PubMed

Food Funct. 2025 Mar 17. doi: 10.1039/d4fo04478a. Online ahead of print.ABSTRACTFlaxseed-derived peptide IPPF has been reported to effectively inhibit cholesterol micellization and reduce cholesterol accumulation in vitro. However, its effects on hepatic cholesterol accumulation and related dysfunction-associated steatotic liver disease (MASLD) in vivo, along with the underlying mechanisms and specific molecular targets, remain unclear. This study investigated the impact of IPPF on hepatic cholesterol accumulation to ameliorate MASLD and its potential mechanisms in vivo. Six-week-old male C57BL/6J mice were fed a high-cholesterol, high-fat diet and treated with different doses of IPPF via oral gavage for six weeks. IPPF intervention significantly reduced hepatic cholesterol levels and oxidative stress damage while increasing fecal cholesterol and bile acid excretion. Non-targeted metabolomics analysis revealed that IPPF primarily affected pathways related to ABC transporters and bile acid metabolism. IPPF intake upregulated the mRNA expression of Abcg5/8 and Cyp7a1 in the liver. Molecular docking, dynamics and Surface plasmon resonance (SPR) simulations demonstrated that IPPF binds strongly to ABCG5/8 and CYP7A1, forming stable complexes. Furthermore, cholesterol accumulation and MASLD in HepG2 cells induced by palmitic acid (PA) was alleviated by IPPF, but this effect was partly stopped when CYP7A1 or ABCG5/8 was inhibited. In conclusion, flaxseed-derived peptide IPPF targets CYP7A1 and ABCG5/8, promoting cholesterol conversion and excretion, thereby reducing hepatic cholesterol accumulation and offering a potential nutritional treatment for MASLD. IPPF can be used as a novel dietary cholesterol-lowering functional ingredient. This study provides a scientific basis and new perspective for the development of cholesterol-lowering functional foods and dietary supplements.PMID:40094418 | DOI:10.1039/d4fo04478a

Microbiol Spectr. 2025 Mar 17:e0319424. doi: 10.1128/spectrum.03194-24. Online ahead of print.ABSTRACTNative grasses possess rich diversity and contribute to enhancing the nutritional value of silage, promoting digestion and absorption, thus improving the health of livestock such as cattle and sheep. However, in northern China, the silage fermentation process occurs at relatively low temperatures, necessitating the use of cold-tolerant lactic acid bacteria (LAB). This study examined the effect of Pediococcus acidilactici (L10), a strain selected for its low-temperature tolerance, added to native grass silage at 5°C (LT), 15°C (MT), and room temperature 25°C (CK) for 60 days. The organization of the microbial community and the metabolomic profiles were examined. The results showed that temperature significantly (P < 0.05) influenced the pH, lactic acid (LA) concentration, and LAB populations of the silage after 60 days. The water-soluble carbohydrates (WSC) and crude protein (CP) contents in the LT treatment were significantly higher than those in the CK treatment, and the pH in the LT treatment was significantly lower than in the CK treatment. In terms of the dynamic alterations within the microbial community, Pediococcus acidilactici prevailed in the LT treatment, whereas Lactobacillus plantarum was the major genus in the MT treatment, and the CK treatment was characterized by the dominance of Lactobacillus plantarum and Levilactobacillus brevis. The study also revealed that bacterial behavior and metabolism were influenced by two-component systems and quorum sensing. At 5°C the upregulation of citric acid, salicylic acid, and L-proline was ascribed to the modification of glycolysis and the tricarboxylic acid cycle. Salicylic acid was significantly (P < 0.05) positively correlated with Lactiplantibacillus plantarum, while L-proline had significantly (P < 0.05) positive correlations with Pediococcus acidilactici, Lactococcus lactis, and Weissella confusa. These findings suggest that the addition of isolated Pediococcus acidilactici can enhance the quality of low-temperature native grass silage by regulating microbial metabolic pathways and community composition.IMPORTANCEThis study aimed to screen and identify low-temperature-resistant lactic acid bacteria (LAB) strains from native fermented silage of grassland pastures, evaluating their impact on silage quality in cold conditions. Under natural conditions, LAB on forage grasses are present in low numbers and exhibit insufficient activity, which is further hindered by low temperatures during ensiling, leading to slow fermentation. The findings highlighted the effects of low temperatures on the microbial community, fermentation characteristics, and metabolomic profiles of silage. After anaerobic fermentation, the main LAB strains at different temperatures were Levilactobacillus brevis, Lactiplantibacillus plantarum, and Pediococcus acidilactici, with Pediococcus acidilactici being dominant at 5°C. Temperature significantly affected the pH, lactic acid content, and water-soluble carbohydrates of silage, indicating an interaction between LAB strains and fermentation temperature. The study suggests that adding Pediococcus acidilactici can enhance silage quality by regulating microbial metabolic pathways and composition under low-temperature conditions.PMID:40094373 | DOI:10.1128/spectrum.03194-24

mBio. 2025 Mar 17:e0036325. doi: 10.1128/mbio.00363-25. Online ahead of print.ABSTRACTThe human pathogenic fungus Aspergillus fumigatus establishes dual biofilm interactions in the lungs with the pathogenic bacterium Pseudomonas aeruginosa. Screening of 21 A. fumigatus null mutants revealed seven mutants (two G protein-coupled receptors, three mitogen-activated protein kinase receptors, a Gα protein, and one histidine kinase receptor) with reduced biofilm formation, specifically in the presence of P. aeruginosa. Transcriptional profiling and metabolomics analysis of secondary metabolites produced by one of these mutants, ΔgpaB (gpaB encodes a Gα protein), showed GpaB controls the production of several important metabolites for the dual biofilm interaction, including pyripyropene A, a potent inhibitor of mammalian acyl-CoA cholesterol acyltransferase. Deletion of pyr2, encoding a non-reducing polyketide synthase essential for pyripyropene biosynthesis, showed reduced A. fumigatus Δpyr2-P. aeruginosa biofilm growth, altered macrophage responses, and attenuated mouse virulence in a chemotherapeutic murine model. We identified pyripyropene as a novel player in the ecology and pathogenic interactions of this important human fungal pathogen.IMPORTANCEAspergillus fumigatus and Pseudomonas aeruginosa are two important human pathogens. Both organisms establish biofilm interactions in patients affected with chronic lung pulmonary infections, such as cystic fibrosis (CF) and chronic obstructive pulmonary disease. Colonization with A. fumigatus is associated with an increased risk of P. aeruginosa colonization in CF patients, and disease prognosis is poor when both pathogens are present. Here, we identified A. fumigatus genetic determinants important for the establishment of in vitro dual A. fumigatus-P. aeruginosa biofilm interactions. Among them, an A. fumigatus Gα protein GpaB is important for this interaction controlling the production of the secondary metabolite pyripyropene. We demonstrate that the lack of pyripyropene production decreases the dual biofilm interaction between the two species as well as the virulence of A. fumigatus in a chemotherapeutic murine model of aspergillosis. These results reveal a complete novel role for this secondary metabolite in the ecology and pathogenic interactions of this important human fungal pathogen.PMID:40094363 | DOI:10.1128/mbio.00363-25

Pol Arch Intern Med. 2025 Mar 14:16974. doi: 10.20452/pamw.16974. Online ahead of print.ABSTRACTINTRODUCTION: Metabolites can lead to novel discoveries in cardiovascular disease (CVD).OBJECTIVES: The aim of the study was to investigate whether a metabolomic profile is associated with mortality in patients with coronary artery disease (CAD).METHODS: The study group consisted of 170 participants with CAD who were hospitalized due to acute coronary syndrome or elective percutaneous coronary intervention 12-26 months before evaluation (mean[SD] months, 16.3 [2.2]). A total of 132 metabolites were profiled by liquid chromatography-tandem mass spectrometry, and sums/ratios of 102 metabolite concentrations were calculated. Dates of death from all causes were obtained from the Polish Ministry of Digital Affairs.RESULTS: The median age of the group was 62 years (IQR 58-66), 68.8% (n=117) were male. The median follow-up time was 6.4 years (IQR 5.5-6.5). After adjustment for CVD risk factors affecting survival in the population analyzed (i.e. age, statin dose, current smoking, estimated glomerular filtration rate, and high-sensitivity C-reactive protein) with Bonferroni's correction, tryptophan (Trp) was negatively associated with death (HR = 0.558, 95%CI = 0.38-0.82, P = 0.003), whereas indoleamine 2,3-dioxygenase (IDO) activity level was positively associated with death (HR = 2.925, 95%CI = 1.71-5.01, P <0.001). Survival analysis showed that patients with IDO activity levels above he median had statistically worse survival than patients with lower activity levels (log-rank test, P = 0.009). In contrast, patients with Trp concentration below the median had worse survival than those with higher levels (log-rank test, P = 0.03).CONCLUSIONS: In patients with CAD, the increased IDO activity level predicts a worse long-term prognosis independently of known CVD risk factors.PMID:40094276 | DOI:10.20452/pamw.16974

Trends Analyt Chem. 2024 Jun;175:117713. doi: 10.1016/j.trac.2024.117713. Epub 2024 Apr 18.ABSTRACTMetabolites are critical products and mediators of cellular and tissue function, and key signals in cell-to-cell, organ-to-organ and cross-organism communication. Many of these interactions are spatially segregated. Thus, spatial metabolomics can provide valuable insight into healthy tissue function and disease pathogenesis. Here, we review major mass spectrometry-based spatial metabolomics techniques and the biological insights they have enabled, with a focus on brain and microbiota function and on cancer, neurological diseases and infectious diseases. These techniques also present significant translational utility, for example in cancer diagnosis, and for drug development. However, spatial mass spectrometry techniques still encounter significant challenges, including artifactual features, metabolite annotation, open data, and ethical considerations. Addressing these issues represent the future challenges in this field.PMID:40094101 | PMC:PMC11905388 | DOI:10.1016/j.trac.2024.117713

Theranostics. 2025 Feb 26;15(8):3655-3672. doi: 10.7150/thno.102014. eCollection 2025.ABSTRACTRationale: Glioblastoma multiforme (GBM) is the most aggressive primary malignant brain tumor in adults, characterized by high invasiveness and poor prognosis. Glioma stem cells (GSCs) drive GBM treatment resistance and recurrence, however, the molecular mechanisms activating intracranial GSCs remain unclear. Extracellular vesicles (EVs) are crucial signaling mediators in regulating cell metabolism and can cross the blood-brain barrier (BBB). This study aimed to elucidate how EV cargo contributes to the intracranial GSC state and validate a non-invasive diagnostic strategy for GBM relapse. Methods: We isolated plasma extracellular vesicles (pl-EVs) from three groups: recurrent GBM patients post-resection, non-recurrent GBM patients post-resection, and healthy individuals. Newly diagnosed GBM patients served as an additional control. EVs were characterized and co-cultured with primary GBM cell lines to assess their effect on tumor stemness. EV cargo was analyzed using proteomics to investigate specific EV subpopulations contributing to GBM relapse. Based on these findings, we generated engineered LDHA-enriched EVs (LDHA-EVs) and co-cultured them with patient-derived organoids (PDOs). Metabolomics was performed to elucidate the underlying signal transduction pathways. Results: Our study demonstrated that pl-EVs from recurrent GBM patients enhanced aerobic glycolysis and stemness in GBM cells. Proteomic analysis revealed that plasma EVs from recurrent GBMs encapsulated considerable amounts of the enzyme lactate dehydrogenase A (LDHA). Mechanistically, LDHA-loaded EVs promoted glycolysis, induced cAMP/ATP cycling, and accelerated lactate production, thereby maintained the GSC phenotype. Concurrently, post-surgical therapy-induced stress-modulated hypoxia in residual tumors, promoted LDHA-enriched EV release. Clinically, high levels of circulating LDHA-positive EVs correlated with increased glycolysis, poor therapeutic response, and shorter survival in recurrent GBM patients. Conclusion: Our study highlights LDHA-loaded EVs as key mediators promoting GSC properties and metabolic reprogramming in GBM. These findings provide insights into recurrence mechanisms and suggest potential liquid biopsy approaches for monitoring and preventing GBM relapse.PMID:40093910 | PMC:PMC11905145 | DOI:10.7150/thno.102014

IMA Fungus. 2025 Mar 7;16:e142462. doi: 10.3897/imafungus.16.142462. eCollection 2025.ABSTRACTNatural product discovery from fungi for drug development and description of novel chemistry has been a tremendous success. This success is expected to accelerate even further, owing to the advent of sophisticated technical advances of technical advances that recently led to the discovery of an unparalleled biodiversity in the fungal kingdom. This review aims to give an overview on i) important secondary metabolite-derived drugs or drug leads, ii) discuss the analytical and strategic framework of how natural product discovery and drug lead identification transformed from earlier days to the present, iii) how knowledge of fungal biology and biodiversity facilitates the discovery of new compounds, and iv) point out endeavors in understanding fungal secondary metabolite chemistry in order to systematically explore fungal genomes by utilizing synthetic biology. An outlook is given, underlining the necessity for a collaborative and cooperative scenario to harness the full potential of the fungal secondary metabolome.PMID:40093757 | PMC:PMC11909596 | DOI:10.3897/imafungus.16.142462

Food Sci Biotechnol. 2024 Dec 11;34(5):1171-1182. doi: 10.1007/s10068-024-01750-6. eCollection 2025 Mar.ABSTRACTSerratia marcescens produce prodigiosin as a high-value intracellular secondary metabolite. However, the effect of Tween-80 on prodigiosin release remains unclear. This study aimed to elucidate the physiological characteristics and metabolic mechanisms of S. marcescens in the presence of Tween-80. The results showed that Tween-80 significantly affected prodigiosin's synthesis and extracellular release. Significant changes in cell morphology and zeta (ζ) potential were observed during cell growth. In addition, 245 differential metabolites were identified by non-targeted metabolomics analysis, indicating that Tween-80 affects the metabolism of fatty acids, amino acids, extra-long-chain fatty acids, and their derivatives. Enrichment pathway analysis revealed significant enrichment of lipid metabolism, amino acid metabolism, and other pathways. Finally, in conjunction with the metabolomics results, a prodigiosin yield was achieved at 6.5 g/L in 5 L bioreactors using fed-batch fermentation. The results of this study have significant implications for the regulation of prodigiosin synthesis and metabolism.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10068-024-01750-6.PMID:40093553 | PMC:PMC11903977 | DOI:10.1007/s10068-024-01750-6

Front Cell Infect Microbiol. 2025 Feb 28;15:1417403. doi: 10.3389/fcimb.2025.1417403. eCollection 2025.ABSTRACTBACKGROUND: Urinary tract infection is one of the most common comorbidities of urinary stones. Disorders of gut microbiota can affect various infectious diseases and the formation of the stones. Therefore, alterations in the gut bacteria profile may be a potential risk factor for the development of infections in patients with urinary tract stones.METHODS: We conducted a retrospective study to analyze the association of urinary tract infections with gut microbiota and serum metabolism in patients with stones.RESULTS: Patients with urolithiasis were predominantly in combination with diabetes mellitus (11.4% vs. 20%) and hypertension (36.4% vs. 50%). There were no statistically significant differences in hematological and urinary parameters. Compared to negative patients, IL-17A was significantly higher in the positive group (25.0 vs 21.1 pg/ml p = 0.038). The majority of pathogens detected in urine cultures were urease-negative bacteria, and urease-positive bacteria accounted for 15% of the total number of patients. We analyzed the community composition of the two groups of patients and found a significant difference in their β-diversity (p = 0.025), suggesting that dysbiosis of the gut bacteria may be associated with the combination of urinary tract infections in urolithiasis. For identification of crucial bacteria, we found changes in the abundance of both Intestinibacter (p = 0.036) and Dialister (p = 0.039), and abundance of Intestinibacter was positively correlated with IFN-α, IL-12P70 (p<0.05), and especially IL-17A (p<0.01), which may result from differences in translational, ribosomal structural and biosynthetic functions in stone patients (p < 0.05).CONCLUSION: Urolithiasis with gut dysbiosis developed a higher incidence of urinary tract infections, which may be associated with the increasing of Intestinibacter and affect the expression of IL-17A by translational, ribosomal structural and biosynthetic function.PMID:40093533 | PMC:PMC11906712 | DOI:10.3389/fcimb.2025.1417403

PeerJ. 2025 Mar 12;13:e19009. doi: 10.7717/peerj.19009. eCollection 2025.ABSTRACTOctocorals are sessile invertebrates that play a key role in marine habitats, with significant diversity in the Tropical Eastern Pacific, especially in Ecuador's shallow waters. This study focuses on the most representative octocorals within the Marine Protected Area El Pelado, Santa Elena, Ecuador, as a part of a marine biodiscovery project employing an integrative approach. While molecular techniques have advanced, challenges persist in distinguishing closely related species. Octocorals produce a wide range of compounds, characterized by unique chemical structures and diverse biological properties. Therefore, the main objective of this study was to assess the potential of metabolomics and advanced analytical techniques to analyze the metabolome of these organisms, aiming to refine species classification and improve understanding of octocoral systematics in this region. Untargeted metabolomics effectively discriminates 12 octocoral species across five genera: Muricea, Leptogorgia, Pacifigorgia, Psammogorgia, and Heterogorgia, with notable differentiation between species within the genus Muricea, reinforcing its utility as an additional data set for species characterization. Secondary metabolites such as sterols, steroids, and terpenes (furanocembranolides and sesquiterpenes), were identified in Leptogorgia and Muricea. Overall, this method enabled the identification of 11 known species and a potentially new one, Leptogorgia cf. alba, confirming the extreme diversity of this group in the Tropical Eastern Pacific and within the Ecuadorian marine ecosystem. The study highlights the value of metabolomics in octocoral systematics and encourages for its broader application in marine biodiversity research.PMID:40093409 | PMC:PMC11910152 | DOI:10.7717/peerj.19009

Lancet Reg Health Eur. 2025 Feb 19;50:101171. doi: 10.1016/j.lanepe.2024.101171. eCollection 2025 Mar.ABSTRACTBiliary tract cancer (BTC) is becoming more common worldwide, with geographic differences in incidence and risk factors. In Europe, BTC may be associated with primary sclerosing cholangitis, lithiasis, and liver cirrhosis, but is more frequently observed as a sporadic disease. BTC increasingly affects patients under 60 years, resulting in a significant social and economic burden. Early diagnosis remains challenging due to vague symptoms in 50% of patients with BTC, and lack of specific biomarkers, resulting in late presentation and poor prognosis. The identification of patients at increased risk and reliable biomarkers require collaborative efforts to make faster progress. This Series paper highlights the disparities in access to diagnostic tools and multidisciplinary care in Europe, particularly in economically disadvantaged regions, while identifying priority areas for improvement. Addressing these inequities requires harmonised guidelines, accelerated pathways to curative treatments, and improved awareness among healthcare professionals and the public. Multidisciplinary teams (MDTs) are crucial for the diagnosis of BTC and for improving patient outcomes, yet inconsistencies exist in their implementation not only between different countries, but also between different centres within a country. Collaboration and standardisation of diagnostic and treatment protocols across Europe are essential to effectively address the management of patients with BTC.PMID:40093398 | PMC:PMC11910794 | DOI:10.1016/j.lanepe.2024.101171

World J Diabetes. 2025 Mar 15;16(3):102277. doi: 10.4239/wjd.v16.i3.102277.ABSTRACTBACKGROUND: The duodenum plays a significant role in metabolic regulation, and thickened mucous membranes are associated with insulin resistance. Duodenal mucosal resurfacing (DMR), a new-style endoscopic procedure using hydrothermal energy to ablate this thickened layer, shows promise for enhancing glucose and lipid metabolism in type 2 diabetes (T2D) patients. However, the mechanisms driving these improvements remain largely unexplored.AIM: To investigate the mechanisms by which DMR improves metabolic disorders using a rat model.METHODS: Rats with T2D underwent a revised DMR procedure via a gastric incision using a specialized catheter to abrade the duodenal mucosa. The duodenum was evaluated using histology, immunofluorescence, and western blotting. Serum assays measured glucose, lipid profiles, lipopolysaccharide, and intestinal hormones, while the gut microbiota and metabolomics profiles were analyzed through 16S rRNA gene sequencing and ultra performance liquid chromatography-mass spectrum/mass spectrum, severally.RESULTS: DMR significantly improved glucose and lipid metabolic disorders in T2D rats. It increased the serum levels of cholecystokinin, gastric inhibitory peptide, and glucagon-like peptide 1, and reduced the length and depth of duodenal villi and crypts. DMR also enhanced the intestinal barrier integrity and reduced lipopolysaccharide translocation. Additionally, DMR modified the gut microbiome and metabolome, particularly affecting the Blautia genus. Correlation analysis revealed significant links between the gut microbiota, metabolites, and T2D phenotypes.CONCLUSION: This study illustrates that DMR addresses metabolic dysfunctions in T2D through multifaceted mechanisms, highlighting the potential role of the Blautia genus on T2D pathogenesis and DMR's therapeutic impact.PMID:40093272 | PMC:PMC11885968 | DOI:10.4239/wjd.v16.i3.102277

medRxiv [Preprint]. 2025 Mar 3:2025.02.28.25323089. doi: 10.1101/2025.02.28.25323089.ABSTRACTWhile the public health burden of SARS-CoV-2 infection has lessened due to natural and vaccine-acquired immunity, the emergence of less virulent variants, and antiviral medications, COVID-19 continues to take a significant toll. There are > 10,000 new hospitalizations per week in the U.S., many of whom develop post-acute sequelae of SARS-CoV-2 (PASC), or "long COVID", with long-term health issues and compromised quality of life. Early identification of individuals at high risk of severe COVID-19 is key for monitoring and supporting respiratory status and improving outcomes. Therefore, precision tools for early detection of patients at high risk of severe disease can reduce morbidity and mortality. Here we report an untargeted and longitudinal metabolomic study of plasma derived from adult patients with COVID-19. One-carbon metabolism, a pathway previously shown as critical for viral propagation and disease progression, and a potential target for COVID-19 treatment, scored strongly as differentially abundant in patients with severe COVID-19. A follow-up targeted metabolite profiling revealed that one arm of the one-carbon metabolism pathway, the methionine cycle, is a major driver of the metabolic profile associated with disease severity. The methionine cycle produces S-adenosylmethionine (SAM), the methyl group donor important for methylation of DNA, RNA, and proteins, and its high abundance was reported to correlate with disease severity. Further, genomic data from the profiled patients revealed a genetic contributor to methionine metabolism and identified the C677T allele of the MTHFR gene as a pre-existing predictor of disease trajectory - patients homozygous for the MTHFR C677T have higher incidence of experiencing severe disease. Our results raise the possibility that screening for the common genetic MTHFR variant may be an actionable approach to stratify risk of COVID severity and may inform novel precision COVID-19 treatment strategies.PMID:40093216 | PMC:PMC11908298 | DOI:10.1101/2025.02.28.25323089

bioRxiv [Preprint]. 2025 Mar 4:2025.02.28.640731. doi: 10.1101/2025.02.28.640731.ABSTRACTInsulin/insulin growth factor signaling is a conserved pathway that regulates lifespan across many species. Multiple mechanisms are proposed for how this altered signaling slows aging. To elaborate these causes, we recently developed a series of Drosophila insulin-like receptor ( dInr ) mutants with single amino acid substitutions that extend lifespan but differentially affect insulin sensitivity, growth and reproduction. Transheterozygotes of canonical dInr mutants (Type I) extend longevity and are insulin-resistant, small and weakly fecund. In contrast, a dominant mutation ( dInr 353 , Type II) within the Kinase Insert Domain (KID) robustly extends longevity but is insulin-sensitive, full-sized, and highly fecund. We applied transcriptome and metabolome analyses to explore how dInr 353 slows aging without insulin resistance. Type I and II mutants overlap in many pathways but also produce distinct transcriptomic profiles that include differences in innate immune and reproductive functions. In metabolomic analyses, the KID mutant dInr 353 reprograms methionine metabolism in a way that phenocopies dietary methionine restriction, in contrast to canonical mutants which are characterized by upregulation of the transsulfuration pathway. Because abrogation of S-adenosylhomocysteine hydrolase blocks the longevity benefit conferred by dInr 353 , we conclude the methionine cycle reprogramming of Type II is sufficient to slow aging. Metabolomic analysis further revealed the Type II mutant is metabolically flexible: unlike aged wildtype, aged dInr 353 adults can reroute methionine toward the transsulfuration pathway, while Type I mutant flies upregulate the trassulfuration pathway continuously from young age. Altered insulin/insulin growth factor signaling has the potential to slow aging without the complications of insulin resistance by modulating methionine cycle dynamics.AUTHOR SUMMARY: Mutations in the invertebrate insulin/IGF signaling system robustly extend lifespan. Yet these interventions often cause insulin resistance, reduce growth, and impair fertility. In contrast, a dominant gain-of-function mutation in the kinase insert domain of the Drosophila insulin/IGF receptor extends lifespan while maintaining insulin sensitivity, growth, or reproduction. Here, we demonstrate this unique mutation reprograms methionine metabolism pathway in a way that mirrors dietary methionine restriction, which is known to extend lifespan in several animals including Drosophila and mice. Genetic epistasis analysis verifies this methionine cycle inhibition is an underlying cause for how the kinase insert domain mutation slows Drosophila aging while maintaining insulin-sensitivity, growth, and fecundity.PMID:40093182 | PMC:PMC11908128 | DOI:10.1101/2025.02.28.640731

bioRxiv [Preprint]. 2025 Mar 7:2025.03.06.641924. doi: 10.1101/2025.03.06.641924.ABSTRACTVemurafenib constitutes an important therapeutic for BRAFV600 mutant melanomas, but despite high initial response rates, resistance to BRAF and MEK inhibitors quickly develops. Here, we performed an integrative analysis of metabolomic consequences and transcriptome alterations to uncover mechanisms involved in adaptive vemurafenib resistance (VemR) development and their relationship with vemurafenib tolerance thresholds. We developed BRAFV600E isogenic models of VemR utilizing M14 and A2058 lines, and patient-derived melanomas with V600E or normal BRAF to verify vemurafenib selectivity. MEK or PI3K inhibitors only partially inhibited VemR cell proliferation, indicating cross-resistance to these inhibitors. MITF and β-catenin levels were induced and treatment with Wnt/β-catenin inhibitor ICG-001 restored vemurafenib sensitivity with concomitant reductions in β-catenin-regulated gene expressions, phospho-ERK1/2, and VemR-induced mitochondrial mass and respiration. Targeted metabolite, MitoPlate-S1, Mito-stress and transcriptome/metabolomic analysis showed that melanoma cells with elevated vemurafenib tolerance thresholds such as A2058 VemR cells utilize Wnt/β-catenin signaling for mitochondrial metabolism while VemR cells with low tolerance such as M14 VemR cells rely on Wnt/β-catenin signaling for pentose phosphate pathway. Pathways associated with cytokine-cytokine receptor, ECM receptor, and neuroactive ligand receptor interactions were similarly enriched in BRAFV600E patient-derived melanoma as M14 and A2058 cells whereas distinct pathways involving cell cycle, DNA replication, Fanconi anemia and DNA repair pathways are upregulated in wild type BRAF expressing patient derived melanoma. These data show for the first time that the metabolic pathway choices made by VemR BRAF mutant melanomas are controlled by vemurafenib tolerance and endurance thresholds and Wnt/β-catenin signaling plays a central role in coordinating expression of genes controlling VemR and metabolic pathway shifts.PMID:40093038 | PMC:PMC11908245 | DOI:10.1101/2025.03.06.641924

ACS Omega. 2025 Feb 25;10(9):9351-9367. doi: 10.1021/acsomega.4c10085. eCollection 2025 Mar 11.ABSTRACTEpilepsy encompasses a spectrum of chronic brain disorders characterized by transient central nervous system dysfunctions induced by recurrent, aberrant, synchronized neuronal discharges. Hippocampal sclerosis (HS) is identified as the predominant pathological alteration in epilepsy, particularly in temporal lobe epilepsy. This study investigates the metabolic profiles of epileptic hippocampal tissues using proteomics and lipidomics techniques. An epilepsy model was established in Sprague-Dawley (SD) rats via intraperitoneal injection of pentylenetetrazole (PTZ), with hippocampal tissue samples subsequently extracted for histopathological examination. Proteomics analysis was conducted using isobaric tags for relative and absolute quantitation (iTRAQ) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), while lipidomics analysis employed ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC Q-TOF/MS). Proteomic analysis identified 144 proteins with significant differential expression in acute epileptic hippocampal tissue and 83 proteins in chronic epileptic hippocampal tissue. Key proteins, including neurofilament heavy (Nefh), vimentin (Vim), gelsolin (Gsn), NAD-dependent protein deacetylase (Sirt2), 2',3'-cyclic-nucleotide 3'-phosphodiesterase (Cnp), myocyte enhancer factor 2D (Mef2d), and Cathepsin D (Ctsd), were pivotal in epileptic hippocampal tissue injury and validated through parallel reaction monitoring (PRM). Concurrently, lipid metabolomics analysis identified 32 metabolites with significant differential expression in acute epileptic hippocampal tissue and 61 metabolites in chronic epileptic hippocampal tissue. Bioinformatics analysis indicated that glycerophospholipid (GP) metabolism, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, and glycerolipid (GL) metabolism were crucial in epileptic hippocampal tissue injury. Integrated proteomics and lipidomics analysis revealed key protein-lipid interactions in acute and chronic epilepsy and identified critical pathways such as sphingolipid signaling, autophagy, and calcium signaling. These findings provide deeper insights into the pathophysiological mechanisms of epileptic hippocampal tissue damage, potentially unveiling novel therapeutic avenues for clinicians.PMID:40092809 | PMC:PMC11904687 | DOI:10.1021/acsomega.4c10085

Front Cell Dev Biol. 2025 Feb 28;13:1562331. doi: 10.3389/fcell.2025.1562331. eCollection 2025.ABSTRACTINTRODUCTION: Microplastics and nanoplastics are prevalent environmental contaminants. Recent reports indicate that polystyrene nanoparticles may adversely impact male reproductive health. This study aims to examine the effects of polystyrene exposure on sperm metabolism and the development of pre-implantation embryos.METHODS: In this study, male C57BL/6 mice were orally gavage-administered polystyrene nanoplastics (60 nm, 20 mg/kg/day) for 35 days to assess their impact on male reproduction and early embryonic development. Experiments included testicular transcriptome analysis, sperm metabolomics, sperm motility and fertilization assays, embryonic ROS detection, and RNA sequencing of 2-cell embryos, revealing the adverse effects of polystyrene exposure on sperm metabolism and embryo development.RESULTS: The results revealed that oral gavage of polystyrene to male mice induced a pronounced immune-inflammatory response in testicular tissue, reduced sperm motility, and significantly lowered the fertilization rate. Notably, sperm from treated mice exhibited substantial metabolic disruptions, affecting key pathways, including glycerophospholipid biosynthesis and DNA repair. After fertilization, embryos at the 2-cell stage suffered damage in apoptotic and DNA repair pathways, subsequently impairing early embryo development.DISCUSSION: In conclusion, this study demonstrated that the oral gavage administration of polystyrene nanoplastics to male mice significantly affects male reproductive function, resulting in abnormalities in early embryonic development and alterations in associated gene expression profiles. These findings offer essential scientific insights for future research into sperm-mediated transgenerational effects and their impact on early embryonic development.PMID:40092630 | PMC:PMC11906707 | DOI:10.3389/fcell.2025.1562331

Forensic Sci Int Synerg. 2025 Feb 24;10:100580. doi: 10.1016/j.fsisyn.2025.100580. eCollection 2025 Jun.ABSTRACTThe classification of the manner of death (MOD) is a critical step in forensic investigations. The process is based on scene investigation, autopsy, histological and toxicological findings. However, in complex suicide cases, these findings may be insufficient to clearly establish the MOD and need potential biomarkers to assist judicial determinations. This study aims to identify specific biomarkers in the blood that could distinguish suicide from the non-suicidal deaths group. Heart blood samples were collected from suicide (n = 45) and non-suicide cases (n = 45) and metabolomic profiles were analyzed using proton nuclear magnetic resonance spectroscopy. Nineteen blood metabolites were significantly different between the groups (p < 0.05); especially, 4-hydroxyproline, sarcosine and heparan sulfate emerged as potential biomarkers for differentiating between the groups. A logistic regression-based predictive model incorporating sarcosine and heparan sulfate achieved sensitivity and specificity values of 73 % and 72 %, respectively. The integration of machine learning with blood metabolomics holds significant potential in forensic science and may apply to the model to adopt in criminal justice.PMID:40092626 | PMC:PMC11908544 | DOI:10.1016/j.fsisyn.2025.100580

Front Genet. 2025 Feb 28;16:1501876. doi: 10.3389/fgene.2025.1501876. eCollection 2025.ABSTRACTTestes are crucial for male reproduction, and transcriptomic and metabolomic analyses can help identify genes and pathways linked to reproductive performance differences in pig breeds. The present study was conducted to identify the differentially expressed genes and differentially accumulated metabolites (DAMs) through transcriptomic and metabolomic analyses of testicular tissues in Chuanxiang Black and Landrace pigs. Six testis tissue samples from each pig breed were used for transcriptomic analysis. Further liquid chromatography-mass spectrometry analysis was performed for targeted metabolomic analysis to identify differential metabolites in both breeds. RNA-sequencing data identified a total of 6,233 DEGs, including 3,417 upregulated and 2,816 downregulated genes in Chuanxiang Black compared to Landrace pigs. Comparative pathway enrichment analyses revealed that many DEGs and DAMs were associated with critical reproductive pathways, especially those related to male gametogenesis, spermatogenesis, sexual reproduction, development, and reproductive processes. Three major pathways related to signal transduction (PI3K-Akt, Rap1, and MAPK signaling pathways), lipid metabolism (linoleic acid and arachidonic acid metabolism), and cytokine-cytokine receptor interaction were identified as differentially enriched pathways in Chuanxiang Black pigs. Differential circRNA target gene enrichment analysis revealed 4,179 DEGs, including 3,022 genes involved in biological processes, 477 in cellular components, and 680 in molecular functions. Differential analysis of miRNA between the two groups revealed 2,512 DEGs, including 1,628 upregulated and 884 downregulated genes. Both miRNA and circRNA were involved in enriched KEGG pathways mainly including signaling pathways (cAMP signaling pathways, calcium signaling pathways), endocrine secretion (aldosterone synthesis and secretion and GnRH secretion), and signaling molecules and interaction (ECM-receptor interaction). These findings revealed that both circRNA and miRNA play a crucial role in regulating the differential gene expression related to reproductive processes in Chuanxiang Black compared to Landrace pigs.PMID:40092557 | PMC:PMC11906663 | DOI:10.3389/fgene.2025.1501876

Res Sq [Preprint]. 2025 Mar 4:rs.3.rs-5960979. doi: 10.21203/rs.3.rs-5960979/v1.ABSTRACTThe rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), particularly among pediatric populations, requires identification of modifiable risk factors to control disease progression. Per- and polyfluoroalkyl substances (PFAS) have emerged as potential contributors to liver damage; however, their role in the etiology of MASLD remains underexplored. This study aimed to bridge the gap between human epidemiological data and in vitro experimental findings to elucidate the effect of perfluoroheptanoic acid (PFHpA), a short chain, unregulated PFAS congener on MASLD development. Our analysis of the Teen-LABS cohort, a national multi-site study on obese adolescents undergoing bariatric surgery, revealed that doubling of PFHpA plasma levels was associated with an 80% increase in MASLD risk (OR, 1.8; 95% CI: 1.3-2.5) based on liver biospies. To further investigate the underlying mechanisms, we used 3D human liver spheroids and single-cell transcriptomics to assess the effect of PFHpA on hepatic metabolism. Integrative analysis identified dysregulation of common pathways in both human and spheroid models, particularly those involved in innate immunity, inflammation, and lipid metabolism. We applied the latent unknown clustering with integrated data (LUCID) model to assess associations between PFHpA exposure, multiomic signatures, and MASLD risk. Our results identified a proteome profile with significantly higher odds of MASLD (OR = 7.1), whereas a distinct metabolome profile was associated with lower odds (OR = 0.51), highlighting the critical role of protein dysregulation in disease pathogenesis. A translational framework was applied to uncover the molecular mechanisms of PFAS-induced MASLD in a cohort of obese adolescents. Identifying key molecular mechanisms for PFAS-induced MASLD can guide the development of targeted prevention and treatment.PMID:40092438 | PMC:PMC11908348 | DOI:10.21203/rs.3.rs-5960979/v1