.520, 95% CI: 1.004–2.301, p = 0.048). In the low-risk subgroup (n = 347), the presence of LI resulted in a drastic survival divergence, with 5-year OS declining from 96.1% (LI-negative) to 83.8% (LI-positive). Multivariable analysis confirmed LI as an independent adverse prognostic factor in this subgroup (HR: 4.002, 95% CI: 1.567–10.221, p = 0.004). Conclusions: Lymphatic invasion is a robust, independent adverse prognostic factor in resected NSCLC. LI may identify a subset of early-stage N0 NSCLC patients who warrant closer postoperative surveillance and prospective evaluation for adjuvant treatment strategies. Validation in prospective cohorts is required before LI can be formally integrated into staging algorithms or treatment guidelines. Full article

The Kelch-repeat superfamily genes played important roles in regulating plant growth and development; however, their functions in foxtail millet (Setaria italica) have not yet been characterized. In this study, SiNL4, a homolog of ZmNL4 controlling leaf width in maize, was knocked out using the CRISPR/Cas9 technology, and two homozygous knockout lines (ko1 and ko2) were obtained. Phenotypic analysis showed that compared with the wild-type Ci846, ko1 and ko2 exhibited reduced leaf width and decreased yield related traits (e.g., panicle weight, grain width, and 1000-grain weight). Cytological analysis showed that changes in leaf width of ko1 and ko2 resulted from a decrease in leaf epidermal cell width and the number of small vascular bundles (SVBs) close to the leaf edge, suggesting that SiNL4 might regulate leaf width by influencing cell expansion and the development of SVB. Spatiotemporal expression analysis indicated that the relative expression level of SiNL4 was high in the stem, leaf, and young panicle. Subcellular localization showed that SiNL4 was mainly localized in the mitochondria and plasma membrane. In addition, the T-DNA insertion mutant (Atnl4) of AT5G18590, the ortholog of SiNL4 in Arabidopsis thaliana, exhibited similar phenotypes with reduced rosette leaf width, seed width, and 1000-seed weight. Moreover, complementary expression of SiNL4 in Atnl4 not only restored the phenotypes, but also significantly increased the 1000-seed weight, indicating that the function of these two genes might be conserved. Meanwhile, we found that SiNL4 knockout caused a decrease in chlorophyll content and net photosynthetic rate (Pn), showing that SiNL4 might be involved in regulating photosynthesis. In summary, this study revealed the function of SiNL4 in regulating leaf width in foxtail millet, providing a potential gene for the genetic improvement of foxtail millet. Full article

Backgrounds: Carotid atherosclerotic plaques (CAPs) are a reliable marker of systemic atherosclerosis and a predictor of cardiovascular events. Despite advances in prevention, the prevalence of CAPs in high-income regions remains uncertain due to heterogeneity in imaging definitions, study designs, and populations. We strived to provide an updated meta-analysis of population-based studies conducted in Europe and North America between 2015 and 2025, estimating the prevalence of CAPs in general populations. Methods: Following the PRISMA 2020 guidelines, PubMed and Web of Science were searched for original studies. Eligible studies reported CAPs prevalence in adult general populations using ultrasonography, computed tomography angiography, and magnetic resonance imaging. Pooled prevalence was calculated using a random-effects meta-analysis of proportions, and heterogeneity was assessed using I² and τ² statistics. Subgroup and meta-regression analyses explored associations with age and comorbidities. Results: A total of 80 studies comprising 177,196 participants were included. The pooled prevalence of CAPs was 39.8% (95% CI 32.6–47.5%) under a random-effects model with substantial heterogeneity (I² = 99.6%). The prevalence of CAPs increased with age, exceeding 59% among individuals aged over 70 years. High-risk populations, particularly those with T2DM, exhibited a prevalence exceeding 50%. Conclusions: CAPs are present in approximately 40% of adults in Europe and North America, with prevalence strongly driven by age and comorbidities. Despite therapeutic advances, the prevalence of CAPs has not declined, reflecting the growing impact of population aging and comorbidities. Standardized imaging definitions, longitudinal outcome linkage, and pragmatic prevention strategies are needed to translate CAPs detection into reduced cardiovascular events. Full article

Background/Objectives: Hearing loss and dementia are highly prevalent conditions in older adults and represent a growing public health challenge. Over the past decade, a substantial body of epidemiological evidence has demonstrated a consistent association between age-related hearing loss and cognitive dysfunction, including incident dementia. However, the nature of this relationship remains incompletely understood. Methods: This narrative review provides a structured overview of current evidence, focusing on epidemiological findings, mechanistic pathways, and clinical implications. Hearing loss has been associated with both accelerated cognitive decline and increased dementia risk, with a clear severity–impact relationship. Results: Several interacting mechanisms have been proposed, including increased cognitive load, structural and functional brain changes, social isolation, and shared vascular and metabolic risk factors. Emerging concepts such as the “auditory brain” and central auditory dysfunction further suggest that hearing impairment may also represent an early manifestation of neurodegenerative processes. Intervention studies have yielded mixed results. While hearing rehabilitation improves communication and quality of life, randomized evidence has not consistently demonstrated a reduction in cognitive decline in the general population, but potential benefits may exist in higher-risk subgroups. Increasing attention has been directed toward the role of neuroplasticity, with evidence suggesting that delayed intervention may limit the effectiveness of rehabilitation due to long-standing auditory deprivation. Conclusions: Taken together, current evidence suggests that hearing loss may represent both a potentially modifiable risk factor and an early marker of cognitive decline. Early identification and timely management of hearing impairment may therefore play an important role in maintaining cognitive and brain health and improving quality of life in older adults. Full article

Chronic lung disease of prematurity (CLD) is a common complication of preterm birth with a complex pathology. Recent epidemiologic studies have identified a link between neonatal exposure to di(2-ethylhexyl) phthalate (DEHP), frequently used in medical equipment, and the development of CLD. We hypothesize that DEHP exposure in the early neonatal period contributes to lung injury in newborn rats. Newborn rat pups were raised in one of the following environments: room air (RA), RA + DEHP, hyperoxia (60% oxygen), and hyperoxia + DEHP. Ambient DEHP was inhaled at a dose of 25 mg/m³ for 6 h daily for 14 days. Lung tissue and blood samples were collected on the 14th day of life. Independent exposure to DEHP and hyperoxia resulted in thicker pulmonary septal walls, fewer alveoli, increased pulmonary polymorphonuclear leukocytes and myeloperoxidase (MPO) activity and decreased expression of CD31 on endothelial cells in lung tissue. Additionally, DEHP-exposed rats showed higher serum malondialdehyde (MDA) levels and reduced vascular endothelial growth factor (VEGF) mRNA and protein levels compared to controls. Our experiments demonstrate that inhaled DEHP, with or without hyperoxia, resulted in a similar pattern of morphological lung injury and inflammation characteristic of CLD, suggesting an association with CLD of prematurity. Full article