Search Results (37,187)

Background: Isorhamnetin (ISO), a dietary O-methylated flavonol, was evaluated for hypoglycemic activity and mechanism in a streptozotocin (STZ) model of type 1 diabetes. Methods: We conducted untargeted plasma metabolomics (ESI±), network integration and docking, and measured pancreatic PI3K, phosphorylated AKT, and COX-2; INS-1 β cells challenged with the PI3K inhibitor LY294002 were used to assess viability, intracellular ROS, and PI3K phosphorylation. Results: ISO lowered fasting glycemia, increased circulating insulin, improved dyslipidemia by reducing low-density lipoprotein cholesterol (LDL-C), and preserved islet architecture. Untargeted plasma metabolomics (ESI±) indicated broad remodeling with enrichment of arachidonic-, linoleic-, starch/sucrose- and glycerophospholipid pathways. Network integration and docking prioritized targets converging on PI3K/AKT and COX-2/eicosanoid signaling. Consistently, in pancreatic tissue, ISO increased PI3K, phosphorylated AKT, and reduced COX-2. In INS-1 beta cells challenged with the PI3K inhibitor LY294002, ISO improved viability, decreased intracellular ROS, and partially restored PI3K phosphorylation at 4 µM. Conclusions: Together, these data indicate that ISO exerts hypoglycemic effects while supporting β-cell integrity through activation of PI3K/AKT and tempering of COX-2–linked lipid-mediator pathways. ISO therefore emerges as a food-derived adjunct candidate for autoimmune diabetes, and the work motivates targeted lipidomics and in vivo pathway interrogation in future studies. Full article

MicroRNA-22 (miR-22) is a negative regulator of mitochondrial biogenesis, as well as lipid and glucose metabolism, in metabolically active tissues. Silencing miR-22 holds promise as a potential treatment of obesity and metabolic syndrome, as it restores metabolic capacity—enhancing oxidative metabolism—and reduces ectopic fat accumulation in chronic obesity, a driver of impaired metabolic flexibility and muscle mass loss. Intramuscular adipose accumulation and defective mitochondrial function are features associated with obese-mediated muscle atrophy and hallmarks of neuromuscular disorders such as Duchenne muscular dystrophy. Therefore, miR-22 could represent a compelling molecular target to improve muscle health across various muscle-wasting conditions. This study describes a pharmacological strategy for the inhibition of miR-22 in skeletal muscle by employing a mixmer antisense oligonucleotide (ASO, anti-miR-22). Administration of the ASO in a mouse model of obesity positively modulated myogenesis while protecting dystrophic mice from muscle function decline, enhancing fatigue resistance, and limiting pathological fibrotic remodeling. Mechanistically, we show that anti-miR-22 treatment promotes derepression of genes involved in mitochondrial homeostasis, favoring oxidative fiber content regardless of the disease model, thus promoting a more resilient phenotype. Furthermore, we suggest that miR-22 inhibition increases autophagy by transcriptional activation of multiple negative regulators of mammalian target of rapamycin (mTOR) signaling to decrease immune infiltration and fibrosis. These findings position miR-22 as a promising therapeutic target for muscle atrophy and support its potential to restore muscle health. Full article

The plasma membrane (PM) of eukaryotic cells plays a key role in the response to stress, acting as the first line of defense against environmental changes and protecting cells against intracellular perturbations. In this work, we explore how membrane-bound chaperones and membrane lipid domains work together to shape plasma membrane properties—a partnership we refer to as the “epichaperome–plasma membrane lipid axis.” This axis influences membrane fluidity, curvature, and domain organization, which in turn shapes the spatial and temporal modulation of signaling platforms and pathways essential for maintaining cellular integrity and homeostasis. Changes in PM fluidity can modulate the activity of ion channels, such as transient receptor potential (TRP) channels. These changes also affect processes such as endocytosis and mechanical signal transduction. The PM proteome undergoes rapid changes in response to membrane perturbations. Among these changes, the expression of heat shock proteins (HSPs) and their accumulation at the PM are essential mediators in regulating the physical state and functional properties of the membrane. Because of the pivotal role in stress adaptation, HSPs influence a wide range of cellular processes, which we grouped into three main categories: (i) mechanistic insights, differentiating in vitro (liposome, reconstituted membrane systems) and in vivo evidence for HSP-PM recruitment; (ii) functional outputs, spanning how ion channels are affected, changes in membrane fluidity, transcytosis, and the process of endocytosis and exosome release; and (iii) pathological effects, focusing on how rewired lipid–chaperone crosstalk in cancer drives resistance to drugs through altered membrane composition and signaling. Finally, we highlight Membrane Lipid Therapy (MLT) strategies, such as nanocarriers targeting specific PM compartments or small molecules that inhibit HSP recruitment, as promising approaches to modulate the functional stability of epichaperome assembly and membrane functionality, with profound implications for tumorigenesis. Full article

Ginsenosides, the primary bioactive components of Panax ginseng, have demonstrated significant immunomodulatory potential. While major ginsenosides have been extensively studied, rare ginsenosides produced through deglycosylation, heating, and steaming show enhanced biological activities with improved bioavailability. This review aimed to comprehensively analyze the immunomodulatory mechanisms, structure-activity relationships (SARs), therapeutic applications, and clinical translation strategies of five emerging rare ginsenosides: F1, Rg5, Rk1, Rh1, and Rg2. We conducted a comprehensive literature review examining the production methods, immunological effects, molecular mechanisms, pharmacokinetics, safety profiles, and clinical applications of these five compounds. Analysis focused on chemical structures, immune cell modulation, signaling pathways, disease model efficacy, and bioavailability enhancement strategies. Ginsenoside F1 uniquely demonstrated immunostimulatory effects, enhancing natural killer (NK) cell cytotoxicity and macrophage phagocytosis through mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) activation. Conversely, Rg5, Rk1, Rh1, and Rg2 exhibited anti-inflammatory properties via distinct mechanisms: Rg5 through Toll-like receptor 4 (TLR4)/NF-κB inhibition, Rk1 via triple pathway modulation (NF-κB, p38 MAPK, signal transducer and activator of transcription (STAT)), Rh1 by selective p38 MAPK and STAT1 inhibition, and Rg2 through modulation of both central nervous system (neuroinflammation) and peripheral organ systems. Structure-activity analysis revealed that sugar moiety positions critically determine immunological outcomes. Crucially, advanced delivery systems including nanostructured lipid carriers, self-microemulsifying systems, and specialized liposomes have overcome the major translational barrier of poor bioavailability, achieving up to 2.6-fold improvements and enabling clinical development. Safety assessments demonstrated favorable tolerability profiles across preclinical and clinical studies. These five rare ginsenosides represent promising immunomodulatory agents with distinct therapeutic applications. F1’s unique immunostimulatory properties position it for cancer immunotherapy, while the complementary anti-inflammatory mechanisms of Rg5, Rk1, Rh1, and Rg2 offer opportunities for precision medicine in inflammatory diseases. Advanced formulation technologies and optimized production methods now enable their significant clinical translation potential, providing promising therapeutic options for immune-related disorders pending further development. Full article

The morphological traits of Vaccinium uliginosum L., including plant height, leaf area, and fruit weight, have changed significantly across an elevational gradient in the Changbai Mountains. To elucidate the molecular mechanisms underlying these morphological variations, RNA-Seq technology was employed to identify differentially expressed genes (DEGs), key metabolic pathways, and associated biological functions of V. uliginosum at seven elevations in the Changbai Mountains. A total of 1190 DEGs significantly associated with morphological variations were identified. These genes are mainly involved in lipid synthesis, carbohydrate metabolism, energy metabolism, and signal transduction. Redundancy analysis (RDA) revealed that fatty acyl-ACP thioesterase B (FATB) and ribulose-bisphosphate carboxylase small subunit (cbbS) exhibited a significant association with morphological variation. Integrated analysis indicated that high-altitude plants likely enhance lipid synthesis and cell wall stability while also inhibiting photosynthesis and carbohydrate metabolism. The regulatory mechanisms underlying hormone signal transduction may be relatively complex, as evidenced by the enhanced activity of gibberellin and reduced biological effects of auxin, abscisic acid, and ethylene. This study is the first to provide transcriptomic evidence elucidating the genetic basis of altitudinal morphological adaptation in V. uliginosum, integrating phenotypic traits with gene expression profiles across an elevational gradient. Full article

Metabolic syndrome (MetS) is a complex condition characterized by a group of interconnected metabolic abnormalities. Due to its increasing prevalence, better predictive markers are needed. Therefore, this study aims to develop predictive models for MetS by integrating adipokines, metabolic and cardiovascular risk factors, and anthropometric indices. Data were collected from 381 subjects aged 20 to 59 years (242 women and 139 men) from Guadalajara, Jalisco, Mexico, who were classified as having MetS or non-MetS based on the ATP-III criteria. Four supervised machine learning models were developed—Logistic Regression (LR), Support Vector Machine (SVM), Random Forest (RF), and eXtreme Gradient Boosting (XGBoost)—and their performance was evaluated using the Area under the Curve (AUC), calibration curves, Decision Curve Analysis (DCA), and local interpretability analysis. The RF and XGBoost models achieved the highest AUCs (0.940 and 0.954). The RF and LR models were the best calibrated and showed the highest net benefit in DCA. Key variables included age, anthropometric indices (BRI and DAI), insulin resistance measures (HOMA-IR), lipid profiles (sdLDL-C and LDL-C), and high-molecular-weight adiponectin, used to classify the presence of MetS. The results highlight the usefulness of specific models and the importance of anthropometric variables, cardiovascular risk factors, metabolic profiles, and adiponectin as indicators of MetS. Full article

Ferroptosis, an iron-dependent form of regulated cell death marked by lipid peroxidation, has emerged as a promising therapeutic target in breast cancer, particularly in aggressive subtypes such as triple-negative breast cancer (TNBC). This systematic review explores the molecular mechanisms underlying ferroptosis sensitivity and resistance, focusing on the interplay between iron metabolism, antioxidant defenses, and tumor microenvironmental factors. Literature retrieved from PubMed and Scopus up to May was analyzed in accordance with PRISMA guidelines, including mechanistic studies, preclinical experiments, and ongoing clinical trials. Findings reveal that breast cancer cells evade ferroptosis through enhanced glutathione synthesis, upregulation of GPX4 and system Xc- and adaptive metabolic reprogramming; yet these same mechanisms create exploitable vulnerabilities, including dependence on cystine, polyunsaturated lipids, and dysregulated iron handling. Therapeutic strategies that target key ferroptosis regulators, such as GPX4, ACSL4, and SLC7A11, or that harness agents like statins, sulfasalazine, and nanoparticle-based iron complexes demonstrate strong potential to overcome chemoresistance and selectively eliminate therapy-resistant cancer cell populations. Taken together, the evidence highlights ferroptosis as a critical Achilles’ heel of breast cancer biology and supports further clinical translation of ferroptosis-inducing therapies to improve outcomes in otherwise refractory breast cancer subtypes. Full article

L-fucose is a monosaccharide derived from brown algae and has potential applications as a functional food ingredient. Previous studies have reported that L-fucose reduces lipid accumulation in murine adipose tissue. Adipose tissue not only regulates energy metabolism but also functions as an endocrine organ involved in inflammation through the production and secretion of various adipokines. L-fucose is expected to exert anti-inflammatory effects and modulate adipokine secretion in adipocytes. In the present study, we investigated the anti-inflammatory effects of L-fucose in adipocytes. L-fucose significantly suppressed the expression of pro-inflammatory mediators and reduced the production of reactive oxygen species induced by inflammatory stimulation with a combination of lipopolysaccharide (LPS), tumor necrosis factor-⍺ (TNF-⍺), and interferon-γ (IFN-γ). These effects are likely mediated through the inhibition of key signaling pathways, including mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways. Additionally, we found that L-fucose promoted the multimerization and secretion of high molecular weight (HMW) adiponectin, even under inflammatory conditions. Our results suggest that although L-fucose downregulates adiponectin expression, it contributes to the formation and/or stabilization of HMW adiponectin, which is functionally more relevant in anti-inflammatory and metabolic regulation. L-fucose thus holds promise as a functional food ingredient for mitigating inflammation in adipocytes. Full article

Previous research has demonstrated that the transient bilateral common carotid artery occlusion and reperfusion (BCCAO/R) effectively models early brain inflammation resulting from sudden hypoperfusion and subsequent reperfusion. According to studies showing that diet and nutrition strongly influence brain neuroplasticity, in this study we evaluated whether kaempferol (KAM), a dietary flavonoid, offers neuroprotection in a rat BCCAO/R model. Adult Wistar rats were gavage fed a single dose of KAM (40 mg) six hours before surgery. Comprehensive lipidomic and molecular analyses were conducted on samples from the frontal and temporal-occipital cortices, as well as the plasma. In the frontal cortex, KAM elevated anti-inflammatory N-acylethanolamines palmitoylethanolamide (PEA), oleoylethanolamide (OEA), and docosahexaenoylethanolamide (DHAEA) and reduced oxidized arachidonic acid metabolites. KAM also downregulated cyclooxygenase- 2 (COX-2) protein and selectively decreased the endocannabinoid 2-arachidonoylglycerol (2-AG), showing a shift in AA metabolism. These molecular changes correlated with increased levels of peroxisome proliferator-activated receptor alpha (PPARα) and cannabinoid receptors CB1R and CB2R, supporting activation of both nuclear and membrane-bound anti-inflammatory pathways. No significant changes were observed in the temporal-occipital cortex. In plasma, DHAEA levels increased similarly to those in the cortex. However, rises in PEA and OEA were detected only in sham-operated KAM-treated animals, suggesting possible central redistribution under hypoperfusion/reperfusion stress. In summary, these findings demonstrate that KAM exerts dual anti-inflammatory effects by inhibiting COX-2-mediated prostanoid synthesis and promoting PPARα-driven lipid signaling. This dual mechanism highlights the potential of KAM as a dietary intervention to reduce neuroinflammation associated with hypoperfusion–reperfusion challenges. Full article

This study investigated the effects of a dietary additive composed of compounds derived from essential oils (carvacrol, eugenol, cinnamaldehyde), capsaicin, and yeast metabolites on the performance, body composition, metabolism, and immune status of pigs under chronic heat stress (HS). A total of 24 crossbred gilts (50 ± 3.98 kg) were assigned to one of two diets: a control diet (CON) or the same diet supplemented with the additive blend (2.5 g/kg; BLEND). Animals were housed collectively, with individual feed intake recorded using automatic precision feeders over a 56-day period at a constant ambient temperature of 35 °C. Heat stress increased rectal temperature initially (p < 0.01), which gradually declined over time. No significant differences were found in overall performance or tissue deposition between treatments (p > 0.05), though pigs fed the BLEND diet tended to have an 18% lower fat deposition compared with the CON group (148.3 vs. 121.3 g/d, p = 0.094). The additive had no effect on inflammatory or most biochemical parameters, except for increased creatinine compared with the CON group (1.76 vs. 1.63 mg/dL; p = 0.032) and a tendency for elevated LDH (1064.87 vs. 939.17 U/L; p = 0.075). In conclusion, chronic HS impaired metabolic and immune parameters and altered body composition. The dietary blend did not enhance performance but showed a tendency to reduce lipid deposition under thermal stress conditions. Further studies are needed to elucidate the individual and combined actions of this feed additive in mitigating the impacts of HS on pigs. Full article

Cannabidiol (CBD) and its derivatives show interesting therapeutic potential, including antioxidant, anti-inflammatory, and anticancer properties; however, their clinical translation remains a complex task due to physicochemical restrictions such as low water solubility, high lipophilicity, and instability under light, oxygen, and high temperatures. Polymeric encapsulation has emerged as a promising strategy to overcome these challenges, offering protection against environmental degradation, improved bioavailability, and controlled release. Natural and synthetic polymers, both biocompatible and biodegradable, provide versatile matrices for CBD delivery, enabling nanoparticle formation, targeted transport, and enhanced pharmacokinetics. This review highlights the structural characteristics of CBD, its interaction mechanisms with polymeric matrices such as hydrogels, electrospun nanofibers, biodegradable microparticles, thin films, and lipid-polymer hybrid systems, and the principal encapsulation techniques, such as emulsion solvent evaporation, electrospinning, and supercritical fluid technologies, that facilitate stability and scalability. Furthermore, material characterization approaches, including microscopy, thermal, and degradation analyses, are discussed as tools for optimizing encapsulation systems. While notable advances have been made, key challenges remain in achieving reproducible large-scale production, ensuring regulatory compliance, and designing smart polymeric carriers personalized for specific therapeutic contexts. By addressing these gaps, polymer-based encapsulation may unlock new opportunities for CBD in pharmaceutical, nutraceutical, and therapeutic applications, providing a guide for future innovation and translation into effective patient-centered products. Full article

Background: Cardiovascular disease (CVD) is a major complication of systemic lupus erythematosus (SLE). This study compared several CV risk scores in Korean female patients with SLE and searched for an association with subclinical atherosclerosis and lipid metabolism. Methods: Female SLE patients and healthy controls (HCs) underwent carotid ultrasonography and pulse wave velocity (PWV), and serum efflux cholesterol capacity was measured. The Framingham risk scores (FRSs), American College of Cardiology/American Heart Association (ACC/AHA) scores, and Korean Risk Prediction Model (KRPM) scores were calculated. Results: While carotid intima-media thickness (IMT) and the prevalence of carotid plaque did not differ between 67 SLE patients and 37 HCs, carotid plaque scores were higher in SLE patients compared with HCs. While the FRS and the ACC/AHA CV risk scores did not differ, the KRPM scores were higher in SLE patients. The carotid IMT, plaque score, and PWV were correlated with the FRS, ACC/AHA CV risk, and KRPM score in SLE patients. SLE patients with carotid plaque had higher FRS, ACC/AHA CV risk, and KRPM scores than those without carotid plaque. In addition, the serum cholesterol efflux capacity did not differ between SLE patients with and without carotid plaque but was correlated with carotid IMT. Conclusions: The scores obtained from the CV risk-prediction models were correlated with subclinical atherosclerosis in SLE. A cardiovascular risk assessment tool developed specifically for Koreans is suitable for evaluating the CV risk in Korean SLE patients. Full article

α-Linolenic acid (ALA) is an important essential omega-3 (ω-3) polyunsaturated fatty acid for the maintenance of human health. Although ALA has traditionally been obtained from plant sources, microbial fermentation has emerged as a promising alternative for its sustainable and cost-effective production. However, most of the present approaches rely on genetically modified organisms, which present regulatory and consumer-acceptance concerns. In this study, we aimed to develop a high-ALA-producing strain of Aspergillus oryzae, a Generally Recognized As Safe (GRAS) microorganism widely used in food production in Japan, through self-cloning, a form of genetic engineering that utilizes only the host’s own DNA. To achieve this, an endogenous ω-3 desaturase gene (fad3), which catalyzes the conversion of linoleic acid to ALA, was identified via BLASTP analysis. Subsequently, a multicopy A. oryzae strain (Aofad3-MC) overexpressing fad3 was constructed. This strain increased ALA production, with ALA comprising 30.7% of the total lipids. Furthermore, k-mer analysis confirmed the absence of foreign vector sequences, verifying that Aofad3-MC was constructed through self-cloning. In addition to the identification of the A. oryzae ω-3 desaturase gene, this study provides a microbial platform for the sustainable production of ALA, with potential applications across the food, feed, and related industries. Full article

Background and Objectives: Avian influenza poses a continuous public health threat, particularly to individuals with occupational exposure to poultry such as farm workers, live animal market employees, and processing plant staff. This study aimed to investigate the systemic metabolic effects of such exposure and to identify potential biomarkers for early detection and health risk assessment. Materials and Methods: An untargeted liquid chromatography–mass spectrometry (LC-MS)-based metabolomics approach was applied to analyze serum samples from occupationally exposed individuals and healthy controls. Multivariate statistical analysis, pathway enrichment, and topology analysis were performed to identify significantly altered metabolites and metabolic pathways. The least absolute shrinkage and selection operator (LASSO) algorithm was employed to select key metabolites. Results: Multivariate statistical analysis revealed a clear separation between the exposure group and control, suggesting distinct metabolic profiles between the two populations. Pathway analysis indicated significant alterations in alanine, aspartate, and glutamate metabolism, as well as tryptophan metabolism, which are closely linked to immune regulation, energy metabolism, and host–pathogen interactions. LASSO feature selection and subsequent manual verification identified 17 key metabolites with strong discriminative power. Furthermore, lipidomic profiling revealed a pronounced increase in lysophosphatidylcholine (LPC) levels and a concurrent decrease in phosphatidylcholine (PC) species in exposed individuals. Conclusions: This study reveals metabolic disruptions associated with occupational avian influenza exposure and identifies potential serum biomarkers related to immune and lipid metabolism. These findings provide novel insights into host responses to avian influenza exposure and may support early detection and health risk assessment in high-risk occupational populations. Full article

Background/Objectives: CLIFAHDD syndrome (OMIM # 616266) is a rare neurodevelopmental disorder caused by mutations in the NALCN gene. It is characterized by hypotonia, developmental delay, and congenital contractures of the limbs and face. We report a 33-year-old Italian woman with a mild form of CLIFAHDD who exhibited early-onset language difficulties and mild intellectual disability and later developed gait and balance impairments in adulthood. Methods and Results: Whole Exome Sequencing (WES) identified a novel missense variant c.1514A>T; p.(Lys505Met) in the NALCN gene. The allele frequency of this variant is not detected (MAF = 0.0), the variant is classified as likely pathogenic according to ACMG criteria, and predicted to be probably damaging by PolyPhen-2. It affects a critical residue within the second pore-forming domain of the NALCN channel, potentially altering lipid interactions and channel regulation. Sanger sequencing and segregation analysis confirmed the variant to be heterozygous and de novo. Conclusions: The patient’s milder symptoms and later onset, compared to severe pediatric cases, suggest that the clinical spectrum of CLIFAHDD syndrome may be broader than previously recognized. These findings underscore the potential influence of mutation location on disease presentation and severity. Full article