Search Results (707)

Background: Liver X receptors (LXRs) are critical regulators of cholesterol homeostasis that modulate T cell function with anti-inflammatory effects. LXR downregulation has been implicated in the pathogenesis of inflammatory bowel disease (IBD), although its underlying mechanisms remain to be fully elucidated. Recent evidence has confirmed the link between T cell senescence and autoimmune diseases. Here, we sought to investigate whether and how LXRs regulate T cell senescence in controlling intestinal inflammation. Methods and Results: We found that LXRβ expression was decreased in the colons of mice with experimental colitis, and LXRβ deficiency (Lxrβ^−/−) significantly aggravated their colitis. Intriguingly, this finding was accompanied by enhanced CD4⁺ T cell senescence both in the colons and spleens of Lxrβ^−/− mice, evidenced by upregulation of SA-β-gal levels and the remarkable expansion of effector memory subclusters in CD4⁺ T cells. Moreover, senescent Lxrβ^−/− CD4⁺ T cells secreted elevated levels of proinflammatory cytokines, especially in effector memory populations, exhibiting a pronounced proinflammatory phenotype. RNA-sequencing further confirmed the role of LXRβ in restricting CD4⁺ T cell senescence. Mechanistically, the absence of LXRβ in CD4⁺ T cells directly enhanced senescence by promoting the cGAS/STING pathway. Blocking STING signaling with a targeted inhibitor significantly alleviated senescence in Lxrβ^−/− CD4⁺ T cells. Conclusions: Our findings demonstrate the role of LXRβ in regulating intestinal CD4⁺ T cell senescence to inhibit colitis development, identifying LXRβ as a potential therapeutic target for treating IBD. Full article

Background/Objectives: Variants in the lipoprotein lipase (LPL) gene have been associated with lipid level variability and obesity; however, their role in energy homeostasis remains unclear. The aim of this study was to investigate the association of LPL single-nucleotide variants (SNVs) with lipid parameters and leptin concentrations in a cohort of prepubertal children. The sample population comprised 635 boys and 631 girls, with available information on lipid profiles and leptin levels. Methods: Five LPL SNVs (rs258, rs316, rs326, rs320, and rs328) were genotyped by Real-Time PCR using predesigned TaqMan™ Genotyping Assays. Results: An association of the LPL SNV rs258 was found with non-esterified fatty acid (NEFA) levels in males and with leptin concentrations in both sexes. On the other hand, an association of the LPL SNV rs326 was observed with low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (Apo-B) levels, displaying opposite trends in males and females. No significant associations with any of the parameters under study were observed for the remaining LPL SNVs. Conclusions: These results suggest that functional differences among LPL SNVs may either be related to an enhancement of catalytic activity or modulation of lipoprotein binding affinity, influencing the efficiency of remnant lipoprotein clearance. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves early disturbances such as excessive lipid accumulation, sterile inflammation, and hepatocellular stress. The results of recent studies have highlighted extracellular ATP and its metabolite adenosine (Ado) as damage-associated molecular patterns (DAMPs) that drive inflammation, endoplasmic reticulum (ER) stress, and steatosis, contributing to MASLD progression. Although vitamin E is clinically used for its antioxidant and anti-inflammatory properties, it remains unclear whether its therapeutic effects involve modulation of DAMP-associated signaling. To address this gap, we used transgenic zebrafish expressing a liver-specific G-protein-coupled receptor activation-based adenosine sensor (GRAB_Ado). We found that a high-cholesterol diet markedly increased hepatic extracellular Ado levels, combined with inflammatory and ER stress-associated gene expression. Vitamin E significantly reduced extracellular Ado levels and hepatic lipid accumulation. Based on RNA sequencing results, vitamin E restored the expression of genes encoding calcium-handling proteins, including atp2a1 and atp1b1b. These genes encode components of the sarco/ER Ca²⁺-ATPase (SERCA) machinery, which is essential for maintaining ER Ca²⁺ homeostasis and preventing stress-induced hepatic injury. CDN1163-mediated SERCA activation phenocopied the protective effect of vitamin E, supporting a Ca²⁺-dependent mechanism. Together, these findings highlight extracellular Ado signaling and impaired SERCA-mediated Ca²⁺ regulation as early drivers of MASLD and demonstrate that vitamin E ameliorates steatosis by targeting both pathways. Full article

Background/Objectives: There is no definitive consensus regarding the effects of melatonin on cardiometabolic risk factors (CMRFs). This systematic review and dose–response meta-analysis of randomized controlled trials (RCTs) evaluated the impacts of melatonin supplementation on CMRFs, including anthropometric, lipid, glycemic, inflammatory, oxidative, and liver function parameters. Methods: A systematic search across multiple databases retrieved 63 eligible RCTs published up to October 2025. Results: This random-effects meta-analysis indicated that melatonin supplementation significantly reduced hip circumference (weighted mean difference (WMD): −1.18 cm, 95% confidence interval (CI): −2.28, −0.08), systolic blood pressure (WMD: −2.34 mmHg, 95% CI: −4.13, −0.55), fasting blood glucose (WMD: −11.63 mg/dL, 95% CI: −19.16, −4.10), low-density lipoprotein cholesterol (WMD: −6.28 mg/dL, 95% CI: −10.53, −2.03), total cholesterol (WMD: −6.97 mg/dL, 95% CI: −12.20, −1.74), C-reactive protein (WMD: −0.59 mg/L, 95% CI: −0.94, −0.23), malondialdehyde (WMD: −1.54 μmol/L, 95% CI: −2.07, −1.01), tumor necrosis factor-alpha (WMD: −1.61 pg/mL, 95% CI: −2.31, −0.90), interleukin-6 (WMD: −6.43 pg/mL, 95% CI: −10.72, −2.15), and alanine aminotransferase (WMD: −2.61 IU/L, 95% CI: −4.87, −0.34). Supplementation with melatonin substantially increased serum total antioxidant capacity (WMD: 0.15 mmol/L, 95% CI: 0.08, 0.22) and high-density lipoprotein cholesterol (WMD: 2.04 mg/dL, 95% CI: 0.50, 3.57). No significant effects of melatonin were observed on body weight, waist circumference, body fat percentage, body mass index, fasting insulin, homeostasis model assessment of insulin resistance, hemoglobin A1c, triglycerides, diastolic blood pressure, aspartate aminotransferase, or gamma-glutamyl transferase. Conclusions: Melatonin supplementation significantly ameliorated multiple CMRFs. Full article

This study investigates the adaptive mechanisms that enable a single wild barley (Hordeum spontaneum) accession to withstand extreme salinity. Salt stress reshapes plant metabolism and gene expression, offering targets for breeding salt-tolerant cereals. A time-course RNA-Seq experiment was conducted on leaves exposed to 500 mM NaCl, followed by differential expression and functional annotations to characterize transcriptomic responses. Transcriptomic profiling identified 140 dynamically upregulated genes distributed across 19 interconnected metabolic pathways, with phased activation of oxidative phosphorylation, nitrogen assimilation, lipid remodeling, and glutathione metabolism. Central metabolic nodes, including acetyl-CoA, hexadecanoyl-CoA, and ubiquinone, coordinated bioenergetic output, membrane stabilization, and redox homeostasis. Ribose-5-phosphate and ribulose-5-phosphate linked glycolysis and the pentose phosphate pathway, supplying NADPH for antioxidant defense and nucleotide repair, while riboflavin derived from Ru5P enhanced flavoprotein activity. In parallel, glucose and fructose-6-phosphate supported osmotic adjustment and glycolytic flux, and increased sterol and cuticular lipid biosynthesis, including cholesterol-like compounds, reinforced membrane integrity and calcium signaling. Glutathione and N-acetyl-glutamate together mitigated oxidative stress and modulated polyamine metabolism, strengthening cellular resilience under salt stress. These findings outline a coordinated network of metabolic and redox pathways that can guide the engineering of salt-tolerant cereals for sustainable production in saline agroecosystems. Full article

Artemisia indica Willd., a traditional medicinal and dietary herb, has been widely recognized for its diverse bioactivities. This study aimed to evaluate the effects of Artemisia indica Willd. aqueous extract (AAE) on dysglycemia and dyslipidemia. HPLC–ESI–MS/MS analysis identified 4,5-dicaffeoylquinic acid as the major active constituent of AAE. BALB/cByJNarl mice subjected to a high-fat diet (HFD) and streptozotocin (STZ) injection were supplemented with AAE for 6 weeks. To elucidate the underlying mechanisms, we examined multiple metabolic pathways, including oxidative stress, lipid metabolism, and the polyol pathway. AAE administration attenuated fasting blood glucose and reduced fructosamine levels and also ameliorated protein kinase C α (PKC-α) and nuclear factor kappa B (NF-κB) expression. Histopathological evaluation showed that AAE reduced lipid accumulation by modulating sterol regulatory element-binding protein 1 (SREBP-1) and fatty acid synthase (FAS) expression. Additionally, AAE inhibited polyol pathway activation and restored antioxidant enzyme activities. Collectively, these findings indicate that AAE modulates glucose and cholesterol metabolism, attenuates oxidative stress, and improves metabolic homeostasis, supporting its potential as a natural herbal therapeutic agent. Full article

Extracellular vesicles (EVs), particularly exosomes, are key mediators of intercellular communication, transporting biomolecules such as nucleic acids, lipids, and proteins that influence immune and metabolic pathways. In adipose tissue (AT), adipocyte-derived EVs (AdEVs) play a crucial role in maintaining metabolic homeostasis and have been implicated in obesity-related dysfunction. Among their bioactive cargo, microRNAs regulate post-transcriptional gene expression and participate in immunometabolic regulation. This study aimed to determine whether miR-34a expression in serum and circulating EVs varies according to body fat percentage, to explore its potential utility as a non-invasive biomarker of AT dysfunction. A total of 142 adults (mean age 36 ± 11 years) were classified by body fat percentage (≥25% in men, ≥35% in women). Exosomes were isolated (Invitrogen^®) and characterized by cryo-TEM, and miR-34a expression was quantified by qRT-PCR. miR-34a expression correlated negatively with Total Cholesterol, Triglycerides, LDLc/HDLc, TG/HDLc, BMI, C3, CRP, fasting insulin, HOMA-IR, HOMA-B, Body adiposity, Chemerin, CCL2, AdipoQT, and AdipoQ-H, but positively with HDLc and QUICKI. Notably, LDLc, sdLDLc, sdLDLc/LDLc, TC/HDLc, and fasting glucose showed opposite correlation patterns between serum and exosomes. Overall, serum miR-34a levels were higher than in exosomes, suggesting its potential as a biomarker of metabolic dysfunction and insulin resistance. Full article

Serum Amyloid A (SAA) is an acute-phase apolipoprotein that acts as both a sensitive biomarker of systemic inflammation and an active modulator of lipid metabolism and vascular homeostasis. This review summarises current insights into the interaction between SAA and high-density lipoproteins (HDL), with particular emphasis on its role in inflammation-driven cardiovascular disease (CVD). The incorporation of SAA into HDL markedly alters its composition and function. The displacement of apolipoprotein A-I impairs cholesterol efflux capacity, reduces antioxidative activity, and promotes a pro-inflammatory phenotype, transforming protective HDL into a dysfunctional particle. These changes contribute to endothelial dysfunction, foam cell formation, and atherogenesis. Elevated SAA levels are also associated with adverse cardiovascular and metabolic outcomes, including coronary artery disease, type 2 diabetes, and chronic kidney disease. Isoform-specific variations in SAA–HDL interactions are emerging as key modulators of these effects. This review also discusses emerging therapeutic and nutritional strategies to modulate the SAA–HDL axis, including anti-inflammatory therapies, HDL mimetics, and diet-based interventions. Future research should prioritise the standardisation of SAA measurement, characterisation of isoform-specific functions, and translational studies integrating SAA into cardiovascular risk stratification and therapy. Full article

The present study evaluated the impact of precision feeding using Electronic Sow Feeders (ESFs) during lactation on the nutritional status of Iberian sows and the performance of their offspring under intensive farming conditions. Fifty-three second-parity Iberian sows were assigned to three feeding systems: ESFs (PF), feeding ball (FB), and conventional feeders (CON). Results showed that PF sows had a significantly lower feed disappearance, without affecting body weight and condition, when compared to FB and CON groups (p < 0.05). Although milk yield did not differ significantly among groups, PF piglets exhibited higher weaning weights and average daily weight gains (ADWG), particularly during the second half of lactation (p < 0.05 and p < 0.001, respectively). Metabolic profiling revealed an improved glucose and lipid homeostasis in PF sows, with lower Non-Esterified Fatty Acids (NEFAs) levels and more favorable cholesterol profiles (p < 0.05 for all). No remarkable differences were observed in welfare biomarkers (salivary cortisol and alpha-amylase) among treatments. These findings suggest that precision feeding enhances feed efficiency, stabilizes maternal metabolism, and improves piglet growth in traditional swine breeds (“fatty pigs”) like the Iberian pig, offering a sustainable strategy for intensifying production without compromising animal welfare. Full article

Background/Objectives: Both HIV infection and antiretroviral therapy contribute to dyslipidemia and abnormal body fat distribution in people living with HIV (PLWH). Exercise training is an effective intervention to protect against these metabolic changes. However, little is known about the mechanisms underlying the impact of exercise training on lipid metabolism in PLWH. This study aimed to comparatively evaluate the effect of high-intensity functional circuit training on the plasma lipidome of PLWH and HIV-negative subjects (control). Methods: PLWH (n = 13) and control (n = 14) were submitted to 8 weeks of exercise training. Body composition, anthropometric, and biochemical parameters were measured. Plasma was obtained in a fasting state for lipidomic analysis. Results: Anthropometric and biochemical parameters revealed lower levels of leptin, HDL-C, body fat %, and BMI combined with elevated aspartate transaminase (AST) and Homeostasis Model Assessment of β-cell function (HOMA_beta) in PLWH when compared to control subjects that persisted from baseline to post-exercise training. Nonetheless, contrasting levels of adiponectin, fasting insulin, and phosphatidylcholine-containing lipids observed at baseline were equalized after training in PLWH. In control subjects, significant reductions in concentrations of triglycerides alongside phosphatidylinositol and glycosylated ceramides were observed post-exercise training. By contrast, PWLH displayed an increase in diglycerides, acylcarnitines, and free cholesterol levels after exercise training, together with decreased concentrations of free fatty acids, cholesteryl esters, and glycosylated ceramides. Conclusions: In addition to specific lipidome alterations in each group, particularly driven by improved insulin resistance in PLWH, this study showed concomitant modulation of several glycerophospholipids and sphingolipids, suggesting health-promoting effects of short-term exercise training. Collectively, these modulated lipid species represent interesting targets for future lipidomic-based studies evaluating not only the effects of exercise training but also the molecular mechanisms resulting in a healthier plasma lipidome profile. Full article

This study investigated the systemic metabolic effects of feeding a Fusarium-contaminated diet to early-lactation Holstein cows, with or without a mycotoxin-deactivating product (MDP; Mycofix^® Plus, BIOMIN Holding GmbH, Tulln, Austria). Thirty cows were divided into three dietary groups: a mildly contaminated control (CTR), a moderately contaminated diet containing zearalenone and deoxynivalenol (MTX), and the same contaminated diet supplemented with MDP. Plasma collected at 56 days in milk was analyzed by untargeted ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS), and multivariate models identified discriminant metabolites and pathways. MTX-fed cows showed alterations in sphingolipid metabolism, including accumulation of ceramide (t18:0/16:0), lactosylceramide, and sphinganine 1-phosphate, consistent with ceramide synthase inhibition and lipid remodeling stress. Increases in estradiol, estrone, and cholesterol sulfate suggested endocrine disruption, while elevated 8-oxo-dGMP indicated oxidative DNA damage. MDP supplementation mitigated these alterations, reducing sphingolipid intermediates, modulating tryptophan and glycerophospholipid pathways, and lowering oxidative stress markers. Metabolites such as riboflavin, pipecolic acid, and N-acetylserotonin could be likely associated with an improved mitochondrial function and redox homeostasis, although future studies are required to confirm this hypothesis. Additionally, MDP-fed cows exhibited distinct shifts in pyrimidine and nucleotide metabolism. Overall, MDP effectively counteracted Fusarium-related metabolic disturbances, supporting its protective role in maintaining lipid balance, hormonal stability, oxidative control, and metabolic resilience. Full article

Background/Objectives: Insulin resistance (IR) is a key feature of metabolic disorders and a major precursor of type 2 diabetes and cardiovascular disease. The triglyceride–glucose (TyG) index and TyG-based indices—including TyG–body mass index (TyG–BMI), TyG–waist circumference (TyG–WC), and TyG–waist-to-height ratio (TyG–WHtR), have been proposed as simple, cost-effective surrogate markers of IR. However, population-based data from Türkiye are limited. To evaluate the association between TyG-based indices, triglycerides/high-density lipoprotein cholesterol (TG/HDL-C) ratio, and IR defined by Homeostasis Model Assessment–IR (HOMA-IR) in adults from the TEKHAP study—a province-wide, population-based survey in Tokat, Türkiye. Methods: A total of 1854 adults (≥20 years) were included in the analysis. Physiologically implausible HOMA-IR outliers were identified using statistical criteria and excluded. IR was defined as HOMA-IR ≥ 2.46, previously validated in this population. TyG and its derivatives were calculated from fasting triglyceride, glucose, and anthropometric measurements. Group comparisons between IR and non-IR individuals, correlation analyses, receiver operating characteristic (ROC) curves, and multivariate logistic regression models were conducted to evaluate the diagnostic and independent associations of these surrogate markers with IR. Results: IR prevalence was 27.2%. Participants with IR had significantly higher triglycerides, fasting glucose, insulin, C-peptide, BMI, and waist circumference and lower HDL-C levels (all p < 0.001). All TyG-based indices were higher in the IR group and showed weak-to-moderate positive correlations with HOMA-IR. TyG–BMI showed the highest diagnostic accuracy in ROC curve analyses (AUC = 0.765); however, this association could not be interpreted as an independent predictive effect in adjusted models because of collinearity with BMI. In multivariable logistic regression, the TyG index demonstrated the strongest independent association with IR (OR = 4.14; 95% CI: 3.32–5.18; p < 0.001), while TyG–WC and the TG/HDL-C ratio also retained significant independent predictive value. Conclusions: The TyG index showed the strongest independent association with IR, while the TG/HDL-C ratio and TyG–WC also demonstrated significant independent predictive value. TyG-based indices may represent practical, low-cost surrogate markers for early metabolic risk stratification in community settings; however, their role in formal screening strategies requires external validation and calibration in independent populations. Full article

Background: Two natural steroids derived from cholesterol pathways are testosterone and progesterone, androgen and antiandrogen receptor binding. Steroid androgen antagonists can be prescribed to treat an array of diseases and disorders such as gender dysphoria. In men, androgen antagonists are frequently used to treat prostate cancer and hyperplasia. Sex hormones regulate the expression of the viral receptors in COVID-19 progression, and these hormones may act as a metabolic signal-mediating response to changes in glucose and Reactive Oxygen Species (ROS). The objective of the present study is to use artificial intelligence (AI) applications in healthcare to predict the targets and to assess biological assays of novel steroid derivatives prepared in house from the commercially available 16-dehydropregnenolone acetate (DPA^®) aimed at achieving the metabolic stability of glucose and steroid brain homeostasis. This suggests the introduction of aromatic or aliphatic structures in the steroid B-ring and D-ring. This is important since the roles of 5α-reductase and ROS in brain control of glucose and novel steroids homeostasis remain unclear. Methods: A tool prediction was used as a tuned algorithm, with the novel steroid derivatives data in web interface to carry out their pharmacological evaluation. The new steroidal derivatives were determined with neuroprotection effect using the select biomarkers of oxidative stress on induced hypoglycemic male rat brain and liver. The enzyme kinetics was established by the inhibition of the 5α-reductase enzyme on the brain myelin. Results: We used novel chemical structures to order the information of a Swiss data bank that allow target predictions. Biological assays suggest that steroid derivatives with an electrophilic center can interact more efficiently with the 5α-reductase enzyme, and by this way, induce neuroprotection in hypoglycemia model. All compounds were synthesized with a yield of 30–80% and evaluated with tool target prediction to understand the molecular mechanisms underlying a given phenotype or bioactivity and to rationalize possible favorable or unfavorable side effects, as well as to predict off-targets of known molecules and to clear the way for drug repurposing. Apart, they turned out to be good inhibitors for the 5α-reductase enzyme. Conclusions: The probed efficacy of these novel steroids with respect to spironolactone control appears to be a promising compound for future hormonal therapy with neuroprotection activity in glucose disorder status. However, further research with clinically meaningful endpoints is needed to optimize the use of androgen antagonists in these hormonal therapies in COVID-19 progression. Full article

We present a mathematical analysis of the sterol regulatory element-binding protein 2 (SREBP-2) pathway, a key regulator of intracellular cholesterol homeostasis. Using a compartment model formulated as a nonlinear system of ordinary differential equations, we investigate stability via M-matrix theory and norm-based criteria. We show that the Frobenius norm ${\parallel B\parallel }_F\ge 1$ cannot ensure stability, whereas the infinity norm condition ${\parallel B\parallel }_{\infty }<1$ provides a practical guarantee that the spectral radius $\rho \left(B\right)<1$. The spectral norm ${\parallel B\parallel }_2$ yields sharper intermediate bounds. Numerical simulations confirm these results, highlighting parameter regions of stability and showing that the dissociation rate $k_{-1}$ has the strongest influence on system behavior. These findings demonstrate the robustness of the ${\mathsf{\ell }}_{\infty }$ criterion, clarify the role of dissociation kinetics in cholesterol regulation, and provide a rigorous framework for assessing homeostatic control in the SREBP-2 pathway. Full article

High-grade serous ovarian cancer (HGSOC) is the most commonly diagnosed ovarian cancer subtype. Approximately half of all patients diagnosed with HGSOC are deficient in homologous recombination (HR), harbor BRCA1/2 mutations, and are treated with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis). FDA-approved PARPis Olaparib, Niraparib, and Rucaparib all contribute to adverse effects in patients due to their poly-pharmacological properties. This feature necessitates investigation of global protein responses to PARPi treatment beyond DNA repair in the context of BRCA mutational status and HR deficiency. We sought to determine the landscape of differential PARPi-induced proteomes in HGSOC cells exhibiting different BRCA1/2 mutational statuses. Here, we applied immunofluorescence microscopy to detect γH2AX, Rad51, and geminin foci as markers of DNA damage and repair upon treatment of HGSOC cells with IC₅₀ doses of PARPis. Global proteome perturbations upon PARPi treatment were measured using quantitative mass spectrometry-based proteomics. The proteomic data highlighted cell line effects, masking high-dose PARPi treatment response. Interrogation of PARPi response within biological pathways identified through gene set enrichment analysis (GSEA) revealed significant changes to proteins involved in Epithelial–Mesenchymal Transition (EMT), E2F targets, and cholesterol homeostasis. Our study establishes proteomic evidence supporting the poly-pharmacological characteristics of Niraparib, Olaparib, and Rucaparib in HGSOC cells. Full article