Search Results (222)

Proper joint function has a significant impact on people’s quality of life. Joints are the point of connection between two or more bones and consist of at least three elements: joint surfaces, the joint capsule, and the joint cavity. Joint diseases are a serious social problem. Risk factors for the development of these diseases include overweight and obesity, gender, and intestinal microbiome disorders. Another factor that is considered to influence joint diseases is trace elements. Under normal conditions, elements such as iron (Fe), copper (Cu), cobalt (Co), iodine (I), manganese (Mn), zinc (Zn), silver (Ag), cadmium (Cd), mercury (Hg), lead (Pb), nickel (Ni) selenium (Se), boron (B), and silicon (Si) are part of enzymes involved in reactions that determine the proper functioning of cells, regulate redox metabolism, and determine the maturation of cells that build joint components. However, when the normal concentration of the above-mentioned elements is disturbed and toxic elements are present, dangerous joint diseases can develop. In this article, we focus on the role of trace elements in joint function. We describe the molecular mechanisms that explain their interaction with chondrocytes, osteocytes, osteoblasts, osteoclasts, and synoviocytes, as well as their proliferation, apoptosis, and extracellular matrix synthesis. We also focus on the role of these trace elements in the pathogenesis of joint diseases: rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and systemic lupus erythematosus (SLE). We describe the roles of increased or decreased concentrations of individual elements in the pathogenesis and development of joint diseases and their impact on inflammation and disease progression, referring to molecular mechanisms. We also discuss their potential application in the treatment of joint diseases. Full article

Background/Objectives: This study aimed to investigate the association between serum ferritin levels and functional impairment in children with Attention Deficit Hyperactivity Disorder (ADHD). In addition, we investigated whether this relationship remained significant after controlling for core symptom severity and examined the correlations between ferritin levels and ADHD symptom levels. Methods: The sample included 88 children aged 6–13 years: 44 diagnosed with ADHD and 44 healthy controls (HCs) matched for age and sex. ADHD symptom severity was assessed using Turgay’s DSM-IV-Based ADHD and Disruptive Behavior Disorders Screening Scale (T-DSM-IV-S; parent-report) and the Clinical Global Impression—Severity (CGI-S) scale (clinician-rated). Functional impairment was measured using the Weiss Functional Impairment Rating Scale—Parent Report (WFIRS-P). Serum ferritin levels were determined through venous blood samples. Statistical analyses included group comparisons, Spearman correlations, and partial correlations controlling for symptom severity. Results: Children with ADHD had significantly lower serum ferritin levels and higher levels of both symptom severity and functional impairment compared to HCs. Ferritin levels were negatively correlated with ADHD symptom severity and with functional impairment in the Life Skills domain. However, after controlling for ADHD symptom severity, the association with Life Skills was no longer statistically significant. Conclusions: Ferritin levels were found to be associated with both ADHD symptom severity and functional impairment in the Life Skills domain. However, this relationship was not independent of symptom severity, suggesting that core ADHD symptoms may mediate the impact of iron status on daily functioning. Due to the study’s limitations (e.g., cross-sectional design, small sample size, gender imbalance, and lack of inflammatory and dietary data), our findings should be interpreted with caution, as they do not establish causality or resolve the ongoing inconsistencies in the literature. These results underscore the relevance of iron metabolism in the clinical presentation of ADHD and highlight the need for future research to determine whether improving iron status could serve as an adjunctive strategy in the management of functional impairments in this population. Full article

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by systemic inflammation, endothelial dysfunction, and placental insufficiency. While inadequate trophoblast invasion and impaired spiral artery remodeling have long been recognized as central to its pathogenesis, emerging evidence underscores the critical roles of dysregulated iron metabolism and its crosstalk with immune responses, particularly macrophage-mediated inflammation, in driving PE development. This review systematically explores the dynamic changes in iron metabolism during pregnancy, including increased maternal iron demand, placental iron transport mechanisms, and the molecular regulation of placental iron homeostasis. We further explore the contribution of ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, to trophoblast dysfunction and pregnancy-related diseases, including PE. Macrophages, pivotal immune regulators at the maternal–fetal interface, exhibit distinct polarization states that shape tissue remodeling and immune tolerance. We outline their origin, distribution, and polarization in pregnancy, and emphasize their aberrant phenotype and function in PE. The bidirectional crosstalk between iron and macrophages is also dissected: iron shapes macrophage polarization and function, while macrophages reciprocally modulate iron homeostasis. Notably, excessive reactive oxygen species (ROS) and pro-inflammatory cytokines secreted by M1-polarized macrophages may exacerbate trophoblast ferroptosis, amplifying placental injury. Within the context of PE, we delineate how iron overload and macrophage dysfunction synergize to potentiate placental inflammation and oxidative stress. Key iron-responsive immune pathways, such as the HO-1/hepcidin axis and IL-6/TNF-α signaling, are discussed in relation to disease severity. Finally, we highlight promising therapeutic strategies targeting the iron–immune axis, encompassing three key modalities—iron chelation therapy, precision immunomodulation, and metabolic reprogramming interventions—which may offer novel avenues for PE prevention and treatment. Full article

Depression affects approximately 280 million people worldwide and is becoming increasingly prevalent, particularly among young people. Despite numerous studies on the pathogenesis of this disorder, many factors remain unclear. New data in the literature suggest that proper concentrations of essential macro- and micronutrients play an important role in maintaining mental health and that disturbances in the metabolism of mineral compounds may contribute to the development and progression of depressive disorders. Numerous clinical and epidemiological studies have shown that low concentrations of these elements are associated with impaired neurotransmitter activity, increased exposure to oxidative stress, and neuroinflammation, all of which may contribute to the onset or exacerbation of depression. Additionally, some macro- and micronutrients may contribute to metabolic and hormonal disorders, thereby exacerbating their impact on mood regulation. A comprehensive literature search of the PubMed database covering the period from 2020 to 2025 yielded relevant human studies on calcium, magnesium, iron, zinc, copper, selenium, and iodine in relation to depression, which were selected based on predefined inclusion and exclusion criteria. This review summarizes the effects of calcium, magnesium, iron, zinc, copper, selenium, and iodine on supporting prevention, slowing progression, and helping treatment of depression. Understanding the impact of proper nutrition, including ensuring optimal concentrations of minerals, can help develop dietary strategies or proper supplementation of macronutrients and micronutrients aimed at preventing and improving the functioning of patients with depression. Full article

Disused muscle atrophy (DMA) is characterized by skeletal muscle loss and functional decline due to prolonged inactivity. Though evidence remains limited, recent studies suggest that ferroptosis, an iron-dependent, lipid peroxidation-driven form of cell death, may contribute to DMA. Taurine, a natural amino acid enriched in energy drinks, can improve the proliferation and myogenic differentiation potential of myoblasts. This study aimed to investigate whether taurine supplementation could protect against DMA and explore its potential role in modulating ferroptosis. Using a hindlimb suspension-induced DMA model in male C57BL/6J mice (6–8 weeks old), we assessed muscle mass, function, ferroptosis-related markers, histopathological changes, and metabolic alterations. The results showed that taurine supplementation improved muscle strength and morphology while attenuating markers of ferroptosis, including iron accumulation, lipid peroxidation, and glutathione and related protein (NRF2, GPX4, and xCT) depletion. Metabolomic analysis suggested that taurine modulates disorders in glutathione and lipid metabolism, potentially associated with the regulation of the xCT-GSH-GPX4 and AMPK-ACC-ACSL4 pathways. While these findings support a protective role for taurine and a possible link between ferroptosis and DMA, further functional studies are needed to confirm causality and assess the compound’s translational potential. This study provides initial in vivo evidence implicating ferroptosis in DMA and highlights taurine as a promising candidate for future therapeutic exploration. Full article

Background/Objectives: Anorexia nervosa (AN) is a chronic eating disorder with the highest mortality rate among psychiatric conditions. Malnutrition and starvation lead to long-term impairments in metabolic processes, hormonal regulation, and immune function, offering potential diagnostic and prognostic value. This study aimed to identify immune–metabolic–hormonal markers associated with treatment response and nutritional rehabilitation. Methods: Fifty hospitalized female patients with AN were included. Anthropometric measurements and venous blood samples were collected at admission and discharge, following partial nutritional recovery. Blood analyses included complete blood count, serum levels of total cholesterol, LDL and HDL, triglycerides, glucose, NT-pro-BNP, TSH, free thyroxine (fT4), sodium, chloride, potassium, calcium, iron, and vitamin D. Composite immune-inflammatory indices calculated were neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), platelet-to-lymphocyte (PLR); neutrophil-to-high-density lipoprotein (NHR), monocyte-to-high-density lipoprotein (MHR), platelet-to-high-density lipoprotein (PHR) and lymphocyte-to-high-density lipoprotein (LHR) ratios; systemic immune-inflammation (SII), and systemic inflammation response (SIRI) indexes. Results: Responders (R) and non-responders (NR) differed significantly at baseline in levels of sodium, chloride, fT4, monocyte count, MCV, NLR, MLR, SII, and SIRI (all: R < NR; p < 0.05). Predictive ability for treatment response was confirmed by AUC values (95%CI): sodium = 0.791 (0.622–0.960), chloride = 0.820 (0.690–0.950), fT4 = 0.781 (0.591–0.972), monocytes = 0.785 (0.643–0.927), MCV = 0.721 (0.549–0.892), NLR = 0.745 (0.578–0.913), MLR = 0.785 (0.643–0.927), SII = 0.736 (0.562–0.911), SIRI = 0.803 (0.671–0.935). The lower levels of inflammation and chloride are particularly predictive of better nutritional recovery, accounting for 26% of the variability in treatment response. Conclusions: The study demonstrated important insights into the hematological, metabolic, hormonal, and immune-inflammatory mechanisms associated with nutritional recovery in AN. Full article

Mitochondrial dysfunction is a key driver of neurological disorders due to the brain’s high energy demands and reliance on mitochondrial homeostasis. Despite advances in genetic characterization, the heterogeneity of mitochondrial diseases complicates diagnosis and treatment. Mitochondrial dysfunction spans a broad clinical spectrum, from early-onset encephalopathies to adult neurodegeneration, with phenotypic and genetic variability necessitating integrated models of mitochondrial neuropathology. Mutations in nuclear or mitochondrial DNA disrupt energy production, induce oxidative stress, impair mitophagy and biogenesis, and lead to neuronal degeneration and apoptosis. This narrative review provides a structured synthesis of current knowledge by classifying mitochondrial-related neurological disorders according to disrupted biochemical pathways, in order to clarify links between genetic mutations, metabolic impairments, and clinical phenotypes. More specifically, a pathway-oriented framework was adopted that organizes disorders based on the primary mitochondrial processes affected: oxidative phosphorylation (OXPHOS), pyruvate metabolism, fatty acid β-oxidation, amino acid metabolism, phospholipid remodeling, multi-system interactions, and neurodegeneration with brain iron accumulation. Genetic, clinical and molecular data were analyzed to elucidate shared and distinct pathophysiological features. A comprehensive table synthesizes genetic causes, inheritance patterns, and neurological manifestations across disorders. This approach offers a conceptual framework that connects molecular findings to clinical practice, supporting more precise diagnostic strategies and the development of targeted therapies. Advances in whole-exome sequencing, pharmacogenomic profiling, mitochondrial gene editing, metabolic reprogramming, and replacement therapy—promise individualized therapeutic approaches, although hurdles including heteroplasmy, tissue specificity, and delivery challenges must be overcome. Ongoing molecular research is essential for translating these advances into improved patient care and quality of life. Full article

Helicobacter pylori is a Gram-negative bacterium that infects almost half of the global population and is linked to gastric conditions like peptic ulcers and gastric cancer, as well as other diseases such as neurological disorders, cardiovascular problems, and iron deficiency anemia. Its survival in the acidic stomach environment is due to virulence factors like urease, flagella, and adhesion proteins (BabA, SabA). Current treatments involve a combination of antibiotics (clarithromycin, metronidazole, amoxicillin, tetracycline) and proton pump inhibitors, but increasing antibiotic resistance, especially to clarithromycin and metronidazole, poses a major challenge. Resistance mechanisms include mutations in drug targets, efflux pump overexpression, and enzymatic degradation of antibiotics. This has prompted exploration of alternative therapies targeting bacterial processes like urease activity, biofilm formation, and metabolic pathways (energy production, amino acid synthesis, iron acquisition). Natural compounds, such as chitosan and plant extracts, show promise in combating H. pylori growth and virulence. Vaccine development is also ongoing, with DNA vaccines showing potential for broad immune responses. However, no vaccine is yet close to widespread clinical use. Full article

Ethylmalonic encephalopathy (EE) is a serious metabolic disorder that usually appears in early childhood development and the effects are seen primarily in the brain, gastrointestinal tract, and peripheral vessels. EE is caused by pathogenic variants in the gene that encodes the ETHE1 protein, and its main features are high levels of acidic compounds in body fluids and decreased activity of the mitochondrial complex IV, which limits energy production in tissues that require a large supply of energy. ETHE1 is a mitochondrial sulfur dioxygenase that plays the role of hydrogen sulfide (H₂S) detoxification, and, when altered, it leads to the accumulation of this gaseous molecule due to its deficient elimination. In this article, we characterised the pathophysiology of ETHE1 deficiency in cellular models, fibroblasts, and induced neurons, derived from a patient with a homozygous pathogenic variant in ETHE1. Furthermore, we evaluated the effect of the activation of the mitochondrial unfolded protein response (mtUPR) on the mutant phenotype. Our results suggest that mutant fibroblasts have alterations in ETHE1 protein expression levels, associated with elevated levels of H₂S and protein persulfidation, mitochondrial dysfunction, iron/lipofuscin accumulation, and oxidative stress. We also identified a cocktail of compounds consisting of pterostilbene, nicotinamide, riboflavin, thiamine, biotin, lipoic acid, and L-carnitine that improved the cellular and metabolic alterations. The positive effect of the cocktail was dependent on sirtuin 3 activation (SIRT3) and was also confirmed in induced neurons obtained by direct reprogramming. In conclusion, personalised precision medicine in EE using patient-derived cellular models can be an interesting approach for the screening and evaluation of potential therapies. In addition, the activation of the SIRT3 axe of mtUPR is a promising therapeutic strategy for rescuing ETHE1 pathogenic variants. Full article

Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a key player in the pathogenesis of gastrointestinal (GI) diseases. Unlike apoptosis or necrosis, ferroptosis is characterized by distinctive metabolic and molecular pathways, including dysregulated iron metabolism, oxidative stress, and impaired antioxidant defenses. This review explores the complex role of ferroptosis in conditions such as inflammatory bowel disease (IBD), non-alcoholic steatohepatitis (NASH), and gastrointestinal cancers. Special attention is given to the molecular mechanisms underlying ferroptosis, including the Xc⁻/GSH/GPX4 axis, ferritinophagy, ACSL4/LPCAT3-mediated lipid remodeling, and the influence of the gut microbiota. Therapeutic strategies targeting ferroptosis—including pharmacological inhibitors, iron chelators, and microbiota-based interventions—are evaluated for their translational potential, underscoring ferroptosis as a promising target for precision therapies in gastroenterology and highlighting the need for further clinical studies to validate its diagnostic and therapeutic implications. Full article

Pontocerebellar hypoplasia (PCH) encompasses a group of autosomal recessive neurodegenerative disorders marked by cerebellar and pontine atrophy. Multiple subtypes of PCH have been identified, among which the rare subtype PCH type 16 is caused by MINPP1 genetic variants. MINPPI encodes an enzyme essential for inositol polyphosphate dephosphorylation, regulating calcium and iron homeostasis. We conducted genome sequencing on a proband from the consanguineous family, who presented with a severe neurodegenerative disorder, to identify the underlying cause of disease. A comprehensive clinical assessment in addition to neuroradiological findings are described. We performed the functional validation of the identified variant and conducted untargeted metabolomic analyses. The clinical and radiological assessment of the patient showed a congenital brain anomaly and neurodegenerative symptoms. Further genetic analysis identified a homozygous loss-of-function variant (c.1401del, p.Ser468Valfs10*) in MINPP1, providing molecular confirmation of a clinical PCH diagnosis. While real-time quantitative PCR (RT-qPCR) showed that MINPP1 gene expression was unaffected in the proband, Western blot analysis demonstrated reduced protein abundance, supporting a pathogenic role of the variant. Metabolomic profiling revealed elevated lipid levels and disrupted inositol metabolism, providing further insights into the disease mechanism. These findings establish the pathogenicity of the p.Ser468Valfs10* variant in MINPP1 and highlight inositol metabolism as a potential pathway involved in PCH16, advancing the understanding of the pathophysiology of the disease. Full article

Emerging evidence links ferroptosis–mitochondrial dysregulation to depression pathogenesis through an oxidative stress–energy deficit–neuroinflammation cycle driven by iron overload. This study demonstrates that iron accumulation initiates ferroptosis via Fenton reaction-mediated lipid peroxidation, compromising neuronal membrane integrity and disabling the GPx4 antioxidant system. Concurrent mitochondrial complex I/IV dysfunction impairs ATP synthesis, creating an AMPK/mTOR signaling imbalance and calcium dyshomeostasis that synergistically impair synaptic plasticity. Bidirectional crosstalk emerges: lipid peroxidation derivatives oxidize mitochondrial cardiolipin, while mitochondrial ROS overproduction activates ACSL4 to amplify ferroptotic susceptibility, forming a self-reinforcing neurodegenerative loop. Prefrontal–hippocampal metabolomics reveal paradoxical metabolic reprogramming with glycolytic compensation suppressing mitochondrial biogenesis (via PGC-1α/TFAM downregulation), trapping neurons in bioenergetic crisis. Clinical data further show that microglial M1 polarization through cGAS-STING activation sustains neuroinflammation via IL-6/TNF-α release. We propose a “ferroptosis–mitochondrial fragmentation–metabolic maladaptation” triad as mechanistic subtyping criteria for depression. Preclinical validation shows that combinatorial therapy (iron chelators + SIRT3 agonists) rescues neuronal viability by restoring mitochondrial integrity and energy flux. This work shifts therapeutic paradigms from monoaminergic targets toward multimodal strategies addressing iron homeostasis, organelle dynamics, and metabolic vulnerability—a framework with significant implications for developing neuroprotective antidepressants. Full article

Myo-inositol-1,2,3,4,5,6-hexakisphosphate (IP6) is commonly found in plant-derived foods and has important pharmacological properties against many pathologies. One of them appears to be neurodegeneration, which is notably stimulated by dysregulated metal metabolism. Consequently, we explore the role of IP6 in mitigating neurodegenerative events catalyzed by dysregulated free iron. More precisely, we performed spectrophotometric measurements in aqueous solutions to investigate the ability of IP6 to chelate Fe³⁺ and inhibit its role in catalyzing the oxidative degradation of dopamine and ascorbic acid, two key molecules in neuronal redox systems. Our results demonstrate that IP6 effectively prevents the formation of harmful intermediates, such as neuromelanin and reactive oxygen species, which are linked to neuronal damage. Additionally, we assessed the effect of IP6 on Fe³⁺-induced protein aggregation, focusing on α-synuclein, which is closely associated with Parkinson’s disease. Our data reveal that IP6 accelerates the conversion of toxic α-synuclein oligomers into less harmful amyloid fibrils, thereby reducing their neurotoxic potential. Our findings highlight the dual function of IP6 as a potent Fe³⁺ chelator and modulator of protein aggregation pathways, reinforcing its potential as a neuroprotective agent. Consequently, IP6 offers promising therapeutic potential for mitigating the progression of neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases. Full article

The BCS1L gene encodes a mitochondrial chaperone which inserts the Fe₂S₂ iron–sulfur Rieske protein into the nascent electron transfer complex III. Variants in the BCS1L gene are associated with a spectrum of mitochondrial disorders, ranging from mild to severe phenotypes. Björnstad syndrome, a milder condition, is characterized by sensorineural hearing loss (SNHL) and pili torti. More severe disorders include Complex III Deficiency, which leads to neuromuscular and metabolic dysfunctions with multi-systemic issues and Growth Retardation, Aminoaciduria, Cholestasis, Iron Overload, and Lactic Acidosis syndrome (GRACILE). The severity of these conditions varies depending on the specific BCS1L mutation and its impact on mitochondrial function. This study describes a 27-month-old child with SNHL, proximal renal tubular acidosis, woolly hypopigmented hair, developmental delay, and metabolic alterations. Genetic analysis revealed a homozygous BCS1L variant (c.38A>G, p.Asn13Ser), previously reported in a patient with a more severe phenotype that, however, was not functionally characterized. In this work, functional studies in a yeast model and patient-derived fibroblasts demonstrated that the variant impairs mitochondrial respiration, complex III activity (CIII), and also alters mitochondrial morphology in affected fibroblasts. Interestingly, we unveil a new possible mechanism of pathogenicity for BCS1L mutant protein. Since the interaction between BCS1L and CIII is increased, this suggests the formation of a BCS1L-containing nonfunctional preCIII unable to load RISP protein and complete CIII assembly. These findings support the pathogenicity of the BCS1L c.38A>G variant, suggesting altered interaction between the mutant BCS1L and CIII. Full article

Substance use disorders (SUDs) are widely prevalent in many countries, with the highest rates observed in nicotine and alcohol use, followed by opioid and cannabis use disorders. Within the field of SUDs, nutrition has become an increasingly important area of focus in both epidemiology and public health, as malnutrition is frequently observed among individuals affected by these disorders. Research indicates that people with SUDs are more likely to experience malnutrition than the general population; however, this issue remains an often-overlooked consequence that can impact disease progression and recovery outcomes. SUDs disrupt brain metabolism, leading to changes in brain function and disturbances in glucose, protein, and lipid metabolism. Evidence shows that individuals with certain SUDs often suffer from poor nutritional status, marked by high sugar consumption and insufficient intake of key micronutrients like iron, as well as vitamins D, C, A, and B—likely due to prioritizing drug use over adequate food intake. Importantly, diet can alter the metabolism and effects of drugs, potentially amplifying or diminishing their impact. While nutrition should play a central role in SUD treatment and rehabilitation, current research—both in animal models and human studies—on the role and benefits of specific nutrients in this context remains limited. This literature review aims to synthesize the available findings on the impact of malnutrition in human and murine models of SUDs, with the goal of identifying which nutrients may provide the most support for treatment and recovery. Full article