PubMed

Front Endocrinol (Lausanne). 2023 Jul 31;14:1212815. doi: 10.3389/fendo.2023.1212815. eCollection 2023.ABSTRACTINTRODUCTION: This study aimed to identify preoperative blood biomarkers related to development of delayed neurocognitive recovery (dNCR) following surgery.METHODS: A total of 67 patients (≥65 years old) who underwent head and neck tumor resection under general anesthesia were assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Preoperative serum metabolomics were determined using widely targeted metabolomics technology.RESULTS: Of the 67 patients, 25 developed dNCR and were matched to 25 randomly selected patients from the remaining 42 without dNCR. Differential metabolites were selected using the criteria of variable importance in projection > 1.0 in orthogonal partial least squares discrimination analysis, false discovery rate <0.05, and fold-change >1.2 or <0.83 to minimize false positives. Preoperative serum levels of oxaloacetate (OR: 1.054, 95% CI: 1.027-1.095, P = 0.001) and 2-aminoadipic acid (2-AAA) (OR: 1.181, 95% CI: 1.087-1.334, P = 0.001) were associated with postoperative dNCR after adjusting for anesthesia duration, education, and age. Areas under the curve for oxaloacetate and 2-AAA were 0.86 (sensitivity: 0.84, specificity: 0.88) and 0.86 (sensitivity: 0.84, specificity: 0.84), respectively. High levels of preoperative oxaloacetate and 2-AAA also were associated with postoperative decreased MoCA (β: 0.022, 95% CI: 0.005-0.04, P = 0.013 for oxaloacetate; β: 0.077, 95%CI: 0.016-0.137, P = 0.014 for 2-AAA) and MMSE (β: 0.024, 95% CI: 0.009-0.039, P = 0.002 for oxaloacetate; β: 0.083, 95% CI: 0.032-0.135, P = 0.002 for 2-AAA) scores after adjusting for age, education level, and operation time.CONCLUSION: High preoperative blood levels of oxaloacetate and 2-AAA were associated with increased risk of postoperative dNCR.CLINICAL TRIAL REGISTRATION: https://classic.clinicaltrials.gov/ct2/show/NCT05105451, identifier NCT05105451.PMID:37583434 | PMC:PMC10424917 | DOI:10.3389/fendo.2023.1212815

Magn Reson Chem. 2023 Aug 15. doi: 10.1002/mrc.5386. Online ahead of print.ABSTRACTThe quick identification of known organic low molecular weight compounds, also known as structural dereplication, is a highly important task in the chemical profiling of natural resource extracts. To that end, a method that relies on carbon-13 nuclear magnetic resonance (NMR) spectroscopy, elaborated in earlier works of the author's research group, requires the availability of a dedicated database that establishes relationships between chemical structures, biological and chemical taxonomy, and spectroscopy. The construction of such a database, called acd_lotus, was reported earlier, and its usefulness was illustrated by only three examples. This article presents the results of structure searches carried out starting from 58 carbon-13 NMR data sets recorded on compounds selected in the metabolomics section of the biological magnetic resonance bank (BMRB). Two compound retrieval methods were employed. The first one involves searching in the acd_lotus database using commercial software. The second one operates through the freely accessible web interface of the nmrshiftdb2 database, which includes the compounds present in acd_lotus and many others. The two structural dereplication methods have proved to be efficient and can be used together in a complementary way.PMID:37583258 | DOI:10.1002/mrc.5386

Endocrinol Metab (Seoul). 2023 Aug 16. doi: 10.3803/EnM.2023.1779. Online ahead of print.ABSTRACTAdrenal incidentalomas represent an increasingly common clinical conundrum with significant implications for patients. The revised 2023 European Society of Endocrinology (ESE) guideline incorporates cutting-edge evidence for managing adrenal incidentalomas. This paper provides a concise review of the updated contents of the revised guideline. In the 2023 guideline, in patients without signs and symptoms of overt Cushing's syndrome, a post-dexamethasone cortisol level above 50 nmol/L (>1.8 μg/dL) should be considered as mild autonomous cortisol secretion. Regarding the criteria of benign adrenal adenomas, a homogeneous adrenal mass with ≤10 Hounsfield units on non-contrast computed tomography requires no further follow-up, irrespective of its size. The updated guideline also discusses steroid metabolomics using tandem mass spectrometry to discriminate malignancy. It underscores the importance of high-volume surgeons performing adrenalectomy and emphasizes the pivotal role of a multidisciplinary team approach in deciding the treatment plan for indeterminate adrenal masses. The guideline advocates for more proactive surgical treatment for indeterminate adrenal masses in young patients (<40 years) and pregnant women. This review of the 2023 ESE guideline underscores the ongoing evolution of the adrenal incidentaloma management landscape, emphasizing the need for further research and adaptation of diagnostic and therapeutic strategies.PMID:37583083 | DOI:10.3803/EnM.2023.1779

Open Biol. 2023 Aug;13(8):230220. doi: 10.1098/rsob.230220. Epub 2023 Aug 16.ABSTRACTMetabolism and DNA replication are the two most fundamental biological functions in life. The catabolic branch of metabolism breaks down nutrients to produce energy and precursors used by the anabolic branch of metabolism to synthesize macromolecules. DNA replication consumes energy and precursors for faithfully copying genomes, propagating the genetic material from generation to generation. We have exquisite understanding of the mechanisms that underpin and regulate these two biological functions. However, the molecular mechanism coordinating replication to metabolism and its biological function remains mostly unknown. Understanding how and why living organisms respond to fluctuating nutritional stimuli through cell-cycle dynamic changes and reproducibly and distinctly temporalize DNA synthesis in a wide-range of growth conditions is important, with wider implications across all domains of life. After summarizing the seminal studies that founded the concept of the metabolic control of replication, we review data linking metabolism to replication from bacteria to humans. Molecular insights underpinning these links are then presented to propose that the metabolic control of replication uses signalling systems gearing metabolome homeostasis to orchestrate replication temporalization. The remarkable replication phenotypes found in mutants of this control highlight its importance in replication regulation and potentially genetic stability and tumorigenesis.PMID:37582405 | DOI:10.1098/rsob.230220

Cell Metab. 2023 Aug 11:S1550-4131(23)00271-1. doi: 10.1016/j.cmet.2023.07.012. Online ahead of print.ABSTRACTAlthough many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease.PMID:37582364 | DOI:10.1016/j.cmet.2023.07.012

Cell Death Dis. 2023 Aug 15;14(8):525. doi: 10.1038/s41419-023-06050-1.ABSTRACTMetabolism vulnerability of cisplatin resistance in BCa cells remains to be discovered, which we applied integrated multi-omics analysis to elucidate the metabolism related regulation mechanism in bladder cancer (BCa) microenvironment. Integrated multi-omics analysis of metabolomics and proteomics revealed that MAT2A regulated methionine metabolism contributes to cisplatin resistance in BCa cells. We further validated MAT2A and cancer stem cell markers were up-regulated and circARHGAP10 was down-regulated through the regulation of MAT2A protein stability in cisplatin resistant BCa cells. circARHGAP10 formed a complex with MAT2A and TRIM25 to accelerate the degradation of MAT2A through ubiquitin-proteasome pathway. Knockdown of MAT2A through overexpression of circARHGAP10 and restriction of methionine up-take was sufficient to overcome cisplatin resistance in vivo in immuno-deficiency model but not in immuno-competent model. Tumor-infiltrating CD8+ T cells characterized an exhausted phenotype in tumors with low methionine. High expression of SLC7A6 in BCa negatively correlated with expression of CD8. Synergistic inhibition of MAT2A and SLC7A6 could overcome cisplatin resistance in immuno-competent model in vivo. Cisplatin resistant BCa cells rely on methionine for survival and stem cell renewal. circARHGAP10/TRIM25/MAT2A regulation pathway plays an important role in cisplatin resistant BCa cells while circARHGAP10 and SLC7A6 should be evaluated as one of the therapeutic target of cisplatin resistant BCa.PMID:37582769 | DOI:10.1038/s41419-023-06050-1

BMC Ophthalmol. 2023 Aug 15;23(1):356. doi: 10.1186/s12886-023-03101-1.ABSTRACTBACKGROUND: To explore differential metabolites in the aqueous humor of patients with different axial lengths and their correlations with axial length and choroidal parameters.METHODS: In this study, we included 12 patients with axial lengths less than 24 mm, 11 patients with axial lengths between 24 and 26 mm, and 11 patients with axial lengths greater than 26 mm. We collected their aqueous humor samples during cataract surgery for liquid chromatography-mass spectrometry metabolomic analysis. Simultaneously, we collected relevant clinical parameters such as axial length, subfoveal choroidal thickness, and choroidal vascular index. Correlations between clinical data, differential metabolites, and clinical indicators were analyzed. In addition, we plotted receiver operating characteristic curves.RESULTS: The results showed that axial length was significantly negatively correlated with choroidal thickness (r=-0.7446, P < 0.0001), and that several differential metabolites were significantly correlated with certain clinical parameters. After analyzing receiver operating characteristic curves, 5-methoxytryptophol and cerulenin were found to have excellent discriminative power, demonstrating their potential as biomarkers. In the enrichment analysis, we found that the differential metabolites among each group were involved in several special pathways (Taurine and Hypotaurine Metabolism, Vitamin B6 Metabolism, Pantothenate, and coenzyme A Biosynthesis), suggesting that abnormalities in these metabolic pathways may play a role in the process of axial myopia.CONCLUSIONS: Our study identified alterations in certain metabolic pathways in different axial lengths. At the same time, we found several metabolites with significant correlation with clinical indicators, among which 5-methoxytryptophol and cerulenin were associated with axial myopia.CLINICAL TRIAL REGISTRATION: Registration date:11/04/2022.TRIAL REGISTRATION NUMBER: ChiCTR2200058575.TRIAL REGISTRY: The First Affiliated Hospital of the Zhejiang University School of Medicine.PMID:37582698 | DOI:10.1186/s12886-023-03101-1

Anal Chem. 2023 Aug 15. doi: 10.1021/acs.analchem.3c01221. Online ahead of print.ABSTRACTFor large-scale lipidomic analyses, accurate and reproducible quantification of endogenous lipids is crucial for comparing results within and across studies. Many lipids present in liquid chromatography-electrospray ionization-mass spectrometry form various adducts with buffer components. The mechanisms and conditions that dictate adduct formation are still poorly understood. In a positive mode, neutral lipids like mono-, di-, and triacylglycerides and cholesteryl esters typically generate [M + NH4]+ adduct ions, although [M + Na]+, [M + K]+, and other (more complex) species can also be significantly abundant in MS1 precursor ion spectra. Variations in the ratios of these adducts (within and between matrices) can lead to dramatic inaccuracies during quantification. Here, we examine 48 unique diacylglycerol (DAG) species across 2366 mouse samples for eight matrix-specific data sets of plasma, liver, kidney, brain, heart muscle, gastrocnemius muscle, gonadal, and inguinal fat. Typically, no single adduct ion species accounted for more than 60% of the total observed abundance across each data set. Even within a single matrix, DAGs showed a high variability of adduct ratios. The ratio of [M + NH4]+ adduct ions was increased for longer-chain DAGs and for polyunsaturated DAGs, at the expense of reduced ratios of [M + Na]+ adducts. When using three deuterated internal DAG standards, we found that absolute concentrations were estimated with up to 70% error when only one adduct ion was used instead of all adducts combined. Importantly, when combining [M + NH4]+ and [M + Na]+ adduct ions, quantification results were within 5% accuracy compared to all adduct ions combined. Additional variance can be caused by other factors, such as instrument conditions or matrix effects.PMID:37582244 | DOI:10.1021/acs.analchem.3c01221

Anal Chem. 2023 Aug 15. doi: 10.1021/acs.analchem.3c02478. Online ahead of print.ABSTRACTRecent efforts in our laboratory have enabled access to an unprecedented number (∼90) of quantifiable metabolites in human blood by a simple nuclear magnetic resonance (NMR) spectroscopy method, which includes energy coenzymes, redox coenzymes, and antioxidants that are fundamental to cellular functions [ J. Magn. Reson. Open 2022, 12-13, 100082]. The coenzymes and antioxidants, however, are notoriously labile and are extremely sensitive to specimen harvesting, extraction, and measurement conditions. This problem is largely underappreciated and carries the risk of grossly inaccurate measurements and incorrect study outcomes. As a part of addressing this challenge, in this study, human blood specimens were comprehensively and quantitatively investigated using 1H NMR spectroscopy. Freshly drawn human blood specimens were treated or not treated with methanol, ethanol, or a mixture of methanol and chloroform, and stored on ice or on bench, at room temperature for different time periods from 0 to 24 h, prior to storing at -80 °C. Interestingly, the labile metabolite levels were stable in blood treated with an organic solvent. However, their levels in blood in untreated samples increased or decreased by factors of up to 5 or more within 3 h. Further, surprisingly, and contrary to the current knowledge about metabolite stability, the variation of coenzyme levels was more dramatic in blood stored on ice than on bench, at room temperature. In addition, unlike the generally observed phenomenon of oxidation of redox coenzymes, reduction was observed in untreated blood. Such preanalytical dynamics of the labile metabolites potentially arises from the active cellular metabolism. From the metabolomics perspective, the massive variation of the labile metabolite levels even in blood stored on ice is alarming and stresses the critical need to immediately quench the cellular metabolism for reliable analyses. Overall, the results provide compelling evidence that warrants a paradigm shift in the sample collection protocol for blood metabolomics involving labile metabolites.PMID:37582233 | DOI:10.1021/acs.analchem.3c02478

Environ Sci Technol. 2023 Aug 15. doi: 10.1021/acs.est.3c03233. Online ahead of print.ABSTRACTLiquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) and untargeted metabolomics are increasingly used in exposome studies to study the interactions between nongenetic factors and the blood metabolome. To reliably and efficiently link detected compounds to exposures and health phenotypes in such studies, it is important to understand the variability in metabolome measures. We assessed the within- and between-subject variability of untargeted LC-HRMS measurements in 298 nonfasting human serum samples collected on two occasions from 157 subjects. Samples were collected ca. 107 (IQR: 34) days apart as part of the multicenter EXPOsOMICS Personal Exposure Monitoring study. In total, 4294 metabolic features were detected, and 184 unique compounds could be identified with high confidence. The median intraclass correlation coefficient (ICC) across all metabolic features was 0.51 (IQR: 0.29) and 0.64 (IQR: 0.25) for the 184 uniquely identified compounds. For this group, the median ICC marginally changed (0.63) when we included common confounders (age, sex, and body mass index) in the regression model. When grouping compounds by compound class, the ICC was largest among glycerophospholipids (median ICC 0.70) and steroids (0.67), and lowest for amino acids (0.61) and the O-acylcarnitine class (0.44). ICCs varied substantially within chemical classes. Our results suggest that the metabolome as measured with untargeted LC-HRMS is fairly stable (ICC > 0.5) over 100 days for more than half of the features monitored in our study, to reflect average levels across this time period. Variance across the metabolome will result in differential measurement error across the metabolome, which needs to be considered in the interpretation of metabolome results.PMID:37582220 | DOI:10.1021/acs.est.3c03233

J Virol. 2023 Aug 15:e0058623. doi: 10.1128/jvi.00586-23. Online ahead of print.ABSTRACTAfrican swine fever (ASF) is a devastating disease caused by the African swine fever virus (ASFV) that adversely affects the pig industry. The spleen is the main target organ of ASFV; however, the function of metabolites in the spleen during ASFV infection is yet to be investigated. To define the metabolic changes in the spleen after ASFV infection, untargeted and targeted metabolomics analyses of spleens from ASFV-infected pigs were conducted. Untargeted metabolomics analysis revealed 540 metabolites with significant differential levels. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that these metabolites were mainly enriched in metabolic pathways, including nucleotide metabolism, purine metabolism, arginine biosynthesis, and neuroactive ligand-receptor interaction. Moreover, 134 of 540 metabolites quantified by targeted metabolomics analysis had differential levels and were enriched in metabolic pathways such as the biosynthesis of cofactors, ABC transporters, and biosynthesis of amino acids. Furthermore, coalition analysis of untargeted and targeted metabolomics data revealed that the levels of acylcarnitines, which are intermediates of fatty acid β-oxidation, were significantly increased in ASFV-infected spleens compared with those in the uninfected spleens. Moreover, inhibiting fatty acid β-oxidation significantly reduced ASFV replication, indicating that fatty acid β-oxidation is essential for this process. To our knowledge, this is the first report presenting the metabolite profiles of ASFV-infected pigs. This study revealed a new mechanism of ASFV-mediated regulation of host metabolism. These findings provide new insights into the pathogenic mechanisms of ASFV, which will benefit the development of target drugs for ASFV replication. IMPORTANCE African swine fever virus, the only member of the Asfarviridae family, relies on hijacking host metabolism to meet the demand for self-replication. However, the change in host metabolism after African swine fever virus (ASFV) infection remains unknown. Here, we analyzed the metabolic changes in the pig spleen after ASFV infection for the first time. ASFV infection increased the levels of acylcarnitines. Inhibition of the production and metabolism of acylcarnitines inhibited ASFV replication. Acylcarnitines are the vital intermediates of fatty acid β-oxidation. This study highlights the critical role of fatty acid β-oxidation in ASFV infection, which may help identify target drugs to control African swine fever disease.PMID:37582206 | DOI:10.1128/jvi.00586-23

J Med Chem. 2023 Aug 15. doi: 10.1021/acs.jmedchem.3c00837. Online ahead of print.ABSTRACTSepsis-associated acute kidney injury (AKI) is a serious clinical problem, without effective drugs. Abnormal activation of the purinergic P2X7 receptor (P2X7R) in septic kidneys makes its antagonist a promising therapeutic approach. Herein, a series of novel P2X7R antagonists were designed, synthesized, and structurally optimized. Based on in vitro potency in human/mouse P2X7R using HEK293 cells, hepatic microsomal stability, and pharmacokinetic and preliminary in vivo assessments, compound 14a was identified by respective human and mouse P2X7R IC50 values of 64.7 and 10.1 nM, together with favorable pharmacokinetic properties. Importantly, 14a dose-dependently alleviated kidney dysfunction and pathological injury in both lipopolysaccharide (LPS)- and cecal ligation/perforation (CLP)-induced septic AKI mice with a good safety profile. Mechanistically, 14a could suppress NLRP3 inflammasome activation to inhibit the expression of cleaved caspase-1, gasdermin D, IL-1β, and IL-18 in the injured kidneys of septic mice. Collectively, these results highlighted that P2X7R antagonist 14a exerted a therapeutic potential against septic AKI.PMID:37582195 | DOI:10.1021/acs.jmedchem.3c00837

PLoS One. 2023 Aug 15;18(8):e0290051. doi: 10.1371/journal.pone.0290051. eCollection 2023.ABSTRACTTo explore the metabolomics of fatty acids and biological information of related markers in a RAW264.7 cell inflammation model. RAW264.7 macrophage inflammation model was induced by LPS, and RAW264.7 cells were treated with non-steroidal anti-inflammatory drugs (NSAIDs). The fatty acid compositions were identified by GC-MS, combined with standard product spectrum information and NIST (National Institute of Standards and Technology) database. Using chemometrics and Analysis of Variance (ANOVA), the components with VIP > 1 and P < 0.05 were selected as significant difference markers, and combined with biological methods to explore the biological significance of them. GC-MS identified 21 fatty acids in RAW264.7 cells, and screened significant difference biomarkers in each group. Among these biomarkers, C20:5 and C22:6 had significant changes in pairwise comparison among each group. Through ELISA, polymerase chain reaction (PCR) and Western Blot methods, the mRNA and protein expressions of IL-1β, NLRP3, GPR120 and β-Arrestin-2 were up-regulated after RAW264.7 cells induced by LPS and nigericin, and decreased after drug intervention. It indicated that the signal pathway centered on NLRP3 inflammasome was involved in the anti-inflammatory process of ibuprofen. It was the first time to study fatty acid metabolomics in RAW264.7 cell inflammatory model by GC-MS combined with chemometrics. The anti-inflammatory mechanism of ibuprofen was explained from NLRP3 inflammasome perspective without precedent, which enriched the research on the signal pathway of ibuprofen anti-inflammatory mechanism.PMID:37582087 | DOI:10.1371/journal.pone.0290051

JCI Insight. 2023 Aug 15:e169308. doi: 10.1172/jci.insight.169308. Online ahead of print.ABSTRACTGlutaminolysis is a hallmark of the activation and metabolic reprogramming of T cells. Isotopic tracer analyses of antigen-activated effector CD8+ T cells revealed that glutamine is the principal carbon source for the biosynthesis of polyamines putrescine, spermidine and spermine. These metabolites play critical roles in activation-induced T-cell proliferation, as well as for the production of hypusine, which is derived from spermidine and is covalently linked to the translation elongation factor eIF5A. Here, we demonstrated that the glutamine-polyamine-hypusine axis controls the expression of CD69, an important regulator of tissue resident memory T cells (TRM). Inhibition of this circuit augmented the development of TRM cells ex vivo and in vivo in the bone marrow, a well-established niche for TRM cells. Furthermore, blocking the polyamine-hypusine axis augmented CD69 expression and IFN-γ and TNF-α production in human CD8+ T cells from peripheral blood and sarcoma tumor infiltrating lymphocytes, as well as in human CD8+ CAR-T cells. Collectively, these findings support the notion that the polyamine-hypusine circuit can be exploited to modulate TRM cells for therapeutic benefit.PMID:37581943 | DOI:10.1172/jci.insight.169308

JMIR Res Protoc. 2023 Aug 15;12:e48014. doi: 10.2196/48014.ABSTRACTBACKGROUND: Fungal-bacterial cocolonization and coinfections pose an emerging challenge among patients suspected of having pulmonary tuberculosis (PTB); however, the underlying pathogenic mechanisms and microbiome interactions are poorly understood. Understanding how environmental microbes, such as fungi and bacteria, coevolve and develop traits to evade host immune responses and resist treatment is critical to controlling opportunistic pulmonary fungal coinfections. In this project, we propose to study the coexistence of fungal and bacterial microbial communities during chronic pulmonary diseases, with a keen interest in underpinning fungal etiological evolution and the predominating interactions that may exist between fungi and bacteria.OBJECTIVE: This is a protocol for a study aimed at investigating the metabolic and molecular ecological evolution of opportunistic pulmonary fungal coinfections through determining and characterizing the burden, etiological profiles, microbial communities, and interactions established between fungi and bacteria as implicated among patients with presumptive PTB.METHODS: This will be a laboratory-based cross-sectional study, with a sample size of 406 participants. From each participant, 2 sputa samples (one on-spot and one early morning) will be collected. These samples will then be analyzed for both fungal and bacterial etiology using conventional metabolic and molecular (intergenic transcribed spacer and 16S ribosomal DNA-based polymerase chain reaction) approaches. We will also attempt to design a genome-scale metabolic model for pulmonary microbial communities to analyze the composition of the entire microbiome (ie, fungi and bacteria) and investigate host-microbial interactions under different patient conditions. This analysis will be based on the interplays of genes (identified by metagenomics) and inferred from amplicon data and metabolites (identified by metabolomics) by analyzing the full data set and using specific computational tools. We will also collect baseline data, including demographic and clinical history, using a patient-reported questionnaire. Altogether, this approach will contribute to a diagnostic-based observational study. The primary outcome will be the overall fungal and bacterial diagnostic profile of the study participants. Other diagnostic factors associated with the etiological profile, such as incidence and prevalence, will also be analyzed using univariate and multivariate schemes. Odds ratios with 95% CIs will be presented with a statistical significance set at P<.05.RESULTS: The study has been approved by the Mbarara University Research Ethic Committee (MUREC1/7-07/09/20) and the Uganda National Council of Science and Technology (HS1233ES). Following careful scrutiny, the protocol was designed to enable patient enrollment, which began in March 2022 at Mbarara University Teaching Hospital. Data collection is ongoing and is expected to be completed by August 2023, and manuscripts will be submitted for publication thereafter.CONCLUSIONS: Through this protocol, we will explore the metabolic and molecular ecological evolution of opportunistic pulmonary fungal coinfections among patients with presumptive PTB. Establishing key fungal-bacterial cross-kingdom synergistic relationships is crucial for instituting fungal bacterial coinfecting etiology.TRIAL REGISTRATION: ISRCTN Registry ISRCTN33572982; https://tinyurl.com/caa2nw69.INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48014.PMID:37581914 | DOI:10.2196/48014

Amino Acids. 2023 Aug 15. doi: 10.1007/s00726-023-03311-3. Online ahead of print.ABSTRACTGut-derived neuroactive metabolites from amino acids perform a broad range of physiological roles in the body. However, the interaction between microbiota and epithelium in the metabolism of amino acids with neuroactive properties remains unclear in the colon of piglets. To investigate the microbial and epithelial metabolism, metagenomics and mucosal metabolomics were performed using colonic samples from 12 ileum-canulated piglets subjected to a 25-day infusion with saline or antibiotics. We categorized 23 metabolites derived from the metabolism of tryptophan, glutamate, and tyrosine, known as precursors of neuroactive metabolites. Microbial enzymes involved in the kynurenine synthesis via arylformamidase, 4-aminobutyric acid (GABA) synthesis via putrescine aminotransferase, and tyramine synthesis via tyrosine decarboxylase were identified in Clostridiales bacterium, uncultured Blautia sp., and Methanobrevibacter wolinii, respectively. Antibiotics significantly affected the microbiota involved in tryptophan-kynurenine and glutamate-GABA metabolism. An increase in the relative abundance of putrescine aminotransferase and Blautia sp. correlated positively with an increase in luminal GABA concentration. Overall, our findings provide new insights into the microbial ability to metabolize key amino acids that are precursors of neuroactive metabolites.PMID:37581868 | DOI:10.1007/s00726-023-03311-3

Environ Sci Technol. 2023 Aug 15. doi: 10.1021/acs.est.3c01922. Online ahead of print.ABSTRACTAs a heterogeneous reproductive disorder, polycystic ovary syndrome (PCOS) can be caused by genetic, diet, and environmental factors. Bisphenol A (BPA) can induce PCOS and nonalcoholic fatty liver disease (NAFLD) due to direct exposure; however, whether these phenotypes persist in future unexposed generations is not currently understood. In a previous study, we observed that transgenerational NAFLD persisted in female medaka for five generations (F4) after exposure to an environmentally relevant concentration (10 μg/L) of BPA. Here, we demonstrate PCOS in the same F4 generation female medaka that developed NAFLD. The ovaries contained immature follicles, restricted follicular progression, and degenerated follicles, which are characteristics of PCOS. Untargeted metabolomic analysis revealed 17 biomarkers in the ovary of BPA lineage fish, whereas transcriptomic analysis revealed 292 genes abnormally expressed, which were similar to human patients with PCOS. Metabolomic-transcriptomic joint pathway analysis revealed activation of the cancerous pathway, arginine-proline metabolism, insulin signaling, AMPK, and HOTAIR regulatory pathways, as well as upstream regulators esr1 and tgf signaling in the ovary. The present results suggest that ancestral BPA exposure can lead to PCOS phenotypes in the subsequent unexposed generations and warrant further investigations into potential health risks in future generations caused by initial exposure to EDCs.PMID:37581432 | DOI:10.1021/acs.est.3c01922

Mol Omics. 2023 Aug 15. doi: 10.1039/d3mo00110e. Online ahead of print.ABSTRACTMicrobial biostimulants have emerged as a sustainable alternative to increase the productivity and quality of important crops. Despite this, the effects of the treatment on plant metabolism are poorly understood. Thus, this study investigated the metabolic response of common bean (Phaseolus vulgaris) related to the treatment with a biostimulant obtained from the extract of Corynebacterium glutamicum that showed positive effects on the development, growth, and yield of crops previously. By untargeted metabolomic analysis using UHPLC-MS/MS, plants and seeds were subjected to treatment with the biostimulant. Under ideal growth conditions, the plants treated exhibited higher concentration levels of glutamic acid, nicotiflorin and glycosylated lipids derived from linolenic acid. The foliar application of the biostimulant under water stress conditions increased the chlorophyll content by 17% and induced the accumulation of flavonols, mainly quercetin derivatives. Also, germination seed assays exhibited longer radicle lengths for seeds treated compared to the untreated control even in the absence of light (13-18% increase, p-value <0.05). Metabolomic analysis of the seeds indicated changes in concentration levels of amino acids (tryptophan, phenylalanine, tyrosine, glutamine, and arginine) and their derivatives. The results point out the enhancement of abiotic stress tolerance and the metabolic processes triggered in this crop associated with the treatment with the biostimulant, giving the first insights into stress tolerance mechanisms in P. vulgaris.PMID:37581345 | DOI:10.1039/d3mo00110e

Pak J Pharm Sci. 2023 May;36(3):801-809.ABSTRACTBased on metabolomics, to study the mechanism of Radix Wikstroemia indica (RWI) "Sweat soaking method" processing detoxification. The raw drug group and processed products was given raw RWI and processed RWI respectively by gavage. The control group was given the same amount of 1% sodium carboxy methyl cellulose distilled water by gavage. After 7 days of continuous gavage, blood samples were collected. The blood samples of rats in each group were analyzed by 1H-NMR technology to explore the changes of endogenous metabolism and the possible metabolic pathways to rats before and after processing. Compared with the control group, the raw RWI could significantly reduce 16 metabolites and increase 10 metabolites. The processed RWI can increase the levels of most metabolites that decrease to the raw RWI, such as 13 metabolites such as alanine, L-glutamine, L-valine, L-serine, betaine and glutamic acid; At the same time, the metabolites that increased in the level of crude products were down-regulated, such as asparagine, lactic acid, 2-hydroxyisobutyric acid, sucrose, glucose and D-glucose. Compared with raw products, RWI treated with "Sweat soaking method" can reversely regulate or reduce amino acid, choline metabolism, energy and carbohydrate metabolism, thereby reducing hepatotoxicity and nephrotoxicity.PMID:37580929

Methods Mol Biol. 2023;2712:149-156. doi: 10.1007/978-1-0716-3433-2_13.ABSTRACTFerroptosis is a form of regulated cell death that occurs due to abnormal lipid metabolism. Lipids, which have been identified in over 45,000 different molecular species, play essential roles in modulating basic life processes. The process of ferroptosis is highly reliant on various lipid species, with polyunsaturated fatty acids (PUFAs) playing a central role in driving this process. Recent advances in mass spectrometry-based lipidomics have led to a surge in studies on ferroptosis. To explore the mechanism of lipid homeostasis in ferroptosis, the development of lipidomics techniques is critical. Currently, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS) are the most widely used analytical techniques in lipidomics. These techniques offer deeper insights into the complex lipid mechanisms that underlie ferroptosis.PMID:37578703 | DOI:10.1007/978-1-0716-3433-2_13