This study aimed to investigate the effects of cocaine- and amphetamine-regulated transcript peptide (CART) on the secretory function of bovine ovarian granulosa cells (GCs) and the metabolic micro-environment of follicular fluid. We employed untargeted metabolomics to analyze the metabolite profile of GC culture medium after treatment with CART55-102, and integrated these data with transcriptomic and intracellular metabolomic data from the same experimental model. In the positive and negative ion modes, we identified 77 and 193 differential metabolites, respectively. Among these, we observed a significant decrease in glucose concentration and a significant increase in cholesterol concentration in the culture medium. Joint pathway enrichment analysis revealed that 6 and 17 Kyoto encyclopedia of genes and genomes (KEGG) pathways were commonly enriched by both differential genes and differential metabolites in the positive and negative ion modes, respectively. KEGG markup language (KGML) network analysis showed direct associations of LRRC51 with cholesterol and 16α-hydroxyestrone in the steroid biosynthesis pathway, ATP2B2 and CALML4 with cholesterol in the aldosterone synthesis and secretion pathway, and UROC1 with thiourocanic acid in the histidine metabolism pathway. On the basis of our previous intracellular metabolomic data (increased intracellular glucose and decreased intracellular cholesterol), the results of this study indicate that CART promotes glucose uptake by GCs but inhibits its intracellular oxidative utilization, leading to an increase in intracellular glucose content. At the same time, CART suppresses de novo cholesterol synthesis and promotes cholesterol release into the extracellular space, resulting in elevated extracellular cholesterol levels. In conclusion, this study proposes a potential novel mechanism hypothesis for CART inhibition of follicular development from a metabolic secretion perspective. That is, CART may remodel GC energy metabolism and cholesterol homeostasis to reshape the follicular fluid microenvironment. Our findings provide a new theoretical basis for understanding the regulatory mechanisms of bovine follicular development and have important reference value for improving the reproductive efficiency of cows and promoting the sustainable development of the cattle industry.

The global trend toward low-fat diets is creating a critical need for efficient fat replacement technologies. This study explored the stabilization behavior of soybean protein isolate (SPI)-citrus pectin (CP) Pickering emulsions and their effectiveness as butter substitutes in pound cakes. The results indicated that emulsions with 5% particle concentration (c) and 50% oil phase volume fraction (ϕ) exhibited excellent storage, centrifugal, thermal, and lipid oxidation stability. It also demonstrated superior structural and rheological properties, effectively replicating the physical characteristics of butter. Moreover, replacing butter with SPI-CP Pickering emulsion significantly enhanced the quality of pound cakes, with a 40% substitution level proving optimal. At this ratio, the specific volume increased by 21.01%, while hardness and chewiness decreased by 57.48% and 52.43%, respectively. Meanwhile, a decrease in fat migration capacity was observed, along with increases in in vitro cholesterol adsorption capacity and sodium cholate adsorption capacity. Electronic nose analysis confirmed similar aroma profiles, and sensory evaluation yielded the highest scores, indicating that the SPI-CP-stabilized emulsion effectively maintained cake quality while serving as a butter alternative. This study offers valuable insights for developing low-fat foods and novel functional ingredients.

Intestinal barrier integrity is of paramount importance for our health. Several food constituents and contaminants have been described for positive or detrimental effects, however, a correlation between gut associated disorders and xenobiotics exposures remains challenging and modeling options limited. This study presents a NAMs-based hybrid in vitro/in silico workflow to investigate, and eventually prioritize, foodborne xenobiotics for their effect on gut barrier homeostasis. Model compounds comprised endocrine-active chemicals, such as plastic components (bisphenol A, bisphenol F), phytoestrogens (chrysin, daidzein, genistein), mycotoxins (alternariol, zearalenone), and natural/synthetic steroids (17-β-estradiol, cholesterol, levonorgestrel). Plasticizer diisodecyl phthalate was included as foodborne, non-endocrine active substance. The Caco-2/HT29-MTX-E12 intestinal epithelial co-culture was used to design a workflow capable of grasping discrete alterations in tight junction organization. The protein claudin-4 was taken as reference to study the structural organization along cell-cell contacts. Complementarily, docking and molecular dynamics simulations were applied to explore ligand-claudin-4 interactions, providing a pipeline which is potentially suitable to screen larger compounds libraries. Finally, proof-of-principle experiments including repeated exposures to reference compound 17-β-estradiol and plasticizer diisodecyl phthalate, supported the plausibility of a functional impairment of claudin-4. Both compounds significantly increased epithelial permeability without altering cell viability, indicating selective modulation of mechanical barrier properties. Together, this work outlines a mechanistic toolbox for the study of the potential of orally derived xenobiotics in modulating intestinal homeostasis.

In 2025, the focused update of the ESC/EAS guidelines on dyslipidemia management introduced clinically relevant refinements in cardiovascular risk stratification and lipid-lowering therapy. The updated recommendations emphasize the integration of additional risk modifiers, including comorbidities, biomarkers and imaging findings, enabling a more individualized assessment of cardiovascular risk. In patients with acute coronary syndrome, the updated guidance highlights the importance of rapid and intensive LDL cholesterol reduction during the index hospitalization, including prompt initiation of high-intensity statin therapy and early combination treatment to facilitate target achievement. Recent evidence further supports early intensive LDL cholesterol lowering, with outcome data for bempedoic acid and PCSK9 inhibitors extending the role of LDL cholesterol lowering beyond secondary prevention. At the same time, emerging evidence on statin safety indicates that a substantial proportion of commonly reported adverse effects are not causally related to statin therapy, underscoring the relevance of patient education and structured communication to improve adherence. Beyond LDL cholesterol, other lipid fractions have gained increasing clinical relevance. Lipoprotein(a) has emerged as an important genetically determined cardiovascular risk factor, and several therapies capable of markedly reducing lipoprotein(a) levels are currently being evaluated in large, randomized outcome trials. In hypertriglyceridemia, conventional therapies have shown limited benefit regarding cardiovascular outcomes. Novel targeted approaches, particularly therapies directed against apolipoprotein C-III, therefore represent promising future treatment strategies. Overall, recent developments highlight a shift toward earlier, more intensive, and more individualized lipid-lowering strategies, with emerging therapies likely to further expand cardiovascular prevention in the coming years.

The pathological hallmarks of neurodegeneration are the aberrant post-translational modification and aggregation of proteins. Genetic factors, like APOE4, increase the prevalence and severity of tau, amyloid, and α-synuclein pathologies. However, the human brain is largely inaccessible during this process, limiting mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, and cerebrovascular cells into a human brain-like tissue ("miBrain"). Single-nucleus RNA sequencing of miBrains confirmed the presence of diverse cell populations and revealed transcriptional responses to α-synuclein pathology. Like the human brain, pathogenic α-synuclein is increased in APOE4/4 miBrains. Combinatorial experiments revealed that endolysosomal dysfunction caused by cholesterol accumulation in APOE4/4 astrocytes impairs the degradation of soluble α-synuclein leading to a pathogenic transformation that seeds α-synuclein inclusions in neurons. Collectively, this study establishes a robust model for investigating protein inclusions in human iPSC-derived brain tissue and highlights the role of astrocytes and cholesterol in APOE4-mediated pathologies.

The function of ovarian granulosa cells is central to follicular development and hormone production. To identify miRNAs associated with estrous status, we performed miRNA sequencing on ovaries from gilts that displayed estrus (ES) or remained non‑estrus (NES). miR‑130a‑5p was significantly upregulated in NES ovarian follicular tissues. In primary porcine granulosa cells, miR-130a-5p overexpression reduced estradiol(E2) secretion and decreased the abundance of key steroidogenic proteins, whereas miR-130a-5p inhibition increased E2 and progesterone(P4) secretion. miR-130a-5p also altered lipid droplet accumulation and the abundance of cholesterol metabolism-related proteins, including HMGCR and LDLR. Integrative target prediction combined with transcriptomic filtering identified apolipoprotein E (APOE) as a candidate target. A dual‑luciferase reporter assay confirmed direct binding of miR‑130a‑5p to the APOE 3'UTR. Functionally, APOE overexpression enhanced E₂ and P₄ secretion and increased lipid accumulation and HMGCR/LDLR expression, whereas APOE knockdown exerted opposite effects. Moreover, APOE overexpression attenuated the inhibitory effects of miR-130a-5p on steroid hormone production and steroidogenesis-related gene expression. Together, these findings identify a miR-130a-5p/APOE axis that links cholesterol metabolism-related processes to steroid hormone synthesis in porcine granulosa cells and provides a candidate pathway for further investigation of endocrine regulation in gilts.

1. This study evaluated the effects of monochromatic lights on lipid metabolism, inflammation and antioxidant capacity in broilers. Eighty newly hatched broilers were assigned to four treatment groups (n = 20/group) and exposed to white (400-700 nm), red (660 nm), green (560 nm), or blue (480 nm) LED light for 35 d.2. Abdominal adipose tissue histology, tissue weight, plasma hormones, blood biochemistry, lipid metabolism gene/protein expression, antioxidant activity and inflammatory levels were assessed.3. Green and blue light exposure increased abdominal adipose tissue weight, adipocyte size and relative area of lipid droplets (p < 0.05). These groups exhibited elevated high-density lipoprotein cholesterol (HDL-C), adiponectin (adipoQ), very low-density lipoprotein (VLDL) and Triglyceride (TG) levels (p < 0.05), concurrent with reduced free fatty acid (FFA) concentrations in plasma and adipose tissue.4. Green and blue light increased fat synthesis gene expression (Scd1andSrebp1; p < 0.05) while downregulating fatty acid (FA) uptake genes (Cd36; p < 0.001), FA β-oxidation genes (Cpt-1andPPARα; p < 0.05) and lipid export genes (ApoB; p < 0.05) in the liver. Additionally, blue light significantly inhibited lipolysis-related genes (ATGL, HSL, LPL; p < 0.001) to a greater extent than it affected fat synthesis compared with white light in abdominal adipose tissue.5. Both green and blue lights upregulated anti-inflammatory factors (IL-4, IL-10; p < 0.05), elevated glutathione (GSH), total glutathione (T-GSH) and oxidised glutathione/glutathione (GSSG/GSH) ratios (p < 0.05) and reduced malondialdehyde (MDA) levels (p < 0.001) and pro-inflammatory markers (IL-6, IL-1β, TNF-α) (p < 0.05). Notably, green light treatment had the highest total antioxidant capacity (T-AOC) in the liver and abdominal adipose tissues.6. The results suggested exposure to monochromatic blue and green light leads to lipid accumulation, decreased inflammation and improved antioxidant capacity and green light may offer superior protection against oxidative stress.

Antipsychotic-associated metabolic abnormalities vary considerably between drugs, but the receptor mechanisms contributing to lipid-related liability remain incompletely resolved. The integrated Ki-defined daily dose-transcriptome-wide association study (Ki-DDD-TWAS) score is a computational prioritization index derived from receptor-binding affinities, defined daily doses, and ancestry-stratified transcriptome-wide association study (TWAS) summary statistics; it is not a validated patient-level clinical risk predictor. We evaluated the sensitivity of an integrated Ki-DDD-TWAS prioritization framework to the removal of literature-derived receptor weights in ancestry-stratified low-density lipoprotein cholesterol (LDL) analyses. Saved outputs were available for 52 antipsychotics and five ancestry-defined LDL datasets: African, East Asian, European, Hispanic, and South Asian groups. Two models were compared: a literature-weighted model incorporating predefined metabolic receptor priors and a uniform model assigning a weight of 1.0 to all recognized receptor genes. Stage 3 analyses reconstructed receptor-level contributions and examined gene-direction consistency, ancestry-specific drivers, drug-rank correlations, rank stability, top-10 Jaccard similarity, leave-one-gene-out sensitivity, high-TWAS/low-weight candidates, and weighted-versus-uniform mean-rank differences. Removing literature priors produced a large shift in relative reconstructed model contribution from histaminergic and serotonergic systems toward dopaminergic receptors. Dopaminergic contribution increased by 26.41 percentage points, whereas histaminergic contribution decreased by 16.76 percentage points. All 39 genes represented in the exported direction-consistency analysis changed in the same direction across all five ancestry datasets. Dopamine Receptor D2 (DRD2) was the leading gene-level contributor under the uniform model in every ancestry. Cross-ancestry drug-rank correlations were very high in both models, with mean off-diagonal Spearman correlations of 0.996 for the weighted model and 0.995 for the uniform model. The weighted model had complete top-10 set identity across ancestry pairs, whereas the mean top-10 Jaccard similarity under uniform weighting was 0.758. ADRB1 was the strongest high-TWAS/low-weight candidate, with a maximum absolute z-score of 6.079, but it met the candidate threshold in only one ancestry. These findings indicate that literature-derived priors strongly shape model-based mechanistic attribution while exerting a smaller influence on broad drug ordering. The weighted model is best regarded as a clinically informed reference model, whereas the uniform model is a sensitivity and hypothesis-generation analysis. Because the five ancestry runs shared the same Ki matrix, defined daily dose (DDD) values, receptor map, and prior dictionary and lacked patient-level LDL validation, these findings describe computational model behavior rather than ancestry-specific clinical risk. Neither model is a validated clinical risk predictor, nor does either provide evidence of causal receptor mechanisms.

Primary pancreatic ductal adenocarcinoma (PDAC) and hepatic metastases grow in anatomically distinct niches defined by organ-specific extracellular matrix (ECM) cues related to matrix composition and biomechanics such as substrate stiffness. Metabolic remodeling is a fundamental mechanism by which PDAC cells adapt to environmental stress. However, whether ECM actively imposes site-dependent metabolic liabilities remains unclear. To this end, we developed a digital light processing-printable GelMA-dECM platform incorporating decellularized pancreas- or liver-derived ECM under controlled three-dimensional culture conditions. Single-cell analysis and immunohistochemical staining of human tissues revealed a site-associated metabolic divergence, with primary pancreatic lesions enriched in cholesterol/mevalonate associated markers and liver metastases displaying stronger fatty acid synthesis signatures. Consistently, pancreas-dECM promoted HMGCS1/HMGCR-associated cholesterol and mevalonate programs in PDAC cells, whereas liver-dECM induced FASN/ACC1-associated fatty acid synthesis and lipid droplet accumulation. Increased matrix stiffness enhanced YAP activation and amplified lipid metabolic output without overriding the dECM-defined metabolic direction, indicating a mechanical amplifier role. Functionally, these matrix-encoded metabolic states predicted therapeutic vulnerability. Cholesterol/mevalonate pathway inhibition preferentially sensitized pancreas-dECM constructs and pancreatic-site tumors to gemcitabine, whereas fatty acid synthesis inhibition was more effective in liver-dECM constructs and liver-site tumors. These findings identify that organ-specific ECM defines the direction of lipid metabolic programming, whereas matrix stiffness amplifies the magnitude of this program. Together, these matrix-encoded metabolic states create site-matched therapeutic vulnerabilities in PDAC. Our study provides a potentially generalizable platform for supporting scalable microenvironment-guided modeling of site-specific tumor metabolism and therapeutic screening.