Search Results (3,669)

Reproductive inefficiency associated with impaired oocyte competence and embryonic loss remains a major limitation in livestock production. Although glycine is classified as a non-essential amino acid, its endogenous synthesis is often insufficient to meet increased metabolic demands during gestation and early embryonic development. This suggests that glycine has a conditionally essential role in reproductive physiology. However, the mechanisms through which glycine integrates metabolic and signaling processes to regulate reproductive outcomes are not fully understood. This review summarizes the recent advances in understanding glycine’s role in animal reproduction, emphasizing its function as a metabolic regulator rather than merely a structural component. Glycine contributes to reproductive processes by maintaining redox homeostasis, supporting mitochondrial function and stabilizing cellular environments as part of its osmolyte function during critical developmental stages. Additionally, glycine participates in one-carbon metabolism, influencing nucleotide synthesis and epigenetic regulation. Furthermore, emerging evidence suggests that glycine may modulate key signaling pathways, including the AMP-activated protein kinase (AMPK)-mechanistic target of rapamycin complex 1 (mTORC1) pathway. Consistent with these mechanistic roles, glycine supplementation has been associated with improvements in oocyte maturation and embryonic development, particularly in vitro. These findings highlight the potential of glycine as a dietary or culture medium supplement to enhance reproductive performance in livestock. However, most current evidence is derived from in vitro systems, and the translation of these findings into livestock production strategies requires validation through well-designed in vivo studies. Full article

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are critical modulators of male reproductive health, influencing sperm function, hormonal regulation, and overall fertility. While physiological levels of ROS and RNS are essential for processes such as sperm capacitation and acrosome reaction, their overproduction leads to oxidative and nitrosative stress, contributing to male infertility. Excessive ROS and RNS can damage sperm DNA, proteins, and lipids, impairing motility, viability, and fertilizing capacity. Moreover, these reactive species disrupt the hypothalamic-pituitary-gonadal (HPG) axis, leading to hormonal imbalances that further compromise reproductive function. Environmental factors, lifestyle choices, and underlying health conditions exacerbate the production of ROS and RNS, highlighting the need for preventive and therapeutic strategies. Clinically, ROS- and RNS-mediated redox imbalance has been implicated in several male reproductive disorders, including varicocele, genital tract infection and inflammation, obesity, diabetes and other metabolic disorders, and toxicant-related reproductive dysfunction. Antioxidant supplementation has shown promise in mitigating oxidative stress; however, its efficacy varies, and further research is necessary to establish standardized treatment protocols. These findings underscore the clinical relevance of integrating oxidative stress assessment with conventional semen analysis to improve risk stratification and guide targeted interventions in male infertility. This review synthesizes current knowledge on the molecular mechanisms by which ROS and RNS affect male reproduction and discusses potential clinical interventions to address oxidative and nitrosative stress in male infertility. Full article

Mitochondrial Lon peptidase 1 (LONP1) is an ATP-dependent AAA⁺ (ATPases associated with diverse cellular activities) protease that has emerged as a key regulator of mitochondrial proteostasis, with functions extending beyond protein quality control. In addition to degrading misfolded and oxidized proteins, LONP1 coordinates mitochondrial DNA maintenance, metabolic remodeling, and stress-responsive signaling. Recent structural and functional advances have expanded the biological significance of LONP1 beyond protein quality control, highlighting its roles in mitochondrial metabolism, genome maintenance, and stress responses. LONP1 dysregulation is increasingly implicated in cancer, metabolic disorders, neurodegeneration, and aging, where it exerts context-dependent effects on cell survival and disease progression. In cancer, LONP1 supports metabolic plasticity, redox adaptation, and therapeutic resistance, whereas in degenerative conditions, its decline contributes to mitochondrial dysfunction and tissue damage. Here, we synthesize recent insights into the structure, mechanisms, and biological functions of LONP1 and discuss their implications for human disease. We further discuss emerging therapeutic strategies and key challenges for targeting LONP1 in human disease. Full article

The pineal gland regulates circadian physiology through the periodic production of melatonin (MLT). In addition to its established role as a chronobiotic agent, MLT regulates redox homeostasis and mitochondrial physiology. Mitochondria and redox-active molecules, particularly reactive oxygen species (ROS), play essential roles in reproduction, including gamete physiology, fertilization, and early embryonic development. Although excessive oxidative stress (OS) impairs fertility, controlled ROS signaling is necessary for normal reproductive function. This comprehensive review synthesizes current evidence regarding MLT as a key intermediary linking circadian signaling with mitochondrial physiology and redox homeostasis. We discuss molecular pathways through which MLT regulates mitochondrial function, including activation of the Nrf2 signaling pathway, modulation of mitochondrial permeability transition, regulation of electron transport chain (ETC) efficiency, and apoptotic signaling. Furthermore, this study investigates MLT’s ability to scavenge free radicals and activate antioxidant defense mechanisms. Moreover, we review novel findings regarding the effects of MLT in experimental animals and humans, assisted reproductive technologies (ART) such as in vitro fertilization (IVF), and consider the translational significance of the hormone as an enhancer of fertility. We also highlight gaps in the literature, including methodological inconsistencies, supraphysiologic doses, and insufficient data from large human cohorts. Lastly, we discuss an integrative model whereby MLT may function as an important regulator of mitochondrial redox balance, with potential implications for reproductive physiology and reproductive outcomes, and propose new avenues for investigation. Full article

Background: Cytarabine (Ara-C) remains the cornerstone of remission-induction and consolidation chemotherapy for acute myeloid leukemia (AML) and related hematological malignancies. Despite more than six decades of clinical use, its multi-organ toxicity continues to be managed almost exclusively through dose attenuation and supportive care, with no approved upstream pharmacological prevention strategy available. Objectives: This scoping review aimed to systematically map the breadth and nature of pharmacological agents tested in vivo for their capacity to mitigate cytarabine-induced multi-organ toxicity, to characterize their mechanisms of action and organ targets, and to identify evidence gaps and agents with translational potential. Methods: The review was designed and reported in accordance with the PRISMA-ScR checklist. A structured electronic search was conducted across PubMed/MEDLINE, Scopus, Cochrane Library and Embase, and Web of Science from database inception to 15 July 2025. Eligible studies were restricted to full-text, peer-reviewed, English-language research involving in vivo mammalian models administered cytarabine as the principal toxin, with at least one pharmacological co-intervention and at least one quantitative or histopathological organ-injury outcome. Results: From 5701 retrieved records, 36 eligible in vivo mammalian studies (spanning 1964–2024) were identified. Included studies addressed neurotoxicity (n = 6), gastrointestinal mucositis (n = 9), ocular toxicity (n = 3), hepatotoxicity (n = 3), bone marrow suppression (n = 4), chemotherapy-induced alopecia (n = 5), and reproductive and developmental toxicity (n = 4). Five recurring mechanistic strategies were identified across the heterogeneous agents tested: redox buffering (N-acetylcysteine, α-lipoic acid, rutin, swertiamarin, α-tocopherol), mitochondrial preservation (betanin, thymoquinone, vitamin D, sodium zinc dihydrolipoylhistidinate [DHLHZn]), tissue-microenvironment reprogramming (apraglutide, BADGE, plerixafor, short-chain fatty acids, β-glucan), molecular antagonism (deoxycytidine, dCMP), and immunomodulation (lienal peptide, IL-1β, AHCC). Conclusions: This scoping review provides the first systematic cartography of pharmacological mitigation strategies for cytarabine-induced multi-organ toxicity. Five mechanistic pathways converge across eight organ systems, with apraglutide and N-acetylcysteine representing the most clinically translatable candidates. Plerixafor and PPARγ blockade by BADGE constitute high-priority candidates for bone marrow niche protection, while the deoxycytidine antagonism principle warrants formal pharmacokinetic evaluation. The complete absence of cardiotoxicity mitigation data defines the most critical gap for future research. Full article

Oxidative stress has been recognized as a repeatedly validated pathophysiological factor in schizophrenia, but its mechanistic role and translational relevance remain incompletely defined. Prior work has advanced redox dysregulation, neuroinflammation, and NMDA receptor hypofunction as a putative central hub in schizophrenia. This narrative review proposes an evidence-weighted redox–mitochondria–immune framework that integrates peripheral biomarkers, magnetic resonance spectroscopy, postmortem findings, and preclinical mechanisms while explicitly distinguishing established observations from candidate pathways. Existing studies support increased oxidative damage and altered antioxidant buffering in schizophrenia, particularly involving the glutathione system. However, these abnormalities are neither uniform across disease stages nor equally represented across patient subgroups, and may be markedly prominent only in certain biological subgroups. Mechanistically, redox imbalance may interact with mitochondrial bioenergetic deficits and innate immune signaling; however, pathway-specific links such as cGAS-STING activation, nitrosative/peroxynitrite stress, and GPx4-ferroptosis should currently be treated as testable extensions rather than validated human mechanisms in schizophrenia. Importantly, the pathological consequences of oxidative stress are unlikely to be cell-type neutral. Parvalbumin-positive interneurons and oligodendrocyte lineage cells are more vulnerable because of their high metabolic load, limited antioxidant buffering capacity, and lipid/iron-related susceptibility, thereby providing a mechanistic bridge to excitation–inhibition imbalance, myelin abnormalities, and reduced circuit synchrony. Microglial redox–inflammatory signaling may further exacerbate these processes. On the basis of this framework, we argue that the key for future research is not to continue demonstrating the universality of oxidative stress, but to improve the translational efficiency. Biomarker-guided stratification, stage-sensitive study designs, and cell-type-informed therapeutic strategies may therefore provide a more productive path toward redox-targeted interventions in schizophrenia. Full article

Osmotic stress severely limits the growth and development of tomato (Solanum lycopersicum L.) by reducing cellular water potential, disrupting redox homeostasis, and impairing physiological functions. Micro–nano bubble (MNB) treatment can increase dissolved oxygen in the root-zone solution and improve the root-zone environment, which may benefit root metabolic activity and stress adaptation. However, the underlying molecular mechanisms are still not elucidated. To explore the underlying molecular mechanisms of how MNB-mediated root oxygenation alleviates osmotic stress in tomato, we have integrated the physiological and biochemical alterations, variable-pressure scanning electron microscopy (VP-SEM), and transcriptomic analysis (RNA-seq) under osmotic stress. The results revealed that MNBs significantly reduced PEG-induced wilting and decreased reactive oxygen species (ROS) accumulation and relative electrical conductivity (REC). Indeed, MNBs also markedly upregulated the expression of root aquaporins PIP2.7 and PIP2.4, suppressed the expression of NCED1 in leaves, and increased levels of endogenous growth-promoting hormones, including IAA and GA₃, under osmotic stress. VP-SEM observations showed that MNB-treated plants exhibited a relatively more open stomatal appearance compared with PEG-treated plants. Together, these findings suggest that MNBs mitigate PEG-induced osmotic stress in tomato, potentially by improving the root-zone aeration environment and coordinating water transport-related gene expression, antioxidant defense, and hormonal balance. These results provide a promising physical approach and theoretical basis for improving tomato stress tolerance under osmotic stress. Full article

Lactate was traditionally considered a metabolic by-product of anaerobic glycolysis, mainly associated with tissue hypoxia and muscle fatigue. However, increasing evidence has redefined lactate as a multifunctional metabolic intermediate and signaling molecule involved in exercise-induced systemic adaptations. During physical activity, circulating lactate levels rise markedly when skeletal muscle production exceeds systemic clearance, allowing lactate to act as an exercise-responsive metabolite, or exerkine, and as a mediator of cardiometabolic adaptation. In the cardiovascular system, lactate serves not only as an efficient substrate for myocardial energy production but also as a regulator of vascular tone, endothelial function, angiogenesis, inflammation, and cardiac remodeling. These effects occur through receptor-dependent and receptor-independent mechanisms, including activation of hydroxycarboxylic acid receptor 1 (HCAR1/GPR81), modulation of intracellular redox balance, and histone or non-histone protein lactylation. This review summarizes current evidence on lactate in cardiovascular physiology and disease, focusing on myocardial lactate metabolism, HCAR1/GPR81 signaling, protein lactylation, extracellular vesicle communication, gut microbiota interactions, and therapeutic implications in heart failure, atherosclerosis, and diabetic cardiomyopathy. Although lactate is also produced under resting, postprandial, and pathological conditions, exercise is characterized by the amplitude and kinetics of lactatemia, coordinated hormonal and hemodynamic responses, and transient high-concentration signaling. These features support exercise-derived lactate as a context-dependent cardiovascular exerkine. Full article

Driven by increasingly severe drought stress associated with global warming, this study investigated a synthetic microbial community, SynCom-SASW01, with strong stress tolerance and plant growth-promoting potential, and systematically elucidated its mechanisms for enhancing drought resistance in wheat (Triticum aestivum L.). Dual-site field trials demonstrated that SynCom-SASW01 significantly alleviated drought-induced growth suppression, increasing grain yields by 10.42% and 8.52% at the Hohhot and Hulunbuir sites, respectively. This improvement was primarily associated with increased effective tiller number and enhanced root vigor. Physiologically, inoculation promoted root proline and glutathione accumulation and enhanced antioxidant enzyme activities, including superoxide dismutase, thereby reducing malondialdehyde levels. Environmental analyses showed that the consortium established rhizosphere “micro-reservoirs” through exopolysaccharide secretion, improving soil relative water content and the availability of alkali-hydrolyzable nitrogen and phosphorus. High-throughput sequencing revealed that SynCom-SASW01 reshaped the endosphere microbiome through early colonization priority effects, selectively enriching beneficial taxa such as Pseudomonas. Functional prediction indicated upregulated branched-chain amino acid biosynthesis, promoting osmotic adjustment and redox homeostasis. These findings provide a microbiome-based strategy for stabilizing wheat productivity in arid regions. Full article

Background: Systemic arterial hypertension (SAH) induced by Nω-nitro-L-arginine methyl ester (L-NAME) is a well-established model characterized by nitric oxide (NO^●) synthase inhibition and vascular dysfunction. The transient receptor potential vanilloid 1 (TRPV1) regulates Ca²⁺ flux and may contribute to mitochondrial homeostasis. We hypothesized that TRPV1 activation modulates mitochondria function and attenuates cardiac damage during SAH. Methods: Hypertension was induced in Wistar rats by administration of L-NAME (200 mg/L) for 40 days. During the last four days, hypertensive animals received capsaicin (5 mg/kg/day), capsazepine (6 mg/kg/day), or their combination. Cardiac function was evaluated in isolated hearts using the Langendorff perfusion system. Myocardial tissue viability was assessed by triphenyltetrazolium chloride (TTC) staining, and mitochondrial function was evaluated by measuring respiratory control and apoptosis-related proteins. Results: Capsaicin treatment was associated with significant cardioprotective effects in hypertensive rats. Although the findings are consistent with a role of TRPV1 activation in mediating these effects, the partial protection observed with capsazepine suggests that TRPV1-independent mechanisms may also contribute. Conclusions: TRPV1 activation contributes to cardioprotection in SAH, likely through preservation of mitochondrial function and redox balance. However, additional mechanisms beyond TRPV1 modulation may also participate in the observed protective effects. Further studies—including direct assessment of mitochondrial Ca²⁺ flux and the use of more selective or genetic approaches—are currently underway to clarify the underlying mechanisms. Full article

Traditional mineral drugs represent an underexploited reservoir of natural antitumor agents; however, their clinical translation has historically been hindered by poor bioavailability, non-specific biodistribution, and dose-limiting toxicity. This review comprehensively examines the pharmacological mechanisms and modern formulation strategies driving the renaissance of mineral-based oncology therapeutics. We highlight how mineral drugs exert potent anticancer effects through interconnected pathways, including regulated cell death (e.g., apoptosis, ferroptosis), cell-cycle arrest, and immunomodulation. Crucially, we evaluate recent advances in drug delivery systems, such as liposomes, polymeric nanoparticles, inorganic frameworks, and stimuli-responsive (e.g., pH, redox, enzyme) release systems that successfully overcome traditional pharmacological barriers. These bioengineering strategies not only improve solubility and tumor targeting but also significantly widen the therapeutic window, as evidenced by enhanced tumor suppression and reduced systemic toxicity in preclinical models. Despite this progress, challenges regarding in vivo chemical transformations and tumor heterogeneity remain. Ultimately, we propose a closed-loop “Composition–Mechanism–Delivery” design paradigm to guide future research, facilitating the translation of ethnopharmacological heritage into precision mineral-based therapeutics. Full article

Hydroperoxides (R–OOH, organic hydroperoxides) constitute a relatively small but structurally diverse class of natural metabolites occurring in higher plants, fungi, and marine organisms. Their formation is closely associated with oxidative processes involving redox-active metal ions, particularly iron and copper, which promote reactive oxygen species (ROS) generation and the oxidative transformation of steroids and triterpenoids. In the present study, approximately 1500 naturally occurring steroids and triterpenoids were screened using the PASS (Prediction of Activity Spectra for Substances) platform to identify compounds with potential relevance to neurodegenerative disorders. Among the analyzed compounds, only 17 hydroperoxide-containing steroids and triterpenoids exhibited notable predicted anti-dementia activity and were selected for detailed evaluation. The selected compounds displayed a broad spectrum of predicted biological activities, including antineoplastic, anti-inflammatory, antiulcerative, antithrombotic, hepatoprotective, and neuroprotective effects. Several hydroperoxide-containing triterpenoids demonstrated particularly high predicted anti-dementia activity, with a norlupane-type hydroperoxide exhibiting the highest probability of activity (Pa = 0.972). The biological significance of these compounds may be related to the unique redox properties of the hydroperoxide functionality, which can participate in both oxidative and adaptive signaling processes. Because hydroperoxides interact with transition metal ions and reactive oxygen species, they occupy a complex position at the interface between oxidative stress, cellular defense mechanisms, and neurodegeneration. The present analysis highlights hydroperoxide-containing steroids and triterpenoids as an underexplored class of natural products with potential relevance to dementia research. However, the reported activities are based primarily on computational predictions and should be interpreted as indicators of pharmacological potential rather than experimentally validated therapeutic effects. Further investigations involving blood–brain barrier permeability assessment, biochemical studies, cellular assays, animal models, and clinical evaluation will be required to determine the true therapeutic value of these compounds in neurodegenerative diseases. Full article

Chronic coronary syndromes (CCSs) are increasingly recognized as complex immunometabolic vascular disorders in which coronary microvascular dysfunction (CMD), persistent low-grade inflammation, oxidative stress, and maladaptive cellular remodeling contribute to ischemic symptoms and adverse outcomes beyond epicardial stenosis. CMD represents a heterogeneous condition comprising both functional and structural endotypes and constitutes a major determinant of myocardial ischemia, heart failure progression, and adverse cardiovascular outcomes, even in the absence of obstructive coronary artery disease. Emerging evidence indicates that immunometabolic reprogramming of endothelial cells, vascular smooth muscle cells, and immune cells sustains microvascular dysfunction in CCSs. Metabolic shifts toward glycolysis, mitochondrial dysfunction, redox imbalance, and dysregulated lipid metabolism promote chronic inflammatory activation within the coronary microenvironment. Convergent mitochondrial stress (including NAD⁺ decline) and redox injury promote endothelial senescence and increase susceptibility to regulated cell death, progressively limiting vasodilatory reserve and predisposing to microvascular rarefaction. Pyroptosis and ferroptosis-like lipid peroxidation further exacerbate endothelial barrier disruption and inflammatory amplification. In parallel, inflammasome activation, iron-dependent lipid peroxidation, impaired autophagy, and endoplasmic reticulum stress form interconnected molecular networks that amplify vascular injury through self-reinforcing mechanisms. This narrative review integrates mechanistic and translational evidence linking immunometabolic dysregulation, mitochondrial stress, thromboinflammatory signaling, endothelial senescence, and regulated cell death to distinct CMD endotypes. We propose a systems-level framework in which coronary microvascular dysfunction is conceptualized as an immunometabolic vascular network disorder, with reduced coronary flow reserve (CFR)—often termed myocardial flow reserve (MFR) in PET studies—emerging as the integrative functional endpoint of these interacting molecular perturbations and a robust predictor of major cardiovascular events. Full article

Burn wound healing is a complex and dynamic process involving coordinated regulation of inflammation, oxidative stress, angiogenesis, and tissue remodeling. Polygonum cuspidatum, a traditional Chinese medicinal herb widely used for trauma- and inflammation-related disorders, represents an important source of bioactive compounds for tissue repair. Piceatannol (PIC), a naturally occurring stilbene constituent of P. cuspidatum, possesses potent anti-inflammatory and antioxidant activities; however, its therapeutic potential in burn wound healing remains insufficiently understood. In the present study, the therapeutic effects and underlying mechanisms of topical PIC were investigated using a murine deep second-degree burn model combined with multiple skin-related cellular models, including keratinocytes, fibroblasts, endothelial cells, and macrophages. PIC markedly accelerated wound closure and improved histological architecture, as evidenced by reduced inflammatory infiltration, enhanced collagen organization, and increased neovascularization. Mechanistically, PIC suppressed NF-κB activation and modulated KEAP1/NRF2-associated redox signaling, thereby alleviating inflammation–oxidative stress crosstalk during wound healing. In keratinocyte–fibroblast co-culture systems, PIC inhibited fibroblast-to-myofibroblast transition, reduced α-smooth muscle actin (α-SMA) expression, and attenuated excessive collagen deposition, suggesting anti-fibrotic activity. In addition, PIC promoted endothelial tube formation through activation of the STAT3–VEGF signaling axis. Collectively, these findings demonstrate that PIC facilitates burn wound repair through coordinated anti-inflammatory, antioxidative, pro-angiogenic, and anti-fibrotic effects. This study provides pharmacological support for the therapeutic potential of P. cuspidatum-derived compounds in burn management and highlights PIC as a promising candidate for topical treatment of burn injuries. Full article

Introduction: Fish skin is the first line of defense against the aquatic environment, acting as a physical, chemical, and immunological barrier. In addition to preventing pathogen entry, the skin and its mucus contribute to osmoregulation, innate immunity, and redox balance. Skin lesions—caused by mechanical damage, parasites, environmental stress, or handling—disrupt this barrier, increasing susceptibility to infections, inflammation, and production losses. Thus, efficient skin regeneration is essential for fish welfare and performance. Nutrition plays a key role in this process by providing substrates for epithelial repair, immune function, and antioxidant defense. Among dietary factors, zinc (Zn) is particularly important due to its involvement in cell proliferation, enzymatic activity, and maintenance of skin integrity. Objective: Our objective is to assess the effectiveness of image-based analysis in quantifying the skin healing process in Atlantic salmon fed diets supplemented with zinc. Methodology: The trial comprised three dietary treatments: a control diet with 42 mg Zn per kg (D1), and two diets supplemented up to 120 mg/kg of zinc, derived from inorganic (D2) or organic (D3) forms. Pit-tagged fish with an initial body weight (78 ± 0.1 g) were fed the diets for 75 days. After 15 days of experimental feeding, a standardized wound lesion (2.5 mm diameter × 0.5 mm depth) was inflicted in deeply anesthetized fish, with a disposable biopsy punch, in the dorsal area. After wound infliction, the fish resumed their normal feeding regime for the rest of the trial days. The progression of skin wound healing was assessed using standardized digital image analysis. High-resolution photographs of individual wounds were collected 8, 16, 24 and 32 days post-wounding. All images were acquired under standardized conditions with the inclusion of ArUco identifiers to enable a subsequent computer-assisted comparison. Morphometric parameters (wound width, diameter, perimeter and area) were used to assess wound contraction and closure over time. In parallel, a semi-quantitative visual scoring system was applied to each wound image to capture qualitative aspects of healing that are not fully described by morphometric data alone. Results: Full data analysis is currently underway, but the first results show beneficial effects of dietary zinc supplementation on the skin regenerative process. Conclusions: The combined use of objective digital measurements and standardized visual scoring enabled a comprehensive evaluation of wound healing progress, bridging quantitative tissue remodeling with biologically relevant phenotypic outcomes. This image-based framework provides a sensitive and reproducible approach for assessing dietary interventions targeting skin regeneration and barrier restoration in Atlantic salmon. Full article