Search Results (6,764)

Mitochondria are central hubs of antiviral immunity and cellular metabolism, yet the links between SARS-CoV-2–induced mitochondrial remodeling, antiviral gene regulation, and post-translational control remain incompletely understood. Here, we investigated mitochondrial–immune remodeling in SARS-CoV-2–infected lung-derived LC-HK2 cells at 48 and 96 h post-infection using confocal and high-content imaging, colocalization analysis, CellProfiler quantification, RT-qPCR, proteomics, cytokine profiling, and conditioned-medium analysis. Infection induced a time-dependent mitochondrial phenotype. At 48 hpi, cells displayed early mitochondrial stress and fission-associated signatures, including increased DRP1, transient upregulation of mitochondrial respiratory genes, and reduced MFN1/2. At 96 hpi, mitochondria shifted toward elongated perinuclear networks, accompanied by increased fusion/biogenesis markers and partial ISG15–MFN2 colocalization, indicating a spatial association between ISG15-related antiviral/stress responses and mitochondrial remodeling. Antiviral and ISG-related transcripts were consistently upregulated, but IFN-α2 secretion remained limited, suggesting partial uncoupling between antiviral transcriptional activation and downstream interferon output. SUMO2/3 was dynamically modulated and showed time-dependent colocalization with mitochondrial dynamics proteins and MAVS. Together, these data support a coordinated mitochondrial–immune regulatory axis involving mitochondrial remodeling, ISG15-associated responses, and SUMO-dependent regulation during SARS-CoV-2 infection. Full article

Sleep and dietary behavior are deeply conserved biological processes that co-evolved under ecological pressures shaping human anatomy, metabolism, immunity, cognition, and life history strategies. Major transitions in human dietary ecology, including plant-dominant hominin foraging, increased meat consumption, control of fire and cooking, agricultural domestication, industrialization, and postindustrial globalization, restructured nutrient intake, pathogen exposure, microbial ecology, metabolic demands, and temporal organization of behavior. Emerging evidence from evolutionary genomics, chronobiology, neuroendocrinology, and microbiome science indicates that sleep–feeding interactions represent a conserved adaptive regulatory module optimized for fluctuating energy availability and strong photoperiodic entrainment. Modern environments characterized by widespread availability of highly palatable, energy-dense foods rich in refined carbohydrates, added sugars, and multiple industrial additives, together with artificial light at night, continuous caloric access, sedentary behavior, and psychosocial stress produce a profound evolutionary mismatch destabilizing circadian–metabolic homeostasis. This mismatch is characterized by circadian disruption, temporal misalignment of feeding and sleep behaviors, and, in many populations, insufficient sleep duration. Within this conceptual landscape, the emerging framework of “evolutionary chrononutrition” proposes that metabolic health and sleep integrity depend not only on what humans eat, but critically on when food is consumed in relation to endogenous circadian architecture shaped across deep evolutionary time. This review synthesizes anthropological, physiological, and molecular evidence to develop an integrative evolutionary framework linking sleep and diet to contemporary cardiometabolic, neurodegenerative, inflammatory, and psychiatric disorders, with particular emphasis on how each major dietary transition plausibly altered sleep duration, architecture, circadian timing, neuroendocrine regulation, and the temporal alignment between feeding behavior and biological rhythms. Full article

The lysosomal enzyme α-galactosidase A (AGAL) degrades globotriaosylceramide (Gb₃). While this enzymatic function in lysosomal metabolism is well characterized, interaction partners and alternative functions are unknown. This study aims to identify new potential AGAL-interacting proteins. AGAL was fused to the mutated biotin ligase BirA from E. coli (TurboID). Expression of the fusion protein was confirmed by Western blot and immunofluorescence, while enzymatic activity was verified by functional assays. In three experimental settings (AGAL wild-type (WT), AGAL missense variant (p.N215S), and the control cell line), TurboID-biotinylated proximal proteins were enriched by streptavidin pull-down and analyzed by mass spectrometry. Gene Ontology (GO) terms were subsequently evaluated to characterize biological functions and localizations of the identified proteins. Selected candidates were co-immunoprecipitated with AGAL to confirm direct interactions. The AGAL-TurboID fusion protein was successfully expressed in AB8/13 podocytes. Immunofluorescence and enzyme activity assays confirmed the presence and functionality of the fusion protein. Subsequent functional analysis (GO term analysis) showed enrichment of driver terms, including extracellular matrix organization (ECM), multicellular organism development, and protein metabolic process, in the biological process category. The identified top-hit proteins were predominantly involved in the organization of ECM, cell proliferation and cytokinesis, unfolded protein response during endoplasmic reticulum stress, and protein ubiquitination. Co-immunoprecipitation confirmed the interaction between AGAL and the candidate Galectin-3-binding protein (Gal-3BP). Our results suggest that AGAL may play a role in other pathways and/or the ECM organization beyond its lysosomal function. The confirmed interaction with Gal-3BP can now be functionally investigated in further studies. Full article

Seasonal changes in leaf coloration are a key ecological and ornamental characteristic of Liquidambar formosana. To clarify the molecular basis of this process, we performed an integrated transcriptomic and metabolomic investigation comparing wild-type L. formosana (FX) with the autumn-red cultivar ‘Jinyu’ (JY). Leaves were sampled before and after the color transition. Analyses revealed distinct metabolic pathways driving coloration in each genotype. In JY, the red phenotype was primarily attributed to the activation of anthocyanin biosynthesis, characterized by coordinated upregulation of key structural genes (LfDFR, LfANS, LfBZ1) and significant accumulation of anthocyanins, especially pelargonidin derivatives. Conversely, FX exhibited enhanced flavonol biosynthesis and carotenoid/terpenoid metabolism, leading to greater yellow pigment accumulation and an orange-yellow hue. Weighted gene co-expression network analysis (WGCNA) identified a core module strongly correlated with anthocyanin content in JY, which was significantly enriched with transcription factors from the MYB, bHLH, and WRKY families. These results demonstrate that different L. formosana genotypes employ divergent metabolic strategies for autumn coloration, governed by specific transcriptional regulatory networks. This study provides crucial insights into pigment regulation in woody plants and offers valuable candidate genes for the molecular breeding of ornamental L. formosana cultivars. Full article

Dysregulated lipid metabolism is a core pathogenic driver of type 2 diabetes. Honokiol (HKL), the major bioactive constituent of Magnolia officinalis, possesses anti-diabetic and lipid-regulatory properties. However, the underlying molecular mechanism remains elusive. This study investigates how HKL ameliorates high-glucose/high-fat (HGHF)-induced hepatic lipid accumulation, with a focus on the role of SIRT3-mediated deacetylation of peroxisome proliferator-activated receptor γ (PPARG). The core targets of HKL were identified through network pharmacology and molecular docking. Human hepatic MIHA cells were treated with glucose (Glu, 40 mM) and palmitic acid (0.2~0.3 mM PA) to establish a lipid accumulation model, followed by treatment with HKL (5–10 μM) with or without a confirmed selective SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP). Lipid accumulation was assessed by Oil Red O staining and by measuring triglyceride (TG) and total cholesterol (TC) levels. Protein expression and the SIRT3-PPARG interaction were analyzed by Western blot and co-immunoprecipitation (Co-IP). SIRT3 and PPARG were identified as core targets of HKL, exhibiting strong binding with calculated energies of −6.834 and −6.579 kcal/mol, respectively. In MIHA cells, HGHF (40 mM Glu + 0.2–0.3 mM PA) induced lipid accumulation, including increased lipid droplets, and elevated TG (2.5–3.2-fold) and TC (2.2–2.8-fold) contents in a dose-dependent manner, accompanied by downregulated SIRT3/PPARG expression and heightened global protein acetylation. The non-cytotoxic HGHF-M condition (40 mM Glu + 0.2 mM PA) was selected for further experiments. HKL (5–10 μM) dose-dependently reduced lipid accumulation by ~38–60%, decreased TG and TC levels by up to ~13% and ~30%, and restored SIRT3/PPARG expression. The protective effects of HKL were reversed by inhibition of SIRT3 with 3-TYP. Co-IP confirmed the interaction between SIRT3 and PPARG, and SIRT3 overexpression significantly decreased the acetylation level of PPARG. This study suggests that HKL ameliorates hepatic lipid accumulation via SIRT3-mediated deacetylation of PPARG, providing an experimental basis for considering HKL as a potential therapeutic agent against metabolic disorders. Full article

The fruit of Crataegi fructus (CF) is a traditional “medicine food” herb widely used for its lipid-lowering properties, but its active ingredients and mechanisms against metabolic dysfunction-associated fatty liver disease (MAFLD) remain poorly understood. This study employed an integrated multi-omics approach, combining serum metabolomics, liver transcriptomics, weighted gene co-expression network analysis (WGCNA), network pharmacology, and molecular docking, to systematically investigate the effects of CF extract (CFE) in a high-fat diet (HFD)-induced mouse model of MAFLD. Our analysis revealed that CFE treatment significantly reduced body weight gain (p < 0.01), improved glucose tolerance and insulin sensitivity (p < 0.01), and alleviated hepatic steatosis, as evidenced by reduced lipid accumulation and decreased NAS scores (p < 0.001). Metabolomics analysis showed that CFE reversed HFD-induced disturbances in serum fatty acids, glycerophospholipids, and bile acid metabolites. Transcriptomics further revealed that the AMPK and PPAR signalling pathways were critically involved in the regulation of lipid metabolism by which CFE alleviated MAFLD. Consistently, CFE treatment resulted in significant upregulation of AMPK and PPARα expression (p < 0.001) and downregulation of CD36 and DPP4 (p < 0.001), as confirmed by Western blotting and qPCR. Furthermore, integration of WGCNA and network pharmacology pinpointed chlorogenic acid (CA), ursolic acid (UA), and oleanolic acid (OA) as the primary bioactive components, and their lipid-lowering effects were validated in FFA-treated THLE-2 cells. In conclusion, this study offers preliminary insights into the lipid-lowering mechanisms of CFE via regulation of the AMPK/PPARα/CD36/DPP4 signalling pathway and support its further development as a functional food ingredient for MAFLD prevention. Full article

Prostate cancer progression and therapy response are strongly influenced by the tumor microenvironment (TME), particularly stromal fibroblasts that regulate survival signaling, metabolism, and drug resistance. In this study, we investigated whether extracts from three Lepidium meyenii (maca) morphotypes, yellow (MY), red (MR), and black (MB), modulate doxorubicin (DOX) responses in 22Rv1 prostate cancer cells under mono-culture and co-culture conditions with human dermal fibroblasts (HDFa). Cell viability, proliferation, apoptosis-related proteins, lipid droplets (LDs) accumulation, and selected signaling markers were analyzed. In mono-culture, maca extracts exhibited limited cytotoxicity, with MB showing the strongest but still moderate effect. Co-treatment with DOX did not enhance cytotoxicity and resulted in context-dependent modulation of caspase-3 and caspase-8. In co-culture, HDFa cells reduced DOX sensitivity, suggesting altered treatment responses under co-culture conditions. Morphometric analysis suggested fibroblast activation-like changes. Across models, maca reduced LDs accumulation, while increased adipose triglyceride lipase (ATGL) levels in co-culture suggested altered lipid utilization. Additionally, maca extracts modulated PI3K, PSMA, FOXO1, FAP, and HAT1 in a morphotype-dependent manner. Overall, maca extracts acted primarily as context-dependent modulators of signaling and lipid metabolism markers rather than direct cytotoxic agents with their effects strongly dependent on both extract type and microenvironmental context. Full article

Baijiu distillers’ grains (BDG), a major fermented cereal by-product of baijiu production, represent an underutilized source of structurally modified dietary fiber with potential value for functional food development. Here, we found that BDG-derived dietary fiber (BDG-DF), mainly composed of mannose (34.83 ± 0.38%) and xylose (35.14 ± 0.25%), promoted short-chain fatty acid production during in vitro fermentation, and its fermentation supernatants reduced IL-1β and TNF-α levels and modestly decreased IL-6 production in a Caco-2/HepG2 co-culture model. In T2D mice, BDG-DF improved glucose tolerance, with high-dose BDG-DF reducing the OGTT area under the curve by 12.4% compared with the T2D group, and alleviated hepatic steatosis. These effects were accompanied by enrichment of Akkermansia and Bifidobacterium and remodeling of bile acid profiles. High-dose BDG-DF was also associated with elevated CA and CDCA levels, altered TGR5/GLP-1 signaling, increased hepatic FXR expression, and reduced CYP7A1 expression. Integrated hepatic proteomics and metabolomics further indicated that BDG-DF was associated with changes in unsaturated fatty acid biosynthesis and PPAR-γ-related metabolic signaling. Overall, these findings suggest that BDG-DF may improve glucose–lipid homeostasis in association with gut microbiota and bile acid remodeling and hepatic PPAR-γ-related metabolic signaling. Full article

Background: Renal ischemia–reperfusion injury (RIRI) is a major cause of acute kidney injury (AKI) and contributes to delayed graft function and progression toward chronic kidney disease. In addition to oxidative stress and inflammation, RIRI induces profound metabolic derangements, particularly suppression of tubular fatty-acid β-oxidation (FAO), leading to energetic stress, lipid accumulation, and maladaptive repair. Peroxisome proliferator–activated receptor-α (PPARα) is a key regulator of tubular FAO, but whether Schisandrin B (Sch B) mitigates RIRI through restoration of a PPARα-associated metabolic program remains unclear. Objective: To determine whether Sch B alleviates RIRI in association with restoration of tubular FAO and attenuation of lipid accumulation and fibrotic remodeling. Methods: A unilateral murine renal I/R model and an HK-2 hypoxia/reoxygenation (H/R) model were used. Mice received Sch B (20 or 40 mg/kg/day) before I/R, and a subset was co-treated with the PPARα antagonist GW6471. Renal function, tubular injury, fibrosis, lipid accumulation, and FAO-related proteins were assessed by serum biochemistry, histopathology, Oil Red O staining, transmission electron microscopy, immunohistochemistry, immunofluorescence, and Western blotting. Bulk RNA-seq and public single-cell RNA-seq datasets were integrated to characterize metabolic pathway remodeling and cell-type-associated PPARα changes. Molecular docking and molecular dynamics simulations were performed to explore the potential interaction between Sch B and PPARα. Results: Sch B significantly improved renal function, reduced tubular injury, and attenuated interstitial collagen deposition after I/R. Sch B also reduced lipid droplet accumulation, preserved mitochondrial ultrastructure, and restored the expression of FAO-related proteins, including CPT1A, CPT2, and ACADM. In vivo and in vitro, Sch B decreased α-SMA, COL1A1, and vimentin expression, indicating attenuation of EMT-associated/profibrotic remodeling. Integrated transcriptomic analyses supported marked metabolic reprogramming after I/R, with enrichment of FAO- and PPAR-related pathways and reduced PPARα expression predominantly in tubular compartments. Sch B was associated with restoration of tubular PPARα expression, while docking and molecular dynamics analyses supported a plausible Sch B–PPARα interaction in silico. GW6471 blunted the beneficial effects of Sch B on fibrosis-related and FAO-related readouts. Conclusions: Sch B alleviates RIRI and limits subsequent fibrotic remodeling in association with restoration of a PPARα-related tubular FAO program, reduced lipid accumulation, and preservation of tubular metabolic homeostasis. These findings identify metabolic reprogramming as an important component of Sch B-mediated renoprotection, although the precise mode by which Sch B regulates PPARα requires further investigation. Full article

Background/Objectives: Chronic hepatitis C (CHC) infection is an independent risk factor for developing type 2 diabetes mellitus (T2DM). However, it is unknown if antiviral treatment, especially with direct-acting antivirals (DAAs), changes long-term glycemic outcomes. Methods: We conducted a retrospective comparative cohort study of 2489 patients with chronic hepatitis C (CHC) in southern Taiwan between 2005 and 2022 who underwent treatment with either an interferon (IFN)-based or direct-acting antiviral agent (DAA) regimen. Given the distinct treatment eras of IFN and DAA therapies, potential temporal confounding was considered in the analytical design. Patients with existing diabetes or co-infections were excluded. The incidence of new-onset T2DM and longitudinal HbA1c levels were compared between treatment groups over a mean follow-up period of 2.56 years. Results: DAA-treated patients demonstrated a lower crude cumulative incidence of T2DM compared with IFN-treated patients (2.46% vs. 6.91%). However, adjusted analyses did not demonstrate a statistically significant difference between treatment groups. The cumulative risk appeared to plateau after the third year among DAA recipients. Post-therapy, HbA1c levels remained stable in both groups at between 5.5% and 6.5% over as long as five years. Splitting regression revealed that BMI ≥ 30 kg/m², and not treatment type or achieved SVR, was an independent T2DM risk factor. The lowest rates of diabetes incidence were associated with pan-genotypic DAA regimens. Conclusion: DAA-treated patients showed lower crude T2DM incidence than IFN-treated patients; however, this difference was not consistently significant after adjustment for baseline factors. Viral eradication may be associated with favorable metabolic trends; however, the present findings do not establish a causal protective effect against incident T2DM. While increased BMI remained an independent predictor of post-treatment diabetes risk. Full article

Background/Objectives: Tuberculosis (TB), caused by Mycobacterium tuberculosis complex, remains a major global health challenge. Recently, D-enantiomer of human lactoferricin 1–11 (D-form hLF 1–11), a short peptide derived from the N-terminal region of lactoferrin, has demonstrated potent antimycobacterial activity. However, its direct mechanism of action has not yet been elucidated. Methods & Results: In the present study, M. smegmatis was employed as a model organism to investigate the mechanism underlying D-form hLF 1–11 activity. Initially, the minimum inhibitory concentration (MIC) was determined and the results revealed growth inhibition at 400 µg/mL. Live/dead fluorescence staining demonstrated mycobactericidal activity, as indicated by increased propidium iodide (PI) uptake relative to the untreated control. Scanning electron microscopy and high-resolution fluorescence microscopy revealed membrane disruption and substantial morphological deformation, along with a time-dependent accumulation of the peptide at the membrane and inside the cells. Furthermore, label-free quantitative proteomic analysis of peptide-treated cells revealed extensive metabolic alterations in carbon metabolism, acetyl-CoA-dependent lipid biosynthesis, oxidative stress defense, translational machinery, and energy production systems. Conclusions: Collectively, these findings provide mechanistic insights into the antimycobacterial activity of D-form hLF 1–11 against M. smegmatis. Full article

Carbon dioxide (CO₂) is essential in beekeeping practices but its optimal dosage and physiological effects on honey bees remain unclear. This study examined CO₂ tolerance and molecular responses across three developmental stages: newly emerged, nurse, and forager bees, using gradient exposure and proteomic analysis. Newly emerged bees demonstrated the highest CO₂ tolerance. Hemolymph and brain exhibited distinct responses: the cytochrome P450 pathway dominated in hemolymph, while the brain displayed stage-specific strategies. Newly emerged bees activated metabolic reorganization and clearance pathways. Nurse bees strengthened antioxidant defenses, while foragers enhanced amino acid metabolism to produce antioxidant precursors. All stages showed role-specific energy metabolism reprogramming to meet increased post-exposure demands. These findings provide critical data and theoretical foundations for honey bee colony management, transportation, and handling practices. The results also contribute valuable insights to the fundamental biology of other insects. Full article

Background/Objectives: Migraine is associated with neurogenic inflammation, trigeminovascular activation, oxidative stress, and systemic metabolic changes. However, circulating antioxidant-related biomarkers in older adults with migraine remain insufficiently characterized. We examined whether self-reported migraine history was associated with serum uric acid (UA), albumin, and total protein levels in the Swedish Adoption/Twin Study of Aging (SATSA), including exploratory analyses in migraine-discordant twin pairs. Methods: This cross-sectional analysis used the first in-person testing wave of SATSA. Participants aged ≥50 years with complete migraine status and biomarker data were included. Serum UA was the primary outcome; albumin and total protein were secondary outcomes. Group differences were assessed using t-tests, Wilcoxon rank-sum tests, or chi-square tests, as appropriate. Linear regression models were adjusted for age, sex, and body mass index. Paired analyses were conducted in 13 migraine-discordant twin pairs. Results: Among 411 participants, 23 reported a migraine history. Participants with migraine had lower serum UA (4.39 vs. 5.15 mg/dL, p = 0.011), albumin (4.40 vs. 4.55 g/dL, p = 0.019), and total protein (7.16 vs. 7.43 g/dL, p = 0.008). These associations remained significant after adjustment. In discordant twin pairs, UA was lower in twins with migraine than in co-twins without migraine (4.34 vs. 4.72 mg/dL, p = 0.050), whereas albumin and total protein differences were not significant. Conclusions: Self-reported migraine history in older adults was associated with lower circulating UA, albumin, and total protein levels. These exploratory, cross-sectional findings should be interpreted as associative rather than causal and require confirmation in longitudinal studies. Full article

Background: Post-COVID syndrome represents a significant medical and public health challenge, particularly among older adults and individuals with type 2 diabetes mellitus (T2DM), in whom disturbances in immune and metabolic homeostasis may contribute to the development and persistence of symptoms following SARS-CoV-2 infection. Objective: To investigate the clinical, immunological, and metabolic characteristics of post-COVID syndrome in older adults with T2DM. Methods: A cross-sectional comparative study was conducted involving 141 patients aged ≥ 60 years who were evaluated more than one year after SARS-CoV-2 infection. Clinical data, anthropometric measurements, complete blood count parameters, biochemical markers, glycated hemoglobin (HbA1c), and SARS-CoV-2-specific IgG antibodies were assessed. Statistical analyses were performed using nonparametric methods, while Pearson’s χ² test was applied for categorical variables. A p-value < 0.05 was considered statistically significant. Results: Symptoms consistent with post-COVID syndrome one year after SARS-CoV-2 infection were identified in 53.2% of participants. No significant differences in anthropometric characteristics, hematological parameters, or most biochemical markers were observed between patients with and without post-COVID syndrome. Patients with T2DM exhibited higher fasting glucose, HbA1c, and SARS-CoV-2–specific IgG antibody levels, reflecting underlying metabolic characteristics and differences in humoral immune responses during the late post-COVID period. Conclusions: Post-COVID syndrome symptoms were frequently observed among older adults at the time of assessment, more than one year after SARS-CoV-2 infection, despite normalization of most laboratory parameters. In patients with T2DM, higher glucose, HbA1c, and antibody levels likely reflect underlying metabolic characteristics rather than a direct effect of post-COVID syndrome. Further longitudinal studies are warranted to clarify the long-term clinical significance of the observed metabolic and immunological findings. Full article

Agaricus bisporus (A. bisporus) is susceptible to rapid postharvest deterioration. Although elevated CO₂ (6%) delays senescence, the metabolic mechanisms remain unclear. In this study, untargeted and targeted metabolomic analyses were employed to explore these pathways in A. bisporus. The results revealed that elevated CO₂ treatment promoted glycolysis by upregulating Hexokinase (HK), Phosphofructokinase (PFK), and Pyruvate Kinase (PK), accumulating Glucose-6-phosphate (G-6-P) and Fructose-6-phosphate (F-6-P). Concurrently, elevated CO₂ treatment upregulated the expression of genes associated with the tricarboxylic acid (TCA) cycle and increased the enzymatic activities of Malate Dehydrogenase (MDH) and Fumarate hydratase (FUM). These changes led to the rapid consumption of key intermediate metabolites (Fumarate (Fum), Malate (Mal), and α-Ketoglutarate (α-KG)), collectively enhancing the efficiency of the TCA cycle. Furthermore, elevated CO₂ treatment significantly suppressed the activities of Glutamine Synthetase (GS) and Xanthine Oxidase (XOD), inhibiting the synthesis of Glutamine (Gln) and Pyroglutamate (pGlu) while promoting the accumulation of Hypoxanthine (Hx). This coordinated reprogramming of amino acid metabolism and purine metabolism contributed to improved energy efficiency and enhanced cellular integrity in postharvest A. bisporus. This study elucidates the specific mechanism by which elevated CO₂ levels regulate the postharvest energy metabolism of A. bisporus from a metabolomics perspective, providing a theoretical basis for developing strategies to control its postharvest quality. Full article