Search Results (537)

Background/Objectives: Metabolic syndrome (MetS) is a pressing global health challenge comprising obesity, hyperglycemia, hypertension, and hyperlipidemia. Conventional polypharmacy often presents long-term compliance issues and side effects. Eucommia ulmoides Oliv., a traditional medicinal and edible plant rich in iridoids, lignans, flavonoids, and polysaccharides, has emerged as a promising natural intervention. This review aims to systematically summarize the bioavailability and multifaceted pharmacological mechanisms of E. ulmoides and its bioactive components in alleviating MetS. Methods: We comprehensively reviewed the recent in vitro and in vivo literature to map the functional evidence, specific signaling pathways, and gut microbiota–host interactions associated with E. ulmoides extracts and its key phytochemicals (e.g., asperuloside) against various metabolic dysfunctions. Results: Current evidence indicates that E. ulmoides operates through a “multi-component, multi-target, and multi-pathway” paradigm. For hyperlipidemia and obesity, it activates hepatic lipid metabolism (PPARα/CPT1A, FXR/CYP7A1) and mitigates oxidative stress (Nrf2/ARE). Furthermore, it dose-dependently reshapes the gut microbiota by enriching beneficial bacteria like Akkermansia and increasing butyrate production, exerting profound gut–liver axis regulation. It also ameliorates hypertension by activating the ACE2-Ang-(1–7)-Mas axis, improves insulin resistance via the AMPK/PI3K/Akt cascade, and manages hyperuricemia by modulating XOD and renal transporters. Notably, the low oral bioavailability of its glycosides highlights the crucial role of gut microbial hydrolysis in its efficacy. Conclusions: E. ulmoides holds substantial therapeutic potential as a multi-target natural supplement for MetS. However, future translational applications necessitate large-scale randomized clinical trials, multi-omics studies to further clarify host–microbiome interactions, and the development of standardized formulations to ensure clinical efficacy. Full article

Background: GDF15 (growth/differentiation factor-15) is part of the transforming growth factor-beta family and represents a cellular stress-induced gene. It might have a role in metaflammation and adipoflammation. We aimed to investigate the effects of Toll-like receptor (TLR) activation and hypoxia-related pathways together with metabolic factors on GDF15 regulation in adipocytes and adipose tissue (AT). Methods: GDF15 mRNA quantities in the human adipocyte cell line SGBS, in visceral (VAT) and subcutaneous adipose tissue (SAT) (resected from n = 96 obese and characterized patients), and in murine 3T3-L1 adipocytes were measured by real-time RT-PCR. GDF15 protein concentrations in cell supernatants and serum were quantified by ELISA. The following stimuli/pathways were investigated: insulin, glucose, TLR ligands (TLR2/6, TLR3, TLR4, TLR7, TLR9), bile acids, synthetic FXR/TGR5 activators, and HIF1α activators. Results: Basal GDF15 expression is low and only marginally induced in SGBS cells. In contrast, GDF15 is expressed in human SAT and VAT and correlates positively with the corresponding GDF15 protein concentration in peripheral blood serum of obese patients. Among metabolic factors, insulin and bile acids such as ursodeoxycholic acid upregulate GDF15 expression in 3T3-L1 adipocytes, the latter via FXR but not via TGR5. Among innate immune regulators, only TLR7 activation and hypoxic mediators upregulate whereas STAT3 signaling downregulates GDF15. Conclusion: GDF15 expression in human SAT and VAT is correlated to peripheral blood GDF15 concentrations and is regulated by metabolic and innate immune response pathways involved in AT inflammation and metaflammation. Full article

Adolescence is a developmental stage marked by dynamic interactions between diet, the gut microbiome and endocrine maturation, creating a physiological environment in which early metabolic disturbances can rapidly translate into long-term cardiovascular vulnerability. This narrative review summarises the latest research on the diet–microbiome–hormone axis in adolescents, focusing on the metabolic pathways through which microbial metabolites influence host physiology. Short-chain fatty acids (SCFAs), microbially transformed bile acids and postbiotic signalling molecules regulate enteroendocrine communication, insulin sensitivity, vascular function and inflammatory tone, thereby linking dietary exposures to early cardiometabolic alterations. Dysbiosis, driven by ultra-processed dietary patterns, low fibre intake and reduced microbial diversity, promotes metabolic endotoxemia, neuroendocrine imbalance and endothelial impairment, all of which are recognised as early indicators of cardiovascular disease. A distinctive contribution of this review is the integration of PF into the adolescent cardiometabolic framework. This emerging biotechnological process enables the controlled production of structurally defined bioactive compounds, including angiotensin-converting enzyme (ACE) inhibitory peptides, targeted prebiotic oligosaccharides, fermentable substrates that promote SCFA formation, microbially derived eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), phytosterols and purified postbiotics. These compounds modulate several regulatory pathways, such as the renin–angiotensin–aldosterone system, lipid and bile acid metabolism, gut barrier stability, inflammatory signalling and endocrine axes involving glucagon-like peptide-1 (GLP-1), peptide YY (PYY), leptin, insulin sensitivity and growth hormone/insulin-like growth factor-1 (GH/IGF-1) dynamics. By situating precision fermentation within the broader context of adolescent metabolic susceptibility, this review highlights its potential to support microbiome resilience, stabilise hormonal regulation and mitigate early cardiovascular risk. However, further adolescent-specific clinical trials and long-term safety assessments are required to translate these advances into effective public health strategies. Full article

Sudden cardiac death (SCD) in athletes often represents the first manifestation of an underlying inherited cardiovascular disorder exposed by adrenergic stress, altered calcium cycling, mechanical loading, and metabolic demand during intense exercise. This review focuses on the molecular architecture that links genotype to arrhythmogenic phenotype in athletes, emphasizing sarcomeric force generation and energetic inefficiency in hypertrophic cardiomyopathy, desmosomal failure and Hippo/Wnt/transforming growth factor-beta (TGF-β) signaling in arrhythmogenic cardiomyopathy, and ion-channel and calcium/calmodulin-dependent protein kinase II (CaMKII)calcium handling abnormalities in inherited channelopathies. This review further examines how exercise-induced physiological remodeling intersects with these pathways through insulin-like growth factor-1 (IGF-1)/phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) signaling, mitochondrial biogenesis, oxidative stress, inflammatory signaling, and epigenetic regulation. Attention is given to the molecular basis of genotype-positive/phenotype-negative states, variable penetrance, and exercise-mediated disease expression. Finally, the integration of molecular biology with genomic data, polygenic risk, and emerging digital phenotyping is discussed to refine mechanism-based risk stratification and identify future therapeutic targets for prevention of SCD in athletes. Full article

Background: Esophageal squamous cell carcinoma (ESCA) represents one of the most common aggressive malignancies worldwide. Insulin-like growth factor binding protein 1 (IGFBP1), a typical member of the IGF superfamily, is closely linked to adverse prognosis in numerous cancers. Up to now, little is known about its functional relevance to cell migration and tumor progression in ESCA. This work focuses on clarifying the relationship between IGFBP1 expression and the progression and migratory characteristics of ESCA. Methods: mRNA expression profiles from ESCA patients were obtained from the TCGA and GEO databases. Differential expression analysis was performed using R software(version 4.2.2), followed by an intersection of DEGs between datasets. The STRING database was applied to establish PPI networks. Cytoscape software(Version 3.7.2) was then used for visual presentation and hub gene identification. IGFBP1 expression was validated in ESCA tissues versus adjacent normal tissues. Prognostic correlation was assessed using GEPIA, while diagnostic and predictive values were evaluated through ROC analysis and Cox regression. Genetic alterations of IGFBP1 were analyzed via cBioPortal. Immune cell infiltration patterns were investigated using TIMER. Functional enrichment analyses (GO, KEGG) were performed on IGFBP1-associated DEGs. In the in vitro experiments, esophageal cancer cell lines (such as Eca109 and TE-1) and normal human esophageal epithelial cell lines (such as HEEC) were selected. The transcriptional level of IGFBP1 was examined using RT-qPCR, while Western blot analysis was conducted to validate its protein expression changes. Changes in the proliferative capacity of cancer cells after IGFBP1 silencing were detected by the CCK-8 assay, and cell migration capacity was determined via wound scratch assays to clarify the related biological effects. Results: Overall, 2870 DEGs were screened from the GEO database, 153 DEGs were screened from the TCGA database, and 34 genes were found to be common to both databases; 10 core genes were screened from the PPI network. IGFBP1 was abnormally expressed in esophageal cancer. Cox regression confirmed that IGFBP1 is an independent risk factor, and prognostic analysis indicated that IGFBP1 is closely associated with poor prognosis. Gene mutation analysis showed that amplification mutations are the most common type of IGFBP1 gene mutation, and genetic alterations in IGFBP1 in ESCA patients are significantly associated with overall survival (OS) (p = 0.0002568). GO analysis indicated that IGFBP1-related differentially expressed genes were enriched in organic anion transport, epidermal development, apical cell components, and metal ion transmembrane transporter activity. Pathway enrichment based on the KEGG database illustrated the main enrichment of target genes in neuroactive ligand–receptor interactions, calcium signaling and cAMP signaling pathways. Additionally, remarkable differences in immune cell infiltration were observed between IGFBP1 high-expression and low-expression subgroups through tumor immune profiling. IGFBP1 expression differed significantly between esophageal cancer cells and normal esophageal epithelial cells, as detected by RT-qPCR (p < 0.05). Moreover, knockdown of IGFBP1 markedly inhibited the proliferation (p < 0.05) and migration abilities (p < 0.05) of TE-1 and Eca109 cells. Conversely, IGFBP1 overexpression facilitated these cellular processes. Conclusions: As a key oncogenic driver for ESCA, IGFBP1 may participate in the oncogenesis of ESCA, possibly influencing clinical outcomes via IGF signaling and the tumor microenvironment. Its dual functions in tumor and immune systems suggest it might be a candidate for ESCA immunotherapy research. Full article

Background: Dietary protein optimization is an important nutritional strategy for improving growth and physiological responses, and antioxidant homeostasis in fish. Methods: In this study, 540 black carp (initial body weight: 10.50 ± 1.00 g) were randomly assigned into recirculating tanks (500 L) fed with six dietary protein levels (30–44% crude protein) for an 8-week feeding trial with triplicates per treatment and 30 fish per replicate. After the trial, fish body, blood, hepatopancreas, and intestinal samples were collected for body composition, serum biochemical parameters, metabolism, and antioxidant indices’ analyses. Results: Results showed fish fed 38% protein (PT38) exhibited the highest weight gain (p < 0.05), with no further improvement at higher protein levels. Compared with PT30 group, PT38 group significantly promoted protein deposition by upregulating transcript levels of insulin-like growth factors (IGFs) via activating mechanistic target of rapamycin (mTOR) signaling pathway. PT38 could improve fatty acid oxidation by heightening levels of carnitine palmitoyl transferase 1α (CPT1α), peroxisome proliferator-activated receptor α (PPARα) and PPARδ. Meanwhile, PT38-PT41 significantly inhibit expression of fatty acid synthesis and lipid droplet deposition-related genes, including acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and perilipin 2 (p < 0.05). PT38 significantly enhanced antioxidant homeostasis by increasing levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) via activating nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Conclusions: Overall, Under the current experimental conditions, 38% dietary protein is suitable for promoting growth performance, improving protein and lipid metabolism, and enhancing antioxidant homeostasis in black carp. Full article

The renin–angiotensin system (RAS) regulates inflammation, tissue homeostasis, and barrier integrity in lung and colon epithelial cells. Beyond classical pathways, non-canonical components including angiotensin-converting enzyme 2 (ACE2), epidermal growth factor receptor (EGFR), insulin-like growth factor 2 receptor (IGF2R) and aminopeptidase N (ANPEP) are implicated in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and bacterial sepsis due to their roles in tissue repair and signaling. Despite their similar inflammatory and coagulopathic features, their impact on RAS-associated non-immune gene expression in epithelial tissues remains unclear. This study investigates the regulation of these targets in lung (BEAS-2B) and colon (CRL-1831) cells following exposure to recombinant SARS-CoV-2 spike protein N-terminal domain fragment (S1-NTD) and Pseudomonas aeruginosa-derived lipopolysaccharide (LPS). Cells were treated with 100 ng/mL of S1-NTD or LPS for 12–72 h. Viability was assessed via XTT assays, and molecular changes were analyzed through qRT-PCR and Western blotting. Both stimuli induced a time and dose-dependent decrease in metabolic activity. ACE2 was significantly downregulated in lung cells, while transient upregulation occurred in colon cells at 24 h. EGFR expression increased in colon cells following LPS exposure but decreased in lung cells after S1-NTD treatment. Both IGF2R and ANPEP were upregulated by S1-NTD in lung cells at 72 h, whereas colon cells showed earlier upregulation at 24–48 h. Our findings reveal that viral and bacterial stimuli elicit distinct, tissue-specific regulatory patterns in RAS-associated pathways. These alterations may contribute to epithelial barrier dysfunction and inflammation, highlighting these proteins as potential targets for managing secondary bacterial infections and inflammatory lung–gut complications in COVID-19. Full article

Breast cancer remains the most frequently diagnosed malignancy among women worldwide, while metabolic dysfunction-associated steatotic liver disease (MASLD) represents the leading cause of chronic liver disease, reflecting a global burden of metabolic dysfunction. Increasing evidence suggests that MASLD is associated with breast cancer development and progression; however, whether this relationship reflects an independent effect of hepatic metabolic dysfunction or the broader metabolic environment remains uncertain. This review synthesizes current epidemiological, clinical, and mechanistic data linking hepatic metabolic dysfunction to breast carcinogenesis. Population-based studies consistently demonstrate an association between hepatic steatosis and increased breast cancer incidence, particularly in postmenopausal and metabolically vulnerable populations, as well as poorer oncological outcomes. Mechanistically, MASLD promotes a systemic pro-tumorigenic environment through interconnected pathways, including insulin resistance, hormonal dysregulation with increased estrogen bioavailability, chronic inflammation, oxidative stress, lipid metabolic reprogramming, and gut–liver axis disruption. Hepatokines, particularly fibroblast growth factor 21 (FGF21), emerge as key mediators of tumor progression and potential biomarkers of metabolic vulnerability, while Fetuin-A and angiopoietin-like protein 8 (ANGPTL8) further support the liver’s endocrine role in oncogenic signaling. Preclinical evidence highlights fatty acid oxidation as a metabolic dependency in aggressive breast cancer subtypes, suggesting novel therapeutic targets. Despite consistent associations, causality remains unproven. Future prospective studies are needed to determine whether targeting metabolic dysfunction can improve breast cancer prevention and outcomes. Full article

Cardiometabolic diseases are increasingly recognized as disorders of chronic low-grade systemic inflammation and gut barrier dysfunction that mutually reinforce one another. Each condition amplifies the other through progressive injury to the intestinal epithelium. Compromise of the mucus layer, altered tight junction dynamics, dysbiosis, and impaired epithelial restitution promote intestinal permeability and enable the translocation of lipopolysaccharide and other microbial products into the circulation, thereby inducing metabolic endotoxemia. This gut derived inflammatory signal activates Toll like receptor 4, nuclear factor kappa B, and inflammasome associated pathways, linking barrier dysfunction to insulin resistance, hepatic steatosis, adipose tissue inflammation, endothelial activation, and vascular injury. Here, we examine the gut barrier as an immunometabolic interface and synthesize current evidence connecting its disruption to endotoxin driven cardiometabolic pathology. We further evaluate selected natural bioactive compounds, including curcumin, resveratrol, quercetin, epigallocatechin gallate, berberine, anthocyanins, omega 3 polyunsaturated fatty acids, and dietary polysaccharides, as gut targeted interventions capable of reinforcing junctional integrity, restoring mucus and microbial homeostasis, lowering endotoxin burden, and attenuating inflammatory signaling. Finally, we highlight the principal translational barriers that currently limit clinical implementation, including pharmacokinetic variability, microbiota dependent biotransformation, source standardization, and the lack of robust, standardized biomarkers of barrier restoration and metabolic endotoxemia. Full article

Gestational diabetes mellitus (GDM) is increasingly recognized as a complex pathology rooted in systemic and organelle-level dysfunction, specifically involving chronic low-grade inflammation (CLGI), mitochondrial impairment, and endoplasmic reticulum (ER) stress. Central to this pathophysiology is mitochondrial dysfunction, characterized by reduced respiration, impaired metabolic flexibility, and dysregulated fission/fusion machinery, which fuels a self-perpetuating cycle of reactive oxygen species (ROS) production. Concurrently, chronic ER stress triggered by hyperglycemia and lipotoxicity activates the unfolded protein response (UPR), further amplifying redox imbalance through the Endoplasmic Reticulum Oxidoreductin 1/Protein Disulfide Isomerase (ERO1/PDI) axis and bridging metabolic toxicity to inflammation via c-Jun N-terminal kinase (JNK) and nuclear factor kappa-light-chain–enhancer of activated B cells (NF-κB) signaling. The Advanced Glycation Endproducts (AGEs) and the Receptor for Advanced Glycation Endproducts (RAGE) axis act as a molecular catalyst that sequester antioxidants and drive pro-inflammatory feedback loops. These converging mechanisms culminate in profound placental maladaptation, including structural abnormalities like chorangiosis and functional defects in nutrient transport mediated by hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling. This review article provides insight into recent evidence to elucidate the meta-inflammatory environment of GDM, where modest but sustained elevations in biomarkers like Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) disrupt redox homeostasis and impair insulin signaling pathways through the activation of stress-sensitive kinases. By integrating these molecular perspectives, the article underscores the necessity of targeting the systemic inflammatory and oxidative continuum spanning pre-conception to the antenatal period through lifestyle interventions and emerging therapeutic strategies to mitigate GDM risk and improve maternal–fetal outcomes. Full article

Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have emerged as potentially promising therapeutic agents for improving ovarian function, especially in women with polycystic ovary syndrome (PCOS) and obesity-related reproductive dysfunction. This comprehensive review synthesizes evidence from 30 highly relevant studies examining the mechanisms of action, clinical outcomes, and safety profile of incretin therapies on ovarian function. The evidence suggests that GLP-1 RAs may exert beneficial effects through multiple molecular pathways, including FOXO1 signaling, modulation of steroidogenesis, and enhancement of insulin sensitivity, although most mechanistic data derive from animal models and in vitro studies without validation in human ovarian tissue. Clinical outcomes from randomized controlled trials and meta-analyses show improvements in menstrual regularity, hormonal profiles, and spontaneous conception rates, though evidence certainty is limited by small sample sizes, short duration, high heterogeneity, and restriction to overweight/obese populations. While preliminary safety data regarding inadvertent early pregnancy exposure are reassuring, animal studies suggest potential dose-dependent risks that warrant careful consideration. Importantly, GLP-1 RAs are not currently approved or guideline-recommended for fertility restoration, and substantial uncertainty remains regarding long-term reproductive safety, optimal patient selection, and clinical guidelines. This review provides a balanced synthesis of current evidence and identifies critical gaps requiring further investigation before routine clinical use can be recommended. Full article

Background: Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and a leading cause of cancer-related mortality worldwide. Growing evidence indicates that metabolic syndrome components, including obesity, insulin resistance, and hyperglycemia, contribute to PCa development, and progression to more aggressive form. At the same time, standard treatments such as androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs) significantly improve oncologic outcomes but are associated with adverse metabolic effects, including increased fat mass, insulin resistance, and sarcopenia, potentially worsening patients’ overall metabolic profile and quality of life. Tumor progression in PCa is strongly driven by androgen receptor (AR) signaling, which is closely linked to cellular metabolic reprogramming, highlighting metabolism as a potential therapeutic target. Aim: The aim of this study was to evaluate and synthesize current evidence on the role of the ketogenic diet (KD) in PCa, with particular emphasis on its interaction with hormonal therapies, underlying metabolic and endocrine mechanisms, and its potential application as an adjunctive strategy in integrated oncologic care. Results: The KD, characterized by high fat and very low carbohydrate intake, induces a metabolic state of ketosis that reduces circulating glucose, insulin, and insulin-like growth factor 1 (IGF-1), potentially counteracting metabolic alterations associated with PCa and its treatments. Preclinical studies consistently demonstrate that carbohydrate restriction and KD can slow tumor growth, modulate key oncogenic pathways such as PI3K/AKT/mTOR, reduce systemic insulin signaling, and enhance survival in prostate cancer models. Additionally, emerging evidence suggests possible synergistic effects when KD is combined with standard therapies, including ADT and immunotherapy. Clinical data, although limited, indicate that low-carbohydrate dietary interventions may improve metabolic parameters and could delay biochemical progression, as suggested by increased prostate-specific antigen (PSA) doubling time. However, results across studies remain heterogeneous, and robust evidence on long-term oncologic outcomes is lacking. Conclusions: Overall, the KD represents a promising but still experimental strategy in PCa management, requiring careful nutritional supervision to avoid adverse effects such as unintended weight loss or sarcopenia. Further well-designed randomized clinical trials are needed to clarify its safety, efficacy, and role in routine clinical practice. Full article

Tauopathies, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal lobar degeneration with tau pathology, are unified by pathogenic tau misfolding, post-translational modification, aggregation, and network-level spread. Yet decades of drug development that predominantly pursued single nodes (e.g., one kinase, one aggregation inhibitor, one monoclonal antibody epitope) have repeatedly delivered late-stage disappointments, underscoring a central lesson: tauopathy behaves less like a linear pathway and more like a coupled system of proteostasis failure, neuroinflammation, synaptic-mitochondrial stress, and metabolic dysregulation. This review examines rhizomes (notably Zingiberaceae genera such as Curcuma, Zingiber, Alpinia, Kaempferia, and Boesenbergia) as chemically diverse “multi-target platforms” whose bioactives can engage several tau-relevant nodes simultaneously. We synthesise evidence across tau phosphorylation (GSK-3β/CDK5 and upstream stress signalling), tau aggregation and seeding, autophagy-lysosome and proteasome pathways, redox-mitochondrial resilience, neuroinflammatory circuits (NF-κB/NLRP3), and neuro-metabolic signalling (insulin-PI3K-AKT, AMPK-mTOR). A translational lens is applied throughout, focusing on drug-likeness and CNS multiparameter optimisation; BBB permeability and efflux; metabolism and bioavailability constraints; and formulation strategies (nanoparticles, phytosomes, engineered exosomes) that may render rhizome-derived scaffolds more clinically plausible. We conclude that rhizomes offer credible mechanistic hypotheses for tau modulation, but progress depends on rigorous standardisation, realistic exposure matching, biomarker-driven study design, and a shift from “single-compound optimism” to network pharmacology with translational discipline. Full article

Background: This study aimed to investigate the anti-aging mechanisms of Alpinia oxyphylla polysaccharides (AOFs) through integrated in vivo experiments, network pharmacology, and molecular docking. Methods: Three purified fractions (AOF1, AOF2, and AOF3) were structurally characterized for monosaccharide composition and molecular weight. Anti-aging and antioxidant activities were evaluated using Caenorhabditis elegans, followed by gene expression analysis, network pharmacology target identification, and molecular docking validation. Results: All AOFs significantly extended lifespan, enhanced resistance to oxidative and heat stress, reduced reactive oxygen species and lipid peroxidation, and upregulated superoxide dismutase and catalase activities. Gene expression analysis revealed activation of the insulin/insulin-like growth factor signaling pathway through upregulation of daf 16, skn 1, sod 3, ctl 1, and hsp 16.2. Network pharmacology identified 254, 85, and 119 core targets for AOF1, AOF2, and AOF3 respectively, enriched in PI3K/AKT, MAPK, hypoxia, and xenobiotic response pathways. KEGG analysis further implicated lipid and atherosclerosis, HIF 1, FoxO, and PI3K Akt signaling. Molecular docking showed that critical monosaccharides and metformin formed stable hydrogen-bonded complexes with AKT1, INS, SRC, and STAT3. Among the fractions, AOF1 and AOF3 exhibited superior activities. Conclusions: These findings demonstrate the multi-target, multi-pathway anti-aging actions of AOFs and support their potential as natural antioxidants and functional food ingredients for anti-aging therapeutics. Full article

This study explored the regulatory role of nuclear factor E2-related factor 2 (Nrf2) in aerobic exercise improving oxidative stress and inflammatory responses in mice with insulin resistance (IR) induced by a high-fat diet. We established an IR mouse model through a high-fat diet, then subjected the IR mice to aerobic exercise, intraperitoneal injection of luteolin, or a combined intervention. After 6 weeks of intervention, we measured serum lipid and glucose profiles; evaluated skeletal muscle morphology by H&E staining; quantified mRNA expression levels of Nrf2 and its downstream targets in the skeletal muscle by RT-qPCR; and determined protein abundance, localization, and expression patterns of Nrf2 and NOD-like receptor protein 3 (NLRP3) inflammasome by Western blotting and immunohistochemistry, respectively. In the skeletal muscle of IR mice, Nrf2 and its downstream targets were significantly down-regulated, whereas NLRP3 inflammasome was markedly up-regulated (p < 0.05 or p < 0.01). IR mice subjected to aerobic exercise exhibited reduced serum glucose and lipid levels together with a lower insulin-resistance index (p < 0.05 or p < 0.01); morphologically, inter-myofibrillar spaces were narrowed, intrafiber vacuoles diminished, and cellular integrity restored. Concomitantly, Nrf2 and its downstream targets were up-regulated, whereas NLRP3 inflammasome components were down-regulated in the skeletal muscle (p < 0.05 or p < 0.01). Intraperitoneal administration of luteolin during exercise, however, partially attenuated or reversed these exercise-induced improvements by inhibiting the activation of Nrf2 (p < 0.05 or p < 0.01). These results indicate that aerobic exercise confers protective effects against IR by activating the Nrf2 signaling pathway, thereby attenuating oxidative stress and inflammation; these benefits are markedly attenuated when Nrf2 activity is pharmacologically inhibited. Full article