PubMed

Transl Cancer Res. 2024 Dec 31;13(12):6956-6969. doi: 10.21037/tcr-2024-2379. Epub 2024 Dec 27.ABSTRACTBACKGROUND: Many cancer cells exhibit aberrant metabolic reprogramming through abnormal mitochondrial respiration. Protein tyrosine phosphatase mitochondrial 1 (PTPMT1) is a protein tyrosine phosphatase localized to the mitochondria and linked to mitochondrial respiration. However, the expression and role of PTPMT1 in regulating the biological characteristics of small cell lung cancer (SCLC) has not yet been explored. The aim of this study was to evaluate the role of PTPMT1 on SCLC cell survival and mitochondrial function.METHODS: SCLC and adjacent normal tissues were obtained from surgery. The expression level of PTPMT1 in the SCLC tissues and cell lines was determined by immunohistochemical staining, western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). PTPMT1 knockdown was induced by lentivirus-mediated short-hairpin RNA (shRNA) transduction and PTPMT1 inhibition (alexidine dihydrochloride). The biological characteristics of the cells were measured by cell counting kit 8 (CCK-8), colony formation assay, and cell migration assay. The mitochondrial function of the cells was measured by 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining. The H69 cells were treated with alexidine dihydrochloride, after which transcriptome sequencing and an untargeted metabolomic analysis were performed. The transcriptome differentially expressed genes were measured by qRT-PCR.RESULTS: PTPMT1 was upregulated in the SCLC tissues compared to the adjacent normal tissues. PTPMT1 inhibition by lentiviral shRNA transduction or specific inhibition resulted in significant growth arrest and apoptosis. The transcriptome sequencing analysis revealed that pathways related to the respiration chain and mitochondrial member protein were disrupted. Several mitochondrial metabolism-related genes, such as FGF21, GDF-15, APLN, and MT-DN6, were dysregulated. Further, PTPMT1 inhibition was found to downregulate Glut expression and disturb mitochondrial function.CONCLUSIONS: PTPMT1 was shown to play a critical role in the survival and growth of SCLC cells, and may become a potential therapeutic target.PMID:39816544 | PMC:PMC11730198 | DOI:10.21037/tcr-2024-2379

Heliyon. 2024 Dec 21;11(1):e41309. doi: 10.1016/j.heliyon.2024.e41309. eCollection 2025 Jan 15.ABSTRACTIsocitrate dehydrogenase wild-type glioblastoma (GBM) is characterised by a heterogeneous genetic landscape resulting from dynamic competition between tumour subclones to survive selective pressures. Improvements in metabolite identification and metabolome coverage have led to increased interest in clinically relevant applications of metabolomics. Here, we use liquid chromatography-mass spectrometry and gene expression microarray to profile integrated intratumour metabolic heterogeneity, as a direct functional readout of adaptive responses of subclones to the tumour microenvironment. Multi-region surgical sampling was performed on five adult GBM patients based on pre-operative brain imaging and fluorescence-guided surgery. Polar and hydrophobic metabolites extracted from tumour fragments were assessed, followed by putative assignment of metabolite identifications based on retention times and molecular mass. Class discrimination between tumour regions through showed clear separation of tumour regions based on polar metabolite profiles. Metabolic pathway assignments revealed several significantly altered metabolites between the tumour core and invasive region to be associated with purine and pyrimidine metabolism. This proof-of-principle study assesses intratumour heterogeneity through mass spectrometry-based metabolite profiling of multi-region biopsies. Bioinformatic interpretation of the GBM metabolome has highlighted the invasive region to be biologically distinct compared to tumour core and revealed putative drug-targetable metabolic pathways associated with purine and pyrimidine metabolism.PMID:39816516 | PMC:PMC11732679 | DOI:10.1016/j.heliyon.2024.e41309

Cancer Manag Res. 2025 Jan 11;17:45-56. doi: 10.2147/CMAR.S499003. eCollection 2025.ABSTRACTOBJECTIVE: Our research has pinpointed the gut microbiome's role in the progression of various pathological types of non-small cell lung cancer (NSCLC). Nonetheless, the characteristics of the gut microbiome and its metabolites across different clinical stages of NSCLC are yet to be fully understood. The current study seeks to explore the distinctive gut flora and metabolite profiles of NSCLC patients across varying TNM stages.METHODS: The research team gathered stool samples from 52 patients diagnosed with non-small cell lung cancer (NSCLC) and 29 healthy individuals. Subsequently, they performed 16S rRNA gene amplification sequencing and untargeted gas/liquid chromatography-mass spectrometry metabolomics analysis.RESULTS: The study revealed that the alpha-diversity of the gut microbiome in NSCLC patients at different stages did not exhibit statistically significant differences. Notably, Lachnospira and Blautia were more abundant in healthy controls. The distribution of gut microbial species in patients with varying stages of NSCLC was uneven, with Bacteroides and Bacteroidaceae being most prevalent in stage T2, and Prevotella dominating in stage T4. Levels of Ruminococcus gnavus were notably elevated in stages N3 and M. The genus levels of Klebsiella, Parabacteroides, and Tannerellaceae were higher in stage II patients. Rodentibacter was the bacterium with increased levels in stage III NSCLC patients. Further metabolomics studies revealed significantly elevated levels of quinic acid and 3-hydroxybenzoic acid in the healthy control group. In contrast, Stage I+II non-small cell lung cancer (NSCLC) patients exhibited reduced levels of L-cystathionine. Notably, quinic acid, phthalic acid, and L-lactic acid were observed to be increased in Stage III+IV NSCLC patients.CONCLUSION: Compared to the analysis of a single microbial dataset, this study provides deeper functional insights by incorporating comprehensive metabolomic profiling. This approach demonstrates that both the gut microbiome and associated metabolites are altered in NSCLC patients across different clinical stages. Our findings may offer novel perspectives on the pathogenesis of NSCLC at various TNM stages. Further research is warranted to validate and clinically apply these potential biomarkers.PMID:39816490 | PMC:PMC11734503 | DOI:10.2147/CMAR.S499003

Food Sci Nutr. 2025 Jan 14;13(1):e4604. doi: 10.1002/fsn3.4604. eCollection 2025 Jan.ABSTRACTOsteoporosis (OP) is a prevalent metabolic bone disease globally. Currently, the development of Traditional Chinese Medicine (TCM) resources to unblock joints, strengthen bones, and enhance muscle function to regulate anti-osteogenic and anabolic metabolism and thus reshape intraosseous homeostasis was an effective way to alleviate OP. The F-E-D formula, comprising Fructus Psoraleae, Eucommia, and Drynariae Rhizoma, has shown efficacy in treating OP. However, its complex natural components necessitate the screening and simplification of bioactive compounds to further elucidate their therapeutic mechanisms and enhance therapeutic efficacy. In this study, we first used drug-target binding to produce different effects, which in turn exhibited different retention characteristics on the stationary phase. Using osteoblasts and osteoclasts as stationary phases, a chromatographic system (Solid-phase Bio-cell Chromatography, SBC) had been constructed to mimic the drug-target interaction, and the separation, analysis, and bioactivity screening of the chemical components of F-E-D had been performed. Then, the above collected eluates were analyzed by fine metabolomics, and 95 effective metabolites were initially screened and combined with database screening to finally select betaine, L-fucose, and itaconic acid as potentially active candidate compound monomers for the interaction with osteoblast-osteoclast in F-E-D. In terms of cell validation experiments, we found that the screened active monomers significantly inhibited the formation of osteoclasts, and the itaconic acid-treated group played a significant inhibitory effect on the expression of inflammatory factors TNF-α and IL-6. The above experimental data showed that the monomeric active ingredients in TCM could be effectively screened by solid-phase bio-chromatography and HPLC-MS, and the in vitro cellular experiments verified that the active monomers of TCM slowed down the progression of OP by inhibiting osteoclast production and alleviating the expression of inflammation.PMID:39816481 | PMC:PMC11732702 | DOI:10.1002/fsn3.4604

Front Parasitol. 2022 Sep 9;1:984152. doi: 10.3389/fpara.2022.984152. eCollection 2022.ABSTRACTParasitic helminths secrete and excrete a vast array of molecules known to help skew or suppress the host's immune response, thereby establishing a niche for sustained parasite maintenance. Indeed, the immunomodulatory potency of helminths is attributed mainly to excretory/secretory products (ESPs). The ESPs of helminths and the identified small molecules (SM) are reported to have diverse biological and pharmacological properties. The available literature reports only limited metabolites, and the identity of many metabolites remains unknown due to limitations in the identification protocols and helminth-specific compound libraries. Many metabolites are known to be involved in host-parasite interactions and pathogenicity. For example, fatty acids (e.g., stearic acid) detected in the infective stages of helminths are known to have a role in host interaction through facilitating successful penetration and migration inside the host. Moreover, excreted/secreted SM detected in helminth species are found to possess various biological properties, including anti-inflammatory activities, suggesting their potential in developing immunomodulatory drugs. For example, helminths-derived somatic tissue extracts and whole crude ESPs showed anti-inflammatory properties by inhibiting the secretion of proinflammatory cytokines from human peripheral blood mononuclear cells and suppressing the pathology in chemically-induced experimental mice model of colitis. Unlike bigger molecules like proteins, SM are ideal candidates for drug development since they are small structures, malleable, and lack immunogenicity. Future studies should strive toward identifying unknown SM and isolating the under-explored niche of helminth metabolites using the latest metabolomics technologies and associated software, which hold potential keys for finding new diagnostics and novel therapeutics.PMID:39816468 | PMC:PMC11731824 | DOI:10.3389/fpara.2022.984152

Front Parasitol. 2022 Aug 5;1:995302. doi: 10.3389/fpara.2022.995302. eCollection 2022.NO ABSTRACTPMID:39816466 | PMC:PMC11732041 | DOI:10.3389/fpara.2022.995302

Brain Commun. 2025 Jan 6;7(1):fcae478. doi: 10.1093/braincomms/fcae478. eCollection 2025.ABSTRACTParkinson's disease is primarily marked by mitochondrial dysfunction and metabolic abnormalities. We recently reported that the combined metabolic activators improved the immunohistochemical parameters and behavioural functions in Parkinson's disease and Alzheimer's disease animal models and the cognitive functions in Alzheimer's disease patients. These metabolic activators serve as the precursors of nicotinamide adenine dinucleotide and glutathione, and they can be used to activate mitochondrial metabolism and eventually treat mitochondrial dysfunction. Here, we designed a randomized, double-blinded, placebo-controlled phase II study in Parkinson's disease patients with 84 days combined metabolic activator administration. A single dose of combined metabolic activator contains L-serine (12.35 g), N-acetyl-L-cysteine (2.55 g), nicotinamide riboside (1 g) and L-carnitine tartrate (3.73 g). Patients were administered either one dose of combined metabolic activator or a placebo daily for the initial 28 days, followed by twice-daily dosing for the next 56 days. The main goal of the study was to evaluate the clinical impact on motor functions using the Unified Parkinson's Disease Rating Scale and to determine the safety and tolerability of combined metabolic activator. A secondary objective was to assess cognitive functions utilizing the Montreal Cognitive Assessment and to analyse brain activity through functional MRI. We also performed comprehensive plasma metabolomics and proteomics analysis for detailed characterization of Parkinson's disease patients who participated in the study. Although no improvement in motor functions was observed, cognitive function was shown to be significantly improved (P < 0.0000) in Parkinson's disease patients treated with the combined metabolic activator group over 84 days, whereas no such improvement was noted in the placebo group (P > 0.05). Moreover, a significant reduction (P = 0.001) in Montreal Cognitive Assessment scores was observed in the combined metabolic activator group, with no decline (P > 0.05) in the placebo group among severe Parkinson's disease patients with lower baseline Montreal Cognitive Assessment scores. We showed that improvement in cognition was associated with critical brain network alterations based on functional MRI analysis, especially relevant to areas with cognitive functions in the brain. Finally, through a comprehensive multi-omics analysis, we elucidated the molecular mechanisms underlying cognitive improvements observed in Parkinson's disease patients. Our results show that combined metabolic activator administration leads to enhanced cognitive function and improved metabolic health in Parkinson's disease patients as recently shown in Alzheimer's disease patients. The trial was registered in ClinicalTrials.gov NCT04044131 (17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131).PMID:39816194 | PMC:PMC11733689 | DOI:10.1093/braincomms/fcae478

Narra J. 2024 Dec;4(3):e1181. doi: 10.52225/narra.v4i2.1181. Epub 2024 Dec 26.ABSTRACTIschemic stroke is a sudden onset of neurological deficit resulting from a blockage in cerebral blood vessels, which can lead to brain tissue damage, chronic disability, and increased risk of mortality. Secretome from hypoxic mesenchymal stem cells (SH-MSC) is a potential therapy to improve neurological deficit by increasing the expression of vascular endothelial growth factor (VEGF) and reducing glial fibrillary acidic protein (GFAP). These effects can reduce the infarction area of ischemic stroke. Therefore, the aim of this study was to analyze the effect of 150 μL and 300 μL SH-MSC injection on VEGF and GFAP expression as well as the improvement of infarction area in ischemic stroke animal model. A post-test-only experimental design with consecutive sampling was used, with Rattus norvegicus as subjects. Stromal mesenchymal stem cells (S-MSCs) were isolated from the umbilical cords of rats at 21 days of gestation. Secretome production by the S- MSCs was induced under a hypoxic condition, and subsequently isolated. The resultant secretome was administered to rats subjected to middle cerebral artery occlusion (MCAO) at doses of 150 μL (P1 group) and 300 μL (P2 group). The results showed that the infarction area was reduced in P1 (p<0.001) and P2 groups (p<0.001). SH-MSC at a dose of 300 μL increased the expression of VEGF (p=0.028) and reduced the expression of GFAP (p=0.001). In conclusion, secretome from hypoxic S-MSC could potentially improve ischemic stroke by upregulating VEGF expression and downregulating GFAP expression.PMID:39816066 | PMC:PMC11732002 | DOI:10.52225/narra.v4i2.1181

Antioxid Redox Signal. 2025 Jan 16. doi: 10.1089/ars.2024.0670. Online ahead of print.ABSTRACTAims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent hepatic disorder worldwide. Arachidonic acid 15-lipoxygenase (ALOX15), an enzyme catalyzing the peroxidation of polyunsaturated fatty acids, plays a crucial role in various diseases. Here, we sought to investigate the involvement of ALOX15 in MASLD. Results: In this study, we observed upregulation of ALOX15 in the liver of high-fat diet (HFD)- and streptozotocin (STZ)-induced mice. Metabolomic analysis revealed elevated levels of ALOX15 metabolites, 12(S)-hydroperoxyeicosatetraenoic acid and 15(S)-hydroperoxyeicosatetraenoic acid. Transcriptomic analysis showed that the increased fatty acid uptake regulated by the PPARγ/CD36 pathway predominated in lipid accumulation. To elucidate the mechanism underlying ALOX15-induced lipid accumulation, HepG2 cells were transfected with a lentivirus expressing ALOX15 or small interfering RNA targeting ALOX15 and exposed to palmitic acid (PA). Both ALOX15 overexpression and PA exposure led to increased intracellular free fatty acid and triglyceride, resulting in lipotoxicity. ALOX15 overexpression aggravated the effect of PA, while the knockdown of ALOX15 attenuated PA-induced lipotoxicity. Moreover, the treatment with PPARγ antagonist GW9662 or CD36 inhibitor sulfosuccinimidyl oleate sodium effectively reduced lipid accumulation and lipotoxicity resulting from ALOX15 overexpression and PA exposure, indicating the involvement of the PPARγ/CD36 pathway in ALOX15-mediated lipid accumulation. Furthermore, liraglutide, a widely used glucagon-like peptide 1 receptor (GLP-1R) agonist (GLP-1RA), improved hepatic lipid accumulation in HFD/STZ-induced mice by suppressing the ALOX15/PPARγ/CD36 pathway. Innovation and Conclusion: Our study underscores the potential of ALOX15 as an emerging therapeutic target for MASLD. In addition, the GLP-1RA may confer hepatoprotection by regulating ALOX15, enhancing our comprehension of the mechanisms underpinning their protection on MASLD. Antioxid. Redox Signal. 00, 000-000.PMID:39815992 | DOI:10.1089/ars.2024.0670

Anim Sci J. 2025 Jan-Dec;96(1):e70021. doi: 10.1111/asj.70021.ABSTRACTWeaning is essential for foal growth and development. We determined the intestinal flora structure of donkey foals at the end of weaning (PreW_4d) and three stages after weaning (PostW_4d, PostW_8d, and PostW_15d) to explore the effects of weaning on intestinal development of donkey foals. The results showed that the main microbial flora in the gut of the donkey foal were Firmicutes and Bacteroides, and the proportion of Firmicutes gradually increased with weaning, which was an important reflection of the donkey foal's adaptability to the transition from lactose liquid feed to plant fiber solid feed. We also identified important microorganisms that maintain intestinal stability and boost immune, such as oscillospiraceae, Firmicutes, and lachnospiraceae. The metabolome showed that serum metabolites were mainly enriched in arachidonic acid metabolism and the tricarboxylic acid cycle (TCA cycle), which can influence energy metabolism, growth, and immunity in weaned donkey foals. We also found that the metabolite resveratrol was positively correlated with g_NK4A214_group and lactobacillus, which may have important implications for the prevention of diseases such as colon-inflammation in donkey foals. In summary, we provide a theoretical basis for studying the mechanism of intestinal microbiome and serum metabolite changes in weaning and postweaning donkey foals.PMID:39815660 | DOI:10.1111/asj.70021

Crit Care. 2025 Jan 15;29(1):26. doi: 10.1186/s13054-025-05258-1.ABSTRACTBACKGROUND: Traumatic brain injury (TBI) is a major public health concern worldwide, contributing to high rates of injury-related death and disability. Severe traumatic brain injury (sTBI), although it accounts for only 10% of all TBI cases, results in a mortality rate of 30-40% and a significant burden of disability in those that survive. This study explored the potential of metabolomics in the diagnosis of sTBI and explored the potential of metabolomics to examine probable primary and secondary brain injury in sTBI.METHODS: Serum samples from 59 adult patients with sTBI and 35 age- and sex-matched orthopedic injury controls were subjected to quantitative metabolomics, including proton nuclear magnetic resonance (1H-NMR) and direct infusion/liquid chromatography-tandem mass spectrometry (DI/LC-MS/MS), to identify and quantify metabolites on days 1 and 4 post-injury. In addition, we used advanced analytical methods to discover metabo-patterns associated with sTBI diagnosis and those related to probable primary and secondary brain injury.RESULTS: Our results showed different serum metabolic profiles between sTBI and orthopedic injury (OI) controls, with significant changes in measured metabolites on day 1 and day 4 post-brain injury. The number of altered metabolites and the extent of their change were more pronounced on day 4 as compared to day 1 post-injury, suggesting an evolution of mechanisms from primary to secondary brain injury. Data showed high sensitivity and specificity in separating sTBI from OI controls for diagnosis. Energy-related metabolites such as glucose, pyruvate, lactate, mannose, and polyamine metabolism metabolites (spermine and putrescine), as well as increased acylcarnitines and sphingomyelins, occurred mainly on day 1 post-injury. Metabolites of neurotransmission, catecholamine, and excitotoxicity mechanisms such as glutamate, phenylalanine, tyrosine, and branched-chain amino acids (BCAAs) increased to a greater degree on day 4. Further, there was an association of multiple metabolites, including acylcarnitines (ACs), lysophosphatidylcholines (LysoPCs), glutamate, and phenylalanine, with injury severity at day 4, while lactate, glucose, and pyruvate correlated with injury severity on day 1.CONCLUSION: The results demonstrate that serum metabolomics has diagnostic potential for sTBI and may reflect molecular mechanisms of primary and secondary brain injuries when comparing metabolite profiles between day 1 and day 4 post-injury. These early changes in serum metabolites may provide insight into molecular pathways or mechanisms of primary injury and ongoing secondary injuries, revealing potential therapeutic targets for sTBI. This work also highlights the need for further research and validation of sTBI metabolite biomarkers in a larger cohort.PMID:39815318 | DOI:10.1186/s13054-025-05258-1

Nat Methods. 2025 Jan 15. doi: 10.1038/s41592-024-02574-2. Online ahead of print.ABSTRACTSpatial molecular profiling has provided biomedical researchers valuable opportunities to better understand the relationship between cellular localization and tissue function. Effectively modeling multimodal spatial omics data is crucial for understanding tissue complexity and underlying biology. Furthermore, improvements in spatial resolution have led to the advent of technologies that can generate spatial molecular data with subcellular resolution, requiring the development of computationally efficient methods that can handle the resulting large-scale datasets. MISO (MultI-modal Spatial Omics) is a versatile algorithm for feature extraction and clustering, capable of integrating multiple modalities from diverse spatial omics experiments with high spatial resolution. Its effectiveness is demonstrated across various datasets, encompassing gene expression, protein expression, epigenetics, metabolomics and tissue histology modalities. MISO outperforms existing methods in identifying biologically relevant spatial domains, representing a substantial advancement in multimodal spatial omics analysis. Moreover, MISO's computational efficiency ensures its scalability to handle large-scale datasets generated by subcellular resolution spatial omics technologies.PMID:39815104 | DOI:10.1038/s41592-024-02574-2

Funct Integr Genomics. 2025 Jan 16;25(1):15. doi: 10.1007/s10142-024-01520-x.ABSTRACTAdvancements in bioinformatic tools and breakthroughs in high throughput RNA sequencing have unveiled the potential role of non-coding RNAs in influencing the overall expression of disease-responsive genes. Owing to the increasing need to develop resilient crop varieties against environmental constraints, our study explores the functional relationship of various non-coding RNAs in wheat during leaf rust pathogenesis. MicroRNAs (miRNAs) and circular RNAs (circRNAs) were retrieved from SAGE and RNA-Seq libraries, respectively, in the susceptible (HD2329) and resistant (HD2329 + Lr28) wheat Near-Isogenic Lines (NILs). Here we explored the previously published circRNAs for their differential expression and correlated the data with the differentially expressed miRNAs (DEMs) through various in silico methods to acquire the target miRNAs of circRNAs and the downstream target mRNAs of miRNAs. Finally, a competing endogenous RNA (ceRNAs) regulatory network was constructed and validated through RT-qPCR method. We have identified the ceRNA regulatory network of four differentially expressed circRNAs (DECs) and five DEMs to highlight their crucial roles in the robust enhancement of the temporal expression profiles of five defense responsive genes (mRNAs) in wheat NILs against leaf rust infection. The study confirms the synergistic expression of circRNAs and mRNAs with an antagonistic correlation with the expression profile of the corresponding miRNAs. The vital role of leaf rust-resistant gene Lr28 has also been highlighted for driving the efficiency of the circRNAs to upregulate target gene expression. Thus, understanding the circRNA-miRNA-target gene interaction during leaf rust pathogenesis can help to identify stress-specific regulatory biomarkers to enhance defense responses in wheat for improved resilience through multi-omics integration of transcriptomics, proteomics and metabolomics.PMID:39815073 | DOI:10.1007/s10142-024-01520-x

Sci Rep. 2025 Jan 15;15(1):1991. doi: 10.1038/s41598-025-86306-2.ABSTRACTRegular aerobic exercise has a significant impact on glucose metabolism and lipid profiles, contributing to overall health improvement. However, evidence for optimal exercise duration to achieve these effects is limited. This study aims to explore the effects of 4 and 8 weeks of moderate-intensity aerobic exercise on glucose metabolism, lipid profiles, and associated metabolic changes in young female students with insulin resistance and varying body mass, seeking to determine the optimal duration for physiological adaptations. Twenty-eight physically semi-active female students were randomly assigned to 4-week (G4, n = 13, age = 23.31 ± 5.19, BMI = 24.78 ± 5.87) and 8-week (G8, n = 15, age = 21.8 ± 2.56, BMI = 24.95 ± 4.81) training groups. The aerobic intervention maintained an intensity of 40-70% of maximum heart rate (HRmax). 6-min-walk test (6MWT), handgrip strength tests, insulin, HOMA-IR, lipid profiles, and metabolic profiles were assessed pre- and post-intervention. Following the intervention, G8, but not G4, exhibited a significant decrease in HOMA-IR (-14.59%, p = 0.047). The improvement in HOMA-IR was accompanied by notable improvements in 6-MWT (+ 38.18%, p < 0.001) and handgrip strength (+ 11.62, p = 0.027 and + 17.59%, p = 0.013), and increased levels of bilirubin degradation products, ribose, and glutarate. The elevated levels of bilirubin degradation products, known for their antioxidant properties, suggested a potential antioxidative response triggered by prolonged aerobic exercise. Additionally, an increase in ribose and glutarate indicated improved metabolic flexibility and enhanced utilization of alternative energy substrates. The 8-week aerobic exercise regimen demonstrated enhanced insulin sensitivity, upper body strength, and cardiovascular performance in young females compared to a 4-week regimen by triggering specific metabolic adaptations. These findings emphasize the complex relationship between exercise duration, metabolic adaptations, and overall well-being in young women, providing valuable insights for optimizing exercise prescriptions in promoting metabolic health.PMID:39815028 | DOI:10.1038/s41598-025-86306-2

Sci Rep. 2025 Jan 15;15(1):2094. doi: 10.1038/s41598-024-84893-0.ABSTRACTThe research highlights the importance of exploring endophytic microbiomes of medicinal plants to uncover their potential for secondary metabolite production and their role in the biosynthesis of host-derived compounds. This study was aimed to isolate leaf endophytic bacteria of Rauvolfia serpentina, investigate their antibacterial, antioxidant potentials and detect host-origin compound reserpine using Reverse Phase High-Performance Liquid Chromatography (RPHPLC). Untargeted analysis via Ultra High-Performance Liquid Chromatography-High-Resolution Mass Spectrometry (UHPLC-HRMS/MS) was conducted for profiling main phytochemicals in the leaves and to explore potential bioactive compounds in bacterial extracts. Nine bacterial isolates were obtained from R. serpentina leaves. These isolates exhibited positive results in various biochemical tests including indole production, methyl red, Voges-Proskauer, citrate utilization, catalase and oxidase production, nitrate reduction, oxidative fermentation, and citrate reduction tests. Endophytic isolates RSLB3 and RSLB18 exhibited most potential antibacterial activity against tested human pathogenic bacteria and were identified as Bacillus sp. The extract of RSLB3 and RSLB18 also showed significant antioxidant activity compared to leaf extract. The total phenol content was similar in both these isolates while flavonoids content and DPPH scavenging activity was higher in isolate RSLB3. RPHPLC analysis confirmed the presence of reserpine in bacterial metabolites when compared to a standard reference. UHPLC-HRMS profiling unveiled a diverse range of host-derived compounds and reaction intermediates with known and unknown bioactive properties in leaf extract, RSLB3, and RSLB18. To our knowledge, this is the first study to achieve a comprehensive profiling.PMID:39814849 | DOI:10.1038/s41598-024-84893-0

Sci Rep. 2025 Jan 15;15(1):2060. doi: 10.1038/s41598-025-85216-7.ABSTRACTPrenatal sonographic diagnosis of congenital heart disease (CHD) can lead to improved morbidity and mortality. However, the diagnostic accuracy of ultrasound, the sole prenatal screening tool, remains limited. Failed prenatal or early newborn detection of cyanotic CHD (CCHD) can have disastrous consequences. We therefore sought to use a Precision Fetal Cardiology based approach combining metabolomic profiling of maternal saliva and machine learning, a major branch of artificial intelligence (AI), for the prenatal detection of isolated, non-syndromic cyanotic CHD. Metabolomic analyses using Ultra-High Performance Liquid Chromatography/Mass Spectrometry identified 468 metabolites in the saliva. Six different AI platforms were utilized for the detection of CCHD and CHD overall. AI achieved excellent accuracy for the CCHD detection: Area Under the ROC curve: AUC (95% CI) = 0.819 (0.635-1.00) with a sensitivity and specificity of 92.5% and 87.0%, and for CHD overall: AUC (95% CI) = 0.828 (0.635-1.00) with a sensitivity of 90.5% and specificity of 88.0%. Similarly high accuracies were achieved for the detection of CHD overall: AUC (95% CI) = 0.8488 (0.635-1.00) with a sensitivity of 92.5% and specificity of 91.0%. Pathway analysis showed significant alterations in Arachidonic Acid, Alpha-linoleic acid, and Tryptophan metabolism indicating significant lipid dysfunction in cyanotic CHD. In summary, we report for the first time, the accurate detection of non-syndromic cyanotic CHD using maternal salivary metabolomics. Further, analysis revealed significant alteration of lipid metabolism.PMID:39814838 | DOI:10.1038/s41598-025-85216-7

Sci Rep. 2025 Jan 15;15(1):2082. doi: 10.1038/s41598-025-86007-w.ABSTRACTThe cytotoxic mechanisms of thymidylate synthase inhibitors, such as the multitarget antifolate pemetrexed, are not yet fully understood. Emerging evidence indicates that combining pemetrexed with histone deacetylase inhibitors (HDACi) may enhance therapeutic efficacy in non-small cell lung cancer (NSCLC). To explore this further, A549 NSCLC cells were treated with various combinations of pemetrexed and the HDACi MS275 (Entinostat), and subsequently assessed for cell viability, cell cycle changes, and genotoxic markers. Proteomic alterations were analyzed using label-free shotgun and targeted LC-MS/MS. MS275 enhanced the sensitivity of A549 cells to pemetrexed, but only when administered following prior treatment with pemetrexed. Both HeLa (p53 negative) and A549 (p53 positive) showed robust activation of γH2AX upon treatment with this combination. Importantly, CRISPR/Cas9 knockout of the uracil-DNA glycosylase UNG did not affect γH2AX activation or sensitivity to pemetrexed. Proteomic analysis revealed that MS275 altered the expression of known pemetrexed targets, as well as several proteins involved in pyrimidine metabolism and DNA repair, which could potentiate pemetrexed cytotoxicity. Contrary to the conventional model of antifolate toxicity, which implicates futile cycles of uracil incorporation and excision in DNA, we propose that ribonucleotide incorporation in nuclear and mitochondrial DNA significantly contributes to the cytotoxicity of antifolates like pemetrexed, and likely also of fluorinated pyrimidine analogs. HDAC inhibition apparently exacerbates cytotoxicity of these agents by inhibiting error-free repair of misincorporated ribonucleotides in DNA. The potential of HDACis to modulate pyrimidine metabolism and DNA damage responses offers novel strategies for improving NSCLC outcomes.PMID:39814799 | DOI:10.1038/s41598-025-86007-w

Sci Rep. 2025 Jan 15;15(1):2048. doi: 10.1038/s41598-024-84495-w.ABSTRACTThe clownfish - sea anemone system is a great example of symbiotic mutualism where host «toxicity» does not impact its symbiont partner, although the underlying protection mechanism remains unclear. The regulation of nematocyst discharge in cnidarians involves N-acetylated sugars like sialic acid, that bind chemoreceptors on the tentacles of sea anemones, leading to the release of stings. It has been suggested that clownfish could be deprived of sialic acid on their skin surface, sparing them from being stung and facilitating mutualism with sea anemones. In this study, we sampled the skin mucus of two anemone symbionts, the clownfish Amphiprion akindynos and the juvenile damselfish Dascyllus trimaculatus, as well as two non-symbiotic adult damselfish Pomacentrus moluccensis and P. pavo. The free and total sialic acid content, including its conjugated form, and three other intermediates of this pathway were quantified using a stable isotope dilution mass spectrometry approach. We found significantly higher levels of sialic acid and its precursor in the non-symbiotic damselfishes. Concentrations of total sialic acid in anemone symbionts ranged between 13 µM and 16 µM, whereas the non-symbiotic damselfishes ranged between 21 µM and 30 µM. The presence of this metabolite and its precursors, as triggers of nematocyst discharge, in anemone symbionts, suggests that this is not the direct mechanism of protection or that the trigger is concentration dependent. This experiment demonstrates that anemone symbionts are not spared by nematocysts because of a lack of N-acetylated sugars, as previously thought, rather the biochemical mechanisms involving N-acetylated sugars are more complex than just a presence/absence of these molecules.PMID:39814757 | DOI:10.1038/s41598-024-84495-w

Nat Commun. 2025 Jan 15;16(1):697. doi: 10.1038/s41467-024-55035-x.ABSTRACTPhotoreceptors are specialized neurons at the core of the retina's functionality, with optical accessibility and exceptional sensitivity to systemic metabolic stresses. Here we show the ability of risk-free, in vivo photoreceptor assessment as a window into systemic health and identify shared metabolic underpinnings of photoreceptor degeneration and multisystem health outcomes. A thinner photoreceptor layer thickness is significantly associated with an increased risk of future mortality and 13 multisystem diseases, while systematic analyses of circulating metabolomics enable the identification of 109 photoreceptor-related metabolites, which in turn elevate or reduce the risk of these health outcomes. To translate these insights into a practical tool, we developed an artificial intelligence (AI)-driven photoreceptor metabolic window framework and an accompanying interpreter that comprehensively captures the metabolic landscape of photoreceptor-systemic health linkages and simultaneously predicts 16 multisystem health outcomes beyond established approaches while retaining interpretability. Our work, replicated across cohorts of diverse ethnicities, reveals the potential of photoreceptors to inform systemic health and advance a multisystem perspective on human health by revealing eye-body connections and shared metabolic influences.PMID:39814712 | DOI:10.1038/s41467-024-55035-x

Int J Biol Macromol. 2025 Jan 13:139826. doi: 10.1016/j.ijbiomac.2025.139826. Online ahead of print.ABSTRACTBasic leucine zipper (bZIP) transcription factors serve as crucial regulators in plants' response to abiotic stress; however, its function in grapevine heat tolerance is still largely unknown. Here, we undertook a comprehensive investigation of grape genome, leading to the identification of 65 VvbZIP genes, among which 16 VvbZIPs were significantly induced under heat stress. Overexpression of VvbZIP36 enhanced heat tolerance in grape calli, while virus-induced gene silencing (VIGS) of VvbZIP36 reflected thermal sensitivity. Additionally, we examined the metabolomic and transcriptomic profiles of grape seedlings, which showed that grapes exhibited increased accumulation of flavonoids, coinciding with the significantly induced expression of the VvFLS (Flavanol synthase) gene under heat stress. Overexpression of VvFLS also improved the heat tolerance in grape calli by scavenging reactive oxygen species (ROS). A yeast one-hybrid assay (Y1H) demonstrated that VvbZIP36 was capable of specifically activating the promoter of VvFLS, which was subsequently confirmed through a luciferase reporter assay. Furthermore, the overexpression of VvbZIP36 resulted in enhanced quercetin content, while the exogenous application of quercetin improved heat tolerance of grape. Collectively, our findings suggest that VvbZIP36 binds to the VvFLS promoter, thereby enhancing heat stress tolerance by increasing quercetin production and mitigating oxidative damage in grapes.PMID:39814305 | DOI:10.1016/j.ijbiomac.2025.139826