Search Results (382)

Background: Exposure to per- and polyfluoroalkyl substances (PFAS, including 7H-Perfluoro-4-methyl-3,6-dioxaoctanesulfonic acid (PFESA-BP2), perfluorooctanoic acid (PFOA), and hexafluoropropylene oxide (GenX), has been associated with liver dysfunction. While previous research has characterized PFAS-induced hepatic lipid alterations, their downstream effects on energy metabolism remain unclear. This study investigates metabolic alterations in the liver following PFAS exposure to identify mechanisms leading to hepatoxicity. Methods: We analyzed RNA sequencing datasets of mouse liver tissues exposed to PFAS to identify metabolic pathways influenced by the chemical toxicant. We integrated the transcriptome data with a mouse genome-scale metabolic model to perform in silico flux analysis and investigated reactions and genes associated with lipid and energy metabolism. Results: PFESA-BP2 exposure caused dose- and sex-dependent changes, including upregulation of fatty acid metabolism, β-oxidation, and cholesterol biosynthesis. On the contrary, triglycerides, sphingolipids, and glycerophospholipids metabolism were suppressed. Simulations from the integrated genome-scale metabolic models confirmed increased flux for mevalonate and lanosterol metabolism, supporting potential cholesterol accumulation. GenX and PFOA triggered strong PPARα-dependent responses, especially in β-oxidation and lipolysis, which were attenuated in PPARα^−/− mice. Mitochondrial fatty acid transport and acylcarnitine turnover were also disrupted, suggesting impaired mitochondrial dysfunction. Additional PFAS effects included perturbations in the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and blood–brain barrier (BBB) function, pointing to broader systemic toxicity. Conclusions: Our findings highlight key metabolic signatures and suggest PFAS-mediated disruption of hepatic and possibly neurological functions. This study underscores the utility of genome-scale metabolic modeling as a powerful tool to interpret transcriptomic data and predict systemic metabolic outcomes of toxicant exposure. Full article

Cholesterol stress profoundly modulates cellular processes, but its underlying mechanisms remain incompletely understood. To investigate cholesterol-responsive networks, we performed integrated transcriptome (RNA-seq) and metabolome (LC-MS) analyses on HeLa cells treated with cholesterol for 6 and 24 h. Through transcriptomic analysis of cholesterol-stressed HeLa cells, we identified stage-specific responses characterized by early-phase stress responses and late-phase immune-metabolic coordination. This revealed 1340 upregulated and 976 downregulated genes after a 6 h cholesterol treatment, including induction and suppression of genes involved in cholesterol efflux and sterol biosynthesis, respectively, transitioning to Nuclear Factor kappa-B (NF-κB) activation and Peroxisome Proliferator-Activated Receptor (PPAR) pathway modulation by 24 h. Co-expression network analysis prioritized functional modules intersecting with differentially expressed genes. We also performed untargeted metabolomics using cells treated with cholesterol for 6 h, which demonstrated extensive remodeling of lipid species. Interestingly, integrated transcriptomic and metabolic analysis uncovered GFPT1-driven Uridine Diphosphate-N-Acetylglucosamine (UDP-GlcNAc) accumulation and increased taurine levels. Validation experiments confirmed GFPT1 upregulation and ANGPTL4 downregulation through RT-qPCR and increased O-GlcNAcylation via Western blot. Importantly, clinical datasets further supported the correlations between GFPT1/ANGPTL4 expression and cholesterol levels in Non-Alcoholic Steatohepatitis (NASH) liver cancer patients. This work establishes a chronological paradigm of cholesterol sensing and identifies GFPT1 and ANGPTL4 as key regulators bridging glycosylation and lipid pathways, providing mechanistic insights into cholesterol-associated metabolic disorders. Full article

Monascus purpureus is a filamentous fungus renowned for producing bioactive secondary metabolites, including lovastatin and azaphilone pigments. Lovastatin is valued for its cholesterol-lowering properties and cardiovascular benefits, while Monascus pigments exhibit anti-cancer, anti-inflammatory, and antimicrobial activities, underscoring their pharmaceutical and biotechnological relevance. This study evaluated the impact of carbohydrate-derived elicitors—mannan oligosaccharides, oligoguluronate, and oligomannuronate—on the enhancement of pigment and lovastatin production in M. purpureus C322 under submerged fermentation. Elicitors were added at 48 h in shake flasks and 24 h in 2.5 L stirred-tank fermenters. All treatments increased the production of yellow, orange, and red pigments and lovastatin compared to the control, with higher titres upon scale-up. OG led to the highest orange pigment yield (1.2 AU/g CDW in flasks; 1.67 AU/g CDW in fermenters), representing 2.3- and 3.0-fold increases. OM yielded the highest yellow and red pigments (1.24 and 1.35 AU/g CDW in flasks; 1.58 and 1.80 AU/g CDW in fermenters) and the highest lovastatin levels (10.46 and 12.6 mg/g CDW), corresponding to 2.03–3.03-fold improvements. These results highlight the potential of carbohydrate elicitors to stimulate metabolite biosynthesis and facilitate scalable optimisation of fungal fermentation. Full article

Our previous study has shown that supplementation of 0.50% benzoic acid (BA) increased growth performance, promoted rumen fermentation, and improved the composition and function of rumen microbiota. This research was designed to conduct a deeper exploration of the impacts of dietary supplementation with BA on the apparent digestibility of nutrients and the composition of rectal microbiota in weaned Holstein dairy calves. Sixteen Holstein heifer calves with similar body weights (91.2 ± 0.7 kg) were selected and randomly allocated into two groups, each comprising eight calves. Calves in the control group (CON group) were fed with a basal diet, while those in the benzoic acid group (BA group) were fed with the basal diet supplemented with 0.50% benzoic acid (on a dry matter basis). The experimental period started at 60 days of age and ended at 102 days of age, lasting for a total of 42 days. The calves were weaned at 60 days of age, with a transition period of 7 days. Feed samples were collected every two weeks, fecal samples were collected from 99 to 101 days of age, and blood samples were collected at 102 days of age. The results showed that supplementation with BA did not influence the digestibility of dry matter, crude protein, ether extract, neutral detergent fiber, acid detergent fiber, calcium, and phosphorus between the two groups. Compared with the CON group, BA supplementation tended to decrease the total cholesterol (TC) in the serum of the calves (p = 0.067). Supplementation with BA increased the relative abundances of the two beneficial bacteria, Bifidobacterium and Bifidobacterium pseudolongum (p < 0.05, LDA > 2), but decreased that of the harmful bacterium, Clostridium sensu stricto 1, in the rectum of dairy calves. The microbial functional prediction revealed that the fecal microbial metabolism involved in primary bile acid biosynthesis was higher in the calves from the BA group. In conclusion, the present study demonstrated that adding 0.50% BA to the diet did not influence the apparent nutrient digestibility, but improved rectal microbiota health, which finally promoted the growth performance in weaned Holstein dairy calves. Full article

Smith–Lemli–Opitz syndrome (SLOS) is a rare, autosomal recessive genetic disorder caused by mutations in the DHCR7 gene, which encodes the enzyme responsible for the final step in cholesterol biosynthesis. Impaired enzyme function leads to cholesterol deficiency, affecting the development and function of the entire organism. The accumulation of cholesterol precursors enhances the formation of oxysterols, which are involved in the pathomechanism of neurological, ophthalmological, and vascular changes in patients. This review analyzes 53 studies published between 2020 and 2025 on the molecular mechanisms underlying the clinical features of SLOS, including cholesterol deficiency, oxysterol accumulation, and the latest diagnostic methods, including LC-MS/MS chromatography and biomarkers such as GFAP for monitoring disease progression. MRI is discussed as a supportive tool for neuroimaging, along with advances in prenatal diagnostics, such as the detection of cholesterol precursors in neonatal hair. Therapeutic options are also reviewed, with particular emphasis on cholesterol supplementation, cholic acid, and experimental treatments such as vitamin E supplementation, statin therapy, gene therapy, and liver transplantation. Current research indicates that expanding knowledge in this area not only improves patient prognosis but also provides hope for the development of effective therapies in the future. Full article

High-grade osteosarcoma (HGOS) is the most common primary malignant bone tumor in children and adolescents. Poor response to chemotherapy is linked to worse prognosis and increased risk of recurrence and metastasis. However, current assessment methods, such as tumor necrosis evaluation, are time-consuming and delay treatment decisions. Thus, identifying molecular pathways and predictive biomarkers is essential for guiding early therapeutic strategies. In this study, RNA-seq analysis of HGOS tissues revealed enrichment of cholesterol biosynthesis and mitotic pathways in poor responders. Additionally, high HMGCR expression, as analyzed from TCGA data, was associated with poor prognosis in sarcoma. Functional validation using SaOS-2 cells, which exhibited poor drug sensitivity and elevated HMGCR levels, demonstrated that simvastatin enhanced the efficacy of cisplatin and doxorubicin by inducing mitochondrial-mediated apoptosis and downregulating anti-apoptotic proteins. Simvastatin also reduced cell migration and invasion by suppressing epithelial–mesenchymal transition and extracellular matrix degradation. Mechanistically, simvastatin disrupted Ras prenylation and inhibited downstream oncogenic signaling pathways, including Akt/mTOR and Akt/GSK3, which regulate survival and metastasis-associated gene expression. These findings suggest that the cholesterol biosynthesis pathway particularly plays a critical role in chemoresistance and metastasis in HGOS and may serve as a promising predictive molecular target for guiding early therapeutic strategies. Full article

Cholesterol homeostasis is necessary for normal vertebrate development. The disruption of cholesterol homeostasis can cause abnormal body and nervous system development and lead to dysfunctional behavior and increased mortality. Commonly prescribed psychopharmaceuticals can alter cholesterol synthesis and may disrupt early vertebrate development. A high-throughput vertebrate zebrafish model system was used to test the hypothesis that exposure to psychopharmaceutical medications alters cholesterol biosynthesis and disrupts gene transcription, early whole-body and brain development, and nervous system function, resulting in abnormal behavior. Exposure to cariprazine, aripiprazole, trazodone, and AY9944 increased 7-dehydrocholesterol levels compared to vehicle-treated zebrafish. Significant differences in disease-associated gene expression, brain structure, and functional behaviors were observed in psychopharmaceutical and AY9944-treated zebrafish compared to controls. These data reveal that the high-throughput zebrafish model system can discern psychopharmaceutical effects on cholesterol synthesis, gene transcription, and key features of early vertebrate development that influences behavior. Full article

This study aims to clarify the dose–response relationship between dietary β-carotene levels and gonadal pigment deposition and regulation mechanisms related to the carotenoid synthesis of Strongylocentrotus intermedius based on a 60-day feeding trial and subsequent transcriptome analysis. Adult sea urchins (initial weight: 9.33 ± 0.21 g) of three cages were given one of the dry feeds with different doses of β-carotene (0 mg/kg, 150 mg/kg, 300 mg/kg) or fresh kelp (Saccharina japonica). The results indicated that the weight gain rate (WGR) of sea urchins increased with the addition of β-carotene, with that of the C300 group being markedly higher than that of the C0 group. The addition of β-carotene significantly improved the redness (a*) and yellowness (b*) values of the gonads, with sea urchins in the C300 group exhibiting closest gonad coloration to those in the kelp-fed group. Meanwhile, β-carotene and echinenone in the gonads of the C300 group showed the highest contents, reaching 1.96 μg/kg and 11.97 μg/kg, respectively. Several differential genes, enriched in the pathways of steroid biosynthesis, oxidative phosphorylation, and ubiquitination, were screened based on transcriptome analysis. Real-time PCR further demonstrated that β-carotene significantly upregulated the expression of cholesterol 25-hydroxylase (CH25H), NADH dehydrogenase subunit 1 (ND1), NADH dehydrogenase subunit 2 (ND2), and NADH dehydrogenase subunit 4 (ND4) while it downregulated the expression of 24-dehydrocholesterol reductase (DHCR24). These results showed that 300 mg/kg β-carotene significantly increased the WGR, redness, and yellowness values, as well as the contents of β-carotene and echinenone in the gonads of S. intermedius. On the one hand, dietary β-carotene increased NADH enzyme activity, which participates in echinenone synthesis by donating electrons for the transformation of β-carotene to echinenone synthesis. On the other hand, the addition of β-carotene inhibited cholesterol synthesis by increasing the expression of CH25H and decreasing the expression of DHCR24, which could in turn increase the fluidity and permeability of the cell membranes and the transport efficiency of β-carotene and echinenone from the digestive tract to the gonads. These results provided fundamental insights into the production of sea urchin gonads with market-favored colors. Full article

Granulosa cell (GC) dysfunction contributes to diminished ovarian reserve (DOR). We collected GC and follicular fluid samples from the patients of normal ovarian reserve (NOR) and DOR. RNA-seq of GCs showed that cholesterol/sterol metabolism and biosynthesis and extracellular matrix organization were enriched in the DOR group. Metabolomics of follicular fluid revealed enrichment in steroid hormone biosynthesis, tryptophan metabolism, and fatty acid β-oxidation in DOR. The apoptosis rate was increased, whereas the proliferative rate was decreased in GCs of DOR. The Prussian blue staining rate was increased whilst GPX4 and SLC7A11 expression were downregulated in GCs of DOR. Mitochondrial morphology displayed the features of ferroptosis in GCs of DOR. FSHR, CYP19A1, NR5A1, and phosphorylated CREB levels were substantially downregulated in GCs, accompanied by increased androgen levels in follicular fluids in DOR. The key factors linked to the mevalonate pathway, HMGCR, SQLE, and SREBF2, were robustly increased in DOR. FSHR and NR5A1 levels were correlated with CYP19A1 levels, whilst CYP19A1 levels were positively correlated with GPX4 and SLC7A11 levels. Our findings indicate ferroptosis and dysregulation of cholesterol/sterol metabolism and biosynthesis occurrence in GCs of DOR, which might be associated with reduced FSHR signaling and decreased conversion of androgen to estrogen. Full article

Cytochromes P450 (CYPs) form one of the largest enzyme superfamilies, with similar structural folds yet biological functions varying from synthesis of physiologically essential compounds to metabolism of myriad xenobiotics. Sterol 14α-demethylases (CYP51s) represent a very special P450 family, regarded as a possible evolutionary progenitor for all currently existing P450s. In metazoans CYP51 is critical for the biosynthesis of sterols including cholesterol. Here we determined the crystal structures of ligand-free CYP51s from the abyssal fish Coryphaenoides armatus and human-. Comparative sequence–structure–function analysis revealed specific structural elements that imply elevated conformational flexibility, uncovering a molecular basis for faster catalytic rates, lower substrate selectivity, and intrinsic resistance to inhibition. In addition, the C. armatus structure displayed a large-scale repositioning of structural segments that, in vivo, are immersed in the endoplasmic reticulum membrane and border the substrate entrance (the FG arm, >20 Å, and the β4 hairpin, >15 Å). The structural distinction of C. armatus CYP51, which is the first structurally characterized deep sea P450, suggests stronger involvement of the membrane environment in regulation of the enzyme function. We interpret this as a co-adaptation of the membrane protein structure with membrane lipid composition during evolutionary incursion to life in the deep sea. Full article

Microcystin-leucine arginine (MC-LR) is a prominent water pollutant known for its potent hepatic toxicity. However, the effects of subchronic exposure to environmentally relevant concentrations of MC-LR on the fish liver remain poorly understood. This study aimed to systematically evaluate the impact of subchronic MC-LR exposure on the liver of darkbarbel catfish (Tachysurus vachelli). A total of 270 one-year-old fish were exposed to MC-LR (0, 2, and 5 μg/L) for 28 days and sampled on days 14 (D14) and 28 (D28). Histopathological analysis revealed marked hepatic inflammation in the MC-LR treatment groups, manifested as cellular degeneration, hyperemia, and inflammation. MC-LR exposure induced oxidative stress, evidenced by elevated malondialdehyde (MDA) levels and compensatory upregulation of superoxide dismutase (SOD) activity on D28. While hepatic lipid profiles were not altered by low-dose MC-LR, significant elevation of low-density lipoprotein cholesterol (LDL-C) specifically on D28 indicated incipient lipid metabolic disorder. Metabolomic analysis demonstrated a higher sensitivity, highlighting the stress response of the liver to low-dose MC-LR exposure. The results suggest MC-LR exposure disrupted hepatic phosphatidylcholine (PC) biosynthesis and inhibited lipoprotein formation, thereby impairing lipid transport and contributing to lipid metabolic disorders. In summary, subchronic exposure to environmentally relevant concentrations of MC-LR-induced hepatic tissue inflammation, oxidative stress, and lipid metabolic disorders in darkbarbel catfish. Full article

Biochanin A, a naturally occurring isoflavone derived from legumes, possesses anti-inflammatory, estrogenic, and anticancer activities. In this study, we investigated the cytotoxic effects and underlying molecular mechanisms of Biochanin A in acute myeloid leukemia (AML) cell lines, U937 and THP-1, using in vitro cytotoxicity assays, RNA sequencing, and bioinformatic analyses. Biochanin A induced dose-dependent apoptosis, as evidenced by caspase-7 activation and PARP1 cleavage. Over-representation analysis (ORA) revealed that differentially expressed genes (DEGs) were significantly enriched in pathways related to inflammatory responses, DNA replication, and cell cycle regulation. Gene set enrichment analysis (GSEA) further confirmed the upregulation of apoptosis- and inflammation-related pathways and the downregulation of MYC targets, cholesterol biosynthesis, and G2/M checkpoint gene sets. RT-qPCR analysis demonstrated that Biochanin A downregulated oncogenes such as RUNX1, BCL2, and MYC while upregulating CHOP (GADD153), CDKN1A (p21), and SQSTM1 (p62), contributing to apoptosis and cell cycle arrest across both cell lines. Notably, Biochanin A downregulated PLK1 and UHRF1 in THP-1 cells, indicating a disruption of mitotic progression and epigenetic regulation. In contrast, in U937 cells, Biochanin A upregulated TXNIP and downregulated CCND2, highlighting the involvement of oxidative stress and G1/S cell cycle arrest. These findings support the potential of Biochanin A as a promising therapeutic candidate for AML through both shared and distinct regulatory pathways. Full article

Tumor cells alter lipid metabolic pathways to meet their demands for energy and membrane biosynthesis. Despite its crucial role in tumor cell growth, survival, and metastasis, the mechanisms underlying tumor cell lipid metabolic reprogramming remain poorly understood. Pre-B-cell leukemia transcription factor 3 (PBX3), a member of the PBX family, could promote tumorigenesis; however, whether it is involved in tumor lipid metabolic reprogramming remains unknown. Herein, we found that PBX3 significantly promotes tumor growth by enhancing lipid accumulation in HCC cells. By assessing the effect of PBX3 on the expression levels of lipid metabolism-related genes, we found that PBX3 could positively regulate the expression of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), a rate-limiting enzyme in the cholesterol biosynthesis pathway. Mechanistically, we revealed that PBX3 could directly bind to the −167/−151 region of HMGCR promoter, thereby increasing its transcriptional activity and, subsequently, its expression level. This leads to the increase of HCC cell cholesterol biosynthesis and, eventually, to the increase of the in vivo tumorigenic potential. Collectively, our research revealed an unprecedented regulatory mechanism of cholesterol metabolism in HCC cells through PBX3 positive regulation on HMGCR expression levels. These findings provide novel insights into tumor metabolic reprogramming and uncover a previously unknown physiological function for PBX3. Moreover, these results suggest the potential of targeting PBX3 as an anti-tumor therapeutic strategy. Full article

Obesity is an important risk factor for the development of metabolic syndrome disorders. We previously showed that the liver fatty acid-binding protein null mouse (LFABP^−/−) becomes obese upon high-fat diet (HFD) feeding but remains metabolically healthy. Here, we find that the obese LFABP^−/− mouse increases subcutaneous adipose tissue (SAT) mass by markedly increasing the number rather than the size of adipocytes, as is typical with HFD. Indeed, while HFD-fed LFABP^−/− mice had almost double the fat mass of WT, SAT adipocyte size was >4-fold smaller and adipocyte number was 5-fold higher in the LFABP^−/−. Transcriptomic analysis of SAT revealed that Lfabp deletion alters the expression of multiple pathways that modulate adipose expansion and function including cholesterol biosynthesis, adipogenesis, and extracellular matrix remodeling. LFABP is expressed in the liver and small intestine but not in adipose tissues; thus, its ablation may promote interorgan crosstalk that drives the hyperplastic expansion of metabolically beneficial SAT, contributing to the healthy obese phenotype of the LFABP^−/− mouse. Full article

(1) Background: This study evaluated the potential of an aqueous extract from Quercus robur L. leaves for chronic wound healing. Its composition, rich in bioactive compounds (tannins and flavonoids), confers antioxidant and antimicrobial properties. (2) Methods: The toxicity and ability of the extract to enhance cell migration were tested in human keratinocytes (HaCaT cell line). Additionally, a proteomic analysis was performed on treated cells. (3) Results: The extract exhibited low cytotoxicity (IC50 = 943 µg·mL⁻¹) compared to other plant extracts. At 5 mg·mL⁻¹, it significantly accelerated wound closure at 8 h, surpassing negative control and Reoxcare; however, results were comparable at 12 h. Proteomic analysis identified 117 differentially expressed proteins (21 upregulated, 96 downregulated) involved in essential processes such as cell migration, blood clotting, and cholesterol biosynthesis. Specifically, the extract increased the expression of CYP51A1, LSS, and SQLE, while inhibiting Delta (14)-sterol reductase, key enzymes in cholesterol metabolism, suggesting a potential mechanism for tissue regeneration. (4) Conclusions: The aqueous extract of Q. robur leaves shows promise as a natural therapeutic agent for chronic wound healing, potentially aiding tissue regeneration and modulation of cholesterol metabolism. Full article