PubMed

Environ Sci Technol. 2025 Feb 13. doi: 10.1021/acs.est.4c13531. Online ahead of print.ABSTRACTUnder changing climates, engineering drought-resistant crops is critical for reducing food insecurity. Here, we leverage plant "stress memory" and ROS-generating silica nanoparticles (NPs) to enhance the drought tolerance of cucumber plants. Under PEG-mimicking drought conditions, cucumber seeds primed with fumed silica NPs (40 mg/L, 4 h) exhibited an increased seed germination rate (from 66.7 to 80.0%), enhanced seedling vigor (59.3%), and improved root and shoot length (24.4 and 74.1%, respectively) compared to seeds primed with water. In contrast, silicic acid and traditional silicon fertilizers at the same dose did not show priming effects, indicating that the released Si did not contribute to the observed outcomes. Metabolomics reveals that silica seed priming accelerated the mobilization of seed-stored reserves. Vegetative tissues also exhibit enhanced drought resistance, and metabolomics analysis reveals that the drought resistance strategy involves the upregulation of sugars (glucose, sucrose, trehalose, maltose; 34.7-74.8%), amino acids (methionine, 6-fold), signaling molecules (salicylic acid, 2.5-fold), and antioxidants (ascorbic acid, 2-hydroxycinnamic acid, ferulic acid, P-coumaric acid; 16.0-83.8%). Transcriptomics analysis reveals that several drought- and even desiccation-tolerant associated genes exert more pronounced transcript changes in silica-primed leaves. The life cycle study shows that silica seed priming does not generate any yield penalty or compromise the nutritional quality of the fruits. Importantly, offspring seeds exhibit enhanced vigor and drought tolerance, indicating the transgenerational transmission of the acquired drought resilience. The findings of this study provide a promising approach for engineering crops that are resilient to climate change.PMID:39948725 | DOI:10.1021/acs.est.4c13531

J Ovarian Res. 2025 Feb 13;18(1):27. doi: 10.1186/s13048-025-01610-9.ABSTRACTBACKGROUND: While increasing evidence suggests that alterations in the gut microbiota and metabolites are associated with ovarian cancer (OC) risk, whether these associations imply causation remains to be identified.METHODS: We conducted a two-sample Mendelian randomization (MR) study utilizing a large-scale genome-wide association study (GWAS) to explore the causal effects of the gut microbiota of 196/220 individuals and 1,400 plasma metabolites on OC and epithelial ovarian cancer (EOC) subtypes. Data on the gut microbiota were obtained from the MiBioGen consortium of 18,340 subjects and the Dutch Microbiome Project of 7,738 volunteers. Data on plasma metabolites were derived from a GWAS of plasma metabolites in 8,299 participants. Ovarian cancer (n = 25,509) and EOC subtypes were obtained from the Ovarian Cancer Association Consortium (OCAC). Metabolites and associated targets were analyzed via network pharmacology and molecular docking.RESULTS: At the genus and species levels, we identified seven risk factors for the gut microbiota: the genus Dialister (P = 0.024), genus Ruminiclostridium5 (P = 0.0004), genus Phascolarctobacterium (P = 0.0217), species Bacteroides massiliensis (P = 0.011), species Phascolarctobacterium succinatutens (P = 0.0212), species Paraprevotella clara (P = 0.0247) and species Bacteroides dorei (P = 0.0054). In addition, five gut microbes at the genus and species levels were found to be protective: genus Family XIII AD3011 group (P = 0.006), genus Butyrivibrio (P = 0.0095), genus Oscillibacter (P = 0.0206), species Roseburia hominis (P = 0.0241), and species Bifidobacterium bifidum (P = 0.0224). For plasma metabolites, we revealed five positive and four negative correlations with OC. Among these, caffeic acid and caffeine metabolites and sphingomyelin and ceramide metabolites were identified as risk factors, whereas phenylalanine metabolites, butyric acid metabolites, and some lipid metabolites were recognized as protective factors. A series of sensitivity analyses revealed no abnormalities, including pleiotropy and heterogeneity analyses.CONCLUSION: Our MR analysis demonstrated that the gut microbiota and metabolites are causally associated with OC, which has significant potential for the early detection and diagnosis of OC and EOC subtypes, providing valuable insights into this area of research.PMID:39948579 | DOI:10.1186/s13048-025-01610-9

Acta Neuropathol Commun. 2025 Feb 13;13(1):29. doi: 10.1186/s40478-025-01946-9.ABSTRACTMutations in CHRNE encoding the epsilon subunit of acetylcholine receptor result in impaired neuromuscular transmission and congenital myasthenic syndrome (CMS) with variying severity of symptoms. Although the pathophysiology is well-known, blood biomarker signatures enabling a patient-stratification are lacking. This retrospective two-center-study includes 19 recessive CHRNE-patients (AChR deficiency; mean age 14.8 years) from 13 families which were clinically characterized according to disease severity. 15 patients were classified as mildly and 4 patients as moderate to severely affected. Seven known pathogenic and one unreported variant (c.1032 + 2_1032 + 3delinsGT) were identified. Biomarker discovery was carried out on blood samples: proteomics was performed on white blood cells (WBC; n = 12) and on extracellular vesicles (EV) purified from serum samples (n = 7) in addition to amino acid profiling (n = 9) and miRNA screening (n = 18). For miRNA studies, 7 patients with other CMS-subtypes were moreover included. WBC-proteomics unveiled a significant increase of 7 and a decrease of 36 proteins. In silico studies of these proteins indicated affection of secretory granules and the extracellular space. Comparison across patients unveiled increase of two vesicular transport proteins (SCAMP2 and SNX2) in severely affected patients and indeed EV-proteomics revealed increase of 7 and decrease of 13 proteins. Three of these proteins (TARSH, ATRN & PLEC) are known to be important for synaptogenesis and synaptic function. Metabolomics showed decrease of seven amino acids/ amino acid metabolites (aspartic and glutamic acids, phosphoserine, amino adipate, citrulline, ornithine, and 1-methyhistidine). miRNA-profiling showed increase miR - 483 - 3p, miR-365a-3p, miR - 365b - 3p and miR-99a, and decrease of miR-4433b-3p, miR-6873-3p, miR-182-5p and let-7b-5p in CHRNE-patients whereas a comparison with other CMS subtypes showed increase of miR - 205 - 5p, miR - 10b - 5p, miR-125a-5p, miR-499-5p, miR-3120-5p and miR - 483 - 5p and decrease of miR - 1290. Our combined data introduce a molecular fingerprint on protein, metabolic and miRNA level with some of those playing different roles along the neuromuscular axis.PMID:39948634 | DOI:10.1186/s40478-025-01946-9

Cancer Metab. 2025 Feb 13;13(1):9. doi: 10.1186/s40170-025-00379-1.ABSTRACTINTRODUCTION: This study aimed to evaluate the metabolic differences between MM cells derived from patients with elevated serum LDH levels and those without elevated serum LDH levels to identify biological differences that could be exploited for therapeutic purposes.METHODS: We performed transcriptome assessments of CD138 + MM cells derived from patients with elevated serum LDH levels compared to those without elevated serum LDH levels and validated the findings in a larger public dataset. Functional metabolic assessments of our findings were performed using a combination of stable isotope resolved metabolomics (SIRM), bioenergetic flux measurement assays, and live cell analysis in human myeloma cell lines and primary MM patient cells.RESULTS: We identified SLC16A1, responsible for the formation of MCT1, a well-defined bi-directional transporter of lactate in and out of a cell with a predilection to importing extracellular lactate, as differentially expressed between the two groups. This finding was functionally confirmed by higher membranous MCT1 protein expression and SIRM on MM cells derived from patients with elevated serum LDH levels compared to those without elevated serum LDH levels. Finally, disrupting lactate transport in and out of CD138 + MM cells was maximally achievable only with dual inhibition of MCT1 and its partner, MCT4, which was preferentially more cytotoxic in MM cells derived from patients with elevated serum levels of LDH.CONCLUSION: MCT1 mRNA and protein expression distinguish MM cells derived from patients with elevated serum LDH levels from those without elevated serum LDH levels. However, only dual inhibition of MCT1 and MCT4 can disrupt lactate transport in multiple myeloma (MM) cells, with preferential cytotoxicity in MM cells from patients with high serum LDH levels.PMID:39948621 | DOI:10.1186/s40170-025-00379-1

Cardiooncology. 2025 Feb 13;11(1):17. doi: 10.1186/s40959-025-00309-6.ABSTRACTBACKGROUND: Cancer-therapy related cardiac dysfunction (CTRCD) remains a significant cause of morbidity and mortality in cancer survivors. In this study, we aimed to identify differential plasma proteins and metabolites associated with left ventricular dysfunction (LVD) in cancer patients.METHODS: We analyzed data from 50 patients referred to the Cleveland Clinic Cardio-Oncology Center for echocardiograph assessment, integrating electronic health records, proteomic, and metabolomic profiles. LVD was defined as an ejection fraction ≤ 55% based on echocardiographic evaluation. Classification-based machine learning models were used to predict LVD using plasma metabolites and proteins as input features.RESULTS: We identified 13 plasma proteins (P < 0.05) and 14 plasma metabolites (P < 0.05) associated with LVD. Key proteins included markers of inflammation (ST2, TNFRSF14, OPN, and AXL) and chemotaxis (RARRES2, MMP-2, MEPE, and OPN). Notably, sex-specific associations were observed, such as uridine (P = 0.003) in males. Furthermore, metabolomic features significantly associated with LVD included 1-Methyl-4-imidazoleacetic acid (P = 0.015), COL1A1 (P = 0.009), and MMP-2 (P = 0.016), and pointing to metabolic shifts and heightened inflammation in patients with LVD.CONCLUSION: Our findings suggest that circulating metabolites may non-invasively detect clinical and molecular differences in patients with LVD, providing insights into underlying disease pathways and potential therapeutic targets.PMID:39948601 | DOI:10.1186/s40959-025-00309-6

BMC Psychiatry. 2025 Feb 13;25(1):122. doi: 10.1186/s12888-025-06579-9.ABSTRACTPeople with severe mental illness have high rates of obesity, type 2 diabetes, and cardiovascular disease. Emerging evidence suggests that metabolic dysfunction may be causally linked to the risk of severe mental illness. However, more research is needed to identify reliable metabolic markers which may have an impact on mental health outcomes, and to determine the mechanisms behind their impact. In the METPSY research study, we will investigate the relationship between metabolic markers and clinical outcomes of severe mental illness in young adults. We will recruit 120 young adults aged 16-25 years living in Scotland with major depressive disorder, bipolar disorder, schizophrenia, or no severe mental illness (controls) for a prospective observational study. We will assess clinical symptoms at three in-person visits (baseline, 6 months, and 12 months) using the Structured Clinical Interview for DSM-5, and collect blood samples at each of these visits for agnostic profiling of metabolic biomarkers through an untargeted metabolomic screen, using the rapid hydrophilic interaction liquid chromatography ion mobility mass spectrometry method (RHIMMS). Participants will also complete remote assessments at 3 and 9 months after the baseline visit: Ecological Momentary Assessments to measure mental health, wrist actigraphy to measure rhythms of rest and activity, and continuous glucose monitoring to measure metabolic changes. Throughout the 12-month enrolment period, we will also measure objective markers of sleep using a radar sleep monitor (Somnofy). Using advanced statistical techniques and machine learning analysis, we will seek to better understand the mechanisms linking metabolic health with mental health in young adults with schizophrenia, bipolar disorder, and severe depression. Clinical trial number: Not applicable.PMID:39948527 | DOI:10.1186/s12888-025-06579-9

BMC Plant Biol. 2025 Feb 13;25(1):190. doi: 10.1186/s12870-025-06057-0.ABSTRACTBACKGROUND: The Colletotrichum fructicola (C. fructicola) is a hemibiotrophic fungus, which causes devastating anthracnose in strawberry. At present, the resistance mechanism to C. fructicola remains poorly understood.RESULTS: Here, we used RNA-sequencing and liquid chromatography-mass spectrometry (LC-MS) metabolomics to excavate the molecular mechanism of strawberry resistance to C. fructicola. The differentially accumulated metabolites (DAMs) and differentially expressed genes (DEGs) were screened at different stages after C. fructicola infection in the susceptible 'Benihoppe' and resistant cultivar 'Sweet Charlie'. The core common DEGs with high association of common DAMs were identified by multi-omics integration analysis, and showed convergence and divergence in the two strawberry cultivars. Strikingly, the phenylpropanoids biosynthesis was simultaneously enriched in a multi-level omics at different stages after C. fructicola infection in the resistant (R) and susceptible (S) strawberries. Furthermore, we constructed the DEGs-DAMs map of phenylpropanoid biosynthesis. More importantly, we showed that chloroplasts and starch and sugar metabolism related genes, such as chlorophyII A-B binding genes, glycosyl hydrolase (GH) family genes and so on, were differentially expressed.CONCLUSIONS: Taken together, our study revealed major changes in genes and metabolites expression associated with C. fructicola resistance, and identified the multi-level regulatory network based on phenylpropanoid biosynthesis, useful for further mechanistic excavation of resistance to C. fructicola in strawberries.PMID:39948459 | DOI:10.1186/s12870-025-06057-0

BMC Infect Dis. 2025 Feb 13;25(1):211. doi: 10.1186/s12879-025-10606-1.ABSTRACTBACKGROUND: Metabolomics is an analytical approach utilized to explore the metabolic profiles of biological systems. This process typically involves the application of techniques such as nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). In the case of schistosomiasis, metabolomics has been employed to identify potential diagnostic biomarkers, examine the host's metabolic response, and explore more effective therapeutic strategies. The objective of this scoping review is to assess the scope and characteristics of metabolomic research on schistosomiasis conducted over the past decade.METHODS: To identify relevant original publications, a systematic search was conducted in the PubMed and Web of Science databases using the following search terms: ("Metabolomics" OR "Metabolomic" OR "Metabonomics" OR "Metabonomic") AND ("Schistosomiasis" OR "Schistosoma"). These terms were applied to the titles and abstracts of the publications, with a focus on the period from January 2014 to December 2024.RESULTS: The initial search yielded 48 articles. However, after a thorough evaluation of the abstracts, 14 articles were selected based on the established inclusion criteria. The selection process is visually depicted in the PRISMA flowchart. The majority of the studies included in this review were conducted in China (7 articles) and Brazil (3 articles). Approximately two-thirds of the studies utilized animal models, with serum serving as biofluid in 66% of the studies. The findings of this scoping review suggest that chromatographic techniques coupled with mass spectrometry are predominantly used in metabolomic research on schistosomiasis, accounting for 75% of the studies. The identified metabolites are associated with metabolic pathways related to glycolysis, the TCA cycle, and amino acid metabolism, as well as demonstrating alterations resulting from intestinal dysbiosis observed during the infection. As exemplified by succinate and citrate, which are present in the alterations of energy pathways in Schistosoma mansoni and Schistosoma japonicum species. The serum levels of these metabolites are modified, reflecting the host's metabolic and immunological responses induced by the infections.CONCLUSIONS: These studies successfully elucidated the metabolic pathways and key metabolites involved in schistosomiasis. The findings are significant for the future identification of diagnostic biomarkers and the development of novel antiparasitic agents targeting Schistosoma species.CLINICAL TRIAL: Not Applicable.PMID:39948455 | DOI:10.1186/s12879-025-10606-1

BMC Plant Biol. 2025 Feb 13;25(1):189. doi: 10.1186/s12870-025-06174-w.ABSTRACTDecalepis arayapathra is an important medicinal plant known for several medicinal values, however, due to overharvesting, habitat destruction, and its limited geographical distribution, D. arayapathra faces severe threats of extinction. A synthetic seed protocol was developed for this plant, representing a novel approach in its propagation and conservation. Nodal segments (NS) were encapsulated in a sodium alginate (SA) matrix. 3% SA with 100 mM CaCl2 solutions was best to obtain ideal beads with fine texture. Murashige and Skoog (MS) medium consisting of BA 5.0 µM + NAA 0.5 µM + ADS 20.0 µM resulted in a maximum regrowth frequency of 71.26% with 3.13 shoots per bead and a shoot length of 4.10 cm after six weeks of culture. Rooting in the microshoots was better observed with half- strength MS + 2.5 µM NAA, resulting in 3.1 roots per microshoot and a root length of 3.0 cm after four weeks of culture, followed by successful acclimatization. The study investigated the effect of photosynthetic photon flux density (PPFD) levels of 50 and 300 PPFD on various physiological and biochemical parameters during the acclimatization of in vitro-derived plants. Results showed an increase in photosynthetic pigments, including chlorophyll and carotenoids, as well as an enhanced net photosynthetic rate (PN) and stomatal conductance (gs) with prolonged acclimatization, with higher PPFD being more effective. Antioxidant enzyme activities, including SOD, CAT, APX, and GR, increased over time, except for SOD, which began to decline after 21 days under both light conditions. Stress markers such as malondialdehyde (MDA) and electrolyte leakage decreased over time, indicating successful acclimatization. Genetic fidelity was confirmed through clear and monomorphic banding patterns obtained using RAPD and ISSR markers. Quantification of 2H4MB (2-hydroxy-4-methoxy benzaldehyde) in synseed-derived roots using HPLC revealed a concentration of 16.27 µg/ml. Metabolic profiling of the synseed-derived root tuber using GC-MS identified several major and minor metabolites. This study offers a breakthrough in the conservation of D. arayapathra through synthetic seed technology, enabling sustainable propagation while preserving genetic stability. It ensures a consistent supply of the bioactive compound 2H4MB, promoting medicinal research and commercial applications.PMID:39948454 | DOI:10.1186/s12870-025-06174-w

Nat Genet. 2025 Feb 13. doi: 10.1038/s41588-025-02081-w. Online ahead of print.ABSTRACTCell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. While transcription master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether plasticity is actively suppressed by lineage-specific repressors. Here we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternative fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and was sufficient to prevent liver tumorigenesis. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo and enabled the transition of hepatocellular carcinoma to cholangiocarcinoma. Conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide evidence for PROX1 as a hepatocyte-specific safeguard and support a model where cell-type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and thus prevent disease.PMID:39948437 | DOI:10.1038/s41588-025-02081-w

Commun Biol. 2025 Feb 13;8(1):230. doi: 10.1038/s42003-025-07631-w.ABSTRACTFluid-filled cysts are the key feature of polycystic kidney disease, which eventually leads to renal failure. We analyzed the composition of cyst fluid from a rat model of autosomal recessive polycystic kidney disease, the PCK rat, and identified sexual differences. Our results demonstrate that the ion composition of cyst fluid differs from that of urine or plasma. Untargeted metabolomics combined with transcriptomic data identified tryptophan metabolism, enzyme metabolism, steroid hormone biosynthesis, and fatty acid metabolism as pathways differing between male and female PCK rats. We quantified 42 amino acids in the cyst fluid (PCK only), plasma, and urine of male and female PCK rats and Sprague Dawley rats. Taurine was the most concentrated amino acid present in the cyst fluid, and PCK rat urinary taurine excretion was over 3-fold greater than Sprague Dawley rats. Understanding the composition of cyst fluid provides valuable insights into disease pathophysiology and may help identify potential dietary or pharmacological interventions to mitigate disease progression and improve patient outcomes.PMID:39948436 | DOI:10.1038/s42003-025-07631-w

Nature. 2025 Feb 13. doi: 10.1038/s41586-025-08764-y. Online ahead of print.NO ABSTRACTPMID:39948434 | DOI:10.1038/s41586-025-08764-y

Sci Rep. 2025 Feb 13;15(1):5421. doi: 10.1038/s41598-025-85976-2.ABSTRACTThe composition of natural substances varies with plant species and cultivation environment factors, which is also a complex problem. A total of 127 substances of agarwood essential oils (AEOs) extracted by hydro-distillation were identified by GC-MS analysis. Among the components obtained from AEOs, sesquiterpenes and small molecule aromatic substances were the main components, and there were significantly fewer chromones. The aromatic compound 4-phenyl-2-butanone was the only common component. The VIP value and S-plot generated by the OPLS-DA model based on the comparison of regional groups or pairwise genotypes showed up to 26 potential markers at VIP > 1. The more common components of agarwood, such as sesquiterpenes α-guruene, agarospirol, guaiol, γ-eudesmol and chromone 2-phenylethyl-4H-chromen-4-one, contributed the most to the VIP value. Supervised OPLS-DA was better than that of PLS-DA, providing a reference for the quality evaluation of AEOs. This method emphasizes providing more information and obtaining additional information when combined with appropriate multivariate modeling and effective visualization of specific labeled metabolites for identification.PMID:39948379 | DOI:10.1038/s41598-025-85976-2

Nat Commun. 2025 Feb 13;16(1):1400. doi: 10.1038/s41467-025-56761-6.ABSTRACTBacterial death is critical in nutrient recycling. However, the underlying mechanisms that permit macromolecule recycling after bacterial death are largely unknown. We demonstrate that bacteria encode post-mortem protein catabolism via Lon protease released from the dead bacteria. Growth assays reveal that the lysate of Lon protease-null bacteria does not provide a growth benefit to wild type cells. This deficiency is reversed with exogenous recombinant Lon protease, confirming its post-mortem role and is independent of Lon ATPase activity. Biochemistry, growth assays and metabolomics demonstrate that Lon protease facilitates peptide nutrient release, benefitting living cells and acting as a cooperative public good. We also show that the production of Lon protease cannot be explained by a personal benefit to living cells. Although Lon protease can also provide a benefit to living cells under stressful conditions by helping control protein quality, this private benefit does not outweigh the cost under the conditions examined. These results suggest that Lon protease represents a post-mortem adaptation that can potentially be explained by considering the post-mortem indirect benefit to other cells (kin selection). This discovery highlights an unexpected post-mortem biochemistry, reshaping our understanding of nutrient recycling.PMID:39948360 | DOI:10.1038/s41467-025-56761-6

Metabolomics. 2025 Feb 13;21(2):26. doi: 10.1007/s11306-024-02212-0.ABSTRACTINTRODUCTION: Despite considerable advances in cancer research, the increasing prevalence and high mortality rate of clear cell renal cell carcinoma (ccRCC) remain a significant challenge. A more detailed comprehension of the distinctive metabolic characteristics of ccRCC is vital to enhance diagnostic, prognostic, and therapeutic strategies.OBJECTIVES: This study aimed to investigate the metabolic signatures of ccRCC tumours and, for the first time, their correlation with the urinary metabolome of the same patients.METHODS: We applied a gas chromatography-mass spectrometry (GC-MS)-based metabolomic approach to analyse matched tissue and urine samples from a cohort of 18 ccRCC patients and urine samples from 18 cancer-free controls. Multivariate and univariate statistical methods, as well as pathway and correlation analyses, were performed to assess metabolic dysregulations and correlations between tissue and urine.RESULTS: The results showed a ccRCC metabolic signature characterized by reprogramming in amino acid, energy, and sugar and inositol phosphate metabolisms. Our study identified, for the first time, significantly decreased levels of asparagine, proline, gluconate, 3-aminoisobutanoate, 4-aminobutanoate and urea in ccRCC tumours, highlighting the involvement of arginine biosynthesis, β-alanine metabolism and purine and pyrimidine metabolism in ccRCC. The correlations between tissue and urine metabolomes provide evidence for the potential usefulness of urinary metabolites in understanding systemic metabolic changes driven by RCC tumours.CONCLUSIONS: These findings significantly advance our understanding of metabolic reprogramming in ccRCC and the systemic metabolic changes associated with the disease. Future research is needed to validate these findings in larger cohorts and to determine their potential implications for diagnosis and targeted therapies.PMID:39948318 | DOI:10.1007/s11306-024-02212-0

Metabolomics. 2025 Jan 20;21(1):18. doi: 10.1007/s11306-025-02221-7.ABSTRACTINTRODUCTION: Melanoma is an aggressive form of cancer characterised by its high metabolic adaptability that contributes to drug resistance. To this end, ruthenium complexes have emerged as a promising class of compounds in the discovery of cancer drugs due to their unique chemical properties and potential to overcome some of the limitations of conventional chemotherapy. In our previous study, we synthesised, characterised, and performed cytotoxicity tests of a ruthenium (II) complex (GA113) against the malignant A375 melanoma cell line. Our previous findings revealed favourable cytotoxicity, with an IC50 value of 8.76 µM which formed the basis current study.OBJECTIVE: Elucidate the metabolic mechanism of GA113 in malignant A753 melanoma cells.METHOD: A two-dimensional gas chromatography time-of-flight mass spectrometry (GCxGC-TOF/MS) cellular metabolomics approach was used, and univariate and multivariate statistical methods were applied to the metabolomics data.RESULTS: 33 metabolites were identified as significant discriminators between GA113-treated and untreated A375 melanoma cells. Changes in 19 of these 33 metabolites were mapped to pantothenate and coenzyme A biosynthesis, citrate cycle, cysteine and methionine metabolism, arginine and proline metabolism, and alanine, aspartate, and glutamate metabolism.CONCLUSION: These findings suggest that GA113 exerts its anticancer effects by disrupting essential metabolic pathways in melanoma cells, which presents a promising therapeutic avenue to target melanoma metabolism.PMID:39948285 | DOI:10.1007/s11306-025-02221-7

Med Microbiol Immunol. 2025 Feb 13;214(1):11. doi: 10.1007/s00430-025-00819-1.ABSTRACTIt is now widely accepted that lungs are colonized by diverse microbes. Dysbiosis of the lung microbiota has been found to affect the progression of lung cancer. Fungi are a major component of the lung microbiota. However, the causal links between the mycobiome or specific species and lung cancer remain unclear. To address this, we conducted a study examining the composition of lung mycobiota in Non-Small-Cell Lung Cancer (NSCLC) patients using shotgun metagenomics. The differential taxa between NSCLC patients and non-cancer controls were defined by the Wilcoxon rank-sum test. Nested PCR was used to measure the abundance of specific fungal species. Metabolomics analysis was performed to investigate the metabolic reprogramming of macrophages triggered by intracellular infection of specific fungal species. In vitro and in vivo assays were conducted to examine the effect of the specific fungus on cancer cell growth. Our findings showed that Ascomycota, Microsporidia and Mucoromycota were the dominant fungal taxa in the lungs. Talaromyces marneffei (T.marneffei) was the most significantly differential fungus between lung cancer patients and non-cancer controls, with its abundance positively correlated with lung cancer. The lung cancer animal model demonstrated that T.marneffei promotes lung cancer growth. Our study also demonstrated that T.marneffei promotes lung cancer cell growth by inducing dose-dependent M2 macrophage polarization through arginine-ornithine-cycle activation. Furthermore, inhibition of arginase can reduce M2 polarization of macrophages and the survival of T. marneffei inside macrophages. In summary, our study reveals that the increased abundance of T. marneffei in the lungs affects lung cancer cell growth by triggering arginine-induced M2 polarization of macrophages. These findings provide potential drug targets for the development of therapies aimed at targeting the survival of fungi inside macrophages in the fight against cancer.PMID:39948184 | DOI:10.1007/s00430-025-00819-1

Sci Rep. 2025 Feb 13;15(1):5409. doi: 10.1038/s41598-025-88636-7.ABSTRACTLysine-specific histone demethylase (KDM) 5 inhibition by KDM5-C70 induces astrocytogenesis and highlights the importance of modulation of histone methylation in cell fate specification. This study investigated the role of the histone demethylase inhibitor KDM5-C70 in modulating the metabolic and lipidomic landscape during astrocyte differentiation of rat neural stem cells (NSCs). Using chemical derivatisation combined with gas chromatography-mass spectrometry, 42 metabolites were detected, indicating potential regulation of phospholipid metabolism. Subsequent lipidomic analysis, employing reverse-phase liquid chromatography with high-resolution quadrupole time-of-flight mass spectrometry, identified 180 lipid species and 9 lipid subclasses. Integrative analysis revealed that KDM5-C70 promoted astrocytogenesis through epigenetic changes linked to the attenuation of phosphatidylethanolamine (PE) biosynthesis pathways. The reduced expression of transcripts related to PE highlighted the significance of the PE pathway in influencing cell fate decisions. These quantitative metabolomic and lipidomic analyses not only advance our understanding of NSC differentiation but also lay the groundwork for potential therapeutic strategies targeting metabolic pathways in neurodegenerative diseases and neural injuries.PMID:39948097 | DOI:10.1038/s41598-025-88636-7

Neurotherapeutics. 2025 Feb 12:e00546. doi: 10.1016/j.neurot.2025.e00546. Online ahead of print.ABSTRACTChildhood dementias, a group of neurological disorders are characterised by neurocognitive decline, with physical and psychosocial impacts for individuals. With therapy available for <5 ​% of childhood dementias, there is a high level of unmet need. Integration of biomarkers in clinical trials are important to characterize distinctive biological activities and interrogate targets for therapeutic development. This study reviewed four clinical trial registries to examine circulating biomarkers in childhood dementias. Findings from 262 studies were synthesized across 49/72 (68 ​%) childhood dementia disorders. Disease-related biomarkers were associated with 1) the primary pathophysiology 2) downstream pathogenic events 3) drug-related pharmacokinetics, safety and/or tolerability. The predominant biological measures were metabolites linked to the primary pathophysiological pathway (102 measures, 185 studies), while use of cytoskeletal proteins (3 measures, 15 studies), inflammatory mediators (19 measures, 24 studies), oxidative stress-related analytes (15 measures, 8 studies), neurotransmitters or related neuro-metabolites (3 measures, 5 studies) were limited. A range of potential biomarkers are used in clinical trials; however, their use is inconsistent and under utilised among conditions. Development of a panel of biomarkers has potential to interrogate and link shared biological pathways across the heterogeneity of childhood dementias to exert a significant impact for the development of disease-modifying therapies.PMID:39948021 | DOI:10.1016/j.neurot.2025.e00546

Arch Bronconeumol. 2025 Jan 31:S0300-2896(25)00033-X. doi: 10.1016/j.arbres.2025.01.009. Online ahead of print.NO ABSTRACTPMID:39948020 | DOI:10.1016/j.arbres.2025.01.009