PubMed

Pediatr Allergy Immunol. 2023 Aug;34(8):e14003. doi: 10.1111/pai.14003.ABSTRACTBACKGROUND: Mechanisms underlying persistent food allergy (FA) are not well elucidated. The intestinal mucosa is the primary exposure route of food allergens. However, no study has examined intestinal metabolites associated with FA persistence. The goal of this study was to investigate intestinal metabolites and associated microbiomes in early life that aid in determining the development and persistence of FA.METHODS: We identified metabolomic alterations in the stool of infants according to FA by mass spectrometry-based untargeted metabolome profiling. The targeted metabolomic analysis of bile acid metabolites and stool microbiome was performed. Bile acid metabolite composition in infancy was evaluated by characterizing the subjects at the age of 3 into FA remission and persistent FA.RESULTS: In untargeted metabolomics, primary bile acid biosynthesis was significantly different between subjects with FA and healthy controls. In targeted metabolomics for bile acids, intestinal bile acid metabolites synthesized by the alternative pathway were reduced in infants with FA than those in healthy controls. Subjects with persistent FA were also distinguished from healthy controls and those with FA remission by bile acid metabolites of the alternative pathway. These metabolites were negatively correlated with specific IgE levels in egg white. The abundance of intestinal Clostridia was decreased in the FA group and was correlated with ursodeoxycholic acid.CONCLUSION: Intestinal bile acid metabolites of the alternative pathway could be predictive biomarkers for persistent FA in early childhood. These findings require replication in future studies.PMID:37622258 | DOI:10.1111/pai.14003

Front Cell Infect Microbiol. 2023 Aug 9;13:1134321. doi: 10.3389/fcimb.2023.1134321. eCollection 2023.ABSTRACTBACKGROUND AND PURPOSE: Microbiome dysfunction is known to aggravate acute pancreatitis (AP); however, the relationship between this dysfunction and metabolite alterations is not fully understood. This study explored the crosstalk between the microbiome and metabolites in AP mice.METHODS: Experimental AP models were established by injecting C57/BL mice with seven doses of cerulein and one dose of lipopolysaccharide (LPS). Metagenomics and untargeted metabolomics were used to identify systemic disturbances in the microbiome and metabolites, respectively, during the progression of AP.RESULTS: The gut microbiome of AP mice primarily included Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria, and "core microbiota" characterized by an increase in Proteobacteria and a decrease in Actinobacteria. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that significantly different microbes were involved in several signaling networks. Untargeted metabolomics identified 872 metabolites, of which lipids and lipid-like molecules were the most impacted. An integrated analysis of metagenomics and metabolomics indicated that acetate kinase (ackA) gene expression was associated with various gut microbiota, including Alistipes, Butyricimonas, and Lactobacillus, and was strongly correlated with the metabolite daphnoretin. The functional gene, O-acetyl-L-serine sulfhydrylase (cysK), was associated with Alistipes, Jeotgalicoccus, and Lactobacillus, and linked to bufalin and phlorobenzophenone metabolite production.CONCLUSION: This study identified the relationship between the gut microbiome and metabolite levels during AP, especially the Lactobacillus-, Alistipes-, and Butyricimonas-associated functional genes, ackA and cysK. Expression of these genes was significantly correlated to the production of the anti-inflammatory and antitumor metabolites daphnoretin and bufalin.PMID:37621874 | PMC:PMC10446838 | DOI:10.3389/fcimb.2023.1134321

Front Microbiol. 2023 Aug 9;14:1175858. doi: 10.3389/fmicb.2023.1175858. eCollection 2023.ABSTRACTMagnesium hydride (MGH), a highly promising hydrogen-producing substance/additive for hydrogen production through its hydrolysis reaction, has the potential to enhance broiler production. However, before incorporating MGH as a hydrogen-producing additive in broiler feed, it is crucial to fully understand its impact on microbiota and metabolites. In vitro fermentation models provide a fast, reproducible, and direct assessment tool for microbiota metabolism and composition. This study aims to investigate the effects of MGH and coated-magnesium hydride (CMG) on fermentation characteristics, as well as the microbiota and metabolome in the culture of in vitro fermentation using cecal inocula from broilers. After 48 h of incubation, it was observed that the presence of MGH had a significant impact on various factors. Specifically, the content of N-NH3 decreased, while the total hydrogen gas and total SCFAs increased. Furthermore, the presence of MGH promoted the abundance of SCFA-producing bacteria such as Ruminococcus, Blautia, Coprobacillus, and Dysgonomonas. On the other hand, the presence of CMG led to an increase in the concentration of lactic acid, acetic acid, and valeric acid. Additionally, CMG affected the diversity of microbiota in the culture, resulting in an enrichment of the relative abundance of Firmicutes, as well as genera of Lactobacillus, Coprococcus, and Eubacterium. Conversely, the relative abundance of the phylum Proteobacteria and pathogenic bacteria Shigella decreased. Metabolome analysis revealed that MGH and CMG treatment caused significant changes in 21 co-regulated metabolites, primarily associated with lipid, amino acid, benzenoids, and organooxygen compounds. Importantly, joint correlation analysis revealed that MGH or CMG treatments had a direct impact on the microbiota, which in turn indirectly influenced metabolites in the culture. In summary, the results of this study suggested that both MGH and coated-MGH have similar yet distinct positive effects on the microbiota and metabolites of the broiler cecal in an in vitro fermentation model.PMID:37621394 | PMC:PMC10445219 | DOI:10.3389/fmicb.2023.1175858

Andrology. 2023 Aug 24. doi: 10.1111/andr.13515. Online ahead of print.ABSTRACTDespite its efficacy for treating androgenetic alopecia, finasteride, an inhibitor of 5α-reductase (i.e., the enzyme converting testosterone, T, into dihydrotestosterone, DHT), is associated with several side effects including sexual dysfunction (e.g., erectile dysfunction). These side effects may persist after drug suspension, inducing the so-called post-finasteride syndrome (PFS). The effects of subchronic treatment with finasteride (i.e., 20 days) and its withdrawal (i.e., 1 month) in rat corpus cavernosum have been explored here. Data obtained show that the treatment was able to decrease the levels of the enzyme 5α-reductase type II in the rat corpus cavernosum with increased T and decreased DHT levels. This local change in T metabolism was linked to mechanisms associated with erectile dysfunction. Indeed, by targeted metabolomics, we reported a decrease in the nitric oxide synthase (NOS) activity, measured by the citrulline/arginine ratio and confirmed by the decrease in NO2 levels, and a decrease in ornithine transcarbamylase (OTC) activity, measured by citrulline/ornithine ratio. Interestingly, the T levels are negatively correlated with NOS activity, while those of DHT are positively correlated with OTC activity. Finasteride treatment also induced alterations in the levels of other molecules involved in the control of penile erection, such as norepinephrine and its metabolite, epinephrine. Indeed, plasma levels of norepinephrine and epinephrine were significantly increased and decreased, respectively, suggesting an impairment of these mediators. Interestingly, these modifications were restored by suspension of the drug. Altogether, the results reported here indicate that finasteride treatment, but not its withdrawal, affects T metabolism in the rat corpus cavernosum, and this alteration was linked to mechanisms associated with erectile dysfunction. Data here reported could also suggest that the PFS sexual side effects are more related to dysfunction in a sexual central control rather than peripheral compromised condition.PMID:37621185 | DOI:10.1111/andr.13515

J Sci Food Agric. 2023 Aug 24. doi: 10.1002/jsfa.12927. Online ahead of print.ABSTRACTBACKGROUND: Amino acids (AAs) are important protein building blocks that play a critical role in the function of the immune system. However, comprehensive comparative metabolomics and antigenicity analyses of cow milk (CM) and enzymatically-treated CM are relatively scarce. Herein, we analyzed the AAs in the CM and flavourzyme-treated milk groups (FT), and their antigenicity was also explored.RESULTS: Overall, 50 AAs were detected in CM and FT, with 23 significantly different AAs. The interaction network of these significantly different AAs was analyzed, and 34 significantly different metabolic pathways were found to be involved. In addition, we found that the antigenicity of FT was significantly reduced compared to that of CM.CONCLUSION: These results enhance our understanding of AAs and antigenicity regarding CM and FT, and provide new ideas and directions for the development of high-quality hypoallergenic dairy products. This article is protected by copyright. All rights reserved.PMID:37621148 | DOI:10.1002/jsfa.12927

Virulence. 2023 Dec;14(1):2249790. doi: 10.1080/21505594.2023.2249790.ABSTRACTTranslocon pores formed in the eukaryotic cell membrane by a type III secretion system facilitate the translocation of immune-modulatory effector proteins into the host cell interior. The YopB and YopD proteins produced and secreted by pathogenic Yersinia spp. harboring a virulence plasmid-encoded type III secretion system perform this pore-forming translocator function. We had previously characterized in vitro T3SS function and in vivo pathogenicity of a number of strains encoding sited-directed point mutations in yopD. This resulted in the classification of mutants into three different classes based upon the severity of the phenotypic defects. To investigate the molecular and functional basis for these defects, we explored the effectiveness of RAW 264.7 cell line to respond to infection by representative YopD mutants of all three classes. Signature cytokine profiles could separate the different YopD mutants into distinct categories. The activation and suppression of certain cytokines that function as central innate immune response modulators correlated well with the ability of mutant bacteria to alter anti-phagocytosis and programmed cell death pathways. These analyses demonstrated that sub-optimal translocon pores impact the extent and magnitude of host cell responsiveness, and this limits the capacity of pathogenic Yersinia spp. to fortify against attack by both early and late arms of the host innate immune response.PMID:37621095 | DOI:10.1080/21505594.2023.2249790

Environ Microbiol. 2023 Aug 24. doi: 10.1111/1462-2920.16485. Online ahead of print.ABSTRACTGlaciers host ecosystems comprised of biodiverse and active microbiota. Among glacial ecosystems, less is known about the ecology of ice caps since most studies focus on valley glaciers or ice sheet margins. Previously we detailed the microbiota of one such high Arctic ice cap, focusing on cryoconite as a microbe-mineral aggregate formed by cyanobacteria. Here, we employ metabolomics at the scale of an entire ice cap to reveal the major metabolic pathways prevailing in the cryoconite of Foxfonna, central Svalbard. We reveal how geophysical and biotic processes influence the metabolomes of its resident cryoconite microbiota. We observed differences in amino acid, fatty acid, and nucleotide synthesis across the cap reflecting the influence of ice topography and the cyanobacteria within cryoconite. Ice topography influences central carbohydrate metabolism and nitrogen assimilation, whereas bacterial community structure governs lipid, nucleotide, and carotenoid biosynthesis processes. The prominence of polyamine metabolism and nitrogen assimilation highlights the importance of recycling nitrogenous nutrients. To our knowledge, this study represents the first application of metabolomics across an entire ice mass, demonstrating its utility as a tool for revealing the fundamental metabolic processes essential for sustaining life in supraglacial ecosystems experiencing profound change due to Arctic climate change-driven mass loss.PMID:37621052 | DOI:10.1111/1462-2920.16485

Cardiovasc Diabetol. 2023 Aug 24;22(1):219. doi: 10.1186/s12933-023-01942-0.ABSTRACTBACKGROUND: Clinical observations suggest a complex relationship between obesity and coronary artery disease (CAD). This study aimed to characterize the intermediate metabolism phenotypes among obese patients with CAD and without CAD.METHODS: Sixty-two participants who consecutively underwent coronary angiography were enrolled in the discovery cohort. Transcriptional and untargeted metabolomics analyses were carried out to screen for key molecular changes between obese patients with CAD (CAD obese), without CAD (Non-CAD obese), and Non-CAD leans. A targeted GC-MS metabolomics approach was used to further identify differentially expressed metabolites in the validation cohorts. Regression and receiver operator curve analysis were performed to validate the risk model.RESULTS: We found common aberrantly expressed pathways both at the transcriptional and metabolomics levels. These pathways included cysteine and methionine metabolism and arginine and proline metabolism. Untargeted metabolomics revealed that S-adenosylhomocysteine (SAH), 3-hydroxybenzoic acid, 2-hydroxyhippuric acid, nicotinuric acid, and 2-arachidonoyl glycerol were significantly elevated in the CAD obese group compared to the other two groups. In the validation study, targeted cysteine and methionine metabolomics analyses showed that homocysteine (Hcy), SAH, and choline were significantly increased in the CAD obese group compared with the Non-CAD obese group, while betaine, 5-methylpropanedioic acid, S-adenosylmethionine, 4-PA, and vitamin B2 (VB2) showed no significant differences. Multivariate analyses showed that Hcy was an independent predictor of obesity with CAD (hazard ratio 1.7; 95%CI 1.2-2.6). The area under the curve based on the Hcy metabolomic (HCY-Mtb) index was 0.819, and up to 0.877 for the HCY-Mtb.index plus clinical variables.CONCLUSION: This is the first study to propose that obesity with hyperhomocysteinemia is a useful intermediate metabolism phenotype that could be used to identify obese patients at high risk for developing CAD.PMID:37620823 | DOI:10.1186/s12933-023-01942-0

BMC Plant Biol. 2023 Aug 25;23(1):406. doi: 10.1186/s12870-023-04404-7.ABSTRACTBACKGROUND: Plants growing in the field are subjected to combinations of abiotic stresses. These conditions pose a devastating threat to crops, decreasing their yield and causing a negative economic impact on agricultural production. Metabolic responses play a key role in plant acclimation to stress and natural variation for these metabolic changes could be key for plant adaptation to fluctuating environmental conditions.RESULTS: Here we studied the metabolomic response of two Arabidopsis ecotypes (Columbia-0 [Col] and Landsberg erecta-0 [Ler]), widely used as genetic background for Arabidopsis mutant collections, subjected to the combination of high salinity and increased irradiance. Our findings demonstrate that this stress combination results in a specific metabolic response, different than that of the individual stresses. Although both ecotypes displayed reduced growth and quantum yield of photosystem II, as well as increased foliar damage and malondialdehyde accumulation, different mechanisms to tolerate the stress combination were observed. These included a relocation of amino acids and sugars to act as potential osmoprotectants, and the accumulation of different stress-protective compounds such as polyamines or secondary metabolites.CONCLUSIONS: Our findings reflect an initial identification of metabolic pathways that differentially change under stress combination that could be considered in studies of stress combination of Arabidopsis mutants that include Col or Ler as genetic backgrounds.PMID:37620776 | DOI:10.1186/s12870-023-04404-7

BMC Plant Biol. 2023 Aug 24;23(1):402. doi: 10.1186/s12870-023-04383-9.ABSTRACTBACKGROUND: Betalain is a natural pigment with important nutritional value and broad application prospects. Previously, we produced betanin biosynthesis transgenic carrots via expressing optimized genes CYP76AD1S, cDOPA5GTS and DODA1S. Betanin can accumulate throughout the whole transgenic carrots. But the effects of betanin accumulation on the metabolism of transgenic plants and whether it produces unexpected effects are still unclear.RESULTS: The accumulation of betanin in leaves can significantly improve its antioxidant capacity and induce a decrease of chlorophyll content. Transcriptome and metabolomics analysis showed that 14.0% of genes and 33.1% of metabolites were significantly different, and metabolic pathways related to photosynthesis and tyrosine metabolism were markedly altered. Combined analysis showed that phenylpropane biosynthesis pathway significantly enriched the differentially expressed genes and significantly altered metabolites.CONCLUSIONS: Results showed that the metabolic status was significantly altered between transgenic and non-transgenic carrots, especially the photosynthesis and tyrosine metabolism. The extra consumption of tyrosine and accumulation of betanin might be the leading causes.PMID:37620775 | DOI:10.1186/s12870-023-04383-9

Anal Bioanal Chem. 2023 Aug 25. doi: 10.1007/s00216-023-04910-5. Online ahead of print.ABSTRACTMetabolomics is a biochemical analysis tool for identifying metabolic phenotypes and used to reveal the pathogenic mechanisms of disease and to inform drug-targeted therapies. Carboxyl-containing metabolites (CCMs) account for an important proportion of the metabolome, but because of the diversity of physical and chemical properties of CCMs in biological samples, traditional liquid chromatography-mass spectrometry (LC-MS) targeted metabolome analysis methods cannot achieve simultaneous quantification of multiple types of CCMs. Therefore, we proposed for the first time a targeted metabolomics strategy using isoniazid derivatization combined with LC-MS/MS to simultaneously quantify 39 CCMs of 5 different types (short-chain fatty acids, amino acids, bile acids, phenylalanine and tryptophan metabolic pathway acids) with large polarity differences associated with Alzheimer's disease (AD) and significantly improve the detection coverage and sensitivity. The yields of isoniazid derivative CCMs were high and could guarantee the accuracy of CCM quantification. The LODs of CCMs increased significantly (1.25-2000-fold) after derivatization. The method showed good selectivity, intra-day and inter-day accuracies and precisions, and repeatability. There was no significant effect on the determination of CCMs in terms of matrix effect and recovery. CCMs showed good stability. And CCMs showed good stability under short-term storage and freeze-thaw cycles. At the same time, the regulatory effects of Schisandrae chinensis Fructus and Ginseng Radix et Rhizoma (SG) herb pair on CCM metabolic disorders in feces, urine, serum, and the brain of AD rats were elucidated from the perspective of targeted metabolomics. In combination with pharmacodynamic evaluation and gut microbiota analysis, the mechanism of SG herb pair on AD rats was comprehensively understood. In summary, this innovative isoniazid derivatization combined with a targeted metabolomics method has great potential for trace biological lineage analysis.PMID:37620605 | DOI:10.1007/s00216-023-04910-5

Nat Commun. 2023 Aug 24;14(1):5176. doi: 10.1038/s41467-023-40861-2.ABSTRACTIdentifying genes whose expression is associated with schizophrenia (SCZ) risk by transcriptome-wide association studies (TWAS) facilitates downstream experimental studies. Here, we integrated multiple published datasets of TWAS, gene coexpression, and differential gene expression analysis to prioritize SCZ candidate genes for functional study. Convergent evidence prioritized Propionyl-CoA Carboxylase Subunit Beta (PCCB), a nuclear-encoded mitochondrial gene, as an SCZ risk gene. However, the PCCB's contribution to SCZ risk has not been investigated before. Using dual luciferase reporter assay, we identified that SCZ-associated SNPs rs6791142 and rs35874192, two eQTL SNPs for PCCB, showed differential allelic effects on transcriptional activities. PCCB knockdown in human forebrain organoids (hFOs) followed by RNA sequencing analysis revealed dysregulation of genes enriched with multiple neuronal functions including gamma-aminobutyric acid (GABA)-ergic synapse. The metabolomic and mitochondrial function analyses confirmed the decreased GABA levels resulted from inhibited tricarboxylic acid cycle in PCCB knockdown hFOs. Multielectrode array recording analysis showed that PCCB knockdown in hFOs resulted into SCZ-related phenotypes including hyper-neuroactivities and decreased synchronization of neural network. In summary, this study utilized hFOs-based multi-omics analyses and revealed that PCCB downregulation may contribute to SCZ risk through regulating GABAergic pathways, highlighting the mitochondrial function in SCZ.PMID:37620341 | DOI:10.1038/s41467-023-40861-2

Nat Commun. 2023 Aug 24;14(1):5160. doi: 10.1038/s41467-023-40874-x.ABSTRACTThe relationship between microbiota, short chain fatty acids (SCFAs), and obesity remains enigmatic. We employ amplicon sequencing and targeted metabolomics in a large (n = 1904) African origin cohort from Ghana, South Africa, Jamaica, Seychelles, and the US. Microbiota diversity and fecal SCFAs are greatest in Ghanaians, and lowest in Americans, representing each end of the urbanization spectrum. Obesity is significantly associated with a reduction in SCFA concentration, microbial diversity, and SCFA synthesizing bacteria, with country of origin being the strongest explanatory factor. Diabetes, glucose state, hypertension, obesity, and sex can be accurately predicted from the global microbiota, but when analyzed at the level of country, predictive accuracy is only universally maintained for sex. Diabetes, glucose, and hypertension are only predictive in certain low-income countries. Our findings suggest that adiposity-related microbiota differences differ between low-to-middle-income compared to high-income countries. Further investigation is needed to determine the factors driving this association.PMID:37620311 | DOI:10.1038/s41467-023-40874-x

Chem Biol Drug Des. 2023 Aug 24. doi: 10.1111/cbdd.14329. Online ahead of print.ABSTRACTRegulation of formate flux by a key folate enzyme, MTHFD2 (methylene tetrahydrofolate dehydrogenase 2) in cancer cells remains poorly understood. Green et al. (Nature Metabolism, 2023; 5: 642-659) showed an interesting phenomenon of "folate trapping" toxicity leads to cancer cell kill using a potent inhibitor (TH9619) against the dehydrogenase and cyclohydrolase (DC) activities of cytosolic methylenetetrahydrofolate dehydrogenase 1 (cMTHFD1) and nuclear methylenetetrahydrofolate dehydrogenase 2 (nMTHFD2), but not the mitochondrial MTHFD2 (mTHFD2). But, mMTHFD2 is required for formate flow to cytosol which leads to the trapping of 10-formyl tetrahydrofolate and causes toxicity by TH9619 treatment, to kill cancer cells expressing mMTHFD2. This article opens new avenues to be evaluated for therapeutic benefits of cancer patients where MTHFD2 shows overexpression viz-a-viz breast, prostate, colorectal, acute myeloid leukemia, and other cancer types.PMID:37620162 | DOI:10.1111/cbdd.14329

J Mass Spectrom. 2023 Aug 24:e4973. doi: 10.1002/jms.4973. Online ahead of print.ABSTRACTOmics studies such as metabolomics, lipidomics, and proteomics have become important for understanding the mechanisms in living organisms. However, the compounds detected are structurally different and contain isomers, with each structure or isomer leading to a different result in terms of the role they play in the cell or tissue in the organism. Therefore, it is important to detect, characterize, and elucidate the structures of these compounds. Liquid chromatography and mass spectrometry have been utilized for decades in the structure elucidation of key compounds. While prediction models of parameters (such as retention time and fragmentation pattern) have also been developed for these separation techniques, they have some limitations. Moreover, ion mobility has become one of the most promising techniques to give a fingerprint to these compounds by determining their collision cross section (CCS) values, which reflect their shape and size. Obtaining accurate CCS enables its use as a filter for potential analyte structures. These CCS values can be measured experimentally using calibrant-independent and calibrant-dependent approaches. Identification of compounds based on experimental CCS values in untargeted analysis typically requires CCS references from standards, which are currently limited and, if available, would require a large amount of time for experimental measurements. Therefore, researchers use theoretical tools to predict CCS values for untargeted and targeted analysis. In this review, an overview of the different methods for the experimental and theoretical estimation of CCS values is given where theoretical prediction tools include computational and machine modeling type approaches. Moreover, the limitations of the current experimental and theoretical approaches and their potential mitigation methods were discussed.PMID:37620034 | DOI:10.1002/jms.4973

Plant Physiol. 2023 Aug 24:kiad471. doi: 10.1093/plphys/kiad471. Online ahead of print.ABSTRACTLipid droplets (LDs) of seed tissues are storage organelles for triacylglycerols (TAGs) that provide the energy and carbon for seedling establishment. In the major route of LD degradation (lipolysis), TAGs are mobilized by lipases. However, LDs may also be degraded via lipophagy, a type of selective autophagy, which mediates LD delivery to vacuoles or lysosomes. The exact mechanisms of LD degradation and the mobilization of their content in plants remain unresolved. Here, we provide evidence that LDs are degraded via a process morphologically resembling microlipophagy in Arabidopsis (Arabidopsis thaliana) seedlings. We observed the entry and presence of LDs in the central vacuole as well as their breakdown. Moreover, we show co-localization of AUTOPHAGY-RELATED PROTEIN 8b (ATG8b) and LDs during seed germination and localization of lipidated ATG8 (ATG8-PE) to the LD fraction. We further demonstrate that structural LD proteins from the caleosin family, CALEOSIN 1 (CLO1), CALEOSIN 2 (CLO2), and CALEOSIN 3 (CLO3), interact with ATG8 proteins and possess putative ATG8-interacting motifs (AIMs). Deletion of the AIM localized directly before the proline knot disrupts the interaction of CLO1 with ATG8b, suggesting a possible role of this region in the interaction between the two proteins. Collectively, we provide insights into LD degradation by microlipophagy in germinating seeds with a particular focus on the role of structural LD proteins in this process.PMID:37619984 | DOI:10.1093/plphys/kiad471

J Ethnopharmacol. 2023 Aug 22:117073. doi: 10.1016/j.jep.2023.117073. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Diabetic nephropathy (DN) was a major cause of end-stage renal failure and a common microvascular complication in patients with diabetes mellitus (DM). Acteoside (ACT) was the main ingredient extracted from the leaves of Rehmannia glutinosa, which had the functions of entering the lung, moisturizing the skin and relieving itching, nourishing yin and tonifying the kidney, cooling blood, and stopping bleeding. ACT had attracted worldwide interest because of its therapeutic effects on DM and its complications.AIM OF THE STUDY: To clarify the metabolic profiles and targets of ACT in db/db mice based on metabolomics and network pharmacology studies.MATERIALS AND METHODS: Db/db mice were used to observe the biochemical indices and histopathological changes in the kidney to evaluate the pharmacological effects of ACT on DN. Untargeted metabolomics studies were performed to investigate by UHPLC-LTQ-Orbitrap MS on urine, serum, and kidney samples. The key targets and pathways were analyzed by network pharmacology. For the pathways enriched by untargeted metabolomics, targeted metabolomics by UHPLC-QQQ-MS/MS was performed in kidney samples for validation. Sensitive biomarkers in kidney samples were evaluated. The effect of ACT on the improvement of DN from the perspective of metabolism of small molecules in vivo was described.RESULTS: ACT could delay the progression of DN and improve the degree of histopathological damage to the kidney. The pathways were focused on amino acid metabolism by untargeted metabolomics. Through network pharmacology analysis, the effect pathways were related to signal transduction, carbohydrate, lipid, amino acid metabolism and mainly affected the endocrine and immune systems. Amino acid metabolism was disturbed in the kidney of db/db mice, which could be callback by ACT, such as tryptophan, glutamine, cysteine, leucine, threonine, proline, phenylalanine, histidine, serine, arginine, asparagine by targeted metabolomics.CONCLUSIONS: In conclusion, this study provided strong support for ACT on DN treatment in clinics. The Rehmannia glutinosa was used fully to raise the income level of farmers economically, while achieving the social benefit of empowering rural revitalization.PMID:37619856 | DOI:10.1016/j.jep.2023.117073

J Allergy Clin Immunol. 2023 Aug 22:S0091-6749(23)01065-5. doi: 10.1016/j.jaci.2023.08.012. Online ahead of print.ABSTRACTBACKGROUND: Rising rates of peanut allergy motivate investigations of its development to inform prevention and therapy. Microbiota and the metabolites they produce shape food allergy risk.OBJECTIVE: To gain insight into gut microbiome and metabolome dynamics in the development of peanut allergy.METHODS: We performed a longitudinal, integrative study of the gut microbiome and metabolome of infants with allergy risk factors but no peanut allergy from a multi-center cohort who were followed through mid-childhood. We performed 16S rRNA sequencing, short chain fatty acid measurements, and global metabolome profiling of fecal samples at infancy and at mid-childhood.RESULTS: In this longitudinal, multi-center sample (n=122), 28.7% of infants developed peanut allergy by mid-childhood (mean age 9 years). Lower infant gut microbiome diversity was associated with peanut allergy development (P=0.014). Temporal changes in the relative abundance of specific microbiota and gut metabolite levels significantly differed in children who developed peanut allergy. Peanut allergy-bound children had different abundance trajectories of Clostridium sensu stricto 1 sp. (false discovery rate (FDR)=0.015) and Bifidobacterium sp. (FDR=0.033), with butyrate (FDR=0.045) and isovalerate (FDR=0.036) decreasing over time. Metabolites associated with peanut allergy development clustered within the histidine metabolism pathway. Positive correlations between microbiota, butyrate, and isovalerate and negative correlations with histamine marked the peanut allergy-free network.CONCLUSION: The temporal dynamics of the gut microbiome and metabolome in early childhood are distinct for children who develop peanut allergy. These findings inform our thinking on the mechanisms underlying and strategies for potentially preventing peanut allergy.PMID:37619819 | DOI:10.1016/j.jaci.2023.08.012

Transl Res. 2023 Aug 22:S1931-5244(23)00132-9. doi: 10.1016/j.trsl.2023.08.003. Online ahead of print.ABSTRACTOBJECTIVE: To reveal dysregulated metabolism hallmark that was associated with a severe acute pancreatitis (SAP) phenotype.DESIGN: In this study, LC-MS/MS-based targeted metabolomics was used to analyze plasma samples from 106 acute pancreatitis (AP) patients (34 mild, 38 moderate, and 34 severe) admitted within 48 h from abdominal pain onset and 41 healthy controls. Temporal metabolic profiling was performed on days 1, 3 and 7 after admission. A random forest (RF) was performed to significantly determine metabolite differences between SAP and non-SAP (NSAP) groups. Mass spectrometry imaging (MSI) and immunohistochemistry were conducted for the examination of pancreatic metabolite and metabolic enzyme alterations, respectively, on necrosis and paracancerous tissues. Simultaneously determination of serum and pancreatic tissue metabolic alterations using an L-ornithine-induced AP model to discover metabolic commonalities.RESULTS: Twenty-two significant differential metabolites screened by RF were selected to build an accurate model for prediction of SAP from NSAP (AUC = 0.955). Six of 22 markers were found by MSI with significant alterations in pancreatic lesion, reduced ornithine related metabolites were also identified. The abnormally expressed arginase2 and ornithine transcarboxylase were further discovered. And in combination with time-course metabolic profiling in the SAP animal models, the decreased ornithine catabolites were found at a late stage of inflammation, but ornithine-associated metabolic enzymes were activated during the inflammatory process.CONCLUSIONS: The plasma metabolome of AP patients is distinctive, which shows promise for early SAP diagnosis. AP aggravation is linked to the activated ornithine metabolic pathway and its inadequate levels of catabolites in in-situ lesion.PMID:37619665 | DOI:10.1016/j.trsl.2023.08.003

Ecotoxicol Environ Saf. 2023 Aug 22;263:115390. doi: 10.1016/j.ecoenv.2023.115390. Online ahead of print.ABSTRACTThe existing data regarding the effects of polyethylene (PE) microplastics (MPs) smaller than 5 mm in size on earthworms are insufficient to fully comprehend their toxicity. In this study, earthworms Eisenia fetida were exposed to artificially added PE at a concentration ranging from 0.05 to 20 g/kg soil (0.005%-2%) for 60 days to determine the concentration range causing negative effects on earthworms and to uncover the potential toxic mechanisms. The individual growth, reproduction, and metabolic enzyme activities, including phase I enzymes (cytochrome P450 [CYP] 1A2, 2B6, 2C9, and 3A4), and phase II metabolic enzymes (superoxide dismutase (SOD), catalase (CAT), and glutathione sulfotransferase (GST)), and metabolomics were measured. The observed variations in responses of multiple cross-scale endpoints indicated that individual indices are less responsive to PE MPs than metabolic enzymes or metabolomics. Despite the absence of significant alterations in growth inhibition based on body weight, PE MPs at concentrations equal to or exceeding 2.5 g/kg were found to exert a toxic effect on earthworms, which was evidenced by significant changes in metabolic enzyme activities (CYP1A2, 2B6, 2C9, and 3A4, SOD, CAT, and GST) and important small molecule metabolites screened based on metabolomics, likely due to the bioaccumulation of PE. The toxicity of PE MPs to earthworms is inferred to be associated with neurotoxicity, oxidative damage, decreased detoxification capacity, energy metabolism imbalance, and impaired amino acid and purine metabolism due to bioaccumulation. The findings of this study will enhance our understanding of the molecular toxicity mechanisms of PE MPs and contribute to a more accurate assessment of the ecological risks posed by PE MPs in soil.PMID:37619398 | DOI:10.1016/j.ecoenv.2023.115390