Phosphate is often a limiting resource, directly affecting the availability of key biomolecules such as nucleotides. To cope with phosphate scarcity, bacteria have evolved enzymes that utilize alternative phosphorus compounds, including phosphite (Pt). Although a few enzymes oxidize Pt to produce phosphate, the enzymes responsible for Pt oxidation in many environmental bacteria remain unidentified, and the role of microbial Pt oxidation in the global phosphorus cycle is not yet fully understood. In this study, we performed bioinformatic analyses of three Pt-oxidizing enzymes: the native Pt oxidase, phosphite dehydrogenase (PtxD), and two promiscuous Pt oxidases, alkaline phosphatase (PhoA) and carbon-phosphorus lyase. Among these, PhoA was found to be widely distributed across bacteria since the early stages of their evolution. In contrast, PtxD emerged later in a limited number of bacterial lineages that had lost PhoA. Our biochemical characterizations revealed that most extant and reconstructed ancestral PhoAs tested exhibited Pt oxidation activity. Moreover, disruption of active-site residues diminished Pt oxidase activity in PhoA, while only partially affecting its native function. This promiscuous function of PhoA reveals an overlooked mechanism in bacterial phosphate metabolism and underscores the role of Pt in the cycling of bioavailable phosphorus in ecosystems.

Antifungal peptide APTs exerts its fungistatic effect against Candida albicans through interaction with lipid rafts.

Immunofluorescent characterization of Klotho and FGF23 in clear cell renal cell carcinoma: A pilot study.

Fibroblast growth factor 2 promotes matrix vesicle-mediated mineralization of human umbilical cord perivascular cells by regulating phosphate metabolism.

Untangling the metabolome of resistant (VBN4) and susceptible (CO5) blackgram cultivar bacterized with Bacillus pumilus imparts resistance response against yellow mosaic disease.

Unveiling the mechanisms of metolachlor biodegradation and physiological adaptations in Penicillium oxalicum MetF1.

Inflammatory bowel disease (IBD) is a systemic condition with multifactorial origins. Mitochondria and ferroptosis have been implicated in the disease, but their potential interaction in IBD remains unclear. Therefore, investigating the relationship between IBD and these factors, along with elucidating the underlying mechanisms, is essential. Differentially expressed genes (DEGs) from the GSE75214 dataset were intersected with mitochondria-related genes (MRGs) and ferroptosis-related genes (FRGs) retrieved from literature to identify candidate genes. Key genes were finalized through machine learning, receiver operating characteristic (ROC) analysis, and expression validation. Subsequently, an artificial neural network (ANN) disease prediction model based on these key genes was constructed and evaluated. Further analyses included enrichment analysis of key genes, immune infiltration analysis, chromosomal localization, and drug prediction. Finally, the expression levels of key genes were validated using reverse transcription quantitative real-time PCR (RT-qPCR). Four genes (AQP8, ACSF2, ACSL4, and IL1B) were identified as key genes. The ANN model demonstrated a strong association between these key genes and IBD, with reliable performance (GSE75214: area under the curve (AUC) = 0.855; GSE59071: AUC = 0.859). Additionally, adaptive immune response, tricarboxylic acid (TCA) cycle, and inositol phosphate metabolism were found to be associated with these key genes in IBD. Specifically, ACSL4 showed the strongest positive correlation with immature dendritic cells (correlation coefficient (cor) = 0.93, p < 0.01), while ACSF2 exhibited the strongest negative correlation with effector memory CD8⁺ T cells (cor = -0.81, p < 0.01). The key genes were localized to different chromosomes. Potential therapeutic drugs for IBD, such as 1-methyl-3-isobutylxanthine, were identified through target drug prediction. RT-qPCR experiments confirmed that AQP8 and ACSF2 expression levels were significantly reduced in IBD (p < 0.01), whereas ACSL4 and IL1B expression levels were significantly increased (p < 0.05). AQP8, ACSF2, ACSL4, and IL1B were identified as key genes in IBD, providing a foundation for future therapeutic research on this disease.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-27002-z.

Low grade gliomas (LGGs) are heterogeneous tumors with high recurrence rates and variable clinical outcomes. However, metabolic dysregulation within LGG and its prognosis and tumor pathology remain poorly understood. We investigated the significance of inositol phosphate metabolism (IPM) in LGG and constructed an integrated machine learning survival model to improve the prognostic accuracy. By examining the transcriptomic data of LGGs, we identified a prognostic IPM (pIPM) signature consisting of 33 genes, with PLCG1 and MTMR3 showing the highest and lowest hazard ratios, respectively. Subsequent consensus clustering analysis revealed two distinct clusters (C1 and C2) with different pIPM expression levels and overall survival outcomes. Furthermore, IPM pathway analysis revealed an overall poor prognosis except for MGAT4C, suggesting that IPM plays a key role in driving LGG progression. Using machine learning algorithms, we developed and validated a robust survival model based on pIPM, in which Lasso model showed excellent discriminative power and reliability on both training and validation datasets. Furthermore, an increased IPM risk score was associated with increased cell proliferation and inflammation. Remarkably, the score was linked to treatment response, tumor recurrence, and remodeling of the immune microenvironment, emphasizing its potential as both a prognostic biomarker and a therapeutic target for LGG. In conclusion, our findings revealed a complex involvement of phosphatidylinositol metabolism in the LGG pathogenesis and elucidated its clinical significance for prognostic prediction and therapeutic intervention.

Mercury contamination at legacy nuclear sites such as the Savannah River Site and Oak Ridge Reservation poses persistent ecological risks, yet its impact on soil microbiomes remains incompletely understood. This study integrates qPCR, 16S/ITS amplicon sequencing, and shotgun metagenomics to assess bacterial and fungal community structure, diversity, and functional potential across gradients of total mercury, methylmercury, and bioavailable mercury. Bacterial α-diversity declined with increasing Hg levels, while fungal diversity remained stable and highest in low-contamination soils. Dominant bacterial phyla included Pseudomonadota, Bacteroidota, Bacillota, Acidobacteriota, and Actinomycetota; fungal communities were primarily Ascomycota and Basidiomycota. Canonical correspondence analysis revealed distinct taxon-Hg speciation linkages, and functional gene profiling showed enrichment of stress-response genes, membrane transporters, and phosphate metabolism pathways in contaminated soils. Notably, bioavailable Hg did not correlate directly with total Hg, underscoring the importance of speciation in microbial exposure. These findings highlight the adaptive plasticity of native microbiomes and identify microbial taxa and pathways relevant to bioremediation and can guide ecosystem restoration activities in Hg-impacted soil habitats.

Despite being an abundant metal, nature evolved to exclude aluminium (Al) from living organisms. In addition, the complex chemistry of this element makes it a challenging case for researchers. At physiological pH, Al has strong affinity to oxygen donors and negatively charged molecules such as proteins, nucleotides and cellular components bearing phosphates and carboxylic groups. Because of its widespread industrial use, living organisms are increasingly exposed to soluble forms of this light metal and environmental bacteria are in the front line. In this work, we show the disruptive effect of Al at physiological pH on the cellular morphology of Pseudomonas putida KT2440 and on the integrity of its mature biofilms. Proteomic studies revealed that an exposure to 0.78 mM of the aluminium compound used in this study significantly affected key proteins and enzymes involved in the TCA cycle, the respiratory chain, the maintenance of the cell's membrane and the transmembrane transport systems. The expression levels of major metal-resistance proteins (e.g., P-type ATPases and RND tripartite efflux pumps) was not affected, contrary to those of methyltransferases and systems involved in the metabolism of phosphate that might be involved in the maintenance of low Al concentration in the cytoplasm.

To find potential biomarkers and related metabolic pathways based on metabonomics of rat joint tissue, the rats with stable collagen-induced arthritis (CIA) model were taken as the research object. A rat rheumatoid arthritis model was established by injecting type II collagen. Treatment groups received oral doses of puerarin (40 mg/kg), puerarin-gadolinium (40 mg/kg), gadolinium chloride (40 mg/kg), or methotrexate (0.5 mg/kg), while control groups received saline. After 28 days, joint tissue metabolomics was analyzed using UPLC-MS (Shimadzu LC-30A and SCIEX TripleTOF 6600+), revealing significant metabolite changes and altered metabolic pathways. For the animal experiment part, based on observed changes in morphological, histopathological, and biochemical indicators, puerarin-Gd demonstrated significant therapeutic efficacy, surpassing that of puerarin, gadolinium chloride, and the positive control group. For the metabolomics part, compared with the blank group, the number of significantly different metabolites in the model group was 238, and most of the expressions were upregulated. Compared with the model group, the number of significantly different metabolites in the puerarin-gadolinium treatment group was 165, but most of them were downregulated. The KEGG enrichment pathway showed that the differential metabolites enrichment pathways of the puerarin-gadolinium treatment group and model group were mainly: linoleic acid metabolism, α-linolenic acid metabolism, arachidonic acid metabolism, choline metabolism in cancer, retrograde endogenous cannabinoid signal transduction, and glycerol phosphate metabolism pathway. Puerarin-gadolinium has a good therapeutic effect on rheumatoid arthritis rats, and its mechanism may be related to the inhibition of ferroptosis and the regulation of lipid metabolism.

Backgrounds: Objective of this study is to conduct a genome-wide association study (GWAS) of first-parity reproductive traits in Suzi pigs to identify significant single-nucleotide polymorphisms (SNPs) or candidate genes influencing these traits. Methods: This research employed technologies including the Zhongxin 50K SNP chip, simplified genome sequencing, resequencing, and the 100K SNP liquid chip to perform genome-wide SNP detection on 898 Suzi sows. Genotype data and phenotypic data were combined to do GWAS, gene annotation, and enrichment analysis. Results: Results showed that this study obtained phenotypes of 33 first-parity reproductive traits from 574 sows. GWAS results indicated there were 10 first-parity reproductive traits significantly associated with SNPs, and these traits were AFS, AFF, NNB, NH, NW, NS, NM, ND, PB, and CCN. These 10 traits were significantly associated with 60 SNPs, with 15 (25%) located on chromosome 2-the highest proportion. The SNPs significantly associated with AFS and AFF were largely identical. Genome-wide variance component analysis revealed that among the 10 traits with significantly associated SNPs in GWAS, there were 5 traits that exhibited genome-wide heritability ≥ 0.01. Trait of NM showed the highest heritability (0.65–0.7). These significantly associated SNPs annotated 20 candidate genes, including ADAMTS19, PROP1, ZNF354B, PCARE, LUZP2, VIRMA, EPHA5, AAAS, SLCO3A1-SV2B, KIF18A-BDNF, SERGEF, DYNLRB2, HNF4G, CATSPERD, HSD11B1L, DICER1, RARG, PCDHAC2, KRT79, and HSD17B2. GO analysis of candidate genes revealed that the top three biological processes were cell adhesion, positive regulation of cell projection organization, and positive regulation of neuron projection development. KEGG results showed the top three pathways were inositol phosphate metabolism, glutamatergic synapse, and phosphatidylinositol signaling system. Conclusions: These findings provide a foundation for the reproductive breeding of Suzi pigs and offer new insights into biological breeding in pigs.

Inositol phosphate (InsP) and diphosphoinositol phosphate (PP-InsP) analysis in tissues is plagued by multiple difficulties of sensitivity, regioisomer resolution and the need for radiolabeling with metabolic precursors. We describe a liquid chromatography (LC) inductively coupled plasma (ICP) mass spectrometry (MS) method (LC-ICP-MS) that addresses all such issues and use LC-ICP-MS to analyse InsPs in avian tissues. The highly sensitive technique tolerates complex matrices and, by powerful chromatography, resolves in a single run multiple non-enantiomeric myo-inositol tetrakisphosphates, myo-inositol pentakisphosphates and all inositol hexakisphosphates, including myo-inositol 1,2,3,4,5,6-hexakisphosphate (phytate), known in nature. It also separates and quantifies diphospho myo-inositol pentakisphosphate (PP-InsP5) isomers from their biological precursors and from 1,5-bis-diphospho myo-inositol 2,3,4,6 tetrakisphosphate (1,5-[PP]2-InsP4). Gut tissue inositol phosphates, belonging to a non-canonical, lipid-independent pathway, are shown to differ from phytate digestion products and to be responsive to diet.

Background: Cardiogenic shock is caused by a wide range of pathogenic processes that negatively impact myocardial function and is associated with very elevated mortality rates. Case Description: A 19-year-old woman with no significant cardiac history presented with progressive dyspnea and pleuritic chest pain and was found to be in cardiogenic shock with severely reduced left ventricular function. A native heart biopsy was negative for myocarditis, but there was evidence of cardiomyocyte vacuolization and ultrastructural examination revealed a loss of mitochondrial cristae without evidence of glycogen or lipid accumulation. (Figure 1) The patient received cardiopulmonary mechanical circulatory support with venoarterial extracorporeal membrane oxygenation (ECMO), followed by cardiac transplant. Genetic testing of the patient and her parents revealed that the patient inherited biallelic pathogenic DNA variants in the pyrophosphatase 2 (PPA2) gene. (Figure 2) Discussion: For young patients experiencing acute cardiogenic shock, it is critical to rapidly investigate multiple potential causes to determine if there are avenues for targeted treatment. This should include diagnostics imaging and endomyocardial biopsy with electron microscopy to evaluate cardiomyocyte ultrastructure. Although, not performed rapidly, genetic testing provides critical complimentary diagnostic information. When medical management of cardiogenic shock is insufficient, a cardiogenic shock team approach should be employed to determine appropriate temporary mechanical circulatory support and candidacy for heart transplantation or durable VAD. In this particular case, the diagnosis of cardiogenic shock due to biallelic PPA2 variants was confirmed through these diagnostic tests. The PPA2 gene encodes a mitochondrial protein that regulates cellular phosphate metabolism. Biallelic loss of function DNA variants in PPA2 are associated with progressive cardiac failure or cardiac arrest in infants and adolescents, typically after a febrile illness or alcohol consumption. The patient has shown significant improvement and has been doing well for nearly four years after the heart transplant. Conclusion: Tissue analysis and genetic testing are important components of the diagnostic evaluation of patients that present with fulminant heart failure. Cardiac transplant is an effective method to treat cardiogenic shock in patients with biallelic PPA2 DNA variants.

Reduced nicotinamide adenine dinucleotide phosphate (NADPH) metabolism is independently regulated in different compartments in endothelial cells (EC). The metabolic profile and functional impact of NADPH during EC senescence remain largely unknown. Using a genetically encoded fluorescent indicator, we find that cytosolic, but not mitochondrial, NADPH level increases during EC senescence. Upregulation of glucose-6-phosphate dehydrogenase (G6PD) further elevates cytosolic NADPH level during EC senescence. Suppression of G6PD S-nitrosylation at C385 potentiates G6PD activity. G6PD overexpression alleviates, while its knockdown aggravates, vascular aging. NADPH is indispensable for G6PD to protect against vascular aging through increasing reduced glutathione and inhibiting HDAC3 activity. Among 1419 FDA-approved drugs, folic acid, catalyzed by methylenetetrahydrofolate dehydrogenase to generate NADPH, effectively alleviates vascular aging in angiotensin II-infused mice and naturally aged mice. The connection between NADPH metabolism and EC senescence provides a unique angle for understanding vascular aging and an efficient target for therapy.

Nrf2-driven redox coupling of tumour and associated adipose tissue during early tumour growth in an orthotopic breast cancer model.

ABSTRACTCumulus‐oocyte complexes (COCs) used for in vitro production (IVP) of bovine embryos originate from antral follicles of different sizes, leading to variations in developmental competence. To address this, pre‐in vitro maturation (pre‐IVM) allows oocytes with additional time to acquire developmental competence. Given the role of follicular fluid‐derived extracellular vesicles (EVs) in ovarian follicle communication, which has been shown to vary in content and function across folliculogenesis, we investigated whether EVs from early versus late antral follicles influence COCs during pre‐IVM. EV supplementation significantly altered gene expression in cumulus cells and oocytes. In cumulus cells, affected pathways included MAPK signaling, Gap junctions, Cytokine‐cytokine receptor interaction, Axon guidance, cAMP, and Cushing syndrome. In oocytes, fewer genes were altered, with effects on Inositol phosphate metabolism, p53 signaling and Cholesterol metabolism. Despite these changes, no significant effects of the EV treatment were noted on oocyte chromatin configuration and developmental competence, except for a significant increase of mitochondrial membrane potential (Δψm) in blastocysts. In conclusion, EV supplementation during pre‐IVM significantly altered the transcriptional profile of COCs, with EVs from early follicles modulating the expression of genes regulating cumulus cell proliferation and gap junctions, while EVs from late follicles impacted pathways associated with meiotic resumption, cumulus cell expansion, and apoptosis. Along with improved Δψm in blastocysts, these results support a positive effect of EVs on bovine COCs, but further research is needed to better characterize the functional consequences, mainly in terms of the effects of early versus late follicle‐derived EVs on oocyte developmental potential.

Isoprenoids are a diverse class of natural products that are essential in all domains of life. Most bacteria synthesize isoprenoids through either the methylerythritol phosphate (MEP) pathway or the mevalonate (MEV) pathway, while a small subset encodes both pathways, including the pathogen Mycobacterium marinum (Mm). It is unclear whether the MEV pathway is functional in Mm, or why Mm encodes seemingly redundant metabolic pathways. Here, we show that the MEP pathway is essential in Mm, while the MEV pathway is dispensable in culture, with the ΔMEV mutant having no growth defect in axenic culture but a competitive growth defect compared to WT Mm. We found that the MEV pathway does not play a role in ex vivo or in vivo acute infection but does play a role in survival of peroxide stress. Metabolite profiling revealed that modulation of the MEV pathway causes compensatory changes in the concentration of MEP intermediates DOXP and CDP-ME, suggesting that the MEV pathway is functional and that the pathways interact at the metabolic level. Finally, the MEV pathway is upregulated early in the shift down to hypoxia, suggesting that it may provide metabolic flexibility to this bacterium. Interestingly, we found that our complemented strains, which vary in copy number of the polyprenyl synthetase idsB2, responded differently to peroxide and UV stresses, suggesting a role for this gene as a determinant of downstream prenyl phosphate metabolism. Together, these findings suggest that MEV may serve as an anaplerotic pathway to make isoprenoids under stress conditions.IMPORTANCEOrganisms from all domains of life utilize isoprenoids to carry out thousands of critical and auxiliary cellular processes, including signaling, maintaining membrane integrity, stress response, and host-pathogen interactions. The common precursor of all isoprenoids is synthesized via one of two biosynthetic pathways. Importantly, some bacteria encode both pathways, including M. marinum. We found that only one pathway is essential in M. marinum, while the nonessential pathway may confer metabolic flexibility to help the bacterium better adapt to various environmental conditions. We also found that the polyprenyl synthetase IdsB2 plays an important role in driving such phenotypes. Further, we demonstrate metabolic interplay between both functional pathways. These insights represent the first characterization of isoprenoid biosynthesis in dual pathway-encoding mycobacteria.

Phenylalanine-mediated reprogramming of lipid, pentose phosphate, and energy metabolism delays senescence in Rosa roxburghii fruit

IntroductionSkeletal muscles damaged by exercise exhibit disturbed energy metabolism and microvascular function for several days. However, it remains unclear whether these local changes might affect systemic cardiovascular responses to exercise. The present study aimed to investigate whether damaged muscles show changes in energy metabolism and oxygenation that influence systemic cardiovascular responses to exercise and post-exercise circulatory occlusion (PECO).MethodsA novel multi-parametric magnetic resonance imaging and spectroscopy approach was applied. Twelve healthy male participants completed assessments before and 48 h after 40 min of downhill running (20% decline). The assessments included muscle function, inflammation, and multi-parametric imaging at rest, exercise, and post-exercise occlusion using 31P spectroscopy, 1H- and muscle blood oxygen level-dependent imaging, and 23Na+ imaging to assess phosphate metabolism, oxygenation, and sodium disturbances. The mean arterial pressure (MAP) and heart rate (HR) were recorded throughout the MRI sequences.ResultsForty-eight hours after downhill running, muscle inflammation and Na+ disturbances were evident (both p < 0.05). Muscle oxygenation was lower and inorganic phosphates were higher during exercise and PECO than at baseline (both p < 0.05). However, MAP and HR during exercise and PECO remained unchanged at 48 h compared with baseline.ConclusionOur multi-parametric MRI approach provides new insights into the local effects of muscle damage on energy metabolism, oxygenation, and Na+. Despite these local metabolic and microvascular disturbances, systemic cardiovascular responses, as indicated by MAP and HR, remained unchanged. These new findings suggest a dissociation between muscle metabolites, oxygenation, and the cardiovascular response to exercise and PECO 48 h after damaging exercise.