Search Results (2,086)

Obesity is a major global health challenge characterized by chronic low-grade inflammation, oxidative stress, and an increased risk of cardiometabolic disorders. Although sex-related differences in inflammatory and redox biomarkers have been reported in obese populations, the molecular mechanisms underlying this heterogeneity remain incompletely understood. In this study, we applied a proteomics-based approach to investigate urinary extracellular vesicles from 45 obese individuals (BMI 30–40 kg/m²; age 50–70 years) in order to identify molecular signatures associated with metabolic dysregulation. Shotgun proteomics analysis performed by nanoLC–MS/MS enabled the identification of 3822 proteins. Hierarchical clustering of proteomic profiles revealed two distinct molecular groups, predominantly enriched in males (Group I) and females (Group II). Label-free quantitative analysis identified 466 differentially abundant proteins between the two clusters. Functional enrichment analysis highlighted pathways associated with immune response, metabolic regulation, and redox homeostasis, including glycolysis/gluconeogenesis, lysosome activity, leukocyte transendothelial migration, and glutathione, cysteine and methionine metabolism. Notably, proteins related to ferroptosis were enriched, suggesting the involvement of iron-dependent oxidative cell death mechanisms in the metabolic imbalance observed in a subset of subjects. Furthermore, the non-enzymatic glycosylation of urinary proteins was significantly higher in Group I compared with Group II (p = 0.0002), indicating increased formation of advanced glycation products in individuals with a more pronounced pro-oxidant state. Preliminary follow-up data suggested a higher incidence of pathological events, including cardiovascular complications, among individuals belonging to Group I. Overall, these findings demonstrate that urinary proteomic profiling can identify distinct molecular phenotypes among obese individuals and highlight oxidative stress, ferroptosis, and protein glycation as potential determinants of metabolic vulnerability, supporting the use of non-invasive proteomic approaches for improved risk stratification in obesity. Full article

Precision nano-fertilization offers transformative potential for sustainable improvement of grape quality, yet the underlying molecular mechanisms remain poorly understood. Here, we investigated the effects of foliar-applied nano zero-valent iron (nZVI) and potassium dihydrogen phosphate (KH₂PO₄), in combination, on berry quality and secondary metabolic reprogramming in Vitis vinifera cv. Marselan. The combined nZVI/KH₂PO₄ treatment improved photosynthetic capacity, Fe/P co-accumulation, and berry quality traits including soluble solid content, sugar–acid ratio, and phenolic and aroma metabolite profiles. Crucially, integrated transcriptomic and metabolomic profiling identified 631 differentially expressed genes and 838 differentially accumulated metabolites, converging on flavonoid biosynthesis and glutathione metabolism as the dominant regulatory axes. Correlation network analysis pinpointed five hub regulatory genes—VvHCT, VvFLS1, VvLAR1/2, VvUGT88F5, and VvODC—as central orchestrators of nanomaterial-driven metabolic reprogramming: VvHCT and VvFLS1 coordinately redirected carbon flux toward hydroxycinnamic acid conjugates and flavonol accumulation, while VvLAR1/2 governed proanthocyanidin polymerization, and VvUGT88F5 modulated glycosylation-dependent metabolite stabilization. Notably, VvODC linked polyamine metabolism to glutathione-mediated stress buffering, revealing a previously uncharacterized crosstalk between nano-iron signaling and antioxidant reprogramming. These findings establish a mechanistic framework in which nZVI and KH₂PO₄ synergistically remodel the secondary metabolome through discrete yet interconnected transcriptional nodes, providing molecular targets for nano-enabled precision viticulture and broader applications of engineered nanomaterials in high-value crop improvement. Full article

Severe COVID-19 is characterized by profound thromboinflammatory and immune disturbances, but the network-level relationships among complement–coagulation dysregulation, humoral immune remodeling, and iron-associated immune regulation remain incompletely understood. Here, we performed integrative proteomic and transcriptomic analyses across peripheral blood and lung microenvironments using weighted gene co-expression network analysis (WGCNA), differential network analysis (DiNA), and immune deconvolution. Proteomic network analysis identified a disease-associated module enriched in complement activation, coagulation cascades, platelet degranulation, and acute inflammatory responses. Hub proteins, including C9, LBP, vWF, and F11, were prioritized based on module association and intramodular connectivity. Notably, C9 and LBP were repeatedly identified across WGCNA, DiNA, and differential expression analyses, underscoring their robust association with severe COVID-19-associated molecular network remodeling. Transcriptomic and CIBERSORTx-based immune deconvolution analyses showed altered immune-cell composition in blood and lung tissues, including B-cell and plasma-cell-associated changes. Notably, TFRC displayed cell-type-associated expression changes in naïve B cells and plasma cells, suggesting a potential link between iron-associated immune regulation and humoral immune remodeling. Collectively, these computational findings highlight coordinated complement–coagulation dysregulation, humoral immune remodeling, and TFRC-associated iron-related immune alterations in severe COVID-19, and prioritize TFRC, C9, and LBP as candidate molecular indicators requiring further experimental and clinical validation. Full article

Chronic intermittent hypoxia (CIH), the cardinal pathophysiological feature of obstructive sleep apnea, is increasingly recognized as an important modifier of metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying mechanisms remain incompletely understood. In this study, male C57BL/6 mice were fed a standard diet or a high-fat diet (HFD) and exposed to normoxia or CIH for 8 weeks. Histological, ultrastructural, biochemical, transcriptomic, proteomic, and metabolomic analyses were integrated to characterize hepatic alterations induced by CIH under metabolic stress. CIH markedly aggravated HFD-induced liver injury, as evidenced by increased body fat, hepatomegaly, serum transaminases, steatosis, mitochondrial ultrastructural alterations, and inflammatory infiltration. Mechanistically, CIH promoted hepatic lipid metabolic reprogramming by suppressing the PPARα/CPT1A fatty acid β-oxidation axis while enhancing the SREBP-1c/FASN/PLIN2 lipogenic pathway, impaired the Nrf2/HO-1/SLC7A11/GPX4 antioxidant defense system, increased lipid peroxidation and iron accumulation, and activated NF-κB/NLRP3 signaling. These findings support a multifactorial model in which CIH functions as an additional hypoxic stressor that exacerbates HFD-induced MASLD-like liver injury through coordinated metabolic, oxidative, and inflammatory dysregulation. Full article

Staphylococcus aureus (S. aureus) bovine mastitis is a significant public health issue. Despite enormous efforts, important gaps remain regarding host–microenvironmental factors. How intramammary reduced oxygen modulates S. aureus transcription in bovine mammary epithelial cells (MECs) remains unclear. We examined oxygen-associated transcriptional changes in a bovine-mammary adapted S. aureus clone following internalization into MECs and identified functional category enrichments under Normal-O₂ and Reduced-O₂ exposures. Bovine MAC-T monolayers were infected with a dominant bovine mastitis isolate under Normal-O₂ or Reduced-O₂ conditions. Triplicate infection experiments were performed for each oxygen condition. Each condition included matched non-reacted bacterial controls maintained under the same gas condition but without MAC-T exposure serving as the reference condition for expression calling. RNA was extracted and profiled using a high-throughput qRT-PCR platform covering genome-wide loci. Expression calls were mapped to curated BioQT roles and interpreted descriptively. Results indicated 211 loci were upregulated and 99 were downregulated under Normal-O₂ conditions, versus 53 upregulated and 35 downregulated under Reduced-O₂ conditions, relative to their non-reacted controls. Under Normal-O₂ conditions, regulated loci covered multiple functional roles, including cellular processes, transport/binding proteins, regulatory functions, and energy metabolism with downregulated loci enriched in transport/binding and cell-envelope categories. Under Reduced-O₂ conditions, upregulated loci were abundant in cellular process annotations dominated by pathogenesis/toxin-related functions, whereas downregulated loci were enriched in nucleotide biosynthetic and DNA/cell division categories. Thus, this reveals oxygen-associated shifts in the transcriptional response of intramammary S. aureus in MAC-T cells. Normal-O₂ conditions were associated with broader category representation, whereas Reduced-O₂ conditions yielded a narrower distribution enriched for selected toxin/pathogenesis- and iron/cation-associated annotations. These oxygen-linked transcriptional-shifts highlight candidate pathways for the intramammary adaptation of S. aureus, potential diagnostic markers, anti-virulence strategies, and targeted therapeutics. Full article

Retinal pigment epithelium (RPE) degeneration remains a formidable challenge in dry age-related macular degeneration (AMD) research, primarily due to the toxic interplay between iron overload and ferroptosis. We investigated whether EPO-R76E, a non-erythropoietic modified variant of erythropoietin, could effectively interrupt this destructive cycle. Using ARPE-19 cells challenged with ferric ammonium citrate (FAC) to model iron-induced toxicity, we show that EPO-R76E confers protection against ferroptosis. Our results demonstrate that this variant significantly reduces the intracellular labile iron pool, directly quenching the lipid peroxidation that drives ferroptotic cell death. This resilience is fueled by a robust upregulation of Glutathione Peroxidase 4 (GPX4) and the broad transcriptional activation of the NRF2 (Nuclear factor erythroid 2-related factor 2) NRF2 antioxidant axis. Furthermore, we found that EPO-R76E enhances autophagic flux, ensuring that cells maintain essential proteostasis and “housekeeping” functions even under metabolic crisis. By integrating iron sequestration with reinforced antioxidant signaling and cellular clearing mechanisms, EPO-R76E stands out as a potent candidate for preserving RPE health. These findings uncover a novel molecular framework for protecting the retina against iron-mediated injury, positioning EPO-R76E as a versatile and targeted gene-based therapeutic for addressing the fundamental causes of retinal degeneration. Full article

Background and Objectives: SGLT2 inhibitors increase hemoglobin and hematocrit in multiple clinical settings, an effect increasingly attributed to stimulation of erythropoiesis rather than hemoconcentration. However, most mechanistic evidence derives from diabetic populations, leaving uncertainty as to whether this response depends on diabetes-related metabolic changes. To evaluate whether dapagliflozin stimulates erythropoiesis in non-diabetic patients with heart failure and to determine whether hematologic changes correlate with renal, cardiac, inflammatory, hepatic, or iron-related parameters. Materials and Methods: In this retrospective observational study, each of 68 non-diabetic heart failure patients served as their own control. Hematologic, renal, cardiac, inflammatory, hepatic, and iron parameters were assessed at three time points: one year prior to dapagliflozin initiation, at baseline, and one year after initiation of therapy. Changes were analyzed using paired tests and correlation analyses. Results: Hemoglobin, hematocrit, and red blood cell count were significantly lower at the baseline compared with values recorded one year before dapagliflozin initiation and increased significantly during the year following treatment (all p < 0.001), while mean corpuscular indices remained stable. Serum iron decreased before treatment and increased significantly after dapagliflozin initiation (p < 0.05 vs. baseline); however, changes in serum iron did not correlate significantly with changes in hemoglobin after treatment. Inflammatory markers showed a modest reduction in C-reactive protein after treatment, while composite inflammatory indices remained largely stable. Liver enzymes showed no significant longitudinal changes. Correlation analyses demonstrated no association between changes in hemoglobin and changes in eGFR (ρ = 0.202, p = 0.098) or NT-proBNP (ρ = −0.003, p = 0.981) after treatment. Hematologic variables remained strongly intercorrelated, whereas cross-system correlations were minimal, indicating that erythropoietic stimulation occurred largely independently of renal or cardiac functional trajectories. Conclusions: Dapagliflozin robustly stimulates erythropoiesis in non-diabetic patients with heart failure, independent of improvements in kidney or cardiac function. Although serum iron levels improved after treatment, the absence of a direct correlation with hemoglobin suggests that iron mobilization may act as a permissive rather than a primary driver of erythropoietic response. These findings support the concept that erythropoiesis represents a diabetes-independent pharmacologic action of SGLT2 inhibitors and may involve renal, hepatic, inflammatory, and iron-regulatory pathways beyond those described in diabetic physiology. Dedicated mechanistic studies in non-diabetic populations are warranted. Full article

Human herpesvirus 6 (HHV-6) typically remains latent but can reactivate during immunosuppression caused by chemotherapy, potentially driving immune dysregulation. The NLRP3 inflammasome is a critical innate immune complex mediating pro-inflammatory signaling implicated in tumor progression and treatment toxicity. This study investigated the association between HHV-6 antigenemia and NLRP3 inflammasome activation in 193 chemotherapy-treated cancer patients at the Oncology Hospital in Al-Najaf, Iraq. Serological markers for HHV-6 IgG, IgM, and circulating viral antigen, along with serum NLRP3 levels, were quantified using ELISA. Active HHV-6 antigenemia was observed in over half the cohort, with 56.5% positive for IgM and 42.5% exhibiting antigenemia. Elevated serum NLRP3 levels were detected in 65.8% of patients and correlated significantly with HHV-6 antigen presence, particularly in hematological and genitourinary cancers. Viral antigenemia and inflammasome activity were more prominent in females and older patients. Host gene analysis revealed Hepcidin (HAMP) polymorphisms and altered expression compared to healthy controls, suggesting links between iron metabolism, viral antigenemia, and inflammasome activity. These findings highlight a potential mechanistic connection between HHV-6 antigenemia and inflammasome-driven inflammation, which may contribute to chemotherapy-associated immune dysregulation. Monitoring HHV-6 antigenemia and NLRP3 activation may offer valuable insight into the inflammatory status of cancer patients undergoing chemotherapy. Full article

Parkinson’s disease (PD) is a neurodegenerative disorder of the central nervous system with a complex pathogenesis. Current conventional medicines are predominantly symptomatic treatments, which fail to reverse neuronal degeneration and often induce severe motor complications following long-term administration. In this context, the advantages of the multi-target holistic regulation provided by traditional Chinese medicine have become increasingly prominent. As the core active ingredients of Panax ginseng, ginsenosides can penetrate the blood–brain barrier and exhibit broad neuroprotective prospects in PD treatment. This article systematically reviews the neuroprotective mechanisms of different configurations of ginsenosides—mainly including protopanaxadiol (PPD) and protopanaxatriol (PPT) saponins—against PD. Studies indicate that PPD-type saponins (e.g., Rb1, Rg3, Rd) excel in directly inhibiting the abnormal aggregation of α-synuclein (α-syn), reducing oxidative stress, and preventing neuronal apoptosis. Conversely, PPT-type saponins (e.g., Rg1, Re) demonstrate significant advantages in suppressing microglia-mediated neuroinflammation, improving mitophagy, and regulating lipid metabolism networks. Furthermore, this review highlights a novel intervention strategy utilizing ginsenosides based on antioxidation and iron metabolism regulation. By maintaining the homeostasis of iron transport proteins such as DMT1 (Divalent Metal Transporter 1) and FPN1 (Ferroportin 1), and activating the Nrf2/xCT/GPX4 signaling axis, these compounds effectively block the vicious cycle of “iron deposition-oxidative stress-lipid peroxidation (LPO),” thereby inhibiting ferroptosis in dopaminergic neurons. In summary, structurally diverse ginsenosides exhibit distinct characteristics in targeting the core pathological events of PD. The scientific combination of ginsenoside monomers with different mechanisms in the future holds promise for constructing a comprehensive multi-target neuroprotective network, providing a solid theoretical foundation for novel ginsenoside-based combination therapies against PD. Full article

Heme metabolism in the liver has traditionally been described as a linear pathway that supports oxygen utilization, redox balance, and detoxification. Here, we synthesize recent evidence and propose a framework in which heme functions as a system-level regulator, the “queen” of metabolism, whereas its upstream intermediate protoporphyrin IX (PPIX) represents a chemically reactive “dark twin” that emerges when metabolic flux fails to resolve. In this view, metabolic state is defined not only by end products but also by the behavior of pathway intermediates. This system is spatially organized. Hepatocytes dominate heme synthesis and utilization. In contrast, liver stromal compartments, particularly Kupffer cells, play a central role in heme degradation through heme oxygenase-1 (HMOX1), linking heme turnover to iron recycling and stress adaptation. The metabolic state of the liver therefore reflects not only pathway flux but also the degree of coupling between these cellular compartments. We propose a state model of hepatic heme metabolism. In the resolution state, most evident during inflammation, coordinated hepatocyte–macrophage activity maintains flux and limits intermediate accumulation. In contrast, the expansion state, exemplified in cancer, is defined by impaired flux completion, leading to PPIX accumulation, metabolic heterogeneity, and oxidative stress. This framework reframes liver disease through intermediate behavior rather than pathway presence: porphyrias reflect direct overload, metabolic liver diseases partial expansion, and hepatocellular carcinoma a fully developed expansion state. By focusing on the “intermediate space,” this model links biochemistry, spatial organization, and disease pathogenesis, while suggesting new opportunities for diagnosis and therapy based on metabolic state. Full article

Females with iron overload suffer from follicular dysplasia, and effective therapeutic strategies for preserving fertility remain lacking. As a natural aliphatic polyamine, spermidine exerts antioxidant activity and plays an anti-ferroptosis role in the pathogenesis of various diseases. However, the role and underlying mechanism of spermidine in iron overload-induced ovarian ferroptosis remain largely elusive. This study aimed to investigate the therapeutic potential of spermidine against iron overload-induced ferroptosis in ovarian granulosa cells and elucidate its molecular mechanism. As a result, iron overload models were established in female mice (in vivo, ferrous sulfate) and porcine ovarian granulosa cells (in vitro, ferric ammonium citrate), with spermidine administered at 3 mM (in vivo) or 150 μM (in vitro). Ferritin heavy chain (FHC) and solute carrier family 7 member 11 (SLC7A11) silencing were performed via siRNA transfection, and relevant controls were set. In vivo studies showed that spermidine elevated serum estradiol and progesterone levels, enhanced ovarian catalase (CAT) and superoxide dismutase (SOD) activities, improved granulosa cell mitochondrial morphology, and increased estrous cycle regularity from 35.6% (high-iron group) to 63.1%. In vitro, spermidine improved ferric ammonium citrate (FAC)-impaired cell viability; attenuated reactive oxygen species (ROS) accumulation; upregulated FHC, Nrf2/p-Nrf2/GPX4, SLC7A11 and anti-müllerian hormone (AMH) expression; and inhibited excessive autophagy (decreased LC3BII/I ratio). Mechanistically, spermidine activated AKT-mediated autophagy, modulated iron homeostasis and glutathione (GSH) synthesis via FHC, alleviated ferroptosis-related Nrf2/p-Nrf2/HO-1 pathway overactivation, reduced lipid peroxidation and DNA damage, and restored mitochondrial function. SLC7A11 silencing disrupted glutathione metabolism, induced mitochondrial ROS accumulation, and inhibited autophagy. Proteomic analysis identified microsomal glutathione S-transferase 3 (MGST3) as a potential key downstream target of spermidine in suppressing SLC7A11-mediated ferroptosis. This study reveals a novel therapeutic strategy wherein spermidine protects against ovarian ferroptosis and preserves ovarian function by regulating iron homeostasis through the FHC/SLC7A11 axis. Full article

Lactoferrin is a naturally occurring bioactive glycoprotein that is part of the body’s innate immune system and has essential roles in iron metabolism, microbial defense, inflammation regulation, and tissue repair. It supports the natural regulation of iron bioavailability in skin and hair follicles, helping to reduce excess free-iron-driven oxidative stress while preserving levels of necessary iron for cellular functions. Lactoferrin promotes cell regeneration by increasing proliferation across in vitro systems, stimulating wound healing in scratch assays, and boosting matrix production in fibroblast models. Lactoferrin can also modulate inflammatory signaling involved in skin and hair physiology by providing balanced cytokine suppression, suggesting potential value in cosmetic or dermatological applications. Here, we present the first focused summary of lactoferrin’s role specifically in skin and hair biology, distinguished from prior reviews in systemic or multi-system broad health contexts. We link mechanistic insights with clinical and preclinical evidence and uniquely map molecular functions to dermatologic and trichologic outcomes. We also provide an overview of clinical skin studies that have explored lactoferrin as a supportive agent in conditions such as acne, and highlight that, despite mechanistic plausibility, there are no existing available reports of well-controlled human clinical trials leveraging lactoferrin for hair-focused outcomes. In summary, we propose lactoferrin as not just an anti-inflammatory molecule, but also as a microenvironment stabilizer, and particularly relevant for hair and skin support as an alternative to pharmacological interventions. By addressing both established and underexplored applications, this review provides a translational framework for clinical development and provides a comprehensive rationale behind leveraging lactoferrin for hair and skin epithelial health. Full article

Heavy metal pollution remains a major global environmental challenge due to persistent ecological risks and potential threats to food safety. Microbial remediation and phytoremediation represent sustainable alternatives to conventional treatments; however, their effectiveness is strongly influenced by number of factors including nutrient availability. This review critically examines how nutritional regulation governs microbial metabolism, plant physiological responses, and rhizosphere interactions to enhance heavy metal transformation and removal. Metal bioavailability depends on type, concentration, soil pH, redox potential, and microbial processes. Interventions including fertilizers, chelating agents, inoculation with arbuscular mycorrhizal fungi and plant-growth-promoting rhizobacteria enhance phytoremediation processes through regulating plant nutrient and heavy metal uptake, while selection between ammonium/nitrate changes rhizosphere pH consequently affects plant metal uptake. Similarly, nutrients, i.e., phosphate, iron, zinc and manganese competitively affect metal uptake. Organic amendments enhance phytostabilization, especially for selenium and mercury, while enhancing chromium reduction. Sulfur-reducing bacteria precipitate metals as insoluble sulfides with 90% efficiency. In addition, soil amendments including plant-growth-promoting rhizobacteria, arbuscular mycorrhizal fungi, and metal-chelating agents can be strategically used to enhance the phytoextraction from metal from contaminated soils. We suggest that the future integration of modern approaches such as multi-omics and cisgenesis supported by artificial intelligence tools can help to accurately predict the efficiency of nutrient regulation strategies and their remediation outcomes, thereby supporting evidence-based soil management. Full article

Aim: To assess abnormalities in red blood cell parameters, iron metabolism, and vitamin B12 status in children with obesity, and to evaluate the influence of dietary intake and obesity-related complications on these variables. Methods: A retrospective analysis was conducted in 152 children with obesity. Anthropometric, biochemical, and hematological parameters were assessed. Dietary intake was evaluated in a subgroup of 33 participants using 3-day food records. Results: No cases of low hemoglobin levels were identified. However, elevated TIBC and occasional low ferritin levels suggested disturbances in iron metabolism. BMI Z-score was positively associated with red blood cell count and selected iron metabolism markers, whereas higher body fat percentage was negatively associated with hemoglobin and hematocrit. Dietary analysis indicated that protein and vitamin B12 intake were associated with erythrocyte parameters, while no associations were found for iron or folate intake. Elevated liver enzymes were associated with higher hemoglobin, hematocrit, and MCV values. Conclusions: Pediatric obesity was not associated with low hemoglobin levels but may be linked to early, subclinical disturbances in iron metabolism. These findings should be confirmed using more comprehensive biomarkers. Dietary factors, particularly vitamin B12 intake, may contribute to variability in erythrocyte parameters; however, these associations should be interpreted with caution. The observed relationship between liver function and erythrocyte indices warrants further investigation. Full article

Background: In chronic kidney disease (CKD) treatment, a holistic approach, which involves not only nephrologists but also nutritionists, sports physicians, and kinesiologists, is becoming increasingly important, characterized as including not only pharmacological therapy but also integrative treatments, i.e., nutritional therapies (like low protein diet-LPD) and adapted physical exercise (APE) programs. The aim of this study was to evaluate the potential adjuvant therapeutic role of an integrated APE + LPD program on CKD comorbidities, comparing its additional beneficial effects with those induced by the LPD alone. Methods: This clinical study is a randomized controlled trial, where 40 CKD patients (stage G3b-G5) were enrolled and divided into two homogeneous groups: an APE + LPD group, which performed an online APE protocol combined with LPD; and an LPD group, which received only LPD. All enrolled patients were evaluated at baseline (T₀) and after 12 weeks (T₁) for clinical and body composition parameters and for functional assessment and health-related quality of life (HRQoL). Results: Both groups showed a significant reduction in lipid and glucose metabolism parameters. Good adherence to the prescribed LPD led to significantly better control of systolic blood pressure and electrolytes, along with an increase in venous bicarbonate levels. Improvements in body composition and physical performance were also observed. In the APE + LPD group only we observed a significant increase in neutrophil count, serum iron levels, muscle strength, and patients’ HRQoL. Conclusions: Our results suggest that the integrated approach, rather than the LPD alone, is more effective for muscle-related outcomes, HRQoL, and in the positive modulation of the immune system. Full article