Search Results (11,214)

Cardiovascular disease (CVD) persists as the leading cause of global mortality, with adult mammalian hearts exhibiting limited regenerative capacity. Although cardiomyocytes (CMs) can re-enter the cell cycle and undergo DNA synthesis in response to injury, they fail to complete mitosis and cytokinesis, resulting in a functional blockade of productive proliferation following ischemic or aging-related injury. Reactive oxygen species (ROS) exhibit a context-dependent duality in cardiac regeneration: while maintaining redox homeostasis and supporting developmental signaling at physiological concentrations, pathological ROS accumulation exacerbates myocardial decline by inducing DNA damage response (DDR)-mediated cell cycle arrest at G2/M phase, along with structural and functional impairments. This review examines the mechanisms of ROS generation—from its cellular origins to its molecular drivers—in ischemic heart disease, and explores the modulation of regenerative signaling by oxidative stress. We further critically assess emerging therapeutic interventions targeting ROS-mediated myocardial regeneration. By delineating the functional roles of ROS in cardiac injury and repair, this review provides a mechanistic and translational framework for developing redox-based therapies aimed at promoting cardiomyocyte proliferation and myocardial regeneration after ischemic injury. Full article

Reactive oxygen species (ROS) are widely recognized as intracellular signaling mediators and contributors to oxidative damage. Increasing evidence indicates that redox processes in the extracellular space constitute a distinct and functionally relevant layer of immune regulation. Extracellular ROS are generated in a spatially and temporally controlled manner by immune and non-immune cells and are shaped by local antioxidant buffering, redox-active metabolites, and tissue architecture. Rather than acting as diffuse by-products of inflammation, extracellular redox conditions modulate immune cell activation, migration, and intercellular communication by influencing surface-associated signaling events and receptor responsiveness. Physiological redox control in the extracellular compartment supports host defense, tissue repair, and coordinated immune responses. In contrast, disruption of spatial redox regulation promotes chronic inflammation, immune dysfunction, cancer-associated immune suppression, and systemic inflammatory states such as sepsis. Loss of redox confinement and insufficient extracellular buffering uncouple redox signaling from its regulatory function and contribute to endothelial dysfunction, immune dysregulation, and tissue injury. Together, these observations identify the extracellular redox balance as an integral component of immune regulation with important implications for understanding inflammatory pathology and for the development of strategies that preserve localized redox control rather than globally suppressing ROS. Full article

Mechanical unloading of skeletal muscle triggers various signaling alterations that result in muscle atrophy and weakness. Mitochondria are essential to muscle health, acting not only as energy suppliers but also as central mediators of molecular regulation. Mitochondrial activity, content, and dynamics are tightly controlled by multiple signaling pathways; conversely, mitochondria-derived messengers, such as reactive oxygen species (ROS), ATP, and mitokines, are involved in the regulation of nearly all aspects of muscle signaling. During mechanical unloading, altered muscle activity leads to mitochondrial dysfunction. However, the initial triggers, underlying mechanisms, and full consequences of this dysfunction remain poorly understood. Nevertheless, mitochondria-targeted therapies have emerged as a promising strategy for mitigating unloading-induced muscle impairments. In this review, we summarize current data regarding the characteristics, causes, and outcomes of unloading-induced mitochondrial dysfunction, specifically focusing on muscle atrophy and functional decline. We highlight novel findings regarding the roles of mitokines and mitochondrial calcium overload, propose a new hypothesis to explain the biphasic dynamics of ATP accumulation during slow-type muscle unloading, and describe emerging therapeutic strategies to counteract these mitochondrial impairments. Full article

The N88S mutation in human seipin causes a dominant motor neuron disease marked by ER stress and inclusion body formation, lipid imbalance, and oxidative damage. However, the metabolic mechanisms connecting these defects remain poorly understood. Previous proteomic profiling in our yeast model of N88S human seipinopathy revealed decreased protein levels of enzymes involved in the tricarboxylic acid cycle, fatty acid and carboxylic acid metabolism, and the glyoxylate cycle, suggesting impaired downstream utilization of peroxisome-derived acetyl-CoA. Guided by these findings, we investigated how peroxisomal function contributes to cellular dyshomeostasis. N88S seipin-expressing cells exhibited increased peroxisome abundance but defective routing of acetyl-CoA into mitochondrial and glyoxylate pathways, resulting in elevated reactive oxygen species (ROS), impaired glyoxylate cycle activation, and reduced metabolic adaptability to non-fermentable carbon sources. Loss of peroxisomes or forced cytosolic redirection of acetyl-CoA further exacerbated ER stress, ROS accumulation, lipid peroxidation, and the growth defect on N88S seipin-expressing cells, whereas inhibition of fatty acid synthesis mitigated oxidative damage. These findings demonstrate that N88S seipin triggers a futile cycle in which misrouted cytosolic acetyl-CoA drives lipogenesis, amplifying oxidative damage and ER stress. We conclude that defective peroxisome–mitochondria metabolic coupling and acetyl-CoA misrouting may represent central pathogenic mechanisms driving cellular dysfunction in N88S-linked seipinopathy. Full article

Thicklipped grey mullet (Chelon labrosus) shows potential as an appealing species for aquaculture in the EU. Knowledge of its metabolic requirements is essential for species management and control of environmental conditions. We examined routine and postprandial oxygen consumption (OC) in juveniles as a function of body weight (Bw: 2–85 mg) and temperature (T: 14–26 °C), as well as OC and ventilatory frequency (VF) under gradual hypoxia as a function of T (14–22 °C). Multiple regression analyses determined the effects of Bw and T on mean daily (OC_mean), postprandial (OC_SDA), routine (OC_routine), and maximum (OC_max) levels, as well as on OC_max/OC_routine ratio (MSF), postprandial OC duration (D_SDA) and time to reach maximum activity (D_peak). The effects of dissolved oxygen (DO) and T on OC and of T on initial VF (VF_ini), maximum VF (VF_max), critical DO threshold (%DO_crit), and VF change threshold (%VF_ch) were also analysed. All OC levels increased with T and Bw, except MSF, D_SDA, and D_peak, uninfluenced by Bw. Under gradual hypoxia, OC decreased with falling DO, more sharply at higher T, consistent with oxyconformer behaviour. VF remained stable until 50% DO, then rose progressively, reaching higher VF_max at higher T. Simulations using derived equations estimate C. labrosus respiratory response and water flow requirements under aquaculture conditions. Full article

High-temperature Daqu (HTD)’s quality determines the characteristics and yield of the Chinese sauce-aroma baijiu. However, winter production frequently encounters challenges such as fermentation instability and metabolic fluctuations, primarily stemming from complex, unmonitored microenvironmental changes within the HTD pile. This study established a closed-loop system linking the microenvironment, HTD quality, microbiome, and metabolome. Through continuous monitoring of the winter fermentation pile’s microenvironmental conditions and integrating multi-omics analyses, we revealed that CO₂ concentration within fermentation piles is the core factor causing quality variations in HTD. By breaking the respiratory bottleneck formed by carbon dioxide (CO₂) accumulation through the turning anaerobic stress can be alleviated, thereby driving metabolic succession. The study found that vertical CO₂ concentration heterogeneity severely restricts the enrichment of aerobic core functional microbial communities such as the Bacillus species. This directly blocks key metabolic pathways including amino acid metabolism and energy supply via ABC transporters. Moreover, the specific accumulation of Amadori products further confirms that this low-temperature environment under CO₂ stress causes the Maillard reaction to stall at intermediate stages. Consequently, this study proposes a steady-state control strategy centered on oxygen and CO₂ gas characteristics. By actively regulating the gaseous microenvironment to eliminate metabolic heterogeneity, it provides theoretical support for standardizing traditional fermentation processes. Full article

Background: Although the definition of dietary fibre is complex and constantly evolving, today we can identify it as “carbohydrate polymers with at least 10 monomeric units, which are not hydrolysed in the small intestine of humans”. In addition to the numerous and well-known benefits of dietary fibre for human health, our attention is drawn to its antioxidant properties, achieved through polyphenolic compounds linked to polysaccharide complexes. This study investigated the antioxidant effects of an extract from the fruit of Punica granatum (PUN), particularly rich in polyphenols, fibre, flavonoids, vitamins, organic acids, minerals, amino acids, and alkaloids. Furthermore, these effects were evaluated in two human nervous system cell lines under oxidative stress induced by hydrogen peroxide. Methodology: After examining the fibre composition, some polyphenols present in the extract were identified and quantified by HPLC. Furthermore, the antioxidant power of PUN was measured using the DPPH method, the chelating activity assay, the reducing power test, the ORAC method, the measurement of reactive oxygen species accumulation, the quantification of lipid peroxidation, and the detection of mitochondrial superoxide in cell cultures. Results: The results were consistent, and PUN demonstrated a strong antioxidant potential, justified not only by the high content of easily extractable polyphenols (EPPs) but also by a further addition of these more difficult to identify compounds (NEPPs), indicated as “hidden polyphenols”; therefore, the total polyphenol content in the extract resulted from the sum of EPPs + NEPPs (71 ± 7.9 + 55 ± 6.4 mg = 126 ± 14.3 mg gallic acid equivalent (GAE)/g dry weight). The fraction of hidden polyphenols could therefore explain a mechanism by which the fibre exerts an antioxidant effect. Another important result was achieved by the cell lines used, both of which were significantly protected by PUN following oxidative damage generated by a pro-oxidant treatment. However, astrocytes were found to be more responsive and sensitive than were human neurons. At the same time, PUN mitigated the effects of oxidative damage, and it could be hypothesised that this extract could be used to extinguish the A1 phenotype. Conclusions: We can conclude that the fibrous component of pomegranate is related to the antioxidant property exerted, and the neurodegeneration caused by oxidative stress could be slowed following the intake of Punica granatum. It is possible to identify the pomegranate as a “superfood” or “functional food”, with excellent nutritional characteristics and chemical composition. Full article

Background/Objectives: Mild cognitive impairment (MCI) is accompanied by olfactory dysfunction, and few interventions target shared chemosensory–cognitive mechanisms. We retrospectively examined whether a 5-week oxygen–ozone major autohemotherapy (MAH) cycle is associated with coupled improvements in olfactory and cognitive performance in adults with MCI. Methods: We analyzed 81 individuals with MCI who completed 10 MAH sessions (twice weekly) and 93 matched healthy controls. In the MCI group, olfactory function was measured before and after MAH using Sniffin’ Sticks^® threshold–discrimination–identification (TDI) scores; global cognition was assessed with the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). We evaluated between-group and pre–post changes and used Spearman correlations to assess olfactory–cognitive coupling. Results: At baseline, MCI participants showed lower TDI and MoCA scores than controls and more hyposmia/anosmia. Following MAH, the proportion of normosmic patients increased from 32.1% to 50.6%, with fewer anosmic cases. TDI scores improved but remained lower than in controls. MMSE scores were unchanged, whereas MoCA total scores increased, with domain-level gains and a significant improvement in Language Repetition. TDI gains were modestly correlated with MoCA total and selected domain changes. Conclusions: In this retrospective cohort, MAH was associated with partial restoration improvements of olfactory function and improved cognitive performance. Correlated olfactory–cognitive changes were observed within the treated MCI group; however, causal attribution to O₂–O₃ MAH cannot be established without randomized, double-blind, sham-controlled trials with coupled olfactory–cognitive gains consistent with a shared, potentially modifiable substrate. Prospective randomized trials are needed to confirm efficacy and clinical utility. Full article

Oxidative stress-induced endometrial injury has been shown to contribute to infertility; however, effective strategies that can simultaneously scavenge reactive oxygen species (ROS) and restore mitochondrial and antioxidant homeostasis remain elusive. In this study, we isolated extracellular nanovesicles from Artemisia argyi (A-NVs) and investigated their protective effects on H₂O₂-damaged human endometrial stromal cells (hESCs). We discovered that A-NVs possess a typical lipid bilayer structure and contain a variety of bioactive components. Our metabolomic analysis indicates that A-NVs can be regarded as a “natural drug reservoir”, in which flavonoids account for approximately 10.8%. We demonstrate that A-NVs can be efficiently taken up by cells, improve cell viability, reduce intracellular and mitochondrial ROS levels, enhance superoxide dismutase (SOD) activity, upregulate the expression of catalase (CAT), SOD1, and SOD2, and partially restore mitochondrial membrane potential. Mechanistically, A-NVs exert antioxidant effects by activating the SIRT1/PGC-1α/Nrf2 signaling axis. SIRT1 activation further alleviates H₂O₂-induced premature senescence, as evidenced by a 71.8% reduction in SA-β-Gal-positive cells compared with the H₂O₂ group, together with downregulation of p53 and p21 expression. These positive protective effects can be blocked by the SIRT1 inhibitor EX-527, confirming the central role of this pathway. Collectively, our findings demonstrate that A-NVs can maintain redox and mitochondrial homeostasis while inhibiting oxidative stress-related senescence progression, underscoring their application potential in endometrial repair and functional recovery. Full article

Aging is a progressive degenerative process characterized by the depletion of tissue stem cell reserves, organ atrophy, sarcopenia, and an impaired capacity to respond to physiological stress and injury. These changes lead to a reduction in both overall life expectancy and disease-free lifespan. Since aging represents a major risk factor for numerous diseases, including neurodegenerative, cardiovascular, and metabolic disorders, recent research has increasingly focused on identifying effective intervention strategies to promote “healthy aging” by slowing down the aging process as much as possible. At the molecular level, multiple factors contribute to cellular aging and, consequently, to the onset of senescence. These include mitochondrial dysfunction, defective DNA repair mechanisms, epigenetic reprogramming, and chronic low-grade inflammation. Among the mechanisms driving cellular senescence, oxidative stress is recognized as a key contributor to the loss of replicative capacity. When reactive oxygen species (ROS) levels exceed a critical threshold, they can damage essential macromolecules, including DNA. Therefore, ROS and oxidative stress represent crucial therapeutic targets to be considered in strategies aimed at counteracting cellular senescence. Based on these causal factors, several strategies have been identified that target modifiable lifestyle determinants, with a primary focus on nutrition and nutraceutical interventions. In this context, the present review aims to critically analyze scientific evidence regarding nutritional approaches designed to slow down the aging process, including their effects at the molecular level. Specifically, these strategies aim to reduce inflammation, preserve mitochondrial function to modulate ROS production, and protect macromolecules from oxidative stress. Full article

Dissolution of iron oxides in water plays a critical role in corrosion, mineral cycling, and surface reactivity; yet, the atomic-scale mechanisms governing Fe release remain poorly understood. Here, we employ ab initio molecular dynamics and well-tempered metadynamics simulations to investigate the stepwise dissolution of surface Fe atoms from the -Fe₂O₃(0001) surface in aqueous solution. The dissolution process initiates from a stable surface configuration in which Fe is coordinated to three lattice oxygen atoms and one water molecule. It proceeds through a series of metastable states involving additional water coordination, proton-assisted Fe-O bond weakening, and eventual detachment from the substrate. The first major transition, requiring 46.5 kJ/mol, involves breaking the hydrogen-bonding net and overcoming steric hindrance to allow adsorption of a second water molecule. Intermediate barriers (10.9–30.3 kJ/mol) are associated with further coordination and bond cleavage steps. In contrast, the final release of Fe into the solution, corresponding to a state coordinated with four water molecules and no lattice oxygen, exhibits a much higher free-energy barrier of ~ 93.0 kJ/mol. This barrier arises from the formation of a rigid hydrogen-bonded water cage and the loss of proton access to the remaining surface oxygen site, as confirmed by radial distribution function analysis. Our findings reveal why -Fe₂O₃(0001) is highly resistant to complete dissolution yet prone to surface roughening, defect formation, and adatom structures under aqueous conditions. Full article

This study aimed to investigate the impacts of chestnut tannin (CT) on growth performance, immune response, and intestinal health of broilers challenged with necrotic enteritis (NE) through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-ferroptosis pathway. A total of 240 one-day-old male Cobb 500 broilers (44.54 ± 0.51 g) were randomly divided into four groups, including a Control group, NE group, 500 mg/kg CT group (L-CT), and 1000 mg/kg CT group (H-CT), with six replicates per group and ten broilers per replicate. Sporulated coccidia oocysts on day 14 and Clostridium perfringens solution from days 19 to 21 were given to all broilers except the Control group through oral administration to establish the NE infection model. The results demonstrated that dietary supplementation with CT improved (p < 0.05) growth performance, intestinal morphology, and intestinal mucosal barrier function of broilers challenged with NE. CT supplementation decreased (p < 0.05) interleukin (IL)-1β, IL-6, type I interferon, interferon-γ, and tumor necrosis factor-α concentrations and increased (p < 0.05) IL-10 concentration in the jejunal mucosa. Furthermore, CT supplementation decreased (p < 0.05) Fe²⁺ concentration, malondialdehyde concentration, mitochondrial DNA level, and mitochondrial reactive oxygen species level in the jejunal mucosa. Broilers under NE challenge had upregulated (p < 0.05) jejunal protein expression of cGAS, STING, phospho-TANK-binding kinase 1, phospho-interferon regulatory factor 7, phospho-nuclear factor kappa B, ferroptosis suppressor protein 1, prostaglandin-endoperoxide synthase 2, acyl-CoA synthetase long-chain family member 4, WD repeat domain phosphoinositide-interacting protein 2, nuclear receptor co activator factor 4 and autophagy related protein 5 and downregulated (p < 0.05) glutathione peroxidase 4, ferritin heavy chain 1, ferritin light chain and ferroportin 1 compared with the Control group, while the supplementation of CT reversed these effects. In conclusion, CT improved intestinal inflammatory damage of broilers challenged with NE by inhibiting the cGAS-STING-ferroptosis pathway, which was more effective at a dose of 1000 mg/kg in this study. Full article

Hypoxic pulmonary vasoconstriction (HPV) is a rapid and reversible constrictor response of the pulmonary vasculature, and especially its small muscular precapillary arteries, which is initiated by episodes of local alveolar hypoxia. Acting as a protective homeostatic vasomotor mechanism, HPV enables maximal gas exchange by diverting blood from poorly ventilated alveoli into those rich in oxygen, thereby optimizing oxygen uptake and the ventilation–perfusion (V/Q) ratio so as to maintain the arterial oxygen partial pressure (P_aO₂) within the physiological range. HPV is an intrinsic mechanism of pulmonary artery smooth muscle cells (PASMCs), and requires an O₂ sensor which acts through mediator(s) to trigger effector mechanisms within these cells to evoke constriction. Whereas HPV effector mechanisms are reasonably well defined, the nature of the O₂ sensor and mediators remains in dispute, and a number of proposals have been developed to account for these. Some (but not all) of these share a focus on the concept that hypoxia activates effector mechanisms by inducing a change in the PASMC cytoplasmic redox state. Of these, the Redox Theory, first proposed by Kenneth Weir and Stephen Archer in 1995, proposes that hypoxia inhibits mitochondrial production of reactive oxygen species (ROS), thereby causing the cytoplasm to become more reduced. This inhibits ongoing vasorelaxation maintained by the opening of voltage-gated K⁺ channels. In contrast, according to the Mitochondrial ROS hypothesis, introduced by Paul Schumacker and Naveen Chandel in 2001, hypoxia increases mitochondrial ROS production, causing an oxidizing shift in the cytoplasmic redox state that activates several vasoconstricting pathways. In a third redox-based scenario, developed by Michael Wolin and Sachin Gupte, hypoxia evokes contraction by causing a fall in H₂O₂ production by NADPH oxidase and by activating the pentose phosphate pathway. These effects inhibit basal vasorelaxation maintained by the guanylate cyclase and protein kinase G and also stimulate vasoconstricting mechanisms. In this comprehensive review, we first provide a detailed summary of the key studies contributing to the development of these proposals and then subject the evidence supporting them to a critical appraisal, based in part on how well they accord with the wider literature and recent developments in our understanding of how cells shape and deploy redox mechanisms in order to regulate cell function. Full article

Hypertension (HTN) remains a leading modifiable risk factor for cardiovascular disease, and non-pharmacological strategies combining exercise training with plant-derived bioactive supplementation are increasingly recognized as promising adjuncts for blood pressure (BP) management. This evidence-based review synthesizes findings from 31 clinical studies investigating selected plant-based supplements with the strongest available clinical evidence, namely beetroot juice (BRJ), green tea (GT), curcumin (CN), resveratrol (RSV), and garlic, administered alone or in combination with different exercise modalities across acute, short-term, and long-term interventions. Collectively, the evidence indicates that BRJ exerts the most consistent BP-lowering effects, particularly during aerobic training performed at ~50% heart rate reserve (HRR), or ~60% peak oxygen consumption (VO_2peak) in individuals with early-stage vascular dysfunction. CN and garlic also enhance exercise-induced BP reductions, especially in older or metabolically compromised populations. GT shows variable outcomes depending on caffeine content, exercise modality, and participant health status, while RSV provides modest vascular support, often contingent on concurrent training. Mechanistically, these botanicals and exercise converge on key vascular-regulatory pathways, including enhanced nitric oxide (NO) bioavailability, reduced oxidative stress and inflammation, attenuated renin–angiotensin–aldosterone system (RAAS) and sympathetic activity, and improved mitochondrial function through Sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK) signaling. Together, these integrated mechanisms improve endothelial function, lower vascular resistance, and ultimately reduce BP. From a translational standpoint, combining exercise with targeted plant-based supplementation offers a safe, accessible, and physiologically synergistic strategy for BP control in clinical populations. Future research should define optimal dosing, timing relative to exercise, and population-specific efficacy to inform precision-based, integrative interventions for HTN management. Full article

Background: This study investigated the diurnal variation in endurance performance and the corresponding ventilatory/metabolic responses during a maximal incremental cycling test. Methods: Thirty physically active young men (age = 23.5 ± 2.2 years; weekly exercise volume: ≥6 h·wk⁻¹) with regular daily routines were recruited for a randomized crossover study. Each participant completed two maximal incremental cycling tests to volitional exhaustion: one in the morning (07:00–09:00) and another in the evening (17:00–19:00). The two sessions were separated by a one-week washout period. Key ventilatory and metabolic variables, including maximal voluntary ventilation (MVV) and maximal oxygen uptake (VO_2max), were continuously measured, and time to exhaustion (TTE) was monitored. Paired-samples t-tests were used to compare morning versus evening outcomes. Results: Key performance and physiological variables, including MVV (p < 0.01), VO_2max (p < 0.01), and TTE (p < 0.01), were significantly improved in the evening as compared to the morning. Conclusions: Both ventilatory/metabolic function and endurance performance during a maximal incremental cycling test induce a pronounced diurnal rhythm in trained young men, with superior outcomes observed in the evening. Full article