PubMed

Mycotoxin Res. 2023 Jul 19. doi: 10.1007/s12550-023-00500-7. Online ahead of print.ABSTRACTDespite a long history of research, the mode of action of the mycotoxin ochratoxin A (OTA) is still not clear. Based on our observation that OTA-exposed cells consume more glucose and produce more lactate than control cells, with this study, we want to suggest another possible mode of action of OTA, involving cellular metabolism and mitochondria. We exposed human proximal tubule cells (HK2 cells) to OTA and studied its influence on mitochondrial performance as well as on the expression of energy homeostasis-involved routing proteins (AMPK and TXNIP) and on glucose transporting and metabolizing proteins. OTA reduced the capacity of mitochondria to increase their oxygen consumption rate forcing the cells to switch to the ineffective anaerobic glycolysis which demands higher glucose availability. The higher glucose demand is met by augmented cellular glycogen degradation and increased glucose uptake capabilities by increasing glucose transporter expression. We conclude that OTA exposure leads to impaired mitochondria, which forces the cells to alter their metabolism in order to ensure energy supply. We suggest to consider a possible effect of OTA on metabolism and mitochondria and to have a closer look on OTA-induced changes in the metabolome as possible additional players in OTA toxicity.PMID:37466908 | DOI:10.1007/s12550-023-00500-7

Anal Bioanal Chem. 2023 Jul 19. doi: 10.1007/s00216-023-04850-0. Online ahead of print.ABSTRACTSingle-cell (SC) analysis offers new insights into the study of fundamental biological phenomena and cellular heterogeneity. The superior sensitivity, high throughput, and rich chemical information provided by mass spectrometry (MS) allow MS to emerge as a leading technology for molecular profiling of SC omics, including the SC metabolome, lipidome, and proteome. However, issues such as ionization suppression, low concentration, and huge span of dynamic concentrations of SC components lead to poor MS response for certain types of molecules. It is noted that chemical tagging/derivatization has been adopted in SCMS analysis, and this strategy has been proven an effective solution to circumvent these issues in SCMS analysis. Herein, we review the basic principle and general strategies of chemical tagging/derivatization in SCMS analysis, along with recent applications of chemical derivatization to single-cell metabolomics and multiplexed proteomics, as well as SCMS imaging. Furthermore, the challenges and opportunities for the improvement of chemical derivatization strategies in SCMS analysis are discussed.PMID:37466681 | DOI:10.1007/s00216-023-04850-0

Transfusion. 2023 Jul 19. doi: 10.1111/trf.17472. Online ahead of print.ABSTRACTBACKGROUND: Even in the era of the COVID-19 pandemic, trauma remains the global leading cause of mortality under the age of 49. Trauma-induced coagulopathy is a leading driver of early mortality in critically ill patients, and transfusion of platelet products is a life-saving intervention to restore hemostasis in the bleeding patient. However, despite extensive functional studies based on viscoelastic assays, limited information is available about the impact of platelet transfusion on the circulating molecular signatures in trauma patients receiving platelet transfusion.MATERIALS AND METHODS: To bridge this gap, we leveraged metabolomics and proteomics approaches to characterize longitudinal plasma samples (n = 118; up to 11 time points; total samples: 759) from trauma patients enrolled in the Control Of Major Bleeding After Trauma (COMBAT) study. Samples were collected in the field, in the emergency department (ED), and at intervals up to 168 h (7 days) post-hospitalization. Transfusion of platelet (PLT) products was performed (n = 30; total samples: 250) in the ED through 24 h post-hospitalization. Longitudinal plasma samples were subjected to mass spectrometry-based metabolomics and proteomics workflows. Multivariate analyses were performed to determine omics markers of transfusion of one, two, three, or more PLT transfusions.RESULTS: Higher levels of tranexamic acid (TXA), inflammatory proteins, carnitines, and polyamines were detected in patients requiring PLT transfusion. Correlation of PLT units with omics data suggested sicker patients required more units and partially overlap with the population requiring transfusion of packed red blood cell products. Furthermore, platelet activation was likely increased in the most severely injured patients. Fatty acid levels were significantly lower in PLT transfusion recipients (at time of maximal transfusion: Hour 4) compared with non-recipients, while carnitine levels were significantly higher. Fatty acid levels restore later in the time course (e.g., post-PLT transfusion).DISCUSSION: The present study provides the first multi-omics characterization of platelet transfusion efficacy in a clinically relevant cohort of trauma patients. Physiological alterations following transfusion were detected, highlighting the efficacy of mass spectrometry-based omics techniques to improve personalized transfusion medicine. More specialized clinical research studies focused on PLT transfusion, including organized pre and post transfusion sample collection and limitation to PLT products only, are required to fully understand subsequent metabolomic and proteomic alterations.PMID:37466356 | DOI:10.1111/trf.17472

Microbiol Resour Announc. 2023 Jul 19:e0039223. doi: 10.1128/MRA.00392-23. Online ahead of print.ABSTRACTFrom an animal health perspective, our understanding of the metabolites in rumen fluid across different host species is poorly understood. Here, we present a metabolomic data set generated using hydrophilic interaction liquid chromatography and semi-polar (C18) chromatography methods coupled to high-resolution mass spectrometry of fractionated ovine rumen samples.PMID:37466335 | DOI:10.1128/MRA.00392-23

J Agric Food Chem. 2023 Jul 19. doi: 10.1021/acs.jafc.3c02709. Online ahead of print.ABSTRACTLotus japonicus is a leguminous model plant used to gain insight into plant physiology, stress response, and especially symbiotic plant-microbe interactions, such as root nodule symbiosis or arbuscular mycorrhiza. Responses to changing environmental conditions, stress, microbes, or insect pests are generally accompanied by changes in primary and secondary metabolism to account for physiological needs or to produce defensive or signaling compounds. Here we provide an overview of the primary and secondary metabolites identified in L. japonicus to date. Identification of the metabolites is mainly based on mass spectral tags (MSTs) obtained by gas chromatography linked with tandem mass spectrometry (GC-MS/MS) or liquid chromatography-MS/MS (LC-MS/MS). These MSTs contain retention index and mass spectral information, which are compared to databases with MSTs of authentic standards. More than 600 metabolites are grouped into compound classes such as polyphenols, carbohydrates, organic acids and phosphates, lipids, amino acids, nitrogenous compounds, phytohormones, and additional defense compounds. Their physiological effects are briefly discussed, and the detection methods are explained. This review of the exisiting literature on L. japonicus metabolites provides a valuable basis for future metabolomics studies.PMID:37466334 | DOI:10.1021/acs.jafc.3c02709

Mol Omics. 2023 Jul 19. doi: 10.1039/d3mo00063j. Online ahead of print.ABSTRACTParkinson's disease (PD) is a serious neurodegenerative disorder wherein changes in metabolites related to lipids, glutathione, and energy metabolism occur. Currently, metabolite changes in PD have been reported, yet their role in the prognosis of disease remains poorly understood. Functional metabolites can be used to diagnose diseases, especially PD, and can exert neuroprotective effects. This study used a PD animal model and a lipopolysaccharide (LPS)-mediated inflammatory response model (using the BV-2 mouse microglial cell line) to identify functional metabolites that can identify important metabolic disorders during PD, and comprehensively evaluated their profiles using a metabolomics-based approach. Our results showed that co-treatment with myristic acid and heptadecanoic acid downregulated the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in BV-2 cells. Additionally, myristic acid and 10 μM heptadecanoic acid significantly inhibited the LPS-induced inflammatory response through the nuclear factor-κB pathway in BV-2 microglial cells, which provides a potential approach for PD treatment. Myristic acid and heptadecanoic acid were the active metabolites found by active metabolomics technology, but at present, there is no research report about their function for PD treatment, and our findings offer a novel research strategy for PD diagnosis and treatment.PMID:37466104 | DOI:10.1039/d3mo00063j

RSC Adv. 2023 Jul 17;13(31):21448-21458. doi: 10.1039/d3ra03188h. eCollection 2023 Jul 12.ABSTRACTHyperuricemia (HUA) is the fourth most common basic metabolic disease that can cause damage to multiple organs throughout the body. In this study, a hybrid compound consisting of myricetin and nobiletin was synthesized and its biological activity was evaluated. We named the hybrid compound MNH, and its structure was confirmed by spectroscopy. This study used serum metabolomics profiling with LC/MS and 16S rRNA gene sequencing analysis to explore the anti-HUA efficacy of MNH on a yeast paste-induced mouse model. The results showed that serum uric acid (UA), creatinine (CRE) and urea nitrogen (BUN) levels were significantly decreased after the intervention of MNH. The efficacy of MNH in lowering UA was somewhat greater than that of myricetin and nobiletin. In addition, MNH could repair the renal histopathological damage. Moreover, serum metabolomics demonstrated that MNH regulated the metabolic pathways involved in glycerophospholipid metabolism, arachidonic acid metabolism and alanine etc. Furthermore, MNH supplementation restored the composition of gut microbiota with remarkable reductions in Lactobacillus and Limosilactobacillus and significant elevations in norank_f_Muribaculaceae and Bacteroides at the genus level. Taken together, these results indicated that MNH might represent a protective effect against HUA via modulating gut microbiota and metabolomics.PMID:37465570 | PMC:PMC10351364 | DOI:10.1039/d3ra03188h

Neuropsychiatr Dis Treat. 2023 Jul 12;19:1581-1592. doi: 10.2147/NDT.S415098. eCollection 2023.ABSTRACTBACKGROUND: Poststroke depression (PSD) is the most frequent neuropsychiatric consequence of stroke. Electroacupuncture (EA) has been found to be an effective therapy for treating PSD. However, the underlying mechanisms of EA's efficacy remain unclear. This research aimed to investigate the effects of EA on alterations in gut microbiota and fecal metabolome in PSD rats.METHODS: Analyses of gut microbiome and fecal metabolome were performed to identify gut microbes and their functional metabolites in a sham group, PSD group, and EA group. We conducted enrichment analysis to identify the differential metabolic pathways in three groups. Correlations between altered gut microbes and differential metabolites after EA treatment were studied.RESULTS: PSD showed decreased species-richness/diversity indices of microbial composition, characterized by an increase in Muribaculaceae, Peptostreptococcaceae, Oscillospiraceae, Ruminococcaceae, and Clostridiaceae and a decrease in Lactobacillaceae, Lachnospiraceae, and Bacteroidaceae. Of these, the abundance of Muribaculaceae, Lactobacillaceae, Lachnospiraceae, Peptostreptococcaceae, and Clostridiaceae were reversed by EA. Furthermore, PSD was associated with 34 differential fecal metabolites, mainly belonging to steroid hormone biosynthesis, that could be regulated by EA.CONCLUSION: Regulation of gut microbiome and lipid metabolism could be one of the potential mechanisms for EA treatment for alleviating the depressive behaviors of PSD.PMID:37465562 | PMC:PMC10350407 | DOI:10.2147/NDT.S415098

Front Plant Sci. 2023 Jul 3;14:1218426. doi: 10.3389/fpls.2023.1218426. eCollection 2023.ABSTRACTCitrus cultivation involves the widespread practice of grafting, which has a significant impact on citrus development and fruit quality and yield. However, understanding the effect of flavonoid compounds after different rootstock grafting have been limited. Flavonoid compounds, found at the highest levels in citrus peels, contribute to improving fruit quality and nutritional value. In this study, scion-rootstock interaction was investigated at various developmental stages when sweet orange 'Newhall' was hetero-grafted with two commonly used rootstocks (Poncirus trifoliate population, C. junos Siebold ex Tanaka). Physiological index detection showed a higher concentration of total flavonoid content in peels of sweet orange 'Newhall' grafted on Poncirus trifoliate population (ct) than C. junos Siebold ex Tanaka (cj). Further metabolomic analysis identified 703 flavonoid compounds, including flavones, flavonols, and flavanones. Out of the 25 flavonoids affected by different rootstock grafting and developmental stages, most were flavones. Transcriptomic analysis identified 8,562 differentially expressed genes (DEGs). Co-expression and Pearson's correlation analysis discovered six hub structure genes and 19 transcription factors (TFs) that affected flavonoid biosynthesis. In addition to increasing the transcript levels of genes that synthesize flavones, flavonols, and flavanones, the scion-rootstock interaction also affected the expression of many TFs. Taken together, our findings suggested that hetero-grafting could promote the accumulation of flavonoid compounds in citrus peels during the development stages. These results offered fresh perspectives on grafting's application usefulness and the enhancement of the accumulation of nutritive flavonoid components by grafting in citrus.PMID:37465384 | PMC:PMC10351390 | DOI:10.3389/fpls.2023.1218426

Front Microbiol. 2023 Jul 3;14:1177947. doi: 10.3389/fmicb.2023.1177947. eCollection 2023.ABSTRACTMammalian gut microbiota plays an important role in the host's nutrient metabolism, growth, and immune regulation. Hybridization can enable a progeny to acquire superior traits of the parents, resulting in the hybridization advantage. However, studies on the effects of hybridization on the pigs' gut microbiota are lacking. Therefore, this study used multi-omics technologies to compare and analyze the gut microbiota of the primary wild boar and its offspring. The 16S rRNA gene sequencing results revealed that the gut microbiota of F4 exhibited a host-like dominance phenomenon with a significant increase in the abundance of Lactobacillus and Bifidobacterium. The beta diversity of Duroc was significantly different from those of F0, F2, and F4; after the host hybridization, the similarity of the beta diversity in the progeny decreased with the decrease in the similarity of the F0 lineage. The metagenomic sequencing results showed that the significantly enriched metabolic pathways in F4, such as environmental, circulatory system, fatty acid degradation adaptation, and fatty acid biosynthesis, were similar to those in F0. Moreover, it also exhibited similar significantly enriched metabolic pathways as those in Duroc, such as carbohydrate metabolism, starch and sucrose metabolism, starch-degrading CAZymes, lactose-degrading CAZymes, and various amino acid metabolism pathways. However, the alpha-amylase-related KOs, lipid metabolism, and galactose metabolism in F4 were significantly higher than those in Duroc and F0. Non-targeted metabolome technology analysis found that several metabolites, such as docosahexaenoic acid, arachidonic acid, and citric acid were significantly enriched in the F4 pigs as compared to those in F0. Based on Spearman correlation analysis, Lactobacillus and Bifidobacterium were significantly positively correlated with these metabolites. Finally, the combined metagenomic and metabolomic analysis suggested that the metabolic pathways, such as valine, leucine, and isoleucine biosynthesis and alanine aspartate and glutamate metabolism were significantly enriched in F4 pigs. In conclusion, the gut microbiota of F4 showed a similar host "dominance" phenomenon, which provided reference data for the genetics and evolution of microbiota and the theory of microbial-assisted breeding.PMID:37465027 | PMC:PMC10350513 | DOI:10.3389/fmicb.2023.1177947

Microb Biotechnol. 2023 Jul 18. doi: 10.1111/1751-7915.14311. Online ahead of print.ABSTRACTThe construction of microbial consortia is challenging due to many variables to be controlled, including the cross-compatibility of the selected strains and their additive or synergistic effects on plants. In this work, we investigated the interactions in vitro, in planta, and at the molecular level of two elite biological control agents (BCAs), that is Streptomyces microflavus strain AtB-42 and Trichoderma harzianum strain M10, to understand their attitude to cooperate in a consortium. In vitro, we observed a strong cross-antagonism between AtB-42 and M10 in agar plates due to diffusible metabolites and volatile organic compounds. In liquid co-cultures, M10 hindered the growth of AtB-42 very likely because of secondary metabolites and strong competition for the nutrients. The interaction in the co-culture induced extensive transcriptional reprogramming in both strains, especially in the pathways related to ribosomes, protein synthesis, and oxidoreductase activity, suggesting that each strain recognized the counterpart and activated its defence responses. The metabolome of both strains was also significantly affected. In contrast, in the soil, M10 growth was partially contrasted by AtB-42. The roots of tomato seedlings inoculated with the consortium appeared smaller than the control and single-strain-inoculated plants, indicating that plants diverted some energy from the development to defence activation, as evidenced by the leaf transcriptome. The consortium induced a stronger transcriptional change compared to the single inoculants, as demonstrated by a higher number of differentially expressed genes. Although the cross-antagonism observed in vitro, the two strains exerted a synergistic effect on tomato seedlings by inducing resistance responses stronger than the single inoculants. Our observations pose a question on the usefulness of the sole in vitro assays for selecting BCAs to construct a consortium. In vivo experiments should be preferred, and transcriptomics may greatly help to elucidate the activity of the BCAs beyond the phenotypic effects on the plant.PMID:37464583 | DOI:10.1111/1751-7915.14311

Adv Exp Med Biol. 2023;1426:215-235. doi: 10.1007/978-3-031-32259-4_10.ABSTRACTThe application of mathematical and computational analysis, together with the modelling of biological and physiological processes, is transforming our understanding of the pathophysiology of complex diseases. This systems biology approach incorporates large amounts of genomic, transcriptomic, proteomic, metabolomic, breathomic, metagenomic and imaging data from disease sites together with deep clinical phenotyping, including patient-reported outcomes. Integration of these datasets will provide a greater understanding of the molecular pathways associated with severe asthma in each individual patient and determine their personalised treatment regime. This chapter describes some of the data integration methods used to combine data sets and gives examples of the results obtained using single datasets and merging of multiple datasets (data fusion and data combination) from several consortia including the severe asthma research programme (SARP) and the Unbiased Biomarkers Predictive of Respiratory Disease Outcomes (U-BIOPRED) consortia. These results highlight the involvement of several different immune and inflammatory pathways and factors in distinct subsets of patients with severe asthma. These pathways often overlap in patients with distinct clinical features of asthma, which may explain the incomplete or no response in patients undergoing specific targeted therapy. Collaboration between groups will improve the predictions obtained using a systems medicine approach in severe asthma.PMID:37464123 | DOI:10.1007/978-3-031-32259-4_10

Sci Rep. 2023 Jul 18;13(1):11583. doi: 10.1038/s41598-023-38571-2.ABSTRACTIn grafted apple, rootstock-derived signals influence scion cold tolerance by initiating physiological changes to survive over the winter. To understand the underlying molecular interactions between scion and rootstock responsive to cold, we developed transcriptomics and metabolomics data in the stems of two scion/rootstock combinations, 'Gala'/'G202' (cold resistant rootstock) and 'Gala'/'M9' (cold susceptible rootstock). Outer layers of scion and rootstock stem, including vascular tissues, were collected from the field-grown grafted apple during the winter. The clustering of differentially expressed genes (DEGs) and gene ontology enrichment indicated distinct expression dynamics in the two graft combinations, which supports the dependency of scion cold tolerance on the rootstock genotypes. We identified 544 potentially mobile mRNAs of DEGs showing highly-correlated seasonal dynamics between scion and rootstock. The mobility of a subset of 544 mRNAs was validated by translocated genome-wide variants and the measurements of selected RNA mobility in tobacco and Arabidopsis. We detected orthologous genes of potentially mobile mRNAs in Arabidopsis thaliana, which belong to cold regulatory networks with RNA mobility. Together, our study provides a comprehensive insight into gene interactions and signal exchange between scion and rootstock responsive to cold. This will serve for future research to enhance cold tolerance of grafted tree crops.PMID:37463950 | DOI:10.1038/s41598-023-38571-2

Cancer Biol Ther. 2023 Dec 31;24(1):2237200. doi: 10.1080/15384047.2023.2237200.ABSTRACTCancer cells show enhanced nucleotide biosynthesis, which is essential for their unlimited proliferation, but the underlying mechanisms are not entirely clear. Ubiquitin specific peptidase 29 (USP29) was reported to sustain neuroblastoma progression by promoting glycolysis and glutamine catabolism; however, its potential role in regulating nucleotide biosynthesis in tumor cells remains unknown. In this study, we depleted endogenous USP29 in MYCN-amplified neuroblastoma SK-N-BE2 cells by sgRNAs and conducted metabolomic analysis in cells with or without USP29 depletion, we found that USP29 deficiency caused a disorder of intermediates involved in glycolysis and nucleotide biosynthesis. De novo nucleotide biosynthesis was analyzed using 13C6 glucose as a tracer under normoxia and hypoxia. The results indicated that USP29-depleted cells showed inhibition of nucleotide anabolic intermediates derived from glucose, and this inhibition was more significant under hypoxic conditions. Analysis of RNA sequencing data in SK-N-BE2 cells demonstrated that USP29 promoted the gene expression of metabolic enzymes involved in nucleotide anabolism, probably by regulating MYC and E2F downstream pathways. These findings indicated that USP29 is a key regulator of nucleotide biosynthesis in tumor cells.PMID:37463886 | DOI:10.1080/15384047.2023.2237200

FEBS Lett. 2023 Jul 18. doi: 10.1002/1873-3468.14698. Online ahead of print.ABSTRACTThe nicotinamide adenine dinucleotide (NAD+ ) precursor nicotinamide mononucleotide (NMN) is a proposed therapy for age-related disease, whereby it is assumed that NMN is incorporated into NAD+ through the canonical recycling pathway. During oral delivery, NMN is exposed to the gut microbiome, which could modify the NAD+ metabolome through enzyme activities not present in the mammalian host. We show that orally delivered NMN can undergo deamidation and incorporation in mammalian tissue via the de novo pathway, which is reduced in animals treated with antibiotics to ablate the gut microbiome. Antibiotics increased the availability of NAD+ metabolites, suggesting the microbiome could be in competition with the host for dietary NAD+ precursors. These findings highlight new interactions between NMN and the gut microbiome.PMID:37463842 | DOI:10.1002/1873-3468.14698

J Affect Disord. 2023 Jul 16:S0165-0327(23)00940-0. doi: 10.1016/j.jad.2023.07.089. Online ahead of print.ABSTRACTPrenatal stress (PS) increases offspring susceptibility to depression, but the underlying mechanism remains unclear. Our previous results showed that PS can affect depression-like behavior in offspring through neurotransmitters and neuroinflammatory substances in the hippocampus and frontal cortex. In recent years there has been increasing evidence for a role of the gut microbiome in depression. The brain-gut axis theory suggests there is a need to further explore the mechanism involving the gut microbiome in the susceptibility of offspring to depression caused by PS. In the present study we used a stress model relevant to depression in which pregnant female rats undergo prenatal restraint stress and the offspring show susceptibility to depression. High-resolution gene sequencing for 16S ribosomal RNA markers and non-targeted metabolomic analysis were used to evaluate the fecal microbiome and the availability of metabolites, respectively. PS was found to induce depressive-like behavior in susceptible offspring (PS-S), as detected by the sucrose preference and forced swimming tests, as well as altering Alpha and Beta diversity. The different microbiota between the PS-S and control groups were mainly involved in membrane transport, carbohydrate metabolism, amino acid metabolism, and replication and repair pathways. In total, 237 and 136 important differential metabolites with significant influence on modeling analysis were obtained under positive and negative modes, respectively. The main canonical pathways found to be altered were glycerophospholipid metabolism and glycerolipid metabolism. These results suggest that gut microbiota might contribute to the onset of PS-induced depression-like behavior by affecting the glycerophospholipid and glycerolipid metabolic pathways.PMID:37463643 | DOI:10.1016/j.jad.2023.07.089

Cell Host Microbe. 2023 Jul 10:S1931-3128(23)00260-3. doi: 10.1016/j.chom.2023.06.009. Online ahead of print.ABSTRACTEarly administration of azithromycin after allogeneic hematopoietic stem cell transplantation was shown to increase the relapse of hematological malignancies. To determine the impact of azithromycin on the post-transplant gut ecosystem and its influence on relapse, we characterized overtime gut bacteriome, virome, and metabolome of 55 patients treated with azithromycin or a placebo. We describe four enterotypes and the network of associated bacteriophage species and metabolic pathways. One enterotype associates with sustained remission. One taxon from Bacteroides specifically associates with relapse, while two from Bacteroides and Prevotella correlate with complete remission. These taxa are associated with lipid, pentose, and branched-chain amino acid metabolic pathways and several bacteriophage species. Enterotypes and taxa associate with exhausted T cells and the functional status of circulating immune cells. These results illustrate how an antibiotic influences a complex network of gut bacteria, viruses, and metabolites and may promote cancer relapse through modifications of immune cells.PMID:37463582 | DOI:10.1016/j.chom.2023.06.009

Food Chem. 2023 Jul 13;429:136859. doi: 10.1016/j.foodchem.2023.136859. Online ahead of print.ABSTRACTThis study hypothesized the existence of cultivar-associated correlations between grape berry metabolites and its microbial residents, in Douro wine region. Integrated metabolomics with metabarcoding showed that the microbial biodiversity is not associated to berry sugar concentration, but closely connected to the profile of amino acids, flavonoids and wax compounds, which drove cultivar differentiation together with the prevalence of pathogenic fungi, yeasts and bacteria, mainly Dothideomycetes and Gammaproteobacteria. Over 7000 metabolite-microbiota correlations with ρ >|0.99| exposed a core of 15 metabolites linked to 11 microbial taxa. Serine, oxalate, cyanidin-3-O-glucoside, petunidin-3-O-glucoside, gallic acid, germanicol, sitosterol and erythrodiol correlated negatively to the abundance of most taxa, including Alternaria, Aureobasidium, Pseudopithomyces, Pseudomonas and Sphingomonas. In contrast, phenylalanine, asparagine, alanine, (epi)gallocatechin and procyanidin gallate mediated positive metabolite-OTU correlations. E. necator and A. carbonarius correlated negatively with stigmasterol and amyrin. Complex fungi-bacteria relationships ruled by Dothideomycetes and Alphaproteobacteria further suggest tight host-microbe interactions at the carposphere.PMID:37463536 | DOI:10.1016/j.foodchem.2023.136859

J Gerontol A Biol Sci Med Sci. 2023 Jul 18:glad171. doi: 10.1093/gerona/glad171. Online ahead of print.ABSTRACTBACKGROUND: Lower urinary tract syndrome (LUTS) is a group of urinary tract symptoms and signs which can include urinary incontinence. Advancing age is a major risk factors for LUTS; however the underlying biochemical mechanisms of age-related LUTS remain unknown. HX (hypoxanthine) is a purine metabolite associated with generation of tissue damaging reactive oxygen species (ROS). This study tested the hypothesis that exposure of the adult bladder to HX-ROS over time damages key LUT elements, mimicking qualitatively some of the changes observed with aging.METHODS: Adult 3-month-old female Fischer 344 (F344) rats were treated with vehicle or HX (10 mg/kg/day; 3 weeks) administered in drinking water. Targeted purine metabolomics and molecular approaches were used to assess purine metabolites and biomarkers for oxidative stress and cellular damage. Biomechanical approaches assessed LUT structure and measurements of LUT function (using custom-metabolic cages and cystometry) were also employed.RESULTS: HX exposure increased biomarkers indicative of oxidative stress, pathophysiological ROS production and depletion of cellular energy with declines in NAD + levels. Moreover, HX treatment caused bladder remodeling and decreased the intercontraction interval and leak point pressure (surrogate measure to assess stress urinary incontinence).CONCLUSIONS: These studies provide evidence that in adult rats chronic exposure to HX causes changes in voiding behavior and in bladder structure resembling alterations observed with aging. These results suggest that increased levels of uro-damaging HX were associated with ROS/oxidative stress-associated cellular damage which may be central to age-associated development of LUTS, opening up potential opportunities for geroscience-guided interventions.PMID:37463319 | DOI:10.1093/gerona/glad171

Cancer Res. 2023 Jul 18:CAN-22-3481. doi: 10.1158/0008-5472.CAN-22-3481. Online ahead of print.ABSTRACTMultiple myeloma (MM) cells undergo metabolic reprogramming in response to the hypoxic and nutrient-deprived bone marrow microenvironment. Primary oncogenes in recurrent translocations might be able to drive metabolic heterogeneity to survive the microenvironment that can present new vulnerabilities for therapeutic targeting. t(4;14) translocation leads to the universal overexpression of histone methyltransferase NSD2 that promotes plasma cell transformation through a global increase in H3K36me2. Here, we identified PKCα as an epigenetic target that contributes to the oncogenic potential of NSD2. RNA-sequencing of t(4;14) MM cell lines revealed a significant enrichment in the regulation of metabolic processes by PKCα, and the glycolytic gene, hexokinase 2 (HK2), was transcriptionally regulated by PKCα in a PI3K/Akt-dependent manner. Loss of PKCα displaced mitochondria-bound HK2 and reversed sensitivity to the glycolytic inhibitor 3-bromopyruvate. Additionally, the perturbation of glycolytic flux led to a metabolic shift to a less energetic state and decreased ATP production. Metabolomics analysis indicated lactate as a differential metabolite associated with PKCα. As a result, PKCα conferred resistance to the immunomodulatory drugs (IMiD) lenalidomide in a cereblon-independent manner and could be phenocopied by either overexpression of HK2 or direct supplementation of lactate. Clinically, t(4;14) MM patients had elevated plasma lactate levels and did not benefit from lenalidomide-based regimens. Altogether, this study provides insights into the epigenetic-metabolism crosstalk in MM and highlights the opportunity for therapeutic intervention that leverages the distinct metabolic program in t(4;14) myeloma.PMID:37463241 | DOI:10.1158/0008-5472.CAN-22-3481