Search Results (2,595)

Metabolic syndrome (MetS) is associated with ectopic fat deposition, chronic systemic inflammation, oxidative stress, and increased susceptibility to organ dysfunction. While its cardiovascular consequences have been extensively studied, pulmonary al-terations remain less well characterized, particularly with respect to ferropto-sis-regulatory pathways. In this study, we evaluated ectopic fat deposition, TLR4/NF-κB signaling pathway, and ferroptosis-regulatory markers in a MetS rat model and analyzed the therapeutic potential of combined resveratrol plus quercetin (combined R + Q) supplementation. Rats were maintained for five months with 30% sucrose in drinking water to induce MetS and subsequently treated for 4 weeks with the R + Q combination (50 and 0.95 mg/kg/day, respectively). Lung tissue was analyzed by fluorescence microscopy to assess fat deposition, by colorimetric histology to evaluate hemosiderin-containing cells, including the quantification of hemosiderin-laden macrophages (HLMs), and by immunoblotting to determine TLR4, p-p65, and glutathione peroxidase 4 (GPX4), as well as cystine/glutamate antiporter SLC7A11 (xCT) protein expression. Lungs from MetS rats exhibited significantly higher fat deposits, pathological HLMs accumulation, upregulated TLR4/p-p65 signaling, elevated compensatory GPX4 expression, and depressed xCT levels compared with controls. Notably, the combined R + Q treatment markedly attenuated alterations in TLR4/NF-κB signaling and successfully restored xCT expression (p = 0.0116), stabilizing pulmonary redox homeostasis and limiting overall tissue susceptibility to lipotoxic injury. Full article

Chemotherapy-induced neurotoxicity, affecting both the central and peripheral nervous systems, is a frequent and severe adverse effect of paclitaxel (PAC) treatment with limited therapeutic options. We previously demonstrated that PAC triggers neuronal cell death via ferroptosis. αO-Conotoxin GeXIVA[1,2], a marine-derived peptide, has shown efficacy in alleviating chemotherapy-induced neuropathic pain. In the present study, we investigated whether GeXIVA[1,2] protects neurons from PAC-induced neurotoxicity by suppressing ferroptosis. Using SH-SY5Y and HT-22 neuronal cell lines, we found that GeXIVA[1,2] pretreatment rescued PAC-impaired cell viability without exhibiting cytotoxicity. GeXIVA[1,2] markedly attenuated PAC-induced reactive oxygen species (ROS) overproduction and restored intracellular glutathione (GSH) levels. Mechanistically, PAC suppressed the Nrf2/SLC7A11/GSH/GPX4 ferroptosis-defense pathway, and GeXIVA[1,2] reactivated this axis by upregulating Nrf2, SLC7A11, and GPX4 protein expression. These results reveal a novel ferroptosis-suppressive function of GeXIVA[1,2] in the context of PAC-induced neurotoxicity. Our findings provide a mechanistic foundation for developing GeXIVA[1,2] as a ferroptosis-targeted intervention against chemotherapy-induced neurotoxicity. Full article

Glycogen storage disease Ib (GSD Ib) is an ultra-rare metabolic disease caused by variants in the SLC37A4 gene affecting activity of the glucose-6-phosphate transporter (G6PT). G6PT mediates transport of glucose-6 phosphate from the cytoplasm into the lumen of the endoplasmic reticulum, thereby playing a key role in glucose homeostasis. To date, no approved therapies directly restore G6PT function, highlighting a major unmet need. Pharmacological chaperone (PC) therapies, including those targeting membrane transporters, are a known and clinically employed therapeutic strategy. The efficacy of PC therapy is highly dependent on the underlying pathogenic variant. While certain missense variants may respond favorably, particularly those associated with protein misfolding and residual function, null variants are generally considered unsuitable targets due to the absence of a protein that could be rescued. To the best of our knowledge, no previous review has systematically examined the global landscape of SLC37A4 variants. The aim of this review was to collect the spectrum and frequency of SLC37A4 variants reported worldwide and connect them with all available structural and functional data. In 425 GSD Ib patients, we found that approximately 10% of all variants are strong PC candidates and 14–30% are reasonable but lower-confidence candidates (other missense non-deactivating variants), while the rest are poor PC candidates (substrate-pocket variants) and null variants (nonsense, frameshift and splicing). Although functional studies are required to definitely validate PC-responsive missense variants in the SLC37A4 gene, our review suggests, for the first time, the existence of a minimal threshold at which a PC approach may become clinically relevant for GSD Ib patients. Full article

Background: Myelodysplastic neoplasms (MDSs) are clonal hematopoietic stem cell disorders associated with ineffective hematopoiesis, chronic inflammation, and increased cardiovascular morbidity. Although metabolic dysregulation has been implicated in MDS pathogenesis, systemic metabolic alterations remain incompletely characterized. Methods: Plasma samples from treatment-naïve patients with MDS or chronic myelomonocytic leukemia (CMML) and age-matched healthy controls were analyzed using quantitative nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry (LC-MS). Metabolomic profiles were compared using unsupervised and supervised multivariate analyses, validated in an independent external MDS cohort, and integrated with re-analysis of publicly available RNA-sequencing datasets from purified CD14⁺ CMML monocytes. Results: Patients with MDS and CMML exhibited broad reductions in circulating lipoprotein-associated metabolites, including HDL-, LDL-, IDL-, and apolipoprotein-associated fractions, indicating disturbed systemic lipoprotein homeostasis. Within the discovery cohort, CMML samples showed higher concentrations of the ketone bodies 3-hydroxybutyrate and acetoacetate, as well as succinate. LC-MS analysis demonstrated selective increases in C18:1 acylcarnitine, oleic and isopalmitic acids, whereas free carnitine abundance remained unchanged. Elevated 3-hydroxybutyrate levels were not associated with mutational burden, hematologic parameters, disease risk, or immunophenotypic features. Re-analysis of public CMML monocyte transcriptomes demonstrated increased expression of genes involved in lipid uptake and intracellular lipid trafficking, including FABP5, APOE, LPL, and SLC27A2, without coordinated activation of fatty acid oxidation pathways. External cohort analysis confirmed the overall MDS-associated plasma metabolomic profile. Conclusions: MDSs and CMML are associated with reproducible alterations in systemic lipid metabolism characterized by reduced circulating lipoprotein-associated metabolites, while CMML showed more pronounced ketone body- and acylcarnitine-associated metabolic phenotype accompanied by changes in lipid-handling transcriptional programs. These findings support altered systemic lipid metabolism and carnitine-dependent fatty acid handling as characteristic features of myeloid neoplasms and provide a rationale for future functional studies investigating lipid metabolism in disease pathogenesis. Full article

High-intensity interval training (HIIT) is widely recognized as an effective strategy for improving cardiorespiratory fitness and metabolic health. Beyond these physiological benefits, growing evidence indicates that HIIT may also induce beneficial immunometabolic adaptations. A key exercise-responsive metabolite in this context is lactate, which is increasingly being recognized not as a metabolic waste product but as a bioactive signaling metabolite capable of coordinating metabolic, inflammatory, and immune processes. This narrative review examines current evidence suggesting a potential role for exercise-induced lactate in immune responses associated with HIIT. We summarize the molecular pathways through which lactate may interact with immune cells, including uptake via monocarboxylate transporters (MCT1/MCT4) and SLC5A12, receptor-dependent signaling through GPR81/HCAR1, and epigenetic regulation via histone lactylation. We further discuss the cell-specific effects of lactate on macrophages, dendritic cells, neutrophils, and T lymphocytes, highlighting how these mechanisms may influence immune-cell metabolism, inflammatory regulation, and functional remodeling. A central concept emerging from the current literature is that the biological actions of lactate are highly dependent on the kinetics, duration, and physiological context of exposure. Unlike pathological lactate elevations observed in conditions such as cancer, sepsis, or mitochondrial myopathies—the latter potentially involving an exaggerated lactate response during exercise due to impaired oxidative metabolism—HIIT generates transient systemic lactate elevations as part of a coordinated neuroendocrine and metabolic response. When combined with adequate recovery, these repeated metabolic perturbations may promote hormetic adaptations characterized by improved inflammatory regulation, enhanced immune resilience, and more efficient immunometabolic homeostasis. Conversely, excessive training loads or inadequate recovery may shift these responses toward maladaptive immune stress. Overall, current evidence suggests a paradigm shift in exercise immunology in which lactate should be regarded as one component of an integrated immunometabolic signaling network rather than simply as a marker of anaerobic metabolism. Future mechanistic studies integrating lactate kinetics, immune-cell phenotyping, transporter expression, and lactate-dependent post-translational modifications are needed to clarify the extent to which lactate may contribute to exercise-induced immune remodeling and to guide the development of immunologically informed HIIT protocols. Full article

Mutations in SLC26A4, which encodes the anion transporter pendrin, represent one of the most common genetic causes of hereditary hearing loss, including Pendred syndrome and DFNB4. Pendrin plays a critical role in maintaining ion homeostasis within the inner ear, particularly in the endolymphatic sac (ES), making it an important therapeutic target for gene replacement strategies. However, efficient delivery of therapeutic genes to relevant inner ear structures remains a major challenge for clinical translation. In this study, we evaluated the inner ear transduction profile of AAV8BP2, an engineered AAV8-derived capsid, in comparison with AAV2.7m8 and AAV8 in mice. Neonatal mice received posterior semicircular canal (PSCC) injections at postnatal day 0 (P0), and viral transduction in the cochlea and ES was assessed at P7. To examine age-dependent differences in viral transduction, additional experiments were performed in adult mice injected at P21 and analyzed at P28. We also compared three surgical delivery routes for inner ear gene transfer: PSCC injection, round window membrane (RWM) injection, and RWM injection combined with PSCC fenestration. AAV8BP2 effectively transduced the ES in both neonatal and adult mice and showed greater GFP expression in the spiral prominence than AAV8 following neonatal administration. Among the three delivery routes evaluated in adult mice, PSCC injection achieved the highest ES transduction while maintaining cochlear hair cell transduction comparable to that achieved with RWM-based approaches. Together, these findings define the relative transduction profiles of the tested AAV capsids and delivery routes and provide a basis for selecting vector-delivery route combinations for SLC26A4-targeted inner ear gene therapy. Full article

Cigarette smoke exposure is a major preventable risk factor for respiratory disease and drives oxidative and inflammatory lung injury, highlighting the urgent need for safe, multi-target interventions beyond conventional anti-inflammatory therapy. Formononetin (FMN), a naturally occurring isoflavone with antioxidant, anti-inflammatory, and microbiota-modulating potential, may offer a dietary-botanical strategy against smoke-related pulmonary damage. This study evaluated FMN against cigarette smoke extract (CSE)-induced lung injury and explored its associations with intestinal barrier integrity, gut microbiota, taurine metabolism, SLC6A6 expression, and NF-κB activation. In a CSE-challenged mouse model, oral FMN, particularly at 70 mg/kg, improved body weight gain, reduced the lung index, attenuated pulmonary histopathological injury, restored GSH/GSSG and SOD, decreased MDA, and suppressed TNF-α, IL-1β, and IL-6 expression. FMN also ameliorated colonic injury and restored ZO-1 and occludin expression. Exploratory 16S rRNA sequencing and fecal metabolomics indicated FMN-associated alterations in gut microbial composition and metabolic profiles, with taurine and hypotaurine metabolism identified as a candidate pathway for further investigation. FMN further restored lung taurine content and SLC6A6 expression while inhibiting NF-κB activation. These findings suggest that FMN alleviates CSE-induced lung injury and that this improvement is associated with coordinated changes in gut microbiota composition, taurine metabolism, SLC6A6 expression, and NF-κB activation. Full article

Oxidative stress drives skin aging, barrier impairment, and inflammatory amplification, making dietary antioxidants potential systemic contributors to cutaneous redox homeostasis. Edible fungi are distinctive sources of redox-active metabolites, particularly ergothioneine, a stable sulfur-containing antioxidant whose cellular uptake is mediated by the ergothioneine transporter OCTN1 (SLC22A4). This review evaluates ergothioneine, polysaccharides and β-glucans, cordycepin, phenolics, and Ganoderma triterpenoids as processing-sensitive dietary bioactives with redox relevance rather than topical cosmetic ingredients. We examine how cultivation, drying, cooking, extraction, fermentation, and microbial biomanufacturing determine antioxidant formation, retention, oral bioaccessibility, and dose realism, and how antioxidant response, inflammatory, mitochondrial, and gut microbiota-mediated pathways connect intake to skin endpoints. The strongest oral evidence concerns biomarker-linked ergothioneine-rich Pleurotus. Smaller Flammulina velutipes and Sparassis crispa trials report hydration or transepidermal water loss signals without comparable exposure biomarkers, whereas purified ergothioneine provides provisional non-mushroom food evidence. Compared with better-established oral ingredients, edible fungi offer distinctive food technology advantages but a narrower human evidence base. Priorities include processing-aware quality and safety markers, contaminant control, standardized digestion models, dose-realistic exposure estimates, and biomarker-anchored randomized human trials. Full article

This study investigates a simulation-based estimation–control chain that integrates an interactive multiple model adaptive unscented Kalman filter (IMM-AUKF) with a multiple-input multiple-output model predictive controller (MIMO-MPC). A seven-degree-of-freedom vehicle model and a Pacejka tire model are used to represent nonlinear vehicle dynamics. The controller updates model and regression region steering constraints from the estimated adhesion state and jointly allocates front/rear steering and longitudinal force commands. The revised experiments use a 0.5 ms plant integration step and a consistent 20 ms estimator/controller update. Under high-adhesion double lane change (DLC), the proposed chain lowers speed RMSE from 0.7950 to 0.1833 m/s and mean adhesion estimation RMSE from 0.1567 to 0.0812. Under variable-adhesion single lane change (SLC), lateral RMSE decreases from 0.1816 to 0.1649 m, speed RMSE from 0.7983 to 0.2505 m/s, and mean adhesion estimation RMSE from 0.1622 to 0.0949. Heading error is not uniformly improved and is reported as a design trade-off. These results provide reproducible simulation evidence, while hardware-in-the-loop and real-vehicle validation remain future work. Full article

Distributed Scatterer Interferometric Synthetic Aperture Radar (DSInSAR) technology has been widely applied in areas with complex terrain and dense vegetation. However, DSInSAR is computationally intensive and requires considerable processing time. When new observations become available, the entire dataset must be reprocessed without utilizing previously obtained results. This makes DSInSAR unsuitable for long-term continuous monitoring. The Sequential Estimator partitions large datasets into fixed-size subsets and compresses these subsets to avoid redundant processing. The Recursive Sequential Estimator with Flexible Batches (RSEFB) method was proposed to partition large datasets into flexibly sized subsets. However, how to determine appropriate grouping boundaries remains unresolved. In this paper, a Change-Point-Based Deformation Grouping Strategy (CPDGS) is proposed to enhance the deformation estimation accuracy within each group, thereby reducing the attenuation of abrupt deformation signals during estimation. In the proposed method, a Bidirectional Long Short-Term Memory (Bidirectional LSTM) network is employed to identify the potential presence of deformation change points. Bayesian Estimator of Abrupt change, Seasonality and Trend (BEAST) is subsequently used to localize the change points. Considering computational efficiency, an upper limit is also set on the number of Single Look Complex (SLC) per group. Due to the lack of ground truth, simulated data were used for the network training. Comparative experiments show that the proposed Bidirectional LSTM achieves the best overall performance, with an accuracy of 88.43%, a precision of 90.76%, a recall of 86.04%, and an F1-score of 88.34%, outperforming the LSTM and Transformer models. Further comparisons with conventional change point detection methods show that the proposed method achieves an F1-score of 91.23%, higher than Cumulative Sum (CUSUM; 69.20%) and and Bayesian Online Change Point Detection (BOCPD; 84.44%). Experiments using real Interferometric Synthetic Aperture Radar (InSAR) deformation data further demonstrate its effectiveness in identifying deformation change points in practical scenarios. Full article

Diabetic retinopathy, diabetic kidney disease, and diabetic peripheral neuropathy remain major causes of visual loss, kidney failure, pain, disability, and reduced quality of life despite improvements in glycemic and cardiovascular risk management. Oxidative stress, mitochondrial dysfunction, iron dyshomeostasis, lipid peroxidation, and sterile inflammation are shared features of these complications and converge on regulated cell-death programs. Ferroptosis is driven by iron-dependent phospholipid peroxidation when glutathione peroxidase 4 and complementary antioxidant systems are insufficient, whereas pyroptosis is an inflammatory lytic process executed by gasdermins after activation of inflammasome-associated or other inflammatory caspases. Nuclear factor erythroid 2-related factor 2 (NRF2) connects these pathways by regulating glutathione synthesis, lipid peroxide detoxification, iron handling, mitochondrial homeostasis, and redox-sensitive inflammatory signaling. Dietary polyphenols may influence this network through electrophilic or kinase-dependent NRF2 activation, preservation of the SLC7A11-glutathione-GPX4 axis, modulation of iron and lipid metabolism, and inhibition of NF-kappaB, TXNIP, NLRP3, caspase-1, and gasdermin signaling. This integrative review critically examines mechanistic, preclinical, and human evidence for these effects in the diabetic retina, kidney, and peripheral nerve. The strongest direct preclinical evidence currently concerns corilagin, resveratrol, isoquercetin, quercetin, epigallocatechin gallate, punicalagin, and selected anthocyanin-rich or phenolic extracts. Human studies suggest possible benefits for albuminuria, retinal edema, endothelial function, and neuropathic outcomes, but they rarely measure ferroptosis- or pyroptosis-specific biomarkers and their results are heterogeneous. The proposed ferroptosis–pyroptosis–NRF2 network should therefore be viewed as a biologically plausible integrative framework rather than a clinically validated linear pathway. Future trials require chemically characterized interventions, exposure biomarkers, tissue-relevant pharmacokinetics, prespecified regulated-cell-death panels, and clinically meaningful microvascular endpoints. Full article

Monocarboxylate transporter 2 (MCT2; SLC16A7) is a high-affinity pyruvate transporter implicated in cancer metabolism. However, its role in lung cancer progression and the tumor microenvironment remains unclear. This study examined the effects of MCT2 reduction on tumor growth and cell-type-specific transcriptional changes within the tumor microenvironment. MCT2 loxP/loxP mice were crossed with mCre-Tg mice, and MCT2 deletion was induced by tamoxifen. Control (CO) mice received vehicle treatment. TC1 cells (100,000 cells/mouse) were injected subcutaneously, and tumors were harvested after 24 days. Single-nucleus RNA sequencing (snRNA-seq) was performed on isolated tumor nuclei (4000 nuclei/sample; n = 3 per group) using the 10x Genomics Chromium platform. Data were processed with Cell Ranger v3.0.2 and Seurat v5.2.1, followed by differential expression and pathway enrichment analyses integrated with macrophage bulk RNA-seq data. Tumors in mice with systemic MCT2 reduction grew significantly faster than those in control mice, demonstrating an association between host MCT2 reduction and increased tumor growth. Transcriptomic analysis generated high-quality profiles from 6864 CO and 10,055 KO nuclei. Clustering identified 12 cellular populations and cell types. MCT2 reduction altered pathways involved in glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid metabolism across multiple populations. Macrophages showed prominent transcriptional changes, including enrichment of MAPK, PI3K-Akt, IgSF-CAM, ECM, and cytokine–cytokine signaling pathways. These findings were supported by macrophage bulk RNA-seq data. Systemic MCT2 reduction was associated with increased tumor growth and broad transcriptional alterations within the tumor micro-environment. Differences in metabolic and immune-related transcriptional programs, particularly in macrophages, identify potential mechanisms associated with tumor progression that warrant further functional investigation. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent liver disease associated with insulin resistance and hepatic lipid accumulation. Polyphenols have attracted considerable attention for their hepatoprotective and lipid-lowering activities. Our previous studies characterized a bound polyphenol extracted from the inner shell of foxtail millet (BPIS) and identified its major active components. In the present study, we investigated the molecular mechanisms underlying its biological activity using HepG2 cells and Caenorhabditis elegans. BPIS activated AMPK signaling, normalized intracellular glutathione (GSH) levels, and upregulated SLC7A11 and GPX4, suggesting modulation of ferroptosis-related pathways and improved cellular redox homeostasis. BPIS also alleviated endoplasmic reticulum stress by increasing GRP78 expression, inhibiting DRAK2, and regulating the ERK pathway, thereby improving the regulation of key lipid-metabolism-related signaling pathways, including SREBP1c, SCD1, CD36, FASN, and CPT1A. Consistent with these findings, BPIS reduced glucose- and free fatty acid-induced lipid accumulation and improved lipid-related phenotypes in C. elegans. Overall, BPIS attenuated hepatic steatosis through modulation of ferroptosis-related markers, endoplasmic reticulum stress, and lipid metabolism. These findings provide new mechanistic insights into the biological activities of BPIS and support its potential application as a nutraceutical ingredient for the prevention and management of MASLD. Full article

Background: Adolescent and adult citrin deficiency (AACD), formerly known as adult-onset citrullinemia type II, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in SLC25A13. It is an underrecognized cause of recurrent hyperammonemic encephalopathy, particularly when hepatic function is relatively preserved. Methods: We report two unrelated Vietnamese young men, aged 21 and 18 years, who presented with recurrent neuropsychiatric episodes. Clinical, biochemical, imaging, electrophysiological, and genetic findings were evaluated; whole-exome sequencing findings were confirmed by Sanger sequencing. Results: Both patients had long-standing preferences for protein- and fat-rich foods and avoidance of carbohydrate-rich foods, together with episodic hyperammonemia (345.21 and 103.07 µmol/L during symptomatic episodes). The first patient had a history of neonatal jaundice, mild cirrhosis, and severe behavioral disturbances, whereas the second was markedly lean and had no structural liver disease. Acquired causes of hyperammonemia and portosystemic shunting were excluded. Both patients harbored the homozygous pathogenic SLC25A13 variant NM_014251.3.852_855del (p.Met285ProfsTer2). Ammonia-lowering therapy and a low-carbohydrate, protein- and fat-enriched diet supplemented with medium-chain triglycerides resulted in clinical improvement, with no recurrent encephalopathic episodes during 6 months of follow-up in either patient. Conclusions: AACD should be considered in adolescents and adults with otherwise unexplained recurrent hyperammonemic encephalopathy, especially when ammonia elevation is disproportionate to liver disease. Characteristic dietary preferences provide an important diagnostic clue, and molecular testing enables definitive diagnosis and timely management. Full article

Background: Immunometabolic reprogramming is increasingly recognized as a fundamental driver of macrophage inflammatory activation. Although pomegranate polyphenols have been widely investigated for their anti-inflammatory activity, the underlying metabolic mechanisms remain poorly understood. Here, we investigated whether a pomegranate waste extract (PWE), obtained through a sustainable dimethyl carbonate (DMC)-based extraction process, modulates macrophage activation by targeting immunometabolic pathways. Methods: Human PBMC-derived macrophages stimulated with LPS and IFN-γ were treated with PWE. Inflammatory mediators, NF-κB transcription factor, histone H3 acetylation, and markers of inflammatory resolution were evaluated. Furthermore, the enzymatic activity of ATP citrate lyase (ACLY) and malic enzyme 1 (ME1) was determined. Rescue experiments with acetate, malate, and NADPH were performed to investigate the functional contribution of the ACLY–ME1 metabolic axis. Results: PWE significantly reduced NF-κB activation and the production of IL-1β, IL-6, TNF-α, ROS, NO•, and PGE₂ without affecting cell viability. Mechanistically, PWE functionally suppressed ACLY and ME1, two central enzymes linking citrate metabolism to cytosolic acetyl-CoA and NADPH generation. Indeed, acetate supplementation restored PGE₂ production and inflammatory cytokine secretion, whereas malate and NADPH rescued oxidative mediator production. PWE also lowered histone H3 acetylation, indicating that metabolic remodeling affected epigenetic regulation of inflammatory gene expression. Finally, PWE increased the expression of CPT1A, SLC25A20, Annexin A1, and FPR2, while enhancing IL-10 and 15-HETE secretion, consistent with activation of pro-resolving macrophage programs. Conclusions: These findings demonstrate that DMC-extracted PWE suppresses inflammatory macrophage activation primarily through immunometabolic modulation. By targeting the ACLY–ME1 metabolic axis, PWE limits acetyl-CoA- and NADPH-dependent inflammatory processes and fosters a shift toward a pro-resolving macrophage phenotype. Our work identifies this sustainable pomegranate waste extract as a promising modulator of macrophage immunometabolism. Full article