PubMed

J Pharm Biomed Anal. 2023 May 24;234:115484. doi: 10.1016/j.jpba.2023.115484. Online ahead of print.ABSTRACTPolycystic ovary syndrome (PCOS) is a common endocrine disorder that causes reproductive hormones imbalance, missed periods, infertility and distributed steroidogenesis. Reportedly, during PCOS, the endogenous levels of P4 (Progesterone), 17OHP4 (17-α hydroxy progesterone), and T4 (Testosterone) were significantly altered. Thus, quantification of steroid biomarkers involved in the steroidogenesis pathway of PCOS, such as P4, 17OHP4, and T4, holds significant importance. One important drawback of current methods is steroid metabolome traceability. Without adequate traceability, the findings of these techniques will be less reliable for identifying P4, 17OHP4, and T4. These methods also need a high sample size, especially for the most important biomarker that initiates steroidogenesis. To address these challenges, we require a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for steroid biomarker analysis. Herein the present work, using validated LC-MS/MS, PCOS biomarkers were measured and compared between normal control rats and PCOS-induced rats before and after analyte administration. The experiment utilized an isocratic separation method employing an analytical C18 column. The mobile phase consisted of acetonitrile (ACN) and aqueous 0.1% formic acid (FA) in a ratio of 90:10 (v/v). The plasma samples were processed with protein precipitation (PPT) followed by the liquid-liquid extraction (LLE) method. The lower limit of quantification (LLOQ) was 0.5 ng/mL in plasma. According to USFDA criteria, the method's systematic validation took into account linearity (r2 > 0.99), accuracy and precision of intra- and inter-batch measurements, stability, biomarker recovery (60-85%) and matrix effect (<± 15%), all of which were determined to be within range ( ± 15%). The pharmacokinetic data showed that, as compared to normal rats, PCOS-induced animals had significantly higher Cmax values for 17OHP4 and T4 (∼2 fold), while lower Cmax values for P4 (∼2 fold). The present work is novel and provides scientific information to explore systematic processes involved in steroidogenesis and boost clinical applicability for PCOS therapy.PMID:37453143 | DOI:10.1016/j.jpba.2023.115484

Cell Rep. 2023 Jul 14;42(7):112804. doi: 10.1016/j.celrep.2023.112804. Online ahead of print.ABSTRACTThe bone marrow microenvironment (BME) drives drug resistance in acute lymphoblastic leukemia (ALL) through leukemic cell interactions with bone marrow (BM) niches, but the underlying mechanisms remain unclear. Here, we show that the interaction between ALL and mesenchymal stem cells (MSCs) through integrin β1 induces an epithelial-mesenchymal transition (EMT)-like program in MSC-adherent ALL cells, resulting in drug resistance and enhanced survival. Moreover, single-cell RNA sequencing analysis of ALL-MSC co-culture identifies a hybrid cluster of MSC-adherent ALL cells expressing both B-ALL and MSC signature genes, orchestrated by a WNT/β-catenin-mediated EMT-like program. Blockade of interaction between β-catenin and CREB binding protein impairs the survival and drug resistance of MSC-adherent ALL cells in vitro and results in a reduction in leukemic burden in vivo. Targeting of this WNT/β-catenin-mediated EMT-like program is a potential therapeutic approach to overcome cell extrinsically acquired drug resistance in ALL.PMID:37453060 | DOI:10.1016/j.celrep.2023.112804

J Chem Ecol. 2023 Jul 15. doi: 10.1007/s10886-023-01442-1. Online ahead of print.ABSTRACTThe cyclic depsipeptide FR900359 (FR) is derived from the soil bacterium Chromobacterium vaccinii and known to bind Gq proteins of mammals and insects, thereby abolishing the signal transduction of their Gq protein-coupled receptors, a process that leads to severe physiological consequences. Due to their highly conserved structure, Gq family of proteins are a superior ecological target for FR producing organisms, resulting in a defense towards a broad range of harmful organisms. Here, we focus on the question whether bacteria like C. vaccinii are important factors in soil in that their secondary metabolites impair, e.g., plant harming organisms like nematodes. We prove that the Gq inhibitor FR is produced under soil-like conditions. Furthermore, FR inhibits heterologously expressed Gαq proteins of the nematodes Caenorhabditis elegans and Heterodera schachtii in the micromolar range. Additionally, in vivo experiments with C. elegans and the plant parasitic cyst nematode H. schachtii demonstrated that FR reduces locomotion of C. elegans and H. schachtii. Finally, egg-laying of C. elegans and hatching of juvenile stage 2 of H. schachtii from its cysts is inhibited by FR, suggesting that FR might reduce nematode dispersion and proliferation. This study supports the idea that C. vaccinii and its excreted metabolome in the soil might contribute to an ecological equilibrium, maintaining and establishing the successful growth of plants.PMID:37453001 | DOI:10.1007/s10886-023-01442-1

Int Urol Nephrol. 2023 Jul 15. doi: 10.1007/s11255-023-03691-1. Online ahead of print.ABSTRACTBACKGROUND: Membranous nephropathy (MN) and IgA nephropathy (IgAN) are the most common primary glomerulopathies worldwide. The systemic metabolic changes in the progression of MN and IgAN are not fully understood.METHODS: A total of 87 and 70 patients with MN and IgAN, respectively, and 30 healthy controls were enrolled in this study. Untargeted metabolomics was performed to explore the differential metabolites and metabolic pathways in the early stage of MN and IgAN. To judge the diagnostic ability of biomarkers, receiver operating characteristic curve analysis (ROC) were performed.RESULTS: Principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) suggested that patients with MN and IgAN showed an obvious separation trend from the healthy controls. In addition, 155 and 148 metabolites were identified to be significantly altered in the MN and IgAN groups, respectively. Of these, 70 metabolites were markedly altered in both disease groups; six metabolites, including L-tryptophan, L-kynurenine, gamma-aminobutyric acid (GABA), indoleacetaldehyde, 5-hydroxyindoleacetylglycine, and N-alpha-acetyllysine, showed the opposite tendency. The most affected metabolic pathways included the amino acid metabolic pathways, citrate cycle, pantothenate and CoA biosynthesis, and hormone signaling pathways.CONCLUSIONS: Substantial metabolic disorders occurred during the progression of MN and IgAN. L-tryptophan, L-kynurenine, GABA, indoleacetaldehyde, 5-hydroxyindoleacetylglycine, and N-alpha-acetyllysine may show potential as biomarkers for the identification of MN and IgAN.PMID:37452988 | DOI:10.1007/s11255-023-03691-1

Mol Ecol. 2023 Jul 15. doi: 10.1111/mec.17070. Online ahead of print.ABSTRACTWhole-genome duplication has shaped the evolution of angiosperms and other organisms, and is important for many crops. Structural reorganization of chromosomes and repatterning of gene expression are frequently observed in allopolyploids, with physiological and ecological consequences. Recurrent origins from different parental populations are widespread among polyploids, resulting in an array of lineages that provide excellent models to uncover mechanisms of adaptation to divergent environments in early phases of polyploid evolution. We integrate here transcriptomic and ecophysiological comparative studies to show that sibling allopolyploid marsh orchid species (Dactylorhiza, Orchidaceae) occur in different habitats (low nutrient fens vs. meadows with mesic soils) and are characterized by a complex suite of intertwined, pronounced ecophysiological differences between them. We uncover distinct features in leaf elemental chemistry, light-harvesting, photoprotection, nutrient transport and stomata activity of the two sibling allopolyploids, which appear to match their specific ecologies, in particular soil chemistry differences at their native sites. We argue that the phenotypic divergence between the sibling allopolyploids has a clear genetic basis, generating ecological barriers that maintain distinct, independent lineages, despite pervasive interspecific gene flow. This suggests that recurrent origins of polyploids bring about a long-term potential to trigger and maintain functional and ecological diversity in marsh orchids and other groups.PMID:37452724 | DOI:10.1111/mec.17070

Metabolomics. 2023 Jul 14;19(7):66. doi: 10.1007/s11306-023-02029-3.ABSTRACTINTRODUCTION: Type 2 diabetes mellitus (T2DM) is a significant risk factor for the development of critical limb ischemia (CLI), the most advanced stage of peripheral arterial disease. The concurrent existence of T2DM and CLI often leads to adverse outcomes, namely limb amputation.OBJECTIVE: To identify biomarkers for improving the screening of CLI in high-risk people with T2DM.METHODS: We investigated metabolome profiles in serum samples of 113 T2DM people with CLI (n = 23, G2) and without CLI (n = 45, G0: no lower limb stenosis (LLS) and n = 45, G1: LLS < 50%), using hydrogen nuclear magnetic resonance (1H NMR) approach. Principle component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were used to analyze 1H NMR data.RESULTS: Twenty potential metabolites that could discriminate people with T2DM and CLI (G2) from non-CLI patients without LLS (G0) were determined in serum samples. The correct percent of classification for the PLS-DA model for the test set samples was 85% (n = 20) and 100% (n = 5) for G0 and G2 groups, respectively. Non-CLI patients with LLS < 50% (G1) were projected on the PCA abstract space built using 20 discriminatory metabolites. Eleven people with T2DM and LLS < 50% were prospectively followed, and their ankle-brachial index (ABI) was measured after 4 years. A promising agreement existed between the PCA model's predictions and those obtained by ABI values.CONCLUSION: The findings suggest that confirmation of blood potential metabolic biomarkers as a complement to ABI for screening of CLI in a large group of high-risk people with T2DM is needed.PMID:37452163 | DOI:10.1007/s11306-023-02029-3

Nat Commun. 2023 Jul 14;14(1):4221. doi: 10.1038/s41467-023-40022-5.ABSTRACTResistance to endocrine treatments and CDK4/6 inhibitors is considered a near-inevitability in most patients with estrogen receptor positive breast cancers (ER + BC). By genomic and metabolomics analyses of patients' tumours, metastasis-derived patient-derived xenografts (PDX) and isogenic cell lines we demonstrate that a fraction of metastatic ER + BC is highly reliant on oxidative phosphorylation (OXPHOS). Treatment by the OXPHOS inhibitor IACS-010759 strongly inhibits tumour growth in multiple endocrine and palbociclib resistant PDX. Mutations in the PIK3CA/AKT1 genes are significantly associated with response to IACS-010759. At the metabolic level, in vivo response to IACS-010759 is associated with decreased levels of metabolites of the glutathione, glycogen and pentose phosphate pathways in treated tumours. In vitro, endocrine and palbociclib resistant cells show increased OXPHOS dependency and increased ROS levels upon IACS-010759 treatment. Finally, in ER + BC patients, high expression of OXPHOS associated genes predict poor prognosis. In conclusion, these results identify OXPHOS as a promising target for treatment resistant ER + BC patients.PMID:37452026 | DOI:10.1038/s41467-023-40022-5

Nat Commun. 2023 Jul 14;14(1):4129. doi: 10.1038/s41467-023-39672-2.ABSTRACTMammalian retinal metabolism favors aerobic glycolysis. However, the role of glycolytic metabolism in retinal morphogenesis remains unknown. We report that aerobic glycolysis is necessary for the early stages of retinal development. Taking advantage of an unbiased approach that combines the use of eye organoids and single-cell RNA sequencing, we identify specific glucose transporters and glycolytic genes in retinal progenitors. Next, we determine that the optic vesicle territory of mouse embryos displays elevated levels of glycolytic activity. At the functional level, we show that removal of Glucose transporter 1 and Lactate dehydrogenase A gene activity from developing retinal progenitors arrests eye morphogenesis. Surprisingly, we uncover that lactate-mediated upregulation of key eye-field transcription factors is controlled by the epigenetic modification of histone H3 acetylation through histone deacetylase activity. Our results identify an unexpected bioenergetic independent role of lactate as a signaling molecule necessary for mammalian eye morphogenesis.PMID:37452018 | DOI:10.1038/s41467-023-39672-2

BMJ Open. 2023 Jul 14;13(7):e072205. doi: 10.1136/bmjopen-2023-072205.ABSTRACTINTRODUCTION: Multiple cohort studies have been established to investigate the impact of early life factors on development and health outcomes. In Australia the majority of these studies were established more than 20 years ago and, although longitudinal in nature, are inherently susceptible to socioeconomic, environmental and cultural influences which change over time. Additionally, rapid leaps in technology have increased our understanding of the complex role of gene-environment interactions in life course health, highlighting the need for new cohort studies with repeated biological sampling and in-depth phenotype data across the first 1000 days of life from conception.METHODS AND ANALYSIS: The Newcastle 1000 (NEW1000) Study, based in the regional city of Newcastle, New South Wales, was developed after an extensive consultation process involving 3 years of discussion with key stakeholders and healthcare consumer organisations and seven healthcare consumer workshops. This prospective population-based pregnancy cohort study will recruit 500 families per year for 5 years, providing detailed, longitudinal, multisystem phenotyping, repeated ultrasound measures and serial sample collection to investigate healthcare consumer identified health outcomes of priority. Stage 1 will involve recruitment of pregnant participants and their partners at 14 weeks gestation, with dense phenotype data and biological samples collected at 14, 20, 28 and 36 weeks gestation and serial ultrasound measures at 20, 28, 36 and 40 weeks, with postpartum follow-up at 6 weeks and 6 months. Biological samples will be used for biomarker discovery and sequencing of the genome, transcriptome, epigenome, microbiome and metabolome.ETHICS AND DISSEMINATION: Ethics approval was obtained from Hunter New England Local Health District Ethics Committee (2020/ETH02881). Outcomes will be published in peer-reviewed journals, disseminated to participants through the NEW1000 website, presented at scientific conferences, and written reports to local, state and national government bodies and key stakeholders in the healthcare system to inform policy and evidence-based practice.PMID:37451724 | DOI:10.1136/bmjopen-2023-072205

Environ Res. 2023 Jul 12:116661. doi: 10.1016/j.envres.2023.116661. Online ahead of print.ABSTRACTThere is an urgent demand to investigate mechanisms for the improvement of denitrification in carbon-deficient environment, which will effectively reduce the eutrophication in water bodies polluted by nitrate. In this study, denitrifying bacterium Comamonas sp. YSF15 was used to explore the differences in different carbon source concentrations, with the complete genome, metabolomics, and other detecting methods. Results showed that strain YSF15 was able to achieve efficient denitrification, with complete pathways for denitrification and central carbon metabolism. The carbon deficiency prompted the bacteria to use extracellular amino acid-like metabolites initially, to alleviate inhibition and maintain bioactivity, which also facilitated glycogen storage. The biogenic inhibitors (tautomycin, navitoclax, and glufosinate) at extremely low level potentially favored the competitiveness and intraspecific utilization of extracellular polysaccharides (PS). Optimal solutions for bioaggregation in carbon-deficient condition are achieved by regulating the hydrophobicity, and hydrogen bond in extracellular metabolites. The strategy contributes to the maintenance of bioactivity and adaptation to carbon deficiency. Overall, this study provides a new perspective on understanding the denitrification strategies in carbon-deficient environment, and helps to improve the nitrate removal in low-carbon wastewater treatment.PMID:37451570 | DOI:10.1016/j.envres.2023.116661

Toxicology. 2023 Jul 12:153594. doi: 10.1016/j.tox.2023.153594. Online ahead of print.ABSTRACTData is limited on intestinal microbiota and metabolites in healthy residents exposed to cadmium (Cd), a population uniquely susceptible to Cd toxicity through contaminated foods. In this study, the 16S rRNA gene sequencing, serum metabolomics and urine metabolomics were performed to examine the alterations of gut microbiota and metabolomics profile of wistar rats exposed to Cd. These findings indicated that Cd exposure markedly altered the structure of gut microbial community, reduced significantly microbiome diversity, and identified 5 phyla and 6 genera with significant changes. Specifically, the levels of Pseudoxanthomonas and Anaerovibrio upregulated and that of Akkermansia, Brachyspira, Aggregatibacter and SMB53 reduced in rats treated with Cd. Metabolomics profiles of the urine and serum of Cd-treated rats revealed that the abundance of glycerophospholipid metabolites and their derivatives were markedly altered. Glycerophospholipid metabolic pathways that were markedly enriched in metabolomics in both samples was also significantly predicted in gut microbiota analysis. Further, interaction analysis predicted that there might be a relationship between the differential glycerophospholipid metabolites and affected bacteria genera induced by Cd. These results suggested that subacute Cd could disrupt the intestinal microecologica equilibrium and glycerophospholipid metabolic homeostasis, and also provided potential differential microbiota and glycerophospholipid biomarkers between subacute Cd-exposed rats and healthy rats.PMID:37451531 | DOI:10.1016/j.tox.2023.153594

Environ Toxicol Pharmacol. 2023 Jul 12:104219. doi: 10.1016/j.etap.2023.104219. Online ahead of print.ABSTRACTBrain microvascular endothelial cells (BMVECs) from the blood- brain barrier form a highly selective membrane that protects the brain from circulating blood and maintains a stable microenvironment for the central nervous system. BMVEC dysfunction has been implicated in a variety of neurological and psychiatric disorders. Clozapine, a widely used antipsychotics, has been demonstrated to alter the permeability of BMVECs, but the underlying mechanisms of this effect are not fully understood. In this study, we investigated the effects of clozapine in BMVECs using untargeted metabolomics analysis. Our results illustrated that treatment with clozapine led to significant changes in the metabolic profile of BMVECs, including alterations in amino acid and energy metabolism. These findings suggest that clozapine affects BMVEC permeability through its effects on cellular metabolism. Our study could inform the development of more targeted and effective treatments for understanding the relationships among clozapine, cellular metabolism, and BMVECs in more detail.PMID:37451530 | DOI:10.1016/j.etap.2023.104219

J Ethnopharmacol. 2023 Jul 12:116912. doi: 10.1016/j.jep.2023.116912. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Tetrastigma hemsleyanum Diels et Gilg (T. hemsleyanum, Sanyeqing) has been used in the prevention and treatment of repetitive Febrile seizures (FS) over the centuries in China.AIM OF THE STUDY: T. hemsleyanum exerts wide pharmacological action, which has been widely used for treating various diseases, including infantile febrile seizure. However, the systematic study on this herb's material basis and the functional mechanism is lacking. This study intended to systematically elucidate the mechanism of T. hemsleyanum against febrile seizures.MATERIALS AND METHODS: The efficacy of T. hemsleyanum was estimated by using a hot bath as a model of FS, the onset and duration of seizure, morphological structure changes of hippocampal neurons as well as magnetoencephalography were applied to evaluate the effects. Meanwhile, the bioactive components of T. hemsleyanum responsible for the therapeutic effect of T. hemsleyanum on FS were identified by UPLC-MS/MS. Then systematically elucidate the mechanism of T. hemsleyanum based on metabonomics, transcriptomics, network pharmacological and experimental validation.RESULTS: In a hyperthermia-induced FS model of rats, T. hemsleyanum significantly increased the seizure latency and decreased seizure duration, alleviating the abnormal delta and gamma band activity during epileptic discharge. Furthermore, ten chemical components of ethanol extracts from T. hemsleyanum were identified by UPLC-MS/MS, including quercetin, kaempferol, and procyanidin B1 and so on, which was consistent with the network pharmacology prediction. The serum metabolomics indicated that T. hemsleyanum mainly acts on inflammation regulation and neuroprotection by the glycerophospholipid metabolism pathway. Ninety-two potential targets of T. hemsleyanum on FS were identified by network pharmacology, and TNF, IL-6, and IL-1β were considered the pivotal targets. In the hippocampus transcriptomics, 17 KEGG pathways were identified after T. hemsleyanum treatment compared with the FS model group, among which 15 pathways overlapped with those identified by network pharmacology, and the PKC-δ/caspase-1 signaling pathway was a critical node. Finally, in vivo experiments also verified T. hemsleyanum inhibited the activation of microglia and resulted in a significant reduction in the level of PKCδ, NLRC4, caspase-1 and IL-1β, IL-6 and TNF-α in hippocampus of FS rats.CONCLUSIONS: Our study suggested that the therapeutic effect of T. hemsleyanum on FS might be regulated by inhibiting the neuroinflammation, thus exerting an anticonvulsant effect in vivo, and the mechanism might be related to regulating the PKC-δ/caspase-1 signaling pathway.PMID:37451489 | DOI:10.1016/j.jep.2023.116912

Comp Biochem Physiol C Toxicol Pharmacol. 2023 Jul 12:109697. doi: 10.1016/j.cbpc.2023.109697. Online ahead of print.ABSTRACTN-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-quinone) is an emerging contaminant of concern that is generated through the environmental oxidation of the rubber tire anti-degradant 6PPD. Since the initial report of 6PPD-quinone being the cause of urban runoff mortality syndrome of Coho salmon, numerous species have been identified as either sensitive or insensitive to acute lethality caused by 6PPD-quinone. In sensitive species, acute lethality might be caused by uncoupling of mitochondrial respiration in gills. However, little is known about effects of 6PPD-quinone on insensitive species. Here we demonstrate that embryos of fathead minnows (Pimephales promelas) are insensitive to exposure to concentrations as great as 39.97 μg/L for 168 h, and adult fathead minnows are insensitive to exposure to concentrations as great as 9.4 μg/L for 96 h. A multi-omics approach using a targeted transcriptomics array, (EcoToxChips), and proton nuclear magnetic resonance (1H NMR) was used to assess responses of the transcriptomes and metabolomes of gills and livers from adult fathead minnows exposed to 6PPD-quinone for 96 h to begin to identify sublethal effects of 6PPD-quinone. There was little agreement between results of the EcoToxChip and metabolomics analyses, likely because genes present on the EcoToxChip were not representative of pathways suggested to be perturbed by metabolomic analysis. Changes in abundances of transcripts and metabolites in livers and gills suggest that disruption of one‑carbon metabolism and induction of oxidative stress might be occurring in gills and livers, but that tissues differ in their sensitivity or responsiveness to 6PPD-quinone. Overall, several pathways impacted by 6PPD-quinone were identified as candidates for future studies of potential sublethal effects of this chemical.PMID:37451416 | DOI:10.1016/j.cbpc.2023.109697

Mitochondrion. 2023 Jul 12:S1567-7249(23)00067-3. doi: 10.1016/j.mito.2023.07.004. Online ahead of print.ABSTRACTMitochondrial functions play a crucial role in determining the metabolic and thermogenic status of brown adipocytes. Increasing evidence reveals that the mitochondrial oxidative phosphorylation (OXPHOS) system plays an important role in brown adipogenesis, but the mechanistic insights are limited. Herein, we explored the potential metabolic mechanisms leading to OXPHOS regulation of brown adipogenesis in pharmacological and genetic models of mitochondrial respiratory complex I deficiency. OXPHOS deficiency inhibits brown adipogenesis through disruption of the brown adipogenic transcription circuit without affecting ATP levels. Neither blockage of calcium signaling nor antioxidant treatment can rescue the suppressed brown adipogenesis. Metabolomics analysis revealed a decrease in levels of tricarboxylic acid cycle intermediates and heme. Heme supplementation specifically enhances respiratory complex I activity without affecting complex II and partially reverses the inhibited brown adipogenesis by OXPHOS deficiency. Moreover, the regulation of brown adipogenesis by the OXPHOS-heme axis may be due to the suppressed histone methylation status by increasing histone demethylation. In summary, our findings identified a heme-sensing retrograde signaling pathway that connects mitochondrial OXPHOS to the regulation of brown adipocyte differentiation and metabolic functions.PMID:37451354 | DOI:10.1016/j.mito.2023.07.004

Cell Chem Biol. 2023 Jul 3:S2451-9456(23)00193-9. doi: 10.1016/j.chembiol.2023.06.011. Online ahead of print.ABSTRACTDarobactins represent a class of ribosomally synthesized and post-translationally modified peptide (RiPP) antibiotics featuring a rare bicyclic structure. They target the Bam-complex of Gram-negative bacteria and exhibit in vivo activity against drug-resistant pathogens. First isolated from Photorhabdus species, the corresponding biosynthetic gene clusters (BGCs) are widespread among γ-proteobacteria, including the genera Vibrio, Yersinia, and Pseudoalteromonas (P.). While the organization of the BGC core is highly conserved, a small subset of Pseudoalteromonas carries an extended BGC with additional genes. Here, we report the identification of brominated and dehydrated darobactin derivatives from P. luteoviolacea strains. The marine derivatives are active against multidrug-resistant (MDR) Gram-negative bacteria and showed solubility and plasma protein binding ability different from darobactin A, rendering it more active than darobactin A. The halogenation reaction is catalyzed by DarH, a new class of flavin-dependent halogenases with a novel fold.PMID:37451267 | DOI:10.1016/j.chembiol.2023.06.011

Aquat Toxicol. 2023 Jun 20;261:106618. doi: 10.1016/j.aquatox.2023.106618. Online ahead of print.ABSTRACTGlufosinate is a chiral pesticide, with commercial formulations such as racemic glufosinate (rac-glufosinate) and pure L-glufosinate enantiomer (L-glufosinate) on the market. There has been little research on the difference in toxicity to non-target organisms between these two main ingredients. The effects of rac-glufosinate and L-glufosinate on glutathione reductase (GR), catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) levels in zebrafish were investigated in this study. The effect of two glufosinate agents at low concentrations (0.01 and 0.1 mg/L) on these four oxidative indicators was found to be significantly lower than that of high concentrations (1 and 10 mg/L). L-glufosinate had a stronger enhancing effect on CAT, GR, and MDA content than rac-glufosinate and a stronger inhibitory effect on SOD activity than rac-glufosinate. The researchers used ultra-high-performance liquid chromatography coupled with high-resolution mass spectroscopy metabolomics to compare rac-glufosinate and L-glufosinate for metabolic disorders in adult zebrafish. Stable and obvious metabolic maps of the two agents were obtained using multivariate statistical results, such as principal component analysis and orthogonal partial minimum discriminant analysis. Compared to the control group, the rac-glufosinate and L-glufosinate treatment groups shared 151 differential metabolites, which primarily affected zebrafish energy metabolism, amino acid metabolism, and other metabolic pathways. Caffeine metabolism and biotin metabolism were among the unique pathways disrupted in rac-glufosinate-exposed zebrafish. Contrarily, L-glufosinate treatment primarily affected eight metabolic pathways, including arginine biosynthesis, melanogenesis, and glutathione metabolism. These findings may provide more detailed information on the toxicity of rac-glufosinate and L-glufosinate in zebrafish, as well as some context for assessing the environmental risk of the two glufosinate agents to aquatic organisms.PMID:37451187 | DOI:10.1016/j.aquatox.2023.106618

Int Immunopharmacol. 2023 Jul 12;122:110561. doi: 10.1016/j.intimp.2023.110561. Online ahead of print.ABSTRACTAseptic inflammation is a major cause of late failure in total joint arthroplasty, and the primary factor contributing to the development and perpetuation of aseptic inflammation is classical macrophage activation (M1 phenotype polarization) induced by wear particles. CD73 (ecto-5'-nucleotidase) is an immunosuppressive factor that establishes an adenosine-induced anti-inflammatory environment. Although CD73 has been shown to suppress inflammation by promoting alternate macrophage activation (M2 phenotype polarization), its role in wear particle-induced aseptic inflammation is currently unknown. Our experiments were based on metabolomic assay results in a mouse model of aseptic loosening, and studied the function of CD73 in vivo and in vitro using a mouse aseptic loosening model and a mouse bone marrow derived macrophage (BMDM) inflammation model. Results show that aseptic loosening (AL) reduces the purine metabolic pathway and decreases the native expression of the metabolite adenosine. In vivo, CD73 expression was low in the bone tissue surrounding the titanium nail and synovial-like interface tissue, while in vitro experiments demonstrated that CD73 knockdown promoted titanium particles-induced aseptic inflammation. CD73 overexpression mitigated the titanium particle-mediated enhancement of LPS-induced M1 polarization while promoting the titanium particle-mediated attenuation of IL-4-induced M2 polarization. In BMDM exposed to titanium particles, CD73 promotes M2 polarization via the p38 pathway. Meanwhile, local injection of recombinant mouse CD73 protein slightly alleviated the progression of AL. Collectively, our data suggest that CD73 alleviates the process of AL, and this function is achieved by promoting alternate activation of macrophages.PMID:37451018 | DOI:10.1016/j.intimp.2023.110561

Sci Adv. 2023 Jul 14;9(28):eadg7417. doi: 10.1126/sciadv.adg7417. Epub 2023 Jul 14.ABSTRACTPressure-overloaded left ventricular remodeling in young population is progressive and readily degenerate into heart failure. The aims of this study were to identify a plasma metabolite that predicts and is mechanistically linked to the disease. Untargeted metabolomics determined elevated plasma kynurenine (Kyn) in both the patient cohorts and the mice model, which was correlated with remodeling parameters. In vitro and in vivo evidence, combined with single-nucleus RNA sequencing (snRNA-seq), demonstrated that Kyn affected both cardiomyocytes and cardiac fibroblasts by activating aryl hydrocarbon receptors (AHR) to up-regulate hypertrophy- and fibrosis-related genes. Shotgun metagenomics and fecal microbiota transplantation revealed the existence of the altered gut microbiota-Kyn relationship. Supplementation of selected microbes reconstructed the gut microbiota, reduced plasma Kyn, and alleviated ventricular remodeling. Our data collectively discovered a gut microbiota-derived metabolite to activate AHR and its gene targets in remodeling young heart, a process that could be prevented by specific gut microbiota modulation.PMID:37450589 | DOI:10.1126/sciadv.adg7417

Methods Mol Biol. 2023;2695:181-193. doi: 10.1007/978-1-0716-3346-5_12.ABSTRACTLimited knowledge has been reported regarding the performance of plasma metabolomics for predicting lung cancer prognosis. In this chapter, we compared the plasma metabolomics of lung cancer patients with differential disease-free survival (DFS, <3 years vs. >4 years) using liquid chromatography-mass spectrometry. We identified 29 survival-related aqueous metabolites but no lipid metabolites. Amino acids and organic acids constitute the majority of these metabolites. The metabolic pathways of these metabolites were cysteine and methionine metabolism and arginine biosynthesis. The Cox proportional hazards regression models confirmed the predictive values of 18 metabolites for DFS, while the phosphocholine and xanthine showed independent predictive values. Regarding cancer phenotypes, thelephoric acid, phosphocholine, inosine, 3-hydroxyanthranilic acid, hypoxanthine, xanthine, and 4-hydroxybenzoic acid showed good correction with lymph node metastasis. Taken together, plasma metabolomics is a powerful tool for identifying prognostic metabolites of lung cancer.PMID:37450119 | DOI:10.1007/978-1-0716-3346-5_12