PubMed

Vet Med Sci. 2024 Jul;10(4):e1528. doi: 10.1002/vms3.1528.ABSTRACTBACKGROUND: Acute flaccid paralysis (AFP) is a complex clinical syndrome with various aetiologies. If untreated, AFP may lead to death due to failure of respiratory muscles. Tick paralysis, which is a noninfectious neurologic syndrome of AFP, occurs following tick attachment, engorgement, and injection of tick saliva toxins. There is no specific diagnostic test for tick paralysis, and mortality increases as definitive diagnosis is delayed. Although metabolomic investigation of tick saliva was conducted, there is a lack of research on metabolomic evaluation of hosts affected by tick paralysis.OBJECTIVES: Thus, the aim of this study is to investigate metabolomic changes in serum samples of dogs with tick paralysis due to Rhipicephalus sanguineus using NMR-based metabolomics and to identify potential diagnostic/prognostic markers.MATERIALS AND METHODS: Forty dogs infested with R. sanguineus, with clinical findings compatible with AFP and with a confirmed tick paralysis diagnosis ex juvantibus, constituted the Paralysis Group. Ten healthy dogs, which were admitted either for vaccination and/or check-up purposes, constituted the Control Group. After the confirmation tick paralysis, medical history, vaccination and nutritional status, body surface area and estimated tick numbers of all the dogs were noted. Physical examination included body temperature, heart and respiratory rate, capillary refill time evaluation and Modified Glasgow Coma Scale calculation. Serum samples were extracted from venous blood samples of all the dogs and were prepared for NMR analysis, and NMR-based metabolomics identification and quantification were performed.RESULTS: NMR-based serum metabolomics of the present study revealed distinct up/down-regulated expressions, presenting a promising avenue. Moreover, it was observed that energy metabolism and especially liver functions were impaired in dogs with tick paralysis, and not only the respiratory system but also the kidneys were affected.CONCLUSION: It was concluded that the present approach may help to better understand the pathological mechanisms developing in cases of AFP due to tick paralysis.PMID:38952268 | DOI:10.1002/vms3.1528

Mass Spectrom Rev. 2024 Jul 1. doi: 10.1002/mas.21898. Online ahead of print.ABSTRACTBenefits of miniaturized chromatography with various detection modes, such as increased sensitivity, chromatographic efficiency, and speed, were recognized nearly 50 years ago. Over the past two decades, this approach has experienced rapid growth, driven by the emergence of mass spectrometry applications serving -omics sciences and the need for analyzing minute volumes of precious samples with ever higher sensitivity. While nanoscale liquid chromatography (flow rates <1 μL/min) has gained widespread recognition in proteomics, the adoption of microscale setups (flow rates ranging from 1 to 100 μL/min) for low molecular weight compound applications, including metabolomics, has been surprisingly slow, despite the inherent advantages of the approach. Highly heterogeneous matrices and chemical structures accompanied by a relative lack of options for both selective sample preparation and user-friendly equipment are usually reported as major hindrances. To facilitate the wider implementation of microscale analyses, we present here a comprehensive tutorial encompassing important theoretical and practical considerations. We provide fundamental principles in micro-chromatography and guide the reader through the main elements of a microflow workflow, from LC pumps to ionization devices. Finally, based on both our literature overview and experience, illustrated by some in-house data, we highlight the critical importance of the ionization source design and its careful optimization to achieve significant sensitivity improvement.PMID:38952056 | DOI:10.1002/mas.21898

New Phytol. 2024 Jul 1. doi: 10.1111/nph.19917. Online ahead of print.ABSTRACTPlant homeodomain leucine zipper IV (HD-Zip IV) transcription factors (TFs) contain an evolutionarily conserved steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain. While the START domain is required for TF activity, its presumed role as a lipid sensor is not clear. Here we used tandem affinity purification from Arabidopsis cell cultures to demonstrate that PROTODERMAL FACTOR2 (PDF2), a representative member that controls epidermal differentiation, recruits lysophosphatidylcholines (LysoPCs) in a START-dependent manner. Microscale thermophoresis assays confirmed that a missense mutation in a predicted ligand contact site reduces lysophospholipid binding. We additionally found that PDF2 acts as a transcriptional regulator of phospholipid- and phosphate (Pi) starvation-related genes and binds to a palindromic octamer with consensus to a Pi response element. Phospholipid homeostasis and elongation growth were altered in pdf2 mutants according to Pi availability. Cycloheximide chase experiments revealed a role for START in maintaining protein levels, and Pi starvation resulted in enhanced protein destabilization, suggesting a mechanism by which lipid binding controls TF activity. We propose that the START domain serves as a molecular sensor for membrane phospholipid status in the epidermis. Our data provide insights toward understanding how the lipid metabolome integrates Pi availability with gene expression.PMID:38952028 | DOI:10.1111/nph.19917

J Nanobiotechnology. 2024 Jul 1;22(1):383. doi: 10.1186/s12951-024-02645-8.ABSTRACTThe characteristic features of the rheumatoid arthritis (RA) microenvironment are synovial inflammation and hyperplasia. Therefore, there is a growing interest in developing a suitable therapeutic strategy for RA that targets the synovial macrophages and fibroblast-like synoviocytes (FLSs). In this study, we used graphene oxide quantum dots (GOQDs) for loading anti-arthritic sinomenine hydrochloride (SIN). By combining with hyaluronic acid (HA)-inserted hybrid membrane (RFM), we successfully constructed a new nanodrug system named HA@RFM@GP@SIN NPs for target therapy of inflammatory articular lesions. Mechanistic studies showed that this nanomedicine system was effective against RA by facilitating the transition of M1 to M2 macrophages and inhibiting the abnormal proliferation of FLSs in vitro. In vivo therapeutic potential investigation demonstrated its effects on macrophage polarization and synovial hyperplasia, ultimately preventing cartilage destruction and bone erosion in the preclinical models of adjuvant-induced arthritis and collagen-induced arthritis in rats. Metabolomics indicated that the anti-arthritic effects of HA@RFM@GP@SIN NPs were mainly associated with the regulation of steroid hormone biosynthesis, ovarian steroidogenesis, tryptophan metabolism, and tyrosine metabolism. More notably, transcriptomic analyses revealed that HA@RFM@GP@SIN NPs suppressed the cell cycle pathway while inducing the cell apoptosis pathway. Furthermore, protein validation revealed that HA@RFM@GP@SIN NPs disrupted the excessive growth of RAFLS by interfering with the PI3K/Akt/SGK/FoxO signaling cascade, resulting in a decline in cyclin B1 expression and the arrest of the G2 phase. Additionally, considering the favorable biocompatibility and biosafety, these multifunctional nanoparticles offer a promising therapeutic approach for patients with RA.PMID:38951875 | DOI:10.1186/s12951-024-02645-8

Lipids Health Dis. 2024 Jun 29;23(1):207. doi: 10.1186/s12944-024-02198-7.ABSTRACTBACKGROUND: Ketogenic diets are increasingly popular for addressing obesity, but their impacts on the gut microbiota and metabolome remain unclear. This paper aimed to investigate how a ketogenic diet affects intestinal microorganisms and metabolites in obesity.METHODS: Male mice were provided with one of the following dietary regimens: normal chow, high-fat diet, ketogenic diet, or high-fat diet converted to ketogenic diet. Body weight and fat mass were measured weekly using high-precision electronic balances and minispec body composition analyzers. Metagenomics and non-targeted metabolomics data were used to analyze differences in intestinal contents.RESULTS: Obese mice on the ketogenic diet exhibited notable improvements in weight and body fat. However, these were accompanied by a significant decrease in intestinal microbial diversity, as well as an increase in Firmicutes abundance and a 247% increase in the Firmicutes/Bacteroidetes ratio. The ketogenic diet also altered multiple metabolic pathways in the gut, including glucose, lipid, energy, carbohydrate, amino acid, ketone body, butanoate, and methane pathways, as well as bacterial secretion and colonization pathways. These changes were associated with increased intestinal inflammation and dysbiosis in obese mice. Furthermore, the ketogenic diet enhanced the secretion of bile and the synthesis of aminoglycoside antibiotics in obese mice, which may impair the gut microbiota and be associated with intestinal inflammation and immunity.CONCLUSIONS: The study suggest that the ketogenic diet had an unfavorable risk-benefit trade-off and may compromise metabolic homeostasis in obese mice.PMID:38951816 | DOI:10.1186/s12944-024-02198-7

Lipids Health Dis. 2024 Jun 29;23(1):205. doi: 10.1186/s12944-024-02189-8.ABSTRACTBACKGROUND: Glycerophospholipids (GPLs) are essential for cell membrane structure and function. Sphingomyelin and its metabolites regulate cell growth, apoptosis, and stress responses. This study aimed to investigate lipid metabolism in patients experiencing sudden sensorineural hearing loss across all frequencies (AF-SSNHL).METHODS: The study included 60 patients diagnosed with unilateral AF-SSNHL, among whom 30 patients had a level of hearing improvement ≥ 15 dB after 6 months of follow-up. A propensity score-matched (2:1) control group was used. Liquid chromatography‒mass spectrometry based untargeted lipidomics analysis combined with multivariate statistics was performed to investigate the lipids change. The "lipidome" R package and weighted gene co-expression network analysis (WGCNA) were utilised to assess the lipids' structural features and the association between lipids and hearing.RESULTS: Lipidomics successfully differentiated the AF-SSNHL group from the control group, identifying 17 risk factors, mainly including phosphatidylcholine (PC), phosphatidylethanolamine (PE), and related metabolites. The ratios of lysophosphatidylcholine/PC, lysophosphatidylethanolamine/PE, and lysodimethylphosphatidylethanolamine/PE were upregulated, while some glycerophospholipid (GPL)-plasmalogens were downregulated in the AF-SSNHL group, indicating abnormal metabolism of GPLs. Trihexosylceramide (d34:1), PE (18:1e_22:5), and sphingomyelin (d40:3) were significantly different between responders and nonresponders, and positively correlated with hearing improvement. Additionally, the results of the WGCNA also suggested that partial GPL-plasmalogens were positively associated with hearing improvement.CONCLUSION: AF-SSNHL patients exhibited abnormally high blood lipids and pronounced GPLs metabolic abnormalities. Sphingolipids and GPL-plasmalogens had an association with the level of hearing improvement. By understanding the lipid changes, clinicians may be able to predict the prognosis of hearing recovery and personalize treatment approaches.PMID:38951804 | DOI:10.1186/s12944-024-02189-8

Microb Cell Fact. 2024 Jul 1;23(1):188. doi: 10.1186/s12934-024-02462-6.ABSTRACTBACKGROUND: Advancing the engineering of photosynthesis-based prokaryotic cell factories is important for sustainable chemical production and requires a deep understanding of the interplay between bioenergetic and metabolic pathways. Rearrangements in photosynthetic electron flow to increase the efficient use of the light energy for carbon fixation must be balanced with a strong carbon sink to avoid photoinhibition. In the cyanobacterium Synechocystis sp. PCC 6803, the flavodiiron protein Flv3 functions as an alternative electron acceptor of photosystem I and represents an interesting engineering target for reorganizing electron flow in attempts to enhance photosynthetic CO2 fixation and increase production yield.RESULTS: We have shown that inactivation of Flv3 in engineered sucrose-excreting Synechocystis (S02:Δflv3) induces a transition from photoautotrophic sucrose production to mixotrophic growth sustained by sucrose re-uptake and the formation of intracellular carbon sinks such as glycogen and polyhydroxybutyrate. The growth of S02:Δflv3 exceeds that of the sucrose-producing strain (S02) and demonstrates unforeseen proteomic and metabolomic changes over the course of the nine-day cultivation. In the absence of Flv3, a down-regulation of proteins related to photosynthetic light reactions and CO2 assimilation occurred concomitantly with up-regulation of those related to glycolytic pathways, before any differences in sucrose production between S02 and S02:Δflv3 strains were observed. Over time, increased sucrose degradation in S02:Δflv3 led to the upregulation of respiratory pathway components, such as the plastoquinone reductase complexes NDH-11 and NDH-2 and the terminal respiratory oxidases Cyd and Cox, which transfer electrons to O2. While glycolytic metabolism is significantly up-regulated in S02:Δflv3 to provide energy for the cell, the accumulation of intracellular storage compounds and the increase in respiration serve as indirect sinks for photosynthetic electrons.CONCLUSIONS: Our results show that the presence of strong carbon sink in the engineered sucrose-producing Synechocystis S02 strain, operating under high light, high CO2 and salt stress, cannot compensate for the lack of Flv3 by directly balancing the light transducing source and carbon fixing sink reactions. Instead, the cells immediately sense the imbalance, leading to extensive reprogramming of cellular bioenergetic, metabolic and ion transport pathways that favor mixotrophic growth rather than enhancing photoautotrophic sucrose production.PMID:38951789 | DOI:10.1186/s12934-024-02462-6

Mol Metab. 2024 Jun 29:101980. doi: 10.1016/j.molmet.2024.101980. Online ahead of print.ABSTRACTOBJECTIVES: In this investigation, we addressed the contribution of the core circadian clock factor, BMAL1, in skeletal muscle to both acute transcriptional responses to exercise and transcriptional remodelling in response to exercise training. Additionally, we adopted a systems biology approach to investigate how loss of skeletal muscle BMAL1 altered peripheral tissue homeostasis as well as exercise training adaptations in iWAT, liver, heart, and lung of male mice.METHODS: Combining inducible skeletal muscle specific BMAL1 knockout mice, physiological testing and standardized exercise protocols, we performed a multi-omic analysis (transcriptomics, chromatin accessibility and metabolomics) to explore loss of muscle BMAL1 on muscle and peripheral tissue responses to exercise.RESULTS: Muscle-specific BMAL1 knockout mice demonstrated a blunted transcriptional response to acute exercise, characterized by the lack of upregulation of well-established exercise responsive transcription factors including Nr4a3 and Ppargc1a. Six weeks of exercise training in muscle-specific BMAL1 knockout mice induced significantly greater and divergent transcriptomic and metabolomic changes in muscle. Surprisingly, liver, lung, inguinal white adipose and heart showed divergent exercise training transcriptomes with less than 5% of 'exercise-training' responsive genes shared for each tissue between genotypes.CONCLUSION: Our investigation has uncovered the critical role that BMAL1 plays in skeletal muscle as a key regulator of gene expression programs for both acute exercise and training adaptations. In addition, our work has uncovered the significant impact that altered exercise response in muscle and its likely impact on the system plays in the peripheral tissue adaptations to exercise training. Our work also demonstrates that if the muscle adaptations diverge to a more maladaptive state this is linked to increased gene expression signatures of inflammation across many tissues. Understanding the molecular targets and pathways contributing to health vs. maladaptive exercise adaptations will be critical for the next stage of therapeutic design for exercise mimetics.PMID:38950777 | DOI:10.1016/j.molmet.2024.101980

Mech Ageing Dev. 2024 Jun 29:111958. doi: 10.1016/j.mad.2024.111958. Online ahead of print.ABSTRACTBiological age uses biophysiological information to capture a person's age-related risk of adverse outcomes. MetaboAge and MetaboHealth are metabolomics-based biomarkers of biological age trained on chronological age and mortality risk, respectively. Lifestyle factors contribute to the extent chronological and biological age differ. The association of lifestyle factors with MetaboAge and MetaboHealth, potential sex differences in these associations, and MetaboAge's and MetaboHealth's sensitivity to lifestyle changes have not been studied yet. Linear regression analyses and mixed-effect models were used to examine the cross-sectional and longitudinal associations of scaled lifestyle factors with scaled MetaboAge and MetaboHealth in 24,332 middle-aged participants from the Doetinchem Cohort Study, Rotterdam Study, and UK Biobank. Random-effect meta-analyses were performed across cohorts. Repeated metabolomics measurements had a ten-year interval in the Doetinchem Cohort Study and a five-year interval in the UK Biobank. In the first study incorporating longitudinal information on MetaboAge and MetaboHealth, we demonstrate associations between current smoking, sleeping ≥8hours/day, higher BMI, and larger waist circumference were associated with higher MetaboHealth, the latter two also with higher MetaboAge. Furthermore, adhering to the dietary and physical activity guidelines were inversely associated with MetaboHealth. Lastly, we observed sex differences in the associations between alcohol use and MetaboHealth.PMID:38950629 | DOI:10.1016/j.mad.2024.111958

J Agric Food Chem. 2024 Jul 1. doi: 10.1021/acs.jafc.4c00394. Online ahead of print.ABSTRACTUV can serve as an effective light spectrum for regulating plant secondary metabolites, while relevant studies on UV-A are much less extensive than those on UV-B. A comprehensive understanding of the selective effects of UV-A on different secondary metabolites and the specific features of primary metabolism that drive these effects is still lacking. To address this knowledge gap, we conducted a study to analyze the dynamic changes in the metabolome and transcriptome of lettuce leaves irradiated with red plus UV-A light (monochromatic red light as control). Generally, UV-A promoted the synthesis of most phenylpropanoids and terpenoids originating from the shikimate and methylerythritol phosphate (MEP) pathway in plastids but sacrificed the synthesis of terpenoids derived from the mevalonate (MVA) pathway, particularly sesquiterpenes. Increased precursors supply for the shikimate and MEP pathway under UV-A was directly supported by the activation of the Calvin-Benson cycle and phosphoenolpyruvate transport. Whereas, along with phosphoenolpyruvate transport, the TCA cycle was restrained, causing deprivation of the MVA pathway precursor. In addition, UV-A also activated the plastidic oxidative branch of the pentose phosphate pathway, photorespiration, and malate shuttle, to ensure a sufficient supply of nitrogen, circulation homeostasis of the Calvin-Benson cycle, and energy balance, thus indirectly supporting UV-A-induced specific secondary metabolic output. This study provides a comprehensive framework for understanding the flexible primary-secondary metabolism interactions that are able to produce specific metabolites favorable for adaptation to environmental stimuli.PMID:38950542 | DOI:10.1021/acs.jafc.4c00394

J Agric Food Chem. 2024 Jul 1. doi: 10.1021/acs.jafc.4c02519. Online ahead of print.ABSTRACTPeanut southern blight, caused by the soil-borne pathogen Sclerotium rolfsii, is a widespread and devastating epidemic. Frequently, it is laborious to effectively control by labor-intensive foliar sprays of agrochemicals due to untimely find. In the present study, seed treatment with physcion (PHY) at doses of 0.08, 0.16, and 0.32 g AI kg-1 seed significantly improved the growth and photosynthetic activity of peanuts. Furthermore, PHY seed treatment resulted in an elevated enzymatic activity of key enzymes in peanut roots, including peroxidase, superoxide dismutase, polyphenol oxidase, catalase, lipoxygenase, and phenylalanine ammonia-lyase, as well as an increase in callus accumulation and lignin synthesis at the infection site, ultimately enhancing the root activity. This study revealed that PHY seed treatment could promote the accumulation of reactive oxygen species, salicylic acid (SA), and jasmonic acid (JA)/ethylene (ET) in peanut roots, while also decreasing the content of malondialdehyde levels in response to S. rolfsii infection. The results were further confirmed by transcriptome data and metabolomics. These findings suggest that PHY seed treatment activates the plant defense pathways mediated by SA and JA/ET in peanut roots, enhancing the resistance of peanut plants to S. rolfsii. In short, PHY is expected to be developed into a new plant-derived immunostimulant or fungicide to increase the options and means for peanut disease control.PMID:38950526 | DOI:10.1021/acs.jafc.4c02519

Pediatr Res. 2024 Jun 29. doi: 10.1038/s41390-024-03328-8. Online ahead of print.ABSTRACTBACKGROUND: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease (CCHD) with multifactorial etiology. We aimed to investigate the metabolic profiles of CCHD and their independent contributions to TOF.METHODS: A cohort comprising 42 individuals with TOF and atrial septal defect (ASD) was enrolled. Targeted ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) was employed to systematically analyze metabolite levels and identify TOF-associated metabolic profiles.RESULTS: Of 370 identified metabolites in tissue and 284 in plasma, over one-third of metabolites showed an association with microbiome. Differential metabolic pathways including amino acids biosynthesis, ABC (ATP-binding cassette) transporters, carbon metabolism, and fatty acid biosynthesis, shed light on TOF biological phenotypes. Additionally, ROC curves identified potential biomarkers, such as erythronic acid with an AUC of 0.868 in plasma, and 3-β-hydroxy-bisnor-5-cholenic acid, isocitric acid, glutaric acid, ortho-Hydroxyphenylacetic acid, picolinic acid with AUC close to 1 in tissue, whereas the discriminative performance of those substances significantly improved when combined with clinical phenotypes.CONCLUSIONS: Distinct metabolic profiles exhibited robust discriminatory capabilities, effectively distinguishing TOF from ASD patients. These metabolites may serve as biomarkers or key molecular players in the intricate metabolic pathways involved in CCHD development.IMPACT: Distinct metabolic profiles exhibited robust discriminatory capabilities, effectively distinguishing Tetralogy of Fallot from atrial septal defect patients. Similar profiling but inconsistent differential pathways between plasma and tissue. More than one-third metabolites in plasma and tissue are associated with the microbiome. The discovery of biomarkers is instrumental in facilitating early detection and diagnosis of Tetralogy of Fallot. Disturbed metabolism offers insights into interpretation of pathogenesis of Tetralogy of Fallot.PMID:38951655 | DOI:10.1038/s41390-024-03328-8

Commun Biol. 2024 Jul 1;7(1):795. doi: 10.1038/s42003-024-06483-0.ABSTRACTThe peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3β signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury.PMID:38951640 | DOI:10.1038/s42003-024-06483-0

Sci Rep. 2024 Jul 1;14(1):15028. doi: 10.1038/s41598-024-65569-1.ABSTRACTHoney bees are important insect pollinators that provide critical pollination services to fruit and nut crops in the US. They face challenges likely due to pressures associated with agricultural intensification related habitat loss. To better understand this, pollen preferences of foraging bees and the nutritional profile of pollen brought into hives by foraging bees in crop fields and nut orchards can provide valuable information. We trained bees to forage on bee-collected pollen from hives placed for pollination services in almond orchards, sunflower fields, or mixed species from inter-row plantings. Using bees trained to a certain kind of hive pollen, we applied a binary scoring system, to test preferences of these preconditioned foragers. We also performed metabolomic analyses of the hive pollen used for training and testing to elucidate their nutritional content. Irrespective of preconditioning, bees collected all the available choice pollen types, predominantly choosing hive-collected mixed species pollen (MSP), followed by almond orchard pollen. The hive-collected MSP was chemically diverse, richest in cholesterol, vitamins, and phytochemicals quercetin, kaempferol, coumarin, and quinine, but was not consistently high for essential amino acids and polyunsaturated fatty acids. Although diversity in chemical profiles may not directly relate to plant species diversity, our results suggest that foragers collect a variety of pollen types when available reiterating the importance of diverse floral resources.PMID:38951538 | DOI:10.1038/s41598-024-65569-1

NPJ Parkinsons Dis. 2024 Jun 29;10(1):126. doi: 10.1038/s41531-024-00732-z.ABSTRACTMany studies have reported metabolomic analysis of different bio-specimens from Parkinson's disease (PD) patients. However, inconsistencies in reported metabolite concentration changes make it difficult to draw conclusions as to the role of metabolism in the occurrence or development of Parkinson's disease. We reviewed the literature on metabolomic analysis of PD patients. From 74 studies that passed quality control metrics, 928 metabolites were identified with significant changes in PD patients, but only 190 were replicated with the same changes in more than one study. Of these metabolites, 60 exclusively increased, such as 3-methoxytyrosine and glycine, 54 exclusively decreased, such as pantothenic acid and caffeine, and 76 inconsistently changed in concentration in PD versus control subjects, such as ornithine and tyrosine. A genome-scale metabolic model of PD and corresponding metabolic map linking most of the replicated metabolites enabled a better understanding of the dysfunctional pathways of PD and the prediction of additional potential metabolic markers from pathways with consistent metabolite changes to target in future studies.PMID:38951523 | DOI:10.1038/s41531-024-00732-z

Mol Biotechnol. 2024 Jul 1. doi: 10.1007/s12033-024-01226-2. Online ahead of print.ABSTRACTCircular RNAs (circRNAs) perform important functions in the regulation of diverse physiological and pathological processes. CircABHD2 exhibits down-regulation in both endometrial cancer (EC) cells and tissues, but the biological roles and mechanisms of action in EC are still unclear. This study aims to provide a theoretical basis for the role of circABHD2 in EC and potential targets for individualized precision therapy. Dysregulated circRNAs were identified using RNA sequencing (RNA-Seq) from EC tissues and validated using RT-qPCR. CCK-8, colony formation assay, wound healing assay, transwell assay, cell cycle, and apoptosis assay were used to evaluate the effects of circABHD2 on EC cells. Metabolomics assay and western blot analyses were used to investigate the potential mechanisms of circABHD2. From sequencing of RNA (RNA-Seq) analysis of EC tissues, we obtained 19 dysregulated circRNAs, including 8 upregulated ones and 11 downregulated ones. Using RT-qPCR on 32 EC tissues and 19 normal endometrial tissues, we confirmed that circABHD2 was downregulated in EC tissues. The expression levels of circABHD2 were closely relevant to the International Federation of Gynecology and Obstetrics (FIGO) stage and differentiation degree of EC. Functional experiments demonstrated that overexpression of circABHD2 decreased proliferation, migration, invasion, and promoted cell apoptosis. Un-targeted metabolomic assay revealed 31 differential metabolites in EC cells overexpressing circABHD2. KEGG analysis of differential metabolites indicated that NAD+ is the core metabolite regulated by circABHD2. NAMPT is one key enzyme involved in the synthetic pathway responsible for NAD+. Subsequent experiments confirmed that by inhibiting NAMPT protein expression in EC cells, cirABHD2 can inhibit NAD+ level, suggesting that circABHD2 may inhibit EC by regulating the metabolic axis of NAD+/NAMPT. CircABHD2, a downregulated circRNA in EC cells and tissues, inhibits the malignant progression of EC via the NAD+/NAMPT metabolic axis. This discovery presents a promising diagnostic biomarker and potential therapeutic target for EC.PMID:38951482 | DOI:10.1007/s12033-024-01226-2

J Cancer Res Clin Oncol. 2024 Jul 1;150(7):331. doi: 10.1007/s00432-024-05857-5.ABSTRACTOBJECTIVE: To conduct a systematic review and meta-analysis of case-control and cohort human studies evaluating metabolite markers identified using high-throughput metabolomics techniques on esophageal cancer (EC), cancer of the gastroesophageal junction (GEJ), and gastric cancer (GC) in blood and tissue.BACKGROUND: Upper gastrointestinal cancers (UGC), predominantly EC, GEJ, and GC, are malignant tumour types with high morbidity and mortality rates. Numerous studies have focused on metabolomic profiling of UGC in recent years. In this systematic review and meta-analysis, we have provided a collective summary of previous findings on metabolites and metabolomic profiling associated with EC, GEJ and GC.METHODS: Following the PRISMA procedure, a systematic search of four databases (Embase, PubMed, MEDLINE, and Web of Science) for molecular epidemiologic studies on the metabolomic profiles of EC, GEJ and GC was conducted and registered at PROSPERO (CRD42023486631). The Newcastle-Ottawa Scale (NOS) was used to benchmark the risk of bias for case-controlled and cohort studies. QUADOMICS, an adaptation of the QUADAS-2 (Quality Assessment of Diagnostic Accuracy) tool, was used to rate diagnostic accuracy studies. Original articles comparing metabolite patterns between patients with and without UGC were included. Two investigators independently completed title and abstract screening, data extraction, and quality evaluation. Meta-analysis was conducted whenever possible. We used a random effects model to investigate the association between metabolite levels and UGC.RESULTS: A total of 66 original studies involving 7267 patients that met the required criteria were included for review. 169 metabolites were differentially distributed in patients with UGC compared to healthy patients among 44 GC, 9 GEJ, and 25 EC studies including metabolites involved in glycolysis, anaerobic respiration, tricarboxylic acid cycle, and lipid metabolism. Phosphatidylcholines, eicosanoids, and adenosine triphosphate were among the most frequently reported lipids and metabolites of cellular respiration, while BCAA, lysine, and asparagine were among the most commonly reported amino acids. Previously identified lipid metabolites included saturated and unsaturated free fatty acids and ketones. However, the key findings across studies have been inconsistent, possibly due to limited sample sizes and the majority being hospital-based case-control analyses lacking an independent replication group.CONCLUSION: Thus far, metabolomic studies have provided new opportunities for screening, etiological factors, and biomarkers for UGC, supporting the potential of applying metabolomic profiling in early cancer diagnosis. According to the results of our meta-analysis especially BCAA and TMAO as well as certain phosphatidylcholines should be implicated into the diagnostic procedure of patients with UGC. We envision that metabolomics will significantly enhance our understanding of the carcinogenesis and progression process of UGC and may eventually facilitate precise oncological and patient-tailored management of UGC.PMID:38951269 | DOI:10.1007/s00432-024-05857-5

Arch Toxicol. 2024 Jun 28. doi: 10.1007/s00204-024-03810-6. Online ahead of print.ABSTRACTNatural toxins produced by Alternaria fungi include the mycotoxins alternariol, tenuazonic acid and altertoxins I and II. Several of these toxins have shown high toxicity even at low levels including genotoxic, mutagenic, and estrogenic effects. However, the metabolic effects of toxin exposure from Alternaria are understudied, especially in the liver as a key target. To gain insight into the impact of Alternaria toxin exposure on the liver metabolome, rats (n = 21) were exposed to either (1) a complex culture extract with defined toxin profiles from Alternaria alternata (50 mg/kg body weight), (2) the isolated, highly genotoxic altertoxin-II (ATX-II) (0.7 mg/kg of body weight) or (3) a solvent control. The complex mixture contained a spectrum of Alternaria toxins including a controlled dose of ATX-II, matching the concentration of the isolated ATX-II. Liver samples were collected after 24 h and analyzed via liquid chromatography-high-resolution mass spectrometry (LC-HRMS). Authentic reference standards (> 100) were used to identify endogenous metabolites and exogenous compounds from the administered exposures in tandem with SWATH-acquired MS/MS data which was used for non-targeted analysis/screening. Screening for metabolites produced by Alternaria revealed several compounds solely isolated in the liver of rats exposed to the complex culture, confirming results from a previously performed targeted biomonitoring study. This included the altersetin and altercrasin A that were tentatively identified. An untargeted metabolomics analysis found upregulation of acylcarnitines in rats receiving the complex Alternaria extract as well as downregulation of riboflavin in rats exposed to both ATX-II and the complex mixture. Taken together, this work provides a mechanistic view of Alternari toxin exposure and new suspect screening insights into hardly characterized Alternaria toxins.PMID:38951189 | DOI:10.1007/s00204-024-03810-6

Alcohol Clin Exp Res (Hoboken). 2024 Jul 1. doi: 10.1111/acer.15398. Online ahead of print.ABSTRACTBACKGROUND: Excessive alcohol consumption has a multifaceted impact on the body's metabolic pathways and organ systems. The objectives of this study were to characterize global metabolomic changes and identify specific pathways that are altered in individuals with excessive alcohol use.METHODS: This exploratory study included 22 healthy controls with no known history of excessive alcohol use and 38 patients identified as using alcohol excessively. A Fibrosis-4 score was used to determine the risk of underlying alcohol-associated liver disease among the excessive drinkers.RESULTS: We found significantly altered urinary and serum metabolites among excessive drinkers, affecting various metabolic pathways including the metabolism of lipids, amino acids and peptides, cofactors and vitamins, carbohydrates, and nucleotides. Levels of two steroid hormones-5alpha-androstan-3beta,17beta-diol disulfate and androstenediol (3beta,17beta) disulfate-were significantly higher in both the serum and urine samples of excessive drinkers. These elevated levels may be associated with a higher risk of liver fibrosis in individuals with excessive alcohol use.CONCLUSION: Alcohol consumption leads to marked alterations in multiple metabolic pathways, highlighting the systemic impact of alcohol on various tissues and organ systems. These findings provide a foundation for future mechanistic studies aimed at elucidating alcohol-induced changes in these metabolic pathways and their implications.PMID:38951043 | DOI:10.1111/acer.15398

ACS Nano. 2024 Jul 1. doi: 10.1021/acsnano.4c04282. Online ahead of print.ABSTRACTRaman spectroscopy has made significant progress in biosensing and clinical research. Here, we describe how surface-enhanced Raman spectroscopy (SERS) assisted with machine learning (ML) can expand its capabilities to enable interpretable insights into the transcriptome, proteome, and metabolome at the single-cell level. We first review how advances in nanophotonics-including plasmonics, metamaterials, and metasurfaces-enhance Raman scattering for rapid, strong label-free spectroscopy. We then discuss ML approaches for precise and interpretable spectral analysis, including neural networks, perturbation and gradient algorithms, and transfer learning. We provide illustrative examples of single-cell Raman phenotyping using nanophotonics and ML, including bacterial antibiotic susceptibility predictions, stem cell expression profiles, cancer diagnostics, and immunotherapy efficacy and toxicity predictions. Lastly, we discuss exciting prospects for the future of single-cell Raman spectroscopy, including Raman instrumentation, self-driving laboratories, Raman data banks, and machine learning for uncovering biological insights.PMID:38950145 | DOI:10.1021/acsnano.4c04282