Search Results (682)

Background: Physical inactivity is a major contributor to cardiometabolic disease and mortality. Although mitochondrial dysfunction characterizes overt pathology, whether sedentarism constitutes a distinct and measurable bioenergetic disease state, rather than simply reduced fitness, has not been established. Methods: Nine sedentary (SED) and ten physically active (AC) healthy males (42 ± 14 yr) were studied. Skeletal muscle bioenergetics were assessed using high-resolution respirometry, fluxomics, metabolomics, and protein expression analyses. Whole-body physiology was evaluated using cardiopulmonary exercise and lactate testing (CPELT). Results: At rest, SED exhibited marked reductions in mitochondrial capacity, including Complex I (−36%), Complex II (−28%), electron transport system capacity (−34%), and ATP-synthase-coupled respiration (−30%, all p < 0.01). The most pronounced alteration was a 49% reduction in mitochondrial pyruvate carrier (MPC1) expression, which closely correlated with reduced pyruvate oxidation (−37%, p = 0.006) and lower TCA intermediates. SED also showed reduced MCT1 abundance, impaired fatty-acid oxidation capacity (−32% to −35%), decreased CPT1 activity (−51%), altered cardiolipin composition, and elevated ROS/O₂ flux ratios. During exercise, SED demonstrated lower VO₂max (−38%), reduced fat oxidation (−35%), and higher blood lactate accumulation (>60%, p < 0.001). Mitochondrial function was strongly associated with exercise performance (r = 0.57–0.78, p < 0.01). Conclusions: Healthy sedentary adults displayed a coordinated reduction in tissue-level mitochondrial oxidative capacity, substrate-handling markers, cardiolipin abundance, and metabolic flexibility. These findings should be interpreted as an integrated per-mg skeletal-muscle bioenergetic phenotype in which lower mitochondrial density may account for much of the observed reduction. Within this phenotype, the 49% reduction in MPC1 alongside preserved GLUT4, LDHA, and LDHB abundance represents an outstanding differential observation that future studies with direct mitochondrial-content normalization should test. CPELT-derived fat oxidation and blood lactate responses reflected this tissue-level bioenergetic phenotype, providing candidate noninvasive physiological markers for future longitudinal and interventional studies. Full article

Age-related hyperphosphatemia is increasingly recognized as a contributing factor in sarcopenia. This work studies the metabolic effects of elevated phosphate on muscle. C2C12 cells were differentiated in the absence or presence of 10 mM β-glycerophosphate (BGP), an exogenous phosphate donor. In addition, quadriceps muscles from four experimental groups of male C57BL/6J mice were analyzed: young (5 months) and old (24 months) fed with standard diet; old mice fed with hypophosphatemic diet or supplemented with the phosphate binder Velphoro^®, for the last three months of life. Mice were stratified according to sarcopenia degree based on muscle mass, strength and physical performance. Protein levels were determined by immunoblotting and mRNA expression by RT-qPCR. ATP levels were measured by luminescence and L-lactate production, citrate synthase and cytochrome c oxidase activities by colorimetric assays. Mitochondrial content, membrane potential and reactive oxygen species (ROS) were determined by fluorescence assay. BGP-treated cells showed increased glucose transporter 1 (GLUT1) and decreased NADH Dehydrogenase (CI-NDUFB8) protein expression, elevated hexokinase II (HK2), phosphoglycerate kinase 1 (PGK1) and lactate dehydrogenase A (LDHA) mRNA levels, reduced ATP levels, increased lactate production, and decreased mitochondrial enzyme activities. Moreover, BGP increased ROS, diminished mitochondrial membrane potential, and altered fusion–fission dynamics and mitophagy. In aged quadriceps, oxidative phosphorylation (OXPHOS) subunits and superoxide dismutase 2 (SOD2) expression were reduced. The hypophosphatemic diet improved all parameters, whereas Velphoro^® selectively increased Mitochondrial cytochrome C oxidase subunit 1 (CIV-MTCO1) expression. Several altered mitochondrial markers are associated with sarcopenia degree. Altogether, hyperphosphatemia induces metabolic changes that scale with the sarcopenic degree. Our findings show a relevant association between hyperphosphatemia and mitochondrial dysfunction, and they support the potential benefit of phosphate reduction as a strategy to prevent or mitigate sarcopenia. Full article

A fraction of the insulin-stimulated uptake of long-chain fatty acids (FAs) is mediated by the FA translocase cluster of differentiation 36 (CD36) in white adipocytes. Intracellular vesicle-localized CD36 is redistributed to the plasma membrane following insulin stimulation, enhancing the uptake of long-chain FAs across the plasma membrane. We previously developed an epitope-tagged CD36 reporter, which enabled the visualization and quantification of the plasma membrane translocation of CD36. Herein, we demonstrate that the insulin-stimulated CD36 translocation is regulated by the phosphoinositide 3-kinase (PI3K)/Akt2/Rac1/RalA axis in adipocytes of subcutaneous white adipose tissue (WAT) in living mice. The uptake of long-chain FAs by insulin was completely abrogated in white adipocytes isolated from adipocyte-specific rac1-knockout (adipo-rac1-KO) mice. Correspondingly, the translocation of CD36 to the plasma membrane by insulin was also totally inhibited in Rac1-deficient white adipocytes. PI3K and Akt2 acted upstream of Rac1, and the guanin nucleotide exchange factor FLJ00068 served as a regulator for Rac1. Furthermore, the involvement of another small GTPase RalA was suggested by inhibitory effects of a dominant-negative mutant. Taken together, these results support the notion that insulin regulates the plasma membrane translocation of CD36 by mechanisms similar to those for the translocation of the glucose transporter GLUT4 in white adipocytes. Full article

We aimed to investigate the potential antidiabetic effects of an ethanol extract derived from the fruit of Malus floribunda (MF) on insulin resistance, oxidative stress, inflammation, and apoptosis associated with diabetes. In our study, diabetes was induced through the administration of a 10% fructose solution and 40 mg/kg Streptozotocin (STZ). Once diabetes had been induced, metformin (Met) 300 mg/kg and the MF extract (250 mg/kg and 500 mg/kg) were administered orally once daily for 30 days. At the end of the experiment, markers of insulin resistance, oxidative stress, inflammation and apoptosis were evaluated in the serum, muscle and liver tissues of the different groups. The MF extract significantly improved the levels of HOMA-IR, insulin receptor (InR), insulin receptor substrate 1 (IRS-1) and glucose transporter 4 (GLUT4)—key components of peripheral insulin resistance associated with type 2 diabetes. Fructose/streptozotocin induced oxidative stress, inflammation, and apoptosis were mitigated by increasing Nuclear factor erythroid 2-related factor 2 (NRF2) expression, which restored antioxidant levels (Superoxide dismutase (SOD) and Glutathione (GSH)), significantly improved cytokine levels (Tumor necrosis factor alpha (TNF-α) and Interleukin-1 beta (IL-1β)), and downregulated apoptotic proteins (caspase-3 and caspase-9). We demonstrated the antidiabetic effect of MF extract using a fructose/streptozotocin-induced type 2 diabetes model. MF extract shows promise for future use in herbal medicine. Full article

Blue honeysuckle (Lonicera caerulea L.) is a polyphenol-rich berry increasingly recognized as a functional food ingredient for postprandial glycemic management. However, it remains unclear whether its polyphenols can modulate intestinal glucose transport in addition to inhibiting carbohydrate-digesting enzymes. In this study, blue honeysuckle polyphenol extract (BHPE) was characterized by UPLC-QTOF-MS/MS, and its effects on α-glucosidase activity and intestinal glucose transport were evaluated using enzyme kinetics, fluorescence quenching, molecular docking, and differentiated Caco-2 monolayers. A total of 24 phenolic compounds were tentatively identified, with anthocyanins and chlorogenic acid derivatives as the major constituents. BHPE exhibited a mixed-type, static-quenching inhibition of α-glucosidase (IC₅₀ = 75.05 μg/mL). Furthermore, molecular docking revealed that key constituents, including cyanidin-3-O-glucoside, chlorogenic acid, and proanthocyanidin B1, bind the enzyme via hydrogen bonding and hydrophobic interactions. In Caco-2 cell monolayers, BHPE reduced glucose transport by up to 51.56% under simulated postprandial conditions and coordinately downregulated SGLT1 and GLUT2 mRNA expression to 0.58- and 0.51-fold, respectively. These findings extend the bioactivity profile of blue honeysuckle polyphenols from enzyme-level inhibition to functional regulation at the intestinal epithelial barrier, highlighting their potential as multi-target natural ingredients for the attenuation of postprandial hyperglycemia. Full article

Adult intussusception is an uncommon condition that usually indicates an underlying pathological lead point. Ileal perineurioma is an exceptionally rare benign peripheral nerve sheath tumor with limited gastrointestinal reports. We describe a 59-year-old woman presenting with acute severe abdominal pain, vomiting, and distension. Contrast-enhanced computed tomography demonstrated ileal intussusception with small-bowel obstruction. Emergency laparotomy confirmed terminal ileal intussusception, and segmental resection was performed. Histopathological evaluation revealed a spindle-cell neoplasm with characteristic pseudo-onion bulb architecture. Immunohistochemistry showed strong positivity for epithelial membrane antigen (EMA) and Glucose Transporter-1 (GLUT-1), while other markers were negative, confirming perineurioma. The postoperative course was uneventful, with no recurrence on follow-up. This case highlights ileal perineurioma as a rare but important differential diagnosis in adult small-bowel intussusception, with definitive diagnosis reliant on histopathological and immunohistochemical evaluation. Full article

Background: Glucose transporter 1 (GLUT1) is frequently upregulated in solid tumors and may reflect metabolic adaptation of malignant tissues. However, evidence regarding GLUT1 protein levels in salivary gland tumors remains limited. Methods: In this pilot study, GLUT1 protein concentrations were quantified in tissue homogenate supernatants from salivary gland tumors (n = 9) and non-malignant salivary gland tissue obtained from surgical margins (controls; n = 4) using a commercial ELISA kit (BlueGene Biotech; E01G0020) according to the manufacturer’s instructions. Supernatants were stored at −80 °C until analysis. Group comparisons were performed using a non-parametric Mann–Whitney U test. Results: GLUT1 levels showed substantial inter-individual variability. The tumor group exhibited higher values than controls [median (IQR): 15.53 (12.44–26.38) vs. 10.14 (7.40–13.26); mean ± SD: 19.26 ± 11.49 vs. 10.33 ± 4.39 (ng/mL)], although the between-group difference did not reach statistical significance (Mann–Whitney U = 27, two-sided p = 0.199). Conclusions: These preliminary data suggest heterogeneity of GLUT1 levels in salivary gland tumor tissue homogenates and numerically higher concentrations compared with non-malignant margin tissue. These findings should be interpreted as preliminary and hypothesis-generating. Larger, clinically annotated cohorts with orthogonal validation are required before any diagnostic, prognostic, or clinical relevance of GLUT1 can be considered. Full article

Dietary fiber is a critical determinant of intestinal health, yet its optimal inclusion level for WWG during the critical brooding period remains undefined. This study aimed to evaluate the effects of varying dietary CF levels (approximately 3%, 5%, and 9%) on the intestinal morphology, immune function, and microbiome-metabolome axis of brooding WWG. A total of 120 one-day-old goslings were randomly assigned to the three dietary treatments for a 28-day trial. Histological analysis revealed that the 9% CF diet significantly improved gut morphology, yielding superior villus-to-crypt ratios in the jejunum and ileum. Molecular assays indicated that higher fiber levels (5–9%) upregulated the expression of nutrient transporters (SGLT1 and GLUT2). Concurrently, the 9% CF diet effectively suppressed the potent pro-inflammatory cytokine TNF-α in the jejunum while appropriately upregulating IL-6 and NF-κB, indicating enhanced mucosal immune vigilance and structural maturation. Multi-omics integration (shotgun metagenomics and LC-MS metabolomics) demonstrated that specific fiber levels significantly shifted microbial abundances, specifically enriching Bacteroidetes and Actinobacteria. These microbial shifts were strongly correlated with enriched metabolic pathways, notably lysine biosynthesis and purine metabolism, which synergistically support mucosal homeostasis. Collectively, these findings demonstrate that a 9% dietary CF inclusion is an effective nutritional strategy to optimize intestinal architecture and microbial-metabolic profiles in brooding WWG. Full article

Tissue engineering is widely used in research for investigating cellular proliferation, behavior, and responses to various stimuli. However, the predictive value of preclinical studies using cell culture plates is limited by the inability to recapitulate the complexity of the physiological microenvironment. Synthetic three-dimensional (3D) scaffolds can be engineered to mimic the complex morphology of the extracellular matrix of native tissues and can serve as physiologically relevant platforms for preclinical studies. In this study, 3D electrospun scaffolds were characterized to aid in breast cancer research. Unlike previous studies that focused primarily on scaffold fabrication or cell viability, this work systematically evaluates how scaffold morphology influences breast epithelial and breast cancer cell behavior within three-dimensional microenvironments. Breast cancer cell lines and normal breast epithelial cells were seeded on scaffolds of different morphologies, on commercially available mesh scaffolds, and on standard tissue culture plates. Cells were treated with a fluorescent fructose mimic (ManCou-H) that targets the fructose-specific transporter GLUT5 to assess metabolic activity on different scaffolds. The study evaluated cell–cell and cell–matrix interactions through time-lapse experiments, cell metabolism, and variations in the expression of cytoskeletal protein (CK18) and GLUT5. Statistically relevant differences were observed between cells cultured on scaffolds and plates, and different scaffolds morphologies. Results from this study demonstrate that scaffold topology alone can significantly alter cellular phenotype and metabolic responses, highlighting the importance of scaffold selection in the development of predictive non-animal in vitro models and studies of the tumor microenvironment. Full article

Epidemiological and biological evidence indicate a close connection between Alzheimer’s disease (AD) and type-2 diabetes mellitus. Glucose transporter 1 (GLUT1), encoded by the SLC2A1 gene, has a major role in glucose metabolism, the dysregulation of which has been implicated in both diseases. We conducted a case-control association study in a sample of 439 non-diabetic patients with late-onset AD and 304 cognitively healthy, non-diabetic elderly controls to determine the potential risk for developing AD associated with SLC2A1 rs841847 polymorphism. The rs841847 C/C genotype occurrence was higher in the AD group (AD: 60.4%, controls: 50.7%), while the minor T allele-containing genotypes were more frequent among controls (AD: 39.6%, controls: 49.3%). A multivariate logistic regression model adjusted for age, sex, and apolipoprotein E (APOE) ε4 status (ε4 allele carriers versus non-carriers) demonstrated that carriers of the T allele had a significantly reduced risk for AD compared to C/C homozygotes (OR = 0.672; 95% CI: 0.493–0.916; p = 0.012). Although the rs841847 polymorphism has been linked to type-2 diabetes mellitus, the present study investigated this gene variant in AD for the first time. Our findings indicate a moderate protective effect for the rs841847 T allele on the susceptibility to AD. We demonstrated the rs841847 polymorphism as a candidate single nucleotide polymorphism for further examination as a predisposing genetic factor for AD. Full article

Fermentation is widely used to enhance the bioactivity of herbal phytochemicals through microbial bioconversion. Rehmannia glutinosa contains catalpol, an iridoid glycoside with metabolic and immunomodulatory potential; however, its efficacy in the unfermented form is limited. This study investigated whether fermentation enhances catalpol production and improves metabolic and immune-regulating functions via glucagon-like peptide-1 receptor (GLP-1R) signaling. Rehmannia glutinosa extract was fermented under optimized conditions, and catalpol and iridoid precursor levels were quantified to assess bioconversion efficiency. Biological effects were evaluated in intestinal epithelial cells, macrophages, and an Artemia model, focusing on glucose transport, GLP-1 secretion, dipeptidyl peptidase-4 (DPP-4) expression, mucosal defense, and GLP-1R/protein kinase A/cAMP response element-binding protein (PKA/CREB) signaling. Fermentation significantly increased catalpol content while reducing iridoid precursors. The fermented extract suppressed intestinal glucose absorption by downregulating sodium–glucose cotransporter 1 (SGLT1) and glucose transporter 2 (GLUT2). It also enhanced GLP-1 secretion and reduced DPP-4 expression, leading to activation of GLP-1R/PKA/CREB signaling. This activation increased mucin 2 (MUC2) expression and promoted anti-inflammatory. Full article

Background/Objectives: Hyperuricemia is a metabolic disorder characterized by renal dysfunction and systemic inflammation. While Clematis chinensis Osbeck is traditionally used for gout-related conditions, its chemical basis and precise mechanisms remain poorly understood. This study aimed to characterize the bioactive fraction (CWE-60EF) and elucidate its multi-target regulatory mechanisms against hyperuricemia. Methods: Qualitative and quantitative chemical profiling of CWE-60EF was performed using high-resolution LC-MS/MS. Its anti-hyperuricemic activity was validated using in vitro xanthine oxidase (XOD) inhibition, a zebrafish model, and HK-2 cell injury models. Mechanisms were explored through an integrated approach combining bioinformatics, Mendelian randomization (MR), and molecular docking. Results: A total of 50 compounds, primarily alkaloids and flavonoids (e.g., magnoflorine and phloretin), were characterized in CWE-60EF, and major marker compounds were quantitatively standardized. The fraction significantly inhibited XOD activity and rescued hyperuricemia-associated phenotypes in zebrafish. In HK-2 cells, CWE-60EF suppressed adenosine- and urate-induced cellular injury and the transcriptional expression of pro-inflammatory cytokines (IL-6 and IL-1β). MR analysis provided genetic evidence supporting IL-6 as a causal mediator of gout risk. Integrative analysis revealed that the protective effects of CWE-60EF are mediated through the coordinated regulation of purine metabolism, inflammatory cascades, and urate transporters (URAT1/GLUT9). Conclusions: This study demonstrates that CWE-60EF is a quantitatively standardized bioactive fraction that exerts anti-hyperuricemic, renoprotective, and anti-inflammatory effects by modulating uric acid metabolism and inflammation. By integrating genetic causality with phytochemical validation, our findings provide a novel mechanistic foundation for the traditional application of C. chinensis in hyperuricemic disorders. Full article

Background/Objectives: Exploiting the metabolic properties of postbiotics is a novel strategy for managing metabolic disorders, including diabetes. Inactivated microorganisms, a major class of postbiotics, improve glycemic control in preclinical and clinical studies. Here, we examined whether heat-killed (HK) Mycobacterium aurum (M. aurum) exerts prophylactic or therapeutic anti-hyperglycemic effects in diabetic mice. Methods: Diabetes was induced in male BALB/c mice by streptozotocin (STZ; 150 mg/kg) injection. HK M. aurum (1 mg) was given orally (three prophylactic doses before STZ) or intradermally (six weekly therapeutic doses after STZ). We assessed glycemic parameters, serum C-peptide/insulin (ELISA), and tissue protein expression (Western blot). Results: Neither route altered body weight or glucose homeostasis in non-diabetic mice. In STZ-diabetic mice, oral prophylactic treatment significantly attenuated hyperglycemia (39–60% reduction weeks 5–8 post-STZ) and showed a trend toward improved serum C-peptide, but did not affect dysregulated expression of skeletal muscle (SM), hepatic, pancreatic and renal proteins involved in glucose transport (GLUT2, GLUT4, and SGLT2), glycolysis (α-LDH), mitochondrial uncoupling (UCP2 and UCP3), and antioxidant defense (CAT). Therapeutic intradermal administration significantly decreased blood glucose (~30% at week 5, ~40% at week 6) and modestly enhanced insulin secretion. Hepatic UCP2 and α-LDH and SM UCP3 protein levels were normalized toward non-diabetic levels, whereas hepatic GLUT2 and SM GLUT4 remained largely unchanged. These correlative findings suggest effects independent of insulin-dependent glucose transport, but do not demonstrate direct functional improvement in mitochondrial or redox status. Conclusions: HK M. aurum exerts partial anti-hyperglycemic effects in STZ-induced diabetic mice, but the associated protein changes require functional validation before its role as a postbiotic in β-cell dysfunction can be established. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) exhibits enhanced glycolytic activity, primarily facilitated by Class I glucose transporters (GLUTs), particularly GLUT-2. Phloretin, a natural polyphenol, is known to modulate glucose transport; however, its isoform-specific interactions and functional impact on HCC metabolism remain unclear. This study compared phloretin’s inhibitory effects on glucose uptake in HCC cells versus normal liver cell models and assessed its binding affinity across Class I GLUTs using molecular docking. Methods: Cytotoxicity was evaluated in HepG2 (HCC) and THLE-2 (normal hepatocyte) cells using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays to determine biologically relevant concentrations. Glucose uptake at sub-cytotoxic levels was quantified using the fluorescent analog 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose. To elucidate the molecular mechanism, in silico docking simulations were performed to compare the binding affinities of phloretin, glucose, and reference inhibitors (glutor and cytochalasin B) with the outward-facing conformations of GLUT-1 through GLUT-4. Results: Phloretin induced dose- and time-dependent cytotoxicity, with HepG2 cells exhibiting significantly higher sensitivity than THLE-2 cells. Functionally, phloretin markedly reduced glucose uptake in HepG2 cells, whereas THLE-2 cells showed minimal inhibition. Molecular docking revealed that phloretin occupies the central substrate-binding cavity of Class I GLUTs, forming its most stable interaction network with GLUT-2. Conclusions: These results demonstrate that phloretin selectively inhibits glucose uptake in liver cancer cells, likely through its high-affinity interaction with GLUT-2. Collectively, these findings highlight phloretin’s potential as a metabolic therapeutic agent and support GLUT-2 as a viable target for HCC intervention. Full article

Type 2 diabetes mellitus (T2DM) is a major global health challenge that has intensified interest in multi-target nutraceuticals with potential adjunctive benefits. Ganoderma lucidum (Lingzhi/Reishi) is a medicinal mushroom traditionally used in East Asia and is increasingly investigated for its role in glycemic regulation and metabolic disturbances. This review critically synthesizes current evidence on its hypoglycemic effects, focusing on bioactive compounds, molecular mechanisms, and translational limitations. Unlike broader reviews on Ganoderma bioactivity and health-related benefits, this review specifically evaluates the alignment between taxonomic authentication, chemical standardization, preclinical mechanisms, and human clinical evidence in the context of glycemic regulation. This narrative review was based on a targeted literature search conducted in PubMed/MEDLINE, Web of Science, and Scopus for studies published up to October 2025, supplemented by Google Scholar. The included studies comprised in vitro experiments, in vivo animal models, and human clinical trials evaluating glycemic and metabolic outcomes of Ganoderma preparations. In vitro and animal studies indicate that polysaccharides, including β-(1→3)/(1→6)-glucans and proteoglycans such as FYGL, may improve insulin sensitivity via AMPK (AMP-activated protein kinase) and PI3K/Akt pathways, promote GLUT4 (glucose transporter type 4) translocation, suppress hepatic gluconeogenesis, protect pancreatic β-cells, and modulate gut microbiota. In enzyme assays and preclinical models, lanostane-type triterpenoids act primarily by inhibiting α-glucosidase and α-amylase, thereby potentially reducing postprandial glucose excursions. Despite consistent preclinical evidence, clinical findings remain heterogeneous, with the largest randomized controlled trial reporting no significant glycemic benefit. Overall, Ganoderma lucidum shows strong mechanistic plausibility but insufficient clinical evidence for antidiabetic efficacy. Future research should prioritize species authentication, chemical standardization, and adequately powered clinical trials. Full article