Search Results (507)

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

Asthma is the most prevalent chronic respiratory disease in childhood, and the objective assessment of airway inflammation remains a major challenge, particularly in younger children in whom conventional lung function testing is often not feasible. The aim of this narrative review is to evaluate the clinical role of fractional exhaled nitric oxide (FeNO) in pediatric asthma, focusing on its diagnostic utility, role in treatment guidance, and value in disease monitoring. A structured literature search was conducted in PubMed for studies published between January 2015 and October 2025, using predefined keywords related to FeNO, asthma, and pediatric populations. After applying the eligibility criteria, 47 studies were included in the final synthesis. Evidence from systematic reviews and clinical studies indicates that FeNO has moderate-to-good diagnostic accuracy for childhood asthma, with a pooled sensitivity of 0.79 and specificity of 0.81, and is most useful as an adjunct to clinical assessment and lung function testing. FeNO-guided therapy may reduce exacerbation rates in selected pediatric populations, although its effects on symptom control and corticosteroid use remain inconsistent. In the monitoring setting, serial FeNO measurements may provide additional information on inflammatory control, treatment adherence, and risk of future exacerbations. However, interpretation is influenced by multiple confounding factors, including atopy, allergic rhinitis, corticosteroid therapy, and asthma phenotype. In conclusion, FeNO is a valuable complementary biomarker in pediatric asthma, with particular utility in improving diagnostic and therapeutic precision. Its optimal use requires careful integration within a multimodal clinical framework rather than reliance as a standalone tool. Full article

We showed recently that the adenosine system and nitric oxide (NO) can interact differently in the control of renal function in normoglycaemia (NG) versus streptozotocin-induced diabetes (DM). Herein, we investigated if this relationship is modulated by dietary betaine (Bet, food compound possessing antioxidant and anti-inflammatory properties), to examine if adenosine receptor signalling in NG and DM females is altered by chronic Bet supplementation. The effects of intravenous infusion of theophylline, non-selective adenosine receptor antagonist, were examined in anaesthetised Sprague–Dawley female rats, pretreated for 2 weeks with Bet alone or combined with 4-day NO synthesis blockade with L-NAME (Bet + L-NAME). Renal blood flow (RBF, ultrasound artery probe), perfusion of the cortex, outer (OM-BF) and inner medulla (IM-BF; laser-Doppler technique), and tissue NO signal (selective electrode) were determined along with renal excretion. Bet and Bet + L-NAME decreased baseline RBF irrespective of glycaemia, whereas Bet lowered (NG) or elevated (DM) basal OM-BF; Bet + L-NAME treatment abolished these effects. Baseline sodium excretion decreased after Bet and Bet + L-NAME in NG only. Bet modified theophylline effects: IM-BF was lowered in DM rats, while tissue NO changes shown in the control were modified: NO increased in NG and decreased in DM. In NG, these effects were abolished by Bet + L-NAME. Bet pretreatment did not alter diuresis, natriuresis and kaliuresis, but after Bet + L-NAME these parameters increased (NG) or decreased (DM). Dietary Bet has the potential to affect renal medullary blood circulation; however, the eventual effect depends on glycaemia. Bet can modify renal functional changes induced by the interplay of the adenosine and NO systems, both in rats with normoglycaemia and streptozotocin diabetes. Full article

Chronic kidney disease (CKD) is a progressive disorder characterized by declining renal function and increased cardiovascular risk. Experimental models are essential for investigating these mechanisms, and the 5/6 nephrectomy (5/6 Nx) model is widely used to reproduce cardiorenal alterations observed in CKD. This review aims to critically evaluate how effectively the 5/6 Nx model reproduces vasoactive and redox mechanisms relevant for pharmacological testing. A narrative synthesis of experimental studies using the 5/6 Nx model in rodents was performed, focusing on vascular, inflammatory, and oxidative pathways. The 5/6 Nx model reproduces major CKD features, including hypertension, proteinuria, glomerulosclerosis, and cardiovascular remodeling. Early activation of the renin–angiotensin–aldosterone system, endothelin signaling, and sympathetic pathways contributes to vascular dysfunction. Sustained oxidative stress reduces nitric oxide bioavailability and promotes endothelial dysfunction. Dysregulation of natriuretic peptides and increased 20-HETE signaling further contribute to vascular imbalance and remodeling. These alterations occur in a well-defined temporal progression, supporting the use of this model for mechanistic and pharmacological studies. The 5/6 Nx model remains a robust and translationally informative platform for investigating CKD progression, provided that pathway-specific reproducibility and experimental variables are carefully considered. Full article

The global burden of hypertension continues to rise, highlighting an urgent need for effective therapeutic strategies. Angiotensin-converting enzyme (ACE) is central to blood pressure regulation, but commonly used synthetic ACE inhibitors often have adverse side effects, spurring the search for safer natural alternatives. The aim of this study was to investigate Yanbian cattle hemoglobin as a novel precursor for ACE inhibitory peptides. The <1 kDa fraction was identified as exhibiting the highest inhibitory activity through the systematic screening of hydrolysates across multiple molecular weight ranges. LC-MS/MS analysis identified 1980 peptides, of which four were selected for further experiments. Solid-phase synthesis confirmed that NFGYDL exhibited the strongest ACE inhibition (IC₅₀ = 54.95 μM). Inhibition kinetics showed FHDYL acted as a mixed-type inhibitor, DLGHF and NFGYDL as competitive inhibitors and GFHLD as a non-competitive inhibitor. Molecular dynamics simulations validated the stable binding of these bovine blood-derived peptides to the ACE complex. HUVEC functional assays demonstrated that four peptides significantly increased angiotensin II-induced nitric oxide production and endothelin-1 levels, suggesting their potential antihypertensive activity. These findings suggested that bovine blood is a promising natural source of ACE-inhibitory peptides and holds potential for application as a functional component in functional foods targeting hypertension management. Full article

Background: Beets are enriched in bioactive compounds with beneficial effects on cardiovascular function. Nitrate is a precursor for nitric oxide synthesis, exhibiting an effect on cardiomyocytes and myocardial ischemia/reperfusion, improving endothelial function and reducing arterial stiffness. Betanin, saponins and phenolic compounds, other beet compounds, can limit the generation of reactive oxygen species and modulate gene expression. However, it has been a challenge to develop beetroot formulations for the oral administration of these compounds while preserving pleasant sensory characteristics. Objective: The objective of this study was to develop an innovative dairy–beetroot powder drink, microencapsulated in polysaccharides, i.e., maltodextrin, cassava starch or a combination of both, that could be easily reconstituted. Key Results: The microencapsulated formulation following freeze-drying displayed low water activity (<0.30) and high solubility (>90%), with rapid dispersion in aqueous medium. Fourier transform infrared spectroscopy confirmed the preservation of functional groups from the dairy base and sugar beetroots. Thermogravimetry analyses pointed out a slight increase in thermal stability for the powder formulation. The microencapsulation efficiency of betalains reached 81% in the powder formulation that combined cassava starch and maltodextrin as encapsulation agents. The novel dairy–beetroot powder drink can be stored at room temperature, ensuring microbiological safety and preserving good sensory acceptance. Conclusions: Dairy–beetroot powder microcapsules emerge as an efficient food strategy to provide bioaccessible dietary nitrate and antioxidant compounds, overcoming flavor and stability limitations but still aiding in terms of its vascular and hemodynamic-protective effects. Full article

Nitrate-rich vegetables are increasingly recognised as a key subgroup of phytochemical-dense foods that have significant potential for preventing and managing chronic diseases. Although dietary nitrates were historically approached with caution due to concerns about nitrosamine formation, contemporary evidence highlights their beneficial effects on vascular, metabolic and cognitive functions. Ageing is characterised by endothelial dysfunction, impaired nitric oxide (NO) synthesis and increased oxidative stress, which elevates cardiovascular risk. In this context, nitrate-rich vegetables offer a natural way to restore NO bioavailability and support cardiometabolic health. This narrative review provides an integrative overview of nitrate-rich vegetables as sources of bioactive phytochemicals with therapeutic relevance. We summarise the biochemical pathways of nitrate and nitrite metabolism, including the enterosalivary nitrate–nitrite–NO cycle, the role of oral microbiota, and red blood cell-mediated nitrite reduction. Particular emphasis is placed on NOS-independent NO production, which becomes increasingly important with age, and on the synergistic interactions between dietary nitrates and other phytochemicals such as polyphenols, vitamin C, flavonoids and betalains. These compounds enhance NO stability, reduce oxidative stress, modulate inflammatory signalling and support mitochondrial function, thereby amplifying the health benefits of nitrate-rich vegetables. Beetroot, with its high nitrate content and distinctive antioxidant profile, is highlighted as a prime example. Clinical and mechanistic studies suggest that nitrate-rich vegetables may lower blood pressure, improve endothelial function and cerebral perfusion, enhance cognitive performance and muscle oxygenation, and increase exercise efficiency, particularly in older adults. Additional benefits include anti-inflammatory effects, modulation of platelet function and improvements in metabolic parameters, all of which are relevant to the prevention of chronic diseases such as hypertension, type 2 diabetes and atherosclerosis. While dietary nitrate is generally considered low-risk for healthy adults, caution is warranted in susceptible populations, such as infants and individuals with impaired renal function. Finally, significant research gaps remain, including the need for long-term, well-controlled trials and personalised strategies that account for variability in microbiota composition and nitrate metabolism between individuals. Full article

Body Protective Compound-157 (BPC-157) is a synthetic pentadecapeptide derived from gastric proteins that has demonstrated notable reparative and anti-inflammatory properties across diverse preclinical models. Experimental evidence reveals that BPC-157 supports angiogenesis, collagen synthesis, fibroblast activity, and modulation of nitric oxide pathways, contributing to enhanced healing of muscle, tendon, ligament, bone, and gastrointestinal tissue. Studies also report reduced inflammatory cytokine activity, improved microvascular integrity, and beneficial effects on pain modulation through peripheral and dopaminergic mechanisms. Although animal data indicate favorable safety and pharmacokinetics, human research remains limited to small pilot studies investigating musculoskeletal pain, interstitial cystitis, and intravenous administration, all suggesting potential therapeutic value without reported major adverse effects. However, inconsistent preparation standards, limited clinical validation, and regulatory restrictions underscore the need for rigorous controlled trials. BPC-157 remains a promising candidate for regenerative medicine, yet comprehensive evaluation is required before clinical translation can be recommended. Full article

Background: Tyrosine kinase inhibitors (TKIs) have transformed cancer therapy; however, they are associated with cardiovascular toxicity. Metabolomics provides a comprehensive framework for identifying early biochemical disruptions that precede clinical manifestations and for formulating mechanism-based intervention strategies. Methods: We conducted a narrative synthesis of published preclinical and translational studies on TKI cardiotoxicity, focusing on untargeted and targeted metabolomic findings and complementary proteomic and transcriptomic data. Functional validation was performed using rodent and cellular models. Mechanistic themes were identified, and implications for biomarker panels, multi-omic integration, and metabolomics-guided interventions were proposed. Conclusions: Metabolomic analyses of various TKIs identified convergent signatures along three interconnected axes: (1) mitochondrial bioenergetic dysfunction characterized by impaired long-chain fatty acid oxidation and adenylate depletion; (2) disruption of endothelial nitric oxide signaling with redox imbalance, including increased nitrotyrosine, Nox activation, and eNOS uncoupling; and (3) an inflammatory metabolic profile marked by elevated branched-chain and aromatic amino acids, creatine, and osmolytes. Rodent models of sunitinib and sorafenib replicate these signatures and demonstrate histological injury, contractile dysfunction, and fibrosis. Preclinical intervention data, particularly restoration of myocardial carnitine, AMPK signaling, and fatty acid oxidation by L-carnitine, provide proof of concept for metabolomics-guided cardioprotection. Metabolomics can identify mechanistic biomarkers that facilitate the early detection, risk stratification, and targeted prevention of TKI-induced cardiovascular injury. Translation into precision cardio-oncology requires prospective validation, standardized assays, and biomarker-driven interventional trials. Full article

Osteosarcoma (OS) is a highly aggressive bone cancer with limited therapeutic options. Carnosic acid (CA), a phenolic diterpene with well-established antioxidant properties, has shown anticancer activity, yet its mechanisms in OS remain unclear. In this study, we found that CA suppressed proliferation and induced apoptosis in human osteosarcoma cells in a dose-dependent manner. Mechanistically, CA activated the STING/IRF3 signaling pathway and enhanced nitric oxide (NO) production, factors closely linked to redox modulation and mitochondrial apoptotic signaling. Pharmacological inhibition or siRNA-mediated knockdown of STING, as well as blockade of NO synthesis, significantly reduced CA-induced apoptosis in vitro. In a xenograft mouse model, CA treatment suppressed tumor growth, and this effect was partially reversed by STING inhibition. These findings suggest that CA exerts antitumor effects in OS through modulation of innate immune and redox-related signaling pathways, supporting its potential as a therapeutic compound that links antioxidant and immunomodulatory actions. Full article

Aim: Our study aimed to evaluate serum oxidative stress-related biomarkers (three pro-oxidants: total oxidant status (TOS), indirect assessment of nitric oxide synthesis (NOx), and malondialdehyde (MDA), and three anti-oxidants: total anti-oxidant capacity (TAC), catalase (CAT), and thiols) in patients with keratoconus (KCN). Methods: We conducted a single-center, cross-sectional study with the prospective enrollment of adult patients attending an outpatient ophthalmology clinic between 1 January 2024, and 1 September 2025. The diagnosis of KCN was established based on the clinical signs and two or more aberrant Pentacam parameters. Results: We evaluated 44 subjects with KCN (median age, 26 years) and 38 without KCN (median age, 28 years), with similar age and sex distributions (p-values > 0.09). All evaluated biomarkers showed statistically significant differences between subjects with KCN and those without KCN (p-values < 0.001), with higher serum TOS, NOx, MDA, CAT, and oxidative stress index levels and lower levels of TACs and thiols in subjects with KCN than in those without KCN. Conclusions: Our findings indicate a systemic imbalance between pro-oxidant and anti-oxidant biomarkers in subjects with keratoconus. Full article

In this study, ultrasound-assisted extraction (UAE) of Adenophora triphylla root polysaccharides (ATRPs) was optimized using response surface methodology (RSM), and the physicochemical and functional properties of the resulting polysaccharides were investigated. A Box–Behnken Design (BBD) was applied to optimize the UAE conditions for ATRPs. The optimal UAE conditions for ATRPs with the maximum extraction yield were an extraction temperature of 34 °C, an extraction time of 41 min, and a solvent-to-solid ratio of 34 (mL/g). Under these conditions, the maximum extraction yield of UAE-ATRPs (12.46%) was significantly higher than that obtained by water extraction without sonication (WE-ATRPs, 9.76%). The results of monosaccharide composition showed that WE-ATRPs and UAE-ATRPs were heteropolysaccharides, mainly composed of glucose. In addition, FT-IR and ¹H-NMR analyses indicated that both ATRPs had α-pyranose-type glycosidic structures. The optimal UAE process reduced the glucose content from 57.70% to 53.87% relative to WE-ATRPs. Moreover, UAE-ATRPs exhibited lower solution viscosity and improved the emulsifying properties relative to WE-ATRPs. Both ATRPs also exhibited anti-inflammatory activity by inhibiting nitric oxide synthesis. In summary, our findings suggest that UAE is an effective approach for improving the extraction yield and functional properties of ATRPs, highlighting their potential applications in the food industry. Full article

The transient receptor potential vanilloid 4 channel (TRPV4) is thought to play a pivotal role in pulmonary arterial circulation. The present study hypothesizes that TRPV4 activation increases nitric oxide (NO) release and activates calcium-activated potassium of intermediate conductance (KCa3.1) in pulmonary arteries. Pulmonary arteries were isolated from wild-type mice (wt) and mice deficient in KCa3.1 channels (Kcnn4^−/−) and mounted for simultaneous NO concentration and relaxation measurements. Human small pulmonary arteries were isolated and mounted in microvascular myographs for isometric tension recordings. Acetylcholine-induced increases in NO and relaxation of pulmonary arteries were slightly decreased in pulmonary arteries from Kcnn4^−/− versus wt mice. An activator of TRPV4 channels, GSK1016790A, increased NO and relaxation to the same degree in pulmonary arteries from wt and Kcnn4^−/− mice. A blocker of TRPV4 channels, HC06704, inhibited increases in NO concentration with no effect on acetylcholine (ACh) relaxation in pulmonary arteries from wt mice, but blocked increases in NO concentration and relaxation in pulmonary arteries from Kcnn4^−/− mice and responses to GSK1016790A in pulmonary arteries from wt and Kcnn4^−/− mice. Concentration-dependent relaxations induced by an inhibitor of sarcoplasmic Ca-ATPase, cyclopiazonic acid, were blocked in the presence of an inhibitor of NO synthase and a blocker of KCa3.1 channels, TRAM-34, in pulmonary arteries from wt mice, but were unaltered in the presence of TRAM-34 in arteries from Kcnn4^−/− mice, or the presence of a blocker of TRPV4 channels. In small human pulmonary arteries, ACh and sodium nitroprusside (SNP) induced concentration-dependent relaxations, blocked by endothelial cell removal, in the presence of an inhibitor of NO synthase and the KCa3.1 channel blocker TRAM-34. GSK1016790A induced relaxation of human pulmonary arteries with endothelium, but failed to relax arteries without endothelium. The findings suggest that TRPV4 channels are involved in endothelium-dependent relaxation and likely regulate pulmonary vascular tone by modulating NO release. Full article

Background/Objectives: Citalopram is a selective serotonin reuptake inhibitor that is prescribed to relieve anxiety and depression. Widespread use has led to the contamination of freshwater systems downstream of wastewater treatment facilitates. Few studies have investigated the impact of citalopram on early embryonic development in humans or other species, despite the prevalence of intentional or unintentional exposure. Danio rerio (zebrafish) is a model organism for investigating effects of environmental exposure to xenobiotics on developmental outcomes in vertebrates. Methods: In this study, we examined the metabolome of developing zebrafish embryos exposed to citalopram hydrobromide concentrations (0.03–250 ng/mL) spanning environmental to therapeutic doses during the first 24 h post-fertilization. Exposure was followed by 24 h exposure-free development before harvest at 48 h. Results: Gross morphology of the embryos was normal, although changes were observed in the heart rates of citalopram-exposed embryos. Untargeted metabolomic and multivariate analyses revealed significant, nonlinear changes in the metabolome in response to citalopram exposure. Arginine and proline metabolism was significantly altered, potentially reflecting changes in serotonin signaling, nitric oxide metabolism, and polyamine synthesis. Conclusions: Together, these data demonstrate that transient exposure to citalopram can induce long-lasting metabolomic changes during development, including dose-dependent changes that include aberrant metabolic processes in the developing metabolome. As a result, this work reveals potential biomarkers for early developmental exposure. Full article

Background: Caveolin-1 (Cav-1) is a protein found in various forms and locations within cells and tissues throughout the body. Studying its structure and function provides valuable insights into key cellular processes such as growth, death, and cell signaling. This review synthesizes evidence from human studies and animal models to elucidate the complex role of Caveolin-1 (Cav-1) in regulating nitric oxide (NO) synthesis within the vasculature and perivascular adipose tissue (PVAT) during atherosclerosis. Cav-1 is a master regulator of endothelial NO synthase (eNOS), a relationship well-defined in rodent endothelial cells and cell lines. In humans, loss-of-function CAV1 mutations are linked to pulmonary arterial hypertension, suggesting a protective vascular role. Paradoxically, Cav-1 is upregulated in atherosclerotic plaques. Whether this represents a pathological process reducing NO bioavailability or a compensatory response remains unclear. Furthermore, the direct translation of the Cav-1/eNOS axis to PVAT—a metabolically active tissue expressing Cav-1—is not fully established outside of preclinical models. PVAT influences vascular tone and inflammation, potentially contributing to the paradoxical, stage-specific roles of Cav-1 in disease. Resolving these questions requires integrating human observational data with mechanistic insights from animal models to evaluate Cav-1 as a therapeutic target in vascular disease. Full article