PubMed

J Sci Food Agric. 2022 Nov 8. doi: 10.1002/jsfa.12321. Online ahead of print.ABSTRACTBACKGROUND: Fermented capsicum (i.e., pickled pepper) is one of the most popular fermented vegetables. However, the effect of inoculated microbial fermentation on pickled pepper was not yet fully understood.RESULTS: Cyberlindnera rhodanensis J52 with a rich ester flavour and P. pentosaceus AL with a strong inhibitory effect on foodborne pathogenic bacteria were selected to prepare single- and double-strain fermented capsicum under low salt (<10 g L-1 NaCl) conditions. The inhibition zone of P. pentosaceus AL against Escherichia coli was up to 44 mm in diameter. Biochemical indicator analyses found that co-fermentation of P. pentosaceus AL and C. rhodanensis J52 changed the contents of vitamin C and short-chain fatty acids. Analysis of microbial diversity and volatile metabolome showed that 125 microbial species and 72 volatile compounds were detected, and P. pentosaceus was the dominant bacterium that inhibited the growth of other bacteria, while C. rhodanensis was the fungus that contributed the most to flavour. Correlation analysis between microorganisms and flavour compounds showed 725 correlations, and 124 microbial species may have participated in the formation of 69 compounds. Furthermore, 10 and 29 correlations were detected between P. pentosaceus AL or C. rhodanensis J52 and flavour compounds, respectively. Among them, 3-methyl-1-butanol acetate is speculated to be the main substance affecting the flavour of fermented capsicum by inoculation with C. rhodanensis J52.CONCLUSION: The inoculation of P. pentosaceus and C. rhodanensis had a significant impact on the microbial community and volatile compounds of fermented capsicum and helped to improve its organoleptic qualities. This article is protected by copyright. All rights reserved.PMID:36349455 | DOI:10.1002/jsfa.12321

Oral Dis. 2022 Nov 8. doi: 10.1111/odi.14432. Online ahead of print.ABSTRACTOBJECTIVE: Tumor cells can acquire a large amount of energy and structural components by reprogramming energy metabolism; moreover, metabolic profiles slightly differ according to cancer type. This study compared and assessed the metabolic profile of head and neck squamous cell carcinoma (HNSCC) and normal tissues, which were collected from patients without cancer.SUBJECTS AND METHODS: Overall, 23 patients with HNSCC and 6 patients without cancer were included in the analysis. Metabolomic profiles were analyzed using capillary electrophoresis-mass spectrometry. Gene expression was evaluated using real-time reverse transcription-polymerase chain reaction.RESULTS: Glycolysis, the pentose phosphate pathway, tricarboxylic acid cycle, and glutamine metabolism were upregulated in HNSCC tissues based on gene expression analysis. HNSCC could then have enhanced energy production and structural component. The levels of lactate, succinate, glutathione, 2-hydroxyglutarate, and S-adenosylmethionine, considered as oncometabolites, increased and these had accumulated in HNSCC tissues.CONCLUSIONS: The level of metabolites and the expression of enzymes differ between HNSCC and normal tissues. Reprogramming metabolism in HNSCC provides an energy source as well as structural components, creating a system that offers rapid proliferation, progression, and is less likely to be eliminated.PMID:36349421 | DOI:10.1111/odi.14432

Drug Des Devel Ther. 2022 Nov 2;16:3805-3816. doi: 10.2147/DDDT.S379335. eCollection 2022.ABSTRACTPURPOSE: The prevalence of hyperlipidemia and related illnesses is on its rise, and atorvastatin is the frequently used hypolipidemic agent. However, there is still uncertainty about the mechanisms, especially the relationship between the lipid-lowering effect, intestinal microbiome, and metabolic profiles. We aim to intensively explain the mechanism of the hypolipidemic effect of atorvastatin through multi-omics perspective of intestinal microbiome and metabolomics.METHODS: Multi-omics methods play an increasingly important role in the analysis of intestinal triggers and evaluation of metabolic disorders such as obesity, hyperlipidemia, and diabetes. Therefore, we were prompted to explore intestinal triggers, underlying biomarkers, and potential intervention targets of atorvastatin in the treatment of dyslipidemia through multi-omics. To achieve this, SPF Wistar rats were fed a high-fat diet or normal diet for 8 weeks. Atorvastatin was then administered to high-fat diet-fed rats.RESULTS: By altering intestinal microbiome, a high-fat diet can affect feces and plasma metabolic profiles. Treatment with atorvastatin possibly increases the abundance of Bacteroides, thereby improving "propanoate metabolism" and "glycine, serine and threonine metabolism" in feces and plasma, and contributing to blood lipid reduction.CONCLUSION: Our study elucidated the intestinal triggers and metabolites of high-fat diet-induced dyslipidemia from the perspective of intestinal microbiome and metabolomics. It equally identified potential intervention targets of atorvastatin. This further explains the mechanism of the hypolipidemic effect of atorvastatin from a multi-omics perspective.PMID:36349306 | PMC:PMC9637332 | DOI:10.2147/DDDT.S379335

FASEB Bioadv. 2022 Sep 17;4(11):709-723. doi: 10.1096/fba.2022-00073. eCollection 2022 Nov.ABSTRACTIn solid organs, cells of the same "type" can vary in their molecular phenotype. The basis of this state variation is being revealed by characterizing cell features including the expression pattern of mRNAs and the internal distribution of proteins. Here, the variability of metabolic state between cells is probed by enzyme activity profiling. We study individual cells of types that can be identified during the post-mitotic phase of oogenesis in Xenopus laevis. Whole-cell homogenates of isolated oocytes are used for kinetic analysis of enzymes, with a focus on the initial reaction rate. For each oocyte type studied, the activity signatures of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and malate dehydrogenase 1 (MDH1) vary more between the homogenates of single oocytes than between repeat samplings of control homogenates. Unexpectedly, the activity signatures of GAPDH and MDH1 strongly co-vary between oocytes of each type and change in strength of correlation during oogenesis. Therefore, variability of the kinetic behavior of these housekeeping enzymes between "identical" cells is physiologically programmed. Based on these findings, we propose that single-cell profiling of enzyme kinetics will improve understanding of how metabolic state heterogeneity is related to heterogeneity revealed by omics methods including proteomics, epigenomics, and metabolomics.PMID:36349298 | PMC:PMC9635011 | DOI:10.1096/fba.2022-00073

Food Sci Nutr. 2022 Jul 15;10(11):3814-3827. doi: 10.1002/fsn3.2978. eCollection 2022 Nov.ABSTRACTAging is closely related to altered gut function and its microbiome composition. To elucidate the mechanisms involved in the preventive effect of special high-docosahexaenoic acid tuna oil (HDTO) on senescence, the effects of different doses of HDTO on the gut microbiome and metabolome of d-galactose-induced aging mice were studied. Deferribacteres and Tenericutes and uridine might be used as indicator bacteria and characteristic metabolites to identify aging, respectively. HDTO markedly improved the impaired memory and antioxidant abilities induced by d-galactose. At the phylum level, the abundance of Firmicutes and Tenericutes was significantly increased upon d-galactose induction, while that of Bacteroidetes, Proteobacteria, and Deferribacteres was significantly decreased. At the genus level, the variation mainly presented as an increase in the abundance of the Firmicutes genera Ligilactobacillus, Lactobacillus, and Erysipelothrix, the decrease in the abundance of the Bacteroidetes genera Bacteroides and Alistipes, the Firmicutes genus Dielma, and the Deferribacteres genus Mucispirillum. HDTO supplementation reversed the alterations in the intestinal flora by promoting the proliferation of beneficial flora during the aging process; the metabolic pathways, such as glycine-serine-threonine metabolism, valine-leucine-isoleucine biosynthesis, and some metabolic pathways involved in uridine, were also partially restored. Furthermore, the correlation analysis illustrated an obvious correlation between gut microbiota, its metabolites, and aging-related indices. Moreover, it is worth noting that the metabolic regulation by dietary intervention varied with different HDTO doses and did not present a simple additive effect; indeed, each dose showed a unique modulation mechanism.PMID:36348794 | PMC:PMC9632196 | DOI:10.1002/fsn3.2978

Food Sci Nutr. 2022 Aug 24;10(11):3993-4002. doi: 10.1002/fsn3.2995. eCollection 2022 Nov.ABSTRACTAspergillus section Flavi constitutes several species of opportunistic fungi, notable among them are A. flavus and A. parasiticus, capable of surviving harsh conditions and colonizing a wide range of agricultural products pre- and postharvest. Physical and chemical control methods are widely applied in order to mitigate the invasion of A. flavus in crops. However, physical control is not suitable for large scale and chemical control often leads to environmental pollution, whereas biological control offers a safer, environmentally friendly, and economical alternative. The present study aimed to investigate the antagonism of several non-aflatoxigenic A. flavus strains against the aflatoxigenic ones in vitro (semisynthetic peanut growth medium; MPA) in terms of colony growth rate and AFB1 inhibition. Different peanut concentrations were used to obtain the optimum peanut concentration in the formulated growth medium. A dual culture assay was performed to assess the antagonism of nonaflatoxigenic strains against the aflatoxigenic ones. Results revealed that 9% MPA exhibited the highest growth and AFB1 inhibition by nonaflatoxigenic strains. It was also found that different nonaflatoxigenic strains exhibited different antagonism against the aflatoxigenic ones which ranged from 11.09 ± 0.65% to 14.06 ± 0.14% for growth inhibition, and 53.97 ± 2.46% to 72.64 ± 4.54% for AFB1 inhibition. This variability could be due to the difference in antagonistic metabolites produced by different nonaflatoxigenic strains assessed in the present study. Metabolomics study to ascertain the specific metabolites that conferred the growth and aflatoxin inhibition is ongoing.PMID:36348788 | PMC:PMC9632215 | DOI:10.1002/fsn3.2995

BMC Genomics. 2022 Nov 9;23(1):739. doi: 10.1186/s12864-022-08947-1.ABSTRACTHere we respond to Zhou (BMC Genomics 21:734, 2020) "Combined Transcriptome and Metabolome analysis of Pitaya fruit unveiled the mechanisms underlying peel and pulp color formation" published in BMC Genomics. Given the evolutionary conserved anthocyanin biosynthesis pathway in betalain-pigmented species, we are open to the idea that species with both anthocyanins and betalains might exist. However, in absence of LC-MS/MS spectra, apparent lack of biological replicates, and no comparison to authentic standards, the findings of Zhou (BMC Genomics 21:734, 2020) are not a strong basis to propose the presence of anthocyanins in betalain-pigmented pitaya. In addition, our re-analysis of the datasets indicates the misidentification of important genes and the omission of key flavonoid and anthocyanin synthesis genes ANS and DFR. Finally, our re-analysis of the RNA-Seq dataset reveals no correlation between anthocyanin biosynthesis gene expression and pigment status.PMID:36348495 | DOI:10.1186/s12864-022-08947-1

Exp Hematol Oncol. 2022 Nov 8;11(1):88. doi: 10.1186/s40164-022-00334-6.ABSTRACTBACKGROUND: Accumulating evidence implicates that gut fungi are associated with the pathogenesis of colorectal cancer (CRC). Our previous study has revealed that Candida tropicalis (C. tropicalis) promotes colorectal tumorigenesis by enhancing immunosuppressive function of myeloid-derived suppressor cells (MDSCs) and increasing accumulation of MDSCs, but the underlying mechanisms remain unestablished.METHODS: Bone marrow-derived MDSCs were stimulated with C. tropicalis. RNA-sequencing analysis was performed to screen the differentially expressed genes. Quantitative real-time PCR and western blot were used to measure the expression of related proteins. Co-culture assay of MDSCs and CD8+ T cells was used to determine the immunosuppressive ability of MDSCs. Metabolomic analysis was conducted to detect metabolic reprogramming of MDSCs. Aerobic glycolysis of MDSCs was assessed by extracellular acidification rate (ECAR), glucose consumption and lactate production. A CAC mouse model was induced by AOM and DSS to determine the therapeutic action of TEPP-46. IHC and immunofluorescence were performed to examine the expression of PKM2, PKM2 (p-Y105) and iNOS in human CRC-infiltrated MDSCs.RESULTS: C. tropicalis facilitates immunosuppressive function of MDSCs by increasing the expression of iNOS, COX2 and NOX2, production of nitric oxide (NO) and reactive oxygen species (ROS). Mechanistically, C. tropicalis facilitates the immunosuppressive function of MDSCs through the C-type lectin receptors Dectin-3 and Syk. C. tropicalis-enhanced immunosuppressive function of MDSCs is further dependent on aerobic glycolysis. On the one hand, NO produced by MDSCs enhanced aerobic glycolysis in a positive feedback manner. On the other hand, C. tropicalis promotes p-Syk binding to PKM2, which results in PKM2 Tyr105 phosphorylation and PKM2 nuclear translocation in MDSCs. Nuclear PKM2 interacts with HIF-1α and subsequently upregulates the expression of HIF-1α target genes encoding glycolytic enzymes, GLUT1, HK2, PKM2, LDHA and PDK1, which are required for the C. tropicalis-induced aerobic glycolysis of MDSCs. Blockade of PKM2 nuclear translocation attenuates C. tropicalis-mediated colorectal tumorigenesis. The high expression of PKM2, PKM2 (p-Y105) and iNOS in CRC-infiltrated MDSCs correlates with the development of human CRC.CONCLUSION: C. tropicalis enhances immunosuppressive function of MDSCs via Syk-PKM2-HIF-1α-glycolysis signaling axis, which drives CRC. Therefore, we identify the Syk-PKM2-HIF-1α-glycolysis signaling axis as a potential therapeutic target for CRC.PMID:36348389 | DOI:10.1186/s40164-022-00334-6

J Neurovirol. 2022 Nov 8. doi: 10.1007/s13365-022-01102-2. Online ahead of print.ABSTRACTThis study sought to identify neuroimaging and immunological factors associated with substance use and that contribute to neurocognitive impairment (NCI) in people with HIV (PWH). We performed cross-sectional immunological phenotyping, neuroimaging, and neurocognitive testing on virally suppressed PWH in four substance groups: cocaine only users (COC), marijuana only users (MJ), dual users (Dual), and Non-users. Participants completed substance use assessments, multimodal MRI brain scan, neuropsychological testing, and blood and CSF sampling. We employed a two-stage analysis of 305 possible biomarkers of cognitive function associated with substance use. Feature reduction (Kruskal Wallis p-value < 0.05) identified 53 biomarkers associated with substance use (22 MRI and 31 immunological) for model inclusion along with clinical and demographic variables. We employed eXtreme Gradient Boosting (XGBoost) with these markers to predict cognitive function (global T-score). SHapley Additive exPlanations (SHAP) values were calculated to rank features for impact on model output and NCI. Participants were 110 PWH with sustained HIV viral suppression (33 MJ, 12 COC, 22 Dual, and 43 Non-users). The ten highest ranking biomarkers for predicting global T-score were 4 neuroimaging biomarkers including functional connectivity, gray matter volume, and white matter integrity; 5 soluble biomarkers (plasma glycine, alanine, lyso-phosphatidylcholine (lysoPC) aC17.0, hydroxy-sphingomyelin (SM.OH) C14.1, and phosphatidylcholinediacyl (PC aa) C28.1); and 1 clinical variable (nadir CD4 count). The results of our machine learning model suggest that substance use may indirectly contribute to NCI in PWH through both metabolomic and neuropathological mechanisms.PMID:36348233 | DOI:10.1007/s13365-022-01102-2

Cell Mol Life Sci. 2022 Nov 8;79(12):585. doi: 10.1007/s00018-022-04614-6.ABSTRACTAlzheimer's disease (AD) is the most common neurodegenerative disorders presenting with the pathological hallmarks of amyloid plaques and tau tangles. Over the past few years, great efforts have been made to explore reliable biomarkers of AD. High-throughput omics are a technology driven by multiple levels of unbiased data to detect the complex etiology of AD, and it provides us with new opportunities to better understand the pathophysiology of AD and thereby identify potential biomarkers. Through revealing the interaction networks between different molecular levels, the ultimate goal of multi-omics is to improve the diagnosis and treatment of AD. In this review, based on the current AD pathology and the current status of AD diagnostic biomarkers, we summarize how genomics, transcriptomics, proteomics and metabolomics are all conducing to the discovery of reliable AD biomarkers that could be developed and used in clinical AD management.PMID:36348101 | DOI:10.1007/s00018-022-04614-6

Plant Cell Rep. 2022 Nov 8. doi: 10.1007/s00299-022-02947-x. Online ahead of print.ABSTRACTInoculation of wheat seedling with Bacillus sp. wp-6 changed amino acid metabolism and flavonoid synthesis and promoted plant growth. Plant growth-promoting rhizobacteria (PGPR), which can reduce the use of agrochemicals, is vital for the development of sustainable agriculture. In this study, proteomics and metabolomics analyses were performed to investigate the effects of inoculation with a PGPR, Bacillus sp. wp-6, on wheat (Triticum aestivum L.) seedling growth. The results showed that inoculation with Bacillus sp. wp-6 increased shoot and root fresh weights by 19% and 18%, respectively, after 40 days. The expression levels of alpha-linolenic acid metabolism-related proteins and metabolites (lipoxygenase 2, allene oxide synthase 2, jasmonic acid, 17-hydroxylinolenic acid) and flavonoid biosynthesis-related proteins and metabolites (chalcone synthase 2 and PHC 4'-O-glucoside) were up-regulated. In addition, the expression levels of amino acid metabolism-related proteins (NADH-dependent glutamate synthase, bifunctional aspartokinase/homoserine, anthranilate synthase alpha subunit 1, and 3-phosphoshikimate 1-carboxyvinyltransferase) and metabolites (L-aspartate, L-arginine, and S-glutathionyl-L-cysteine) were also significantly up-regulated. Among them, NADH-dependent glutamate synthase and bifunctional aspartokinase/homoserine could act as regulators of nitrogen metabolism. Overall, inoculation of wheat with Bacillus sp. wp-6 altered alpha-linolenic acid metabolism, amino acid metabolism, and flavonoid synthesis and promoted wheat seedling growth. This study will deepen our understanding of the mechanism by which Bacillus sp. wp-6 promotes wheat growth using proteomics and metabolomics.PMID:36348065 | DOI:10.1007/s00299-022-02947-x

Sci Rep. 2022 Nov 8;12(1):19026. doi: 10.1038/s41598-022-23750-4.ABSTRACTKruppel like factor 15 (KLF15), a transcriptional factor belonging to the Kruppel-like factor (KLF) family of genes, has recently been reported as a tumor suppressor gene in breast cancer. However, the specific mechanisms by which KLF15 inhibits BrCa have not been elucidated. Here we investigated the role and mechanism of KLF15 in triple-negative breast cancer (TNBC). KLF15 expression and methylation were detected by RT-qPCR, RT-PCR and methylation-specific PCR in breast cancer cell lines and tissues. The effects of KLF15 on TNBC cell functions were examined via various cellular function assays. The specific anti-tumor mechanisms of KLF15 were further investigated by RNA sequence, RT-qPCR, Western blotting, luciferase assay, ChIP, and bioinformatics analysis. As the results showed that KLF15 is significantly downregulated in breast cancer cell lines and tissues, which promoter methylation of KLF15 partially contributes to. Exogenous expression of KLF15 induced apoptosis and G2/M phase cell cycle arrest, suppressed cell proliferation, metastasis and in vivo tumorigenesis of TNBC cells. Mechanism studies revealed that KLF15 targeted and downregulated C-C motif chemokine ligand 2 (CCL2) and CCL7. Moreover, transcriptome and metabolome analysis revealed that KLF15 is involved in key anti-tumor regulatory and metabolic pathways in TNBC. In conclusion, KLF15 suppresses cell growth and metastasis in TNBC by downregulating CCL2 and CCL7. KLF15 may be a prognostic biomarker in TNBC.PMID:36347994 | DOI:10.1038/s41598-022-23750-4

Nat Biotechnol. 2022 Nov 8. doi: 10.1038/s41587-022-01553-2. Online ahead of print.NO ABSTRACTPMID:36347976 | DOI:10.1038/s41587-022-01553-2

Br J Cancer. 2022 Nov 8. doi: 10.1038/s41416-022-02040-w. Online ahead of print.ABSTRACTBACKGROUND: Naturally occurring germline gene deletions (KO) represent a unique setting to interrogate gene functions. Complete deletions and differential expression of the human glycosyltransferase UGT2B17 and UGT2B28 genes are linked to prostate cancer (PCa) risk and progression, leukaemia, autoimmune and other diseases.METHODS: The systemic metabolic consequences of UGT deficiencies were examined using untargeted and targeted mass spectrometry-based metabolomics profiling of carefully matched, treatment-naive PCa cases.RESULTS: Each UGT KO differentially affected over 5% of the 1545 measured metabolites, with divergent metabolic perturbations influencing the same pathways. Several of the perturbed metabolites are known to promote PCa growth, invasion and metastasis, including steroids, ceramides and kynurenine. In UGT2B17 KO, reduced levels of inactive steroid-glucuronides were compensated by sulfated derivatives that constitute circulating steroid reservoirs. UGT2B28 KO presented remarkably lower levels of oxylipins paralleled by reduced inflammatory mediators, but higher ceramides unveiled as substrates of the enzyme in PCa cells.CONCLUSION: The distinctive and broad metabolic rewiring caused by UGT KO reinforces the need to examine their unique and divergent functions in PCa biology.PMID:36347965 | DOI:10.1038/s41416-022-02040-w

Anal Chem. 2022 Nov 8. doi: 10.1021/acs.analchem.2c02694. Online ahead of print.ABSTRACTSpatial metabolomics describes the spatially resolved analysis of interconnected pathways, biochemical reactions, and transport processes of small molecules in the spatial context of tissues and cells. However, a broad range of metabolite classes (e.g., steroids) show low intrinsic ionization efficiencies in mass spectrometry imaging (MSI) experiments, thus restricting the spatial characterization of metabolic networks. Additionally, decomposing complex metabolite networks into chemical compound classes and molecular annotations remains a major bottleneck due to the absence of repository-scaled databases. Here, we describe a multimodal mass-spectrometry-based method combining computational metabolome mining tools and high-resolution on-tissue chemical derivatization (OTCD) MSI for the spatially resolved analysis of metabolic networks at the low micrometer scale. Applied to plant toxin sequestration in Danaus plexippus as a model system, we first utilized liquid chromatography (LC)-MS-based molecular networking in combination with artificial intelligence (AI)-driven chemical characterization to facilitate the structural elucidation and molecular identification of 32 different steroidal glycosides for the host-plant Asclepias curassavica. These comprehensive metabolite annotations guided the subsequent matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) analysis of cardiac-glycoside sequestration in D. plexippus. We developed a spatial-context-preserving OTCD protocol, which improved cardiac glycoside ion yields by at least 1 order of magnitude compared to results with untreated samples. To illustrate the potential of this method, we visualized previously inaccessible (sub)cellular distributions (2 and 5 μm pixel size) of steroidal glycosides in D. plexippus, thereby providing a novel insight into the sequestration of toxic metabolites and guiding future metabolomics research of other complex sample systems.PMID:36347515 | DOI:10.1021/acs.analchem.2c02694

Clin Chim Acta. 2022 Nov 5:S0009-8981(22)01360-2. doi: 10.1016/j.cca.2022.11.002. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: The vital metabolic signatures for IA risk stratification and its potential biological underpinnings remain elusive. Our study aimed to develop an early diagnosis model and rupture classification model by analyzing plasma metabolic profiles of IA patients.MATERIALS AND METHODS: Plasma samples from a cohort of 105 participants, including 75 IA patients in unruptured and ruptured status (UIA, RIA) and 30 control participants were collected for comprehensive metabolic evaluation using ultra-high-performance liquid chromatography-mass spectrometry-based pseudotargeted metabolomics method. Furthermore, an integrated machine learning strategy based on LASSO, random forest and logistic regression were used for feature selection and model construction.RESULTS: The metabolic profiling disturbed significantly in UIA and RIA patients. Notably, adenosine content was significantly downregulated in UIA, and various glycine-conjugated secondary bile acids were decreased in RIA patients. Enriched KEGG pathways included glutathione metabolism and bile acid metabolism. Two sets of biomarker panels were defined to discriminate IA and its rupture with the area under receiver operating characteristic curve of 0.843 and 0.929 on the validation sets, respectively.CONCLUSIONS: The present study could contribute to a better understanding of IA etiopathogenesis and facilitate discovery of new therapeutic targets. The metabolite panels may serve as potential non-invasive diagnostic and risk stratification tool for IA.PMID:36347333 | DOI:10.1016/j.cca.2022.11.002

Neurotoxicology. 2022 Nov 5:S0161-813X(22)00177-2. doi: 10.1016/j.neuro.2022.11.004. Online ahead of print.ABSTRACTIsoniazid (INH) and rifampicin (RIF) are co-administered in tuberculosis treatment but can cause neurotoxicity, and the mechanism is not known. To explore this mechanism, we employed an integrated approach using metabolomics analysis (MA) and proteomics analysis (PA). Male mice were divided into three groups and administered vehicle (control group), or co-administered INH (120mg/kg) and RIF (240mg/kg), for 7 or 14 days. Mice brains were collected for mass spectrometry-based PA and MA plus lipidomics analysis. Measurement of brain levels of malondialdehyde and superoxide dismutase revealed time-dependent brain injury after exposure to INH+RIF for 7 and 14 days. Also, 422 proteins, 35 metabolites, and 21 lipids were dysregulated and identified. MA demonstrated "purine metabolism," "phenylalanine, tyrosine and tryptophan biosynthesis," "biosynthesis of unsaturated fatty acids," "phenylalanine metabolism," and "arginine biosynthesis" to be disturbed significantly. PA demonstrated pathways such as "lipids," "amino acids," and "energy metabolism" to be disrupted. Peroxisome proliferator-activated receptor (PPAR) pathways were changed in energy metabolism, which led to the neurotoxicity induced by INH+RIF. Immunohistochemical analyses of PPARs in mice brains verified that PPAR-α and -γ expression was downregulated. PPAR-α and -γ activation might be a key target for alleviating INH+RIF-induced neurotoxicity.PMID:36347327 | DOI:10.1016/j.neuro.2022.11.004

J Ethnopharmacol. 2022 Nov 5:115913. doi: 10.1016/j.jep.2022.115913. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Jingfang Granule (JFG) is a classical traditional Chinese medicine prescription to empirically treat skin disease such as urticaria in clinical practice. However, the potential mechanisms of JFG on urticaria are not fully defined.AIM OF STUDY: The aim of this study is to investigate the mechanisms of JFG in treating urticaria through an OVA/aluminum hydroxide induced urticaria mice model.MATERIALS AND METHODS: KM mice were injected intraperitoneally (i.p.) with OVA/aluminium hydroxide to establish the model with urticaria. After the mice were administered JFG, itching degree and hematoxylin and eosin (H&E) staining were used to assess the protective effect of JFG on mice with urticaria. The regulatory networks were investigated by proteomics and central carbon metabolomics. Spleen T lymphocyte subsets were detected by flow cytometry. Peripheral blood cytokines were detected using ELISA kits or Cytometric Bead Array (CBA) kits. The protein expression of skin tissue was detected by western blot or immunohistochemical staining.RESULTS: JFG significantly relived skin tissue lesions and skin pruritus in mice with urticaria. Meanwhile, JFG significantly decreased IgE, IL-1β, IL-6, IL-4, TNF-α and IL-17A levels and increased IFN-γ levels in the serum of urticaria mice by inhibiting the expression of inflammation associated proteins including TLR4 and p-NF-κB p65, p-ERK1/2, p-JNK and p-p38, NLRP3, ASC and cleaved caspase-1. The results of proteomics, central carbon metabolomics, western blot and Immunohistochemical staining confirmed that JFG inhibited Glycolysis/Gluconeogenesis and Pentose phosphate pathway in the skin tissue of urticaria mice by activating the LKB1/AMPK/SIRT1 axis and then downregulating the protein expressions of Glut1, TORC2, p-CREB, PEPCK, HNF4α and G6Pase.CONCLUSION: The current study demonstrates that JFG is effective in treating OVA/aluminum hydroxide-induced skin lesions and inflammation in mice, and JFG exhibits the clinical benefits via modulating LKB1/AMPK/SIRT1 axis, which in turn inhibits Glycolysis/Gluconeogenesis and Pentose phosphate pathway.PMID:36347302 | DOI:10.1016/j.jep.2022.115913

Arch Biochem Biophys. 2022 Nov 5:109453. doi: 10.1016/j.abb.2022.109453. Online ahead of print.ABSTRACTFollicular fluid is the microenvironment of oocytes that plays a crucial role in oocyte development. This study intended to explore the follicular fluid metabolomics in diminished ovarian reserve (DOR), polycystic ovarian syndrome (PCOS), and normal ovary response (NOR) groups. For metabolomic analysis, we collected the follicular fluid samples from 28 patients with DOR, 28 patients with NOR, and 28 patients with PCOS. The identified metabolites were annotated using KEGG to determine the metabolic pathway disturbances in PCOS and DOR. Based on the regression model, we conducted ROC analysis to identify PCOS and DOR biomarkers in the follicular fluid. The present results identified that the DOR and NOR groups' differential metabolites were primarily enriched in the choline pathway. The concentrations of pregnanediol-3-glucuronide and 2-hydroxyestrone sulfate in the ODR and NOR groups were substantially different. The metabolites in the purine metabolism pathway were mainly enriched in the PCOS and NOR groups. N-Acetyl-S-(N-methylcarbamoyl) cysteine and 3,4-dehydrothiomorpholine in the ODR and NOR groups were substantially different. We also identified metabolic alterations in PCOS and DOR follicular fluid, which provides novel ways for PCOS and DOR diagnosis and therapy.PMID:36347279 | DOI:10.1016/j.abb.2022.109453

Cell. 2022 Nov 3:S0092-8674(22)01323-X. doi: 10.1016/j.cell.2022.10.008. Online ahead of print.ABSTRACTLow-molecular-weight (LMW) thiols are small-molecule antioxidants required for the maintenance of intracellular redox homeostasis. However, many host-associated microbes, including the gastric pathogen Helicobacter pylori, unexpectedly lack LMW-thiol biosynthetic pathways. Using reactivity-guided metabolomics, we identified the unusual LMW thiol ergothioneine (EGT) in H. pylori. Dietary EGT accumulates to millimolar levels in human tissues and has been broadly implicated in mitigating disease risk. Although certain microorganisms synthesize EGT, we discovered that H. pylori acquires this LMW thiol from the host environment using a highly selective ATP-binding cassette transporter-EgtUV. EgtUV confers a competitive colonization advantage in vivo and is widely conserved in gastrointestinal microbes. Furthermore, we found that human fecal bacteria metabolize EGT, which may contribute to production of the disease-associated metabolite trimethylamine N-oxide. Collectively, our findings illustrate a previously unappreciated mechanism of microbial redox regulation in the gut and suggest that inter-kingdom competition for dietary EGT may broadly impact human health.PMID:36347253 | DOI:10.1016/j.cell.2022.10.008