Search Results (252)

The maintenance of bone homeostasis requires the coordinated activity of specialized cells (osteoblasts, osteoclasts and osteocytes), soluble factors and hormones with regulatory functions. Disruption of this tightly controlled balance contributes to several skeletal pathological conditions, among which osteoporosis is one of the most prevalent. Iron, an essential element for the basic cellular functions of both osteoblasts and osteoclasts, plays a pivotal role in preserving bone homeostasis and skeletal integrity. Both iron deficiency and iron overload impair bone remodeling through distinct but converging mechanisms. Iron deficiency compromises collagen synthesis, alters hypoxia-dependent signaling, and may affect vitamin D metabolism, collectively predisposing the individual to reduced bone mineral density and increased fracture risk. Conversely, excess iron enhances oxidative stress, promotes osteoclastogenesis, and suppresses osteoblast differentiation and function, thereby favoring bone loss, particularly in the aging population and postmenopausal individuals. Hepcidin, the master regulator of systemic iron availability, has emerged as a key modulator of bone turnover, whereas the bone-derived hormone fibroblast growth factor 23 (FGF23) links iron imbalance to phosphate homeostasis, vitamin D metabolism, and inflammation. Beyond metabolic bone diseases, dysregulated iron handling is increasingly recognized as a hallmark of osteosarcoma biology, influencing tumor growth, metabolic reprogramming, and an individual’s susceptibility to ferroptosis. The emerging, albeit only preclinical, evidence of the roles of iron and ferroptosis in osteosarcoma is therefore also covered. This review summarizes the current understanding of the interactions between iron metabolism and bone biology and addresses how an imbalance in iron metabolism may lead to major skeletal disorders. Overall, iron homeostasis could represent a potential target for preventing and treating osteoporosis and for improving therapeutic strategies for osteosarcoma. Full article

Background: Iron plays a crucial role in neurotransmitter synthesis, myelination, and neuronal metabolism. Iron deficiency has been associated with a variety of neurodevelopmental disorders, particularly attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, the prevalence, clinical impact, and treatment implications differ between these conditions. Objective: To synthesize current evidence on the prevalence, neurobehavioral consequences, and therapeutic implications of iron deficiency in ADHD and ASD, highlighting convergences and disorder-specific findings. Results: In ADHD, studies using serum ferritin and related peripheral markers show inconsistent associations with core symptom severity, with reported ferritin thresholds for deficiency ranging widely. While some studies suggest links between low ferritin and hyperactivity, inattention, or stimulant response, others report null findings. In contrast, emerging neuroimaging evidence consistently demonstrates reduced brain iron in dopaminergic regions in children. In ASD, the strongest link is between low ferritin and sleep-related motor disturbances, and iron supplementation may improve sleep and motor symptoms. Conclusions: Screening for iron status and targeted supplementation may improve sleep and behavioral outcomes in ADHD and ASD, meriting integration into clinical practice and further randomized controlled trials. Full article

This study aimed to provide a synthesis of current knowledge on iron homeostasis, focusing on major metabolic pathways and evolving research perspectives. A systematic review was conducted, analyzing the most relevant pathological conditions associated with iron metabolism, including iron overload and iron deficiency. Iron overload (IO) encompasses a wide range of disorders that lead to systemic iron accumulation and organ damage, while iron deficiency (ID) is characterized by insufficient iron availability for physiological needs. IO is dealt with a focused attention, exploring molecular mechanisms and emerging therapeutic strategies. In this context, hepcidin not only represents a valuable biomarker for iron overload but also serves as a potential target for novel therapies that are currently in the experimental phase. Conversely, for ID, both traditional biomarkers and recently proposed indicators help in diagnosing ID and correlating it with erythropoietic activity. Full article

Background/Objectives: Roux-en-Y gastric bypass (RYGB) improves obesity-related metabolic disorders, yet post-operative dietary composition critically shapes outcomes. This study explored how RYGB and high-fat diet (HFD) differentially regulate hepatic transcriptional programs. Methods: We performed RNA-seq on liver tissues from diet-induced obese C57BL/6 male mice 8 weeks post-RYGB or sham surgery, maintained on chow or HFD. Differentially expressed genes (DEGs) were identified using DESeq2. Gene sets were categorized as RYGB-induced (commonly regulated by surgery across diets), Reversal (RYGB-driven counter-regulation of obesity-induced changes), and HFD-induced (commonly regulated by diet). A subset of RYGB-specific HFD-induced genes was derived by excluding HFD-induced genes from the RYGB Chow vs. RYGB HFD contrast. Pathway enrichment was conducted using STRING. Results: RYGB induced 365 DEGs, including pathways related to extracellular remodeling and reduced mitochondrial/antioxidant activity. Among these, 119 Reversal genes countered obesity-associated transcriptional patterns and accounted for ~27% of the RYGB-induced enrichment results. HFD regulated 860 DEGs, highlighting stress responses and translational repression. Lastly, a set of 426 RYGB-specific HFD-induced genes revealed persistent hepatic inflammation, coagulation, and iron dysregulation under HFD despite surgery. Conclusions: RYGB induces robust hepatic transcriptomic changes that attenuate obesity-driven dysregulation, including a coordinated reprogramming of iron-handling pathways. However, high dietary fat partially overrides these benefits, promoting inflammatory, metabolic stress, and iron-related stress. Optimizing post-operative diets and carefully managing micronutrient intake, especially iron, may enhance RYGB’s metabolic efficacy and long-term liver health. Full article

Myocardial fibrosis (MF) is a common pathological feature of diverse cardiac disorders and is a key driving factor of cardiac dysfunction. It is marked by excessive deposition of extracellular matrix (ECM) proteins, particularly collagen type I and III, and a prolonged activation of cardiac fibroblasts. However, the molecular drivers of this process remain undetermined. Ferroptosis is an iron-catalyzed, lipid-peroxidation-dependent mode of regulated cell death. Research indicates that ferroptosis is significantly involved in the onset and advancement of MF; consequently, developing therapies that selectively modulate ferroptosis presents a promising direction of treatment options. Therefore, this paper systematically discusses the mechanisms associated with ferroptosis to explore the link between ferroptosis and MF from multiple dimensions, including iron metabolism disorders, lipid peroxidation, imbalance of glutathione metabolism, and the dysregulated activation of ferroptosis regulatory pathways, to provide innovative perspectives for the study of the specific molecular mechanisms and treatment of MF. Method: By retrieving the literature on the mechanism of ferroptosis in MF published in PubMed and Web of Science databases from 2020 to July 2025, the mechanism of action was systematically analyzed and reviewed. Full article

Aging is a multifactorial process marked by a progressive decline in physiological function and increased vulnerability to diseases such as neurodegeneration, cancer, cardiovascular disorders, and infections. A central feature of aging is inflammaging, a state of chronic low-grade inflammation driven by cellular senescence, mitochondrial dysfunction, and oxidative stress. Recently, two regulated forms of non-apoptotic cell death—ferroptosis and cuproptosis—have emerged as critical mechanisms linking redox imbalance, mitochondrial stress, and disrupted metal homeostasis to age-related pathology. Ferroptosis, an iron-dependent process characterized by lipid peroxidation and impaired glutathione peroxidase 4 (GPX4) activity, and cuproptosis, a copper-dependent mechanism associated with protein lipoylation stress, both intersect with aging-related changes in mitochondrial and metabolic function. Importantly, these two forms of cell death should not be viewed as entirely separate pathways but rather as interconnected axes within a broader metal–redox–metabolic network. Disturbances in copper or iron homeostasis, glutathione (GSH)/GPX4 dysfunction, mitochondrial and iron-sulfur (Fe–S) cluster compromise, and enhanced lipid peroxidation may converge to lower cellular survival thresholds, thereby exacerbating oxidative damage, immune dysfunction, and tissue degeneration and ultimately fueling aging and inflammaging. This review offers a unique integrated perspective that situates ferroptosis and cuproptosis within a unified framework of aging biology, emphasizing their roles in age-related diseases and the therapeutic potential of targeting these pathways through nutritional, pharmacological, and lifestyle interventions. Full article

Obesity is a systemic metabolic disorder that is known to impair various organ systems; however, its precise impact on salivary gland homeostasis remains unclear. Recent studies have implicated ferroptosis—an iron-dependent form of regulated cell death characterized by lipid peroxidation and oxidative stress—in glandular dysfunction. In this study, we used leptin-deficient (ob/ob) mice to elucidate the role of ferroptosis in obesity-associated salivary gland pathology. The protective effects of ferroptosis inhibition were evaluated by administering ferrostatin-1 (a lipid reactive oxygen species [ROS] scavenger) and deferoxamine (an iron chelator) for an 8-week period. Obese mice exhibited significantly increased body weight, food intake, and hyperglycemia. These systemic changes are accompanied by profound histological alterations in the salivary glands, including lipid droplet accumulation, acinar atrophy, and mitochondrial ultrastructural damage. These alterations correlate with the hallmarks of ferroptotic injury, including increased ROS levels (p < 0.001), elevated malondialdehyde levels (p < 0.01), suppressed glutathione peroxidase 4 activity (p < 0.01), and iron overload (p < 0.001). Salivary gland fibrosis, inflammation, and secretory dysfunction were evident, characterized by the upregulation of TGF-β (p < 0.01) and Collagen I (p < 0.05), reduced expression of aquaporin-5 and amylase, and dysregulated levels of autophagy-related markers (LC3B and p62). Treatment with either ferrostatin-1 or deferoxamine significantly mitigated these pathologies; however, the degree of efficacy varied depending on the specific parameters that were examined. Thus, our findings implicate ferroptosis as a critical contributor to salivary gland dysfunction in obesity and suggest that pharmacological inhibition of this pathway represents a viable therapeutic strategy for preserving glandular integrity under metabolic stress. Full article

Iron is an essential trace element that participates in multiple physiological processes, including oxygen transport, electron transfer, DNA synthesis, and red blood cell production. Iron loss is particularly severe among athletes, so maintaining iron homeostasis is crucial for sports nutrition and health. Excess iron, iron deficiency, and ferroptosis can lead to muscle disorders and health issues, including sarcopenia, muscular atrophy, myocardial fibrosis, skeletal muscle injury, cardiovascular disease, and metabolic disorders. Maintaining iron homeostasis within physiological limits is essential for athletes to sustain high-intensity performance and accelerate recovery. Therefore, a comprehensive review of the effects of iron homeostasis and ferroptosis on muscle health is significant for identifying potential therapeutic targets and developing new disease treatment and prevention strategies. This paper systematically reviews research progress on targeted therapies for iron overload and ferroptosis in muscle diseases, clarifies the impact of iron on athletes’ physiological functions and competitive performance, and explores the potential application of iron in precision nutritional regulation. It aims to provide new insights for preventing exercise-induced muscle injury, myocardial damage, and overtraining syndrome in athletes. Full article

Background/Objectives: Biosimilars are central to the modernization of veterinary pharmacology, improving access to complex biological therapies while maintaining quality, safety, and efficacy. Hemoproteins such as cytochrome c, used to support liver function and manage metabolic disorders in animals, are of particular interest. However, their structural complexity and species-specific pharmacology create significant analytical and regulatory challenges for biosimilar development and life-cycle management. Addressing these issues is critical for improving therapeutic outcomes and enabling the broader adoption of biosimilars in veterinary practice. Methods: This narrative review examines the scientific and regulatory principles underlying the development of veterinary biosimilars of hemoproteins, with cytochrome c as a representative model. Regulatory guidelines and relevant scientific literature were analyzed to identify key challenges, knowledge gaps, and required adaptations from human to veterinary medicine, with a focus on biosimilar assessment and life-cycle management. Results: Veterinary biosimilar frameworks are largely informed by EU and US regulatory pathways, emphasizing the stepwise demonstration of biosimilarity through extensive analytical and functional characterization. Long-term safety and efficacy depend on robust Pharmaceutical Quality Systems and effective life-cycle management to ensure manufacturing consistency. For cytochrome c, interchangeability may be acceptable when analytical similarity is exceptionally high. Critical Quality Attributes include polypeptide integrity, heme–protein interaction, iron redox state, and correct three-dimensional conformation. Quality by Design approaches are essential to control manufacturing variability. Despite regional regulatory differences, core scientific principles remain consistent. Conclusions: Hemoprotein biosimilars hold significant promise in veterinary medicine, provided their development is supported by rigorous analytical characterization, strong life-cycle management, and science-based regulatory approaches. Full article

Tourette syndrome (TS), or Tourette’s, is a tic disorder (TD) belonging to a group of neuropsychiatric conditions marked by recurrent motor movements or vocalizations known as tics. TD, including TS, typically begins in childhood between 4 and 18 years of age and affects approximately 3% of children and adolescents. The etiology and pathogenesis of TD are multifactorial, involving genetic, immunologic, psychological, and environmental factors. Evidence suggests that neurotransmitter dysregulation, particularly within the cortical dopaminergic networks of the basal ganglia and limbic system, which support motor control and cognition, may be involved in the development of TD. Nutritional factors may modulate TD through various mechanisms, including effects on neurotransmitter synthesis and metabolism, neurodevelopment, neural architecture, and neuroimmune activity. This review integrates current evidence on the roles of vitamins D, B6, and A, as well as iron, magnesium, zinc, and copper, in TD. For each micronutrient, its physiological and neurobiological functions are discussed, along with possible mechanistic links to TD pathophysiology. Additionally, we summarize the impact of nutrient deficiencies and assess available evidence regarding their potential therapeutic potential role in TD management. Overall, this synthesis highlights how nutritional status may influence TD onset and symptom severity, suggesting that nutrient-based interventions could potentially serve as valuable adjunctive strategies in treatment. Full article

Ferroptosis is a non-apoptotic form of cell death that is driven by iron and reactive oxygen species (ROS). This process is characterised by lipid peroxidation, which damages cell membranes and distinguishes it from other types of cell death. Excess iron promotes ferroptosis through Fenton chemistry, leading to increased ROS production. While glutathione peroxidase 4 has been identified as a key regulator of this process, other factors, such as the ferroptosis suppressor protein 1 (FSP1), suggest that regulation is more complex. Ferroptosis has been associated with several degenerative diseases, including Alzheimer’s disease, Parkinson’s disease, acute kidney injury, liver disorders, and cancer. The enzyme haemoxygenase-1 (HO-1) plays dual roles: it can promote ferroptosis by releasing iron or provide protection through its antioxidant effects in various organs and tissues. HO-1 increases iron levels through the catabolism of haem which can heighten sensitivity to ferroptosis by influencing iron trafficking and ferritin expression. Conversely, HO-1 has demonstrated nephroprotective effects in cases of renal injury and other disorders. HO-1′s involvement in regulating iron metabolism and its antioxidant capabilities can lead to differing outcomes, highlighting key players in the ferroptosis process. The Nrf2/HO-1 axis is crucial for its antioxidant properties in various disorders. Moreover, dietary sources can enhance HO-1 induction through Nrf2 regulation. Hence, HO-1 acts as both a modulator and a mediator, presenting new therapeutic targets for cancer, neurodegeneration, and kidney and liver diseases. Full article

Erythropoiesis is a multistage process critical for red blood cell production and systemic oxygen transport. It is tightly regulated, and recent advances have highlighted the pivotal regulatory roles of non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in governing both physiological and pathological erythropoiesis. These ncRNAs have roles in the fine-tuning of the classical transcriptional and post-transcriptional control. This review explores the complex landscape of the non-coding RNome in erythroid differentiation, maturation, and function. We summarize how specific miRNAs influence erythroid lineage commitment, hemoglobin switching, iron metabolism, and cellular morphology, as well as their modulation by environmental and pathological cues. We also discuss emerging evidence on lncRNAs regulating chromatin remodeling, alternative splicing, apoptosis, enucleation, and erythroid-specific gene expression. These insights suggest that ncRNAs are instrumental orchestrators of erythropoiesis and accordingly, potential biomarkers and therapeutic targets in anemia and related hematologic disorders. Full article

Introduction/Objectives: Restless legs syndrome (RLS), a chronic neurological disorder related to brain iron metabolism, has been linked to immune-mediated inflammatory conditions such as psoriatic arthritis (PsA). However, the role that inflammation plays in this association and the impact of RLS on PsA outcomes remain unclear. This study aims to investigate the association between RLS and inflammatory/clinical parameters in PsA patients. Materials and Methods: In this cross-sectional study, 230 PsA patients completed the International Restless Legs Syndrome Study Group (IRLSSG) screening questionnaire, with diagnoses confirmed by a neurologist. Data collected included clinical features, disease activity, and comorbidities (obesity, anxiety, depression, insomnia, and fibromyalgia). Results: In total, forty-six patients met the IRLSSG criteria (20%). Those with RLS more frequently had polyarthritis (27% vs. 6%; p < 0.001), more swollen joints (2.0 vs. 1.4; p = 0.04), greater psoriatic involvement (5.7 vs. 3.6; p < 0.001), greater fatigue (39.0 vs. 30.5; p < 0.001), and greater disease activity (14.5 vs. 10.5; p < 0.001). They also exhibited increased disease impact (4.7 vs. 2.9; p < 0.001), poorer functioning (0.7 vs. 0.5; p = 0.01), and higher levels of anxiety (8.0 vs. 5.5; p < 0.001), depression (6.5 vs. 3.9; p < 0.001), and sleep disturbance (13.9 vs. 8.7; p < 0.001). Skin lesions and polyarthritis explained nearly 40% of RLS cases (Odds Ratio (OR) 1.4; 95% Confidence Interval (CI) 1.03–2.0; p = 0.03 and OR 1.03; 95% CI 1.00–1.9; p = 0.04). Conclusions: Psoriatic activity and inflammation may contribute to RLS in PsA. The coexistence of RLS was associated with greater disease activity, greater disease impact, and more emotional and sleep-related comorbidities. Full article

Recently, a growing interest has been focused to the role of vitamin C in chronic diseases. Type 2 Diabetes Mellitus and the Metabolic Syndrome are complex, chronic disorders intrinsically linked by a common underlying element, such as chronic low-grade inflammation and excessive oxidative stress. Vitamin C, or ascorbic acid, is an essential water-soluble micronutrient and a highly potent non-enzymatic antioxidant that is critical for scavenging reactive oxygen species and maintaining cellular redox balance. It represents a cofactor for many enzymes, being involved in many biological functions, such as normal immune system functioning, catecholamine metabolism, dietary iron absorption, and collagen biosynthesis. Individuals with type 2 diabetes mellitus and metabolic syndrome frequently exhibit lower circulating and dietary vitamin C levels compared to healthy controls, a deficiency that may be associated with disease-related inflammation and higher body weight. In this sense, it has been shown that vitamin C improves skeletal muscle insulin sensitivity in experimental settings and modulates critical functions like vascular endothelial health. However, this potential is challenged by the fact that chronic hyperglycemia can interfere with the active cellular uptake and transport of vitamin C, potentially leading to relative intracellular deficiency in diabetic patients regardless of intake. It is interesting to note that different studies have demonstrated an inverse relationship between vitamin C concentrations and the prevalence of metabolic syndrome and type 2 diabetes. Vitamin C supplementation in people with diabetes and metabolic syndrome has controversial effects. While several studies indicate a significant reduction in fasting blood glucose or HbA1c, others revealed no significant effect on insulin resistance. This review aims to explore the pathophysiological role and therapeutic potential of vitamin C in type 2 diabetes and metabolic syndrome. Full article

Neurodegenerative and cardiovascular disorders share multifactorial origins, including oxidative stress, (neuro)inflammation, and lipid dysregulation—factors often addressed independently by single-target therapies. In this study, we report a rational multitarget approach through the design and synthesis of novel (benzo)thiazine derivatives that integrate antioxidant, anti-inflammatory, and antihyperlipidemic functionalities within a single molecular framework. The compounds were obtained in good yields via 3–7 step synthetic routes and evaluated through complementary in vitro and in vivo assays. Several derivatives displayed potent inhibition of lipoxygenase (IC₅₀ < 100 μM), significant reduction in carrageenan-induced edema (up to 60%), strong free radical scavenging and lipid peroxidation inhibition, as well as effective iron chelation. In vivo, most derivatives enhanced total antioxidant capacity (by 50–800%) and significantly improved plasma lipid profiles in mouse, while almost all compounds increased the plasma antiatherogenic index by more than 100% with selected compounds exceeding 600%. Notably, several molecules also showed moderate acetylcholinesterase inhibition, suggesting preliminary neuroprotective potential. Altogether, these multifunctional (benzo)thiazine derivatives represent promising lead structures for the development of agents targeting the complex interplay of oxidative, inflammatory, and metabolic pathways underlying neurodegenerative and cardiovascular diseases. Full article