Downregulation Of Metabolites Research Articles

Win-win cooperation between plant substrates and probiotics: Revealing biotransformation and bioactive metabolites in Elaeagnus moorcroftii Wall. ex Schlecht fermented by Lacticaseibacillus paracasei YL-29

Elaeagnus moorcroftii Wall. ex Schlecht (EWS) was identified as a suitable food substrate for enhancing the proliferation of Lacticaseibacillus paracasei YL-29 (L.cp29). Metabolomics and pathway analyses were employed to explore the effects of L.cp29 on EWS juice (EWSJ) secondary metabolites and reciprocally, EWS effects on L.cp29 bioactivity and fermentation metabolites. Results indicated robust growth of L.cp29 (9.87 Log CFU/mL) associated with 59 significantly altered metabolites, encompassing 6 classes metabolites. Following fermentation, the downregulation of metabolites, coupled with the upregulation of metabolites, facilitated the accumulation of markers correlated with L.cp29 growth through growth regulating metabolic pathways. Moreover, significant enhancement in the antioxidant capacity of L.cp29 fermented EWS was linked to 127 significantly altered metabolites, including 6 classes metabolites. Downregulated metabolites of EWS were bio-transformed by Lactobacillus, yielding products with higher antioxidant and biological activities compared to their metabolic precursors. Overall, EWS, functioning as a prebiotic, supported L.cp29 proliferation, while L.cp29 biotransformed EWS bioactive compounds into structurally enhanced bioactive forms. These findings underscore a mutually beneficial relationship between EWS and L.cp29, offering insights into the mechanisms governing probiotic and plant-based matrix interactions in functional probiotic fermented foods and suggesting avenues for developing potential synbiotics and postbiotics from Lactobacillus-fermented plant substrates.

Impact of Weissella cibaria BYL4.2 and its supernatants on Penicillium chrysogenum metabolism.

Lactic acid bacteria (LAB) can produce a vast spectrum of antifungal metabolites to inhibit fungal growth. The purpose of this study was to elucidate the antifungal effect of isolated Weissella cibaria BYL4.2 on Penicillium chrysogenum, the antifungal activity of W. cibaria BYL4.2 against P. chrysogenum was evaluated by the superposition method, results showed that it had obviously antifungal activity against P. chrysogenum. Studying the probiotic properties of BYL4.2 and determining it as beneficial bacteria. Furtherly, different treatments were carried out to characterize the antifungal activity of cell-free supernatant (CFS) produced by W. cibaria BYL4.2, and it was shown that the CFS was pH-dependent, partly heat-sensitive, and was not influenced by proteinaceous treatment. The CFS of W. cibaria BYL4.2 was analyzed by high-performance liquid chromatography (HPLC) and found the highest content of lactic acid. Screening of metabolic markers by a non-targeted metabolomics approach based liquid chromatography-mass spectrometry (LC-MS). The results speculated that organic acid especially detected D-tartaric acid was the main antifungal substance of CFS, which could cause the down-regulation of metabolites in the ABC transporters pathway, thereby inhibiting the growth of P. chrysogenum. Therefore, this study may provide important information for the inhibitory mechanism of W. cibaria BYL4.2 on P. chrysogenum, and provide a basis for further research on the antifungal effect of Weissella.

Abstract 2331: Metabolic profiling of pre and post treatment ovarian cancer tissues using in situ mass spectrometry imaging

Abstract Chemotherapy resistance represents a major problem in ovarian cancer prognosis and reliable indicators of chemotherapy sensitivity remain an unmet need. Here, we examined metabolic profiles of pre- and post-neoadjuvant chemotherapy (NACT) tumor samples from patients with high-grade serous ovarian cancer (HGSC). We performed spatially resolved, desorption electrospray ionization-mass spectrometry (DESI-MS) on sections from clinically annotated HGSC samples collected according to a laparoscopic triage algorithm from patients pre- and post-NACT. Patients were considered to be either excellent (ER) if they presented complete response or only microscopic disease left at interval surgery, or poor responders (PR) if they presented stable or progressive disease after NACT. Tumor tissues from 50 patients (29 ER and 21 PR, 13 ER matched pre and post NACT, 13 PR matched pre and post-NACT) were eligible for the analyses Data relative to the detected metabolites, were collected from epithelium and stroma separately. We first identified differentially upregulated metabolites in ER and PR groups and performed pathway analysis. The over-represented pathways in the chemo-naïve PR tissues included the nucleotide metabolism pathway in epithelial areas, and degradation of cysteine and homocysteine, metabolism of amino acids and derivatives, as well as sulfur amino acids metabolism in the stromal areas (p values FDR adjusted 0.045). In general, both the epithelium and stroma of PR tissues of chemo-naïve tumors, contained a higher number and a higher variety of lipid species compared with ER tissues. In post-NACT tumor epithelial areas, there was global downregulation of metabolites across all patient samples, compared to the pre-chemo specimens; this was more evident in ER patients. In post-NACT tumors from PR patients, glutathione synthesis and recycling pathway, and sulfite oxidation to sulfate pathway and many glycerolipids species were upregulated in the epithelium, while phosphatidic acids were upregulated in the stroma. Lastly, we evaluated the predictive power of the metabolic data extracted by the epithelial areas of chemo-naïve tissues, in classifying patients as ER or PR. We used 10-fold cross-validation to create a ridge regression model for the classification of ER and PR samples from pre-NACT tumor tissues. This model, based on 78 differentially expressed metabolites (small molecules and lipids), correctly classified patients as ER or PR with an accuracy of 76.2% (sensitivity 84.6% and specificity 62.5%). Our findings indicate altered metabolic pathways in ovarian cancer tissues based on response to NACT. The identification of differentially activated pathways, such as sulfate metabolism and glutathione metabolism in tumors with poor response, suggest novel actionable targets to overcome chemotherapy resistance in patients with HGSC. Citation Format: Sara Corvigno, Meredith Spraldin, Michael Keating, Sunil Badal, Igor Pereira, Elaine Stur, Nicholas Bateman, Waleed Barakat, Thomas Conrads, Sanghoon Lee, George Maxwell, Susan K. Lutgendorf, Premal Thaker, Jinsong Liu, Nicole Fleming, Katheleen Darcy, Livia S. Eberlin, Anil K. Sood. Metabolic profiling of pre and post treatment ovarian cancer tissues using in situ mass spectrometry imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2331.

Dose-Dependent Variation of Synchronous Metabolites and Modules in a Yin/Yang Transformation Model of Appointed Ischemia Metabolic Networks.

AimChinese medicine Danhong injection (DHI) is an effective pharmaceutical preparation for treating cerebral infarction. Our previous study shows that DHI can remarkably reduce the ischemic stroke-induced infarct volume in a dose-dependent manner, but the pharmacological mechanism of the DHI dose-dependent relationship is not clear. Therefore, the dose-dependent efficacy of DHI on cerebral ischemia and the underlying mechanisms were further investigated in this study.MethodsA middle cerebral artery occlusion (MCAO) model was established and the rats were randomly divided into six groups: sham, vehicle, DHI dose-1, DHI dose-2, DHI dose-3, and DHI dose-4. Forty-one metabolites in serum were selected as candidate biomarkers of efficacy phenotypes by the Agilent 1290 rapid-resolution liquid chromatography system coupled with the Agilent 6550 Q-TOF MS system. Then, the metabolic networks in each group were constructed using the Weighted Correlation Network analysis (WGCNA). Moreover, the Yang and Yin transformation of six patterns (which are defined by up- and downregulation of metabolites) and synchronous modules divided from a synchronous network were used to dynamically analyze the mechanism of the drug’s effectiveness.ResultsThe neuroprotective effect of DHI has shown a dose-dependent manner, and the high-dose group (DH3 and DH4) effect is better. The entropy of the metabolic network and the Yin/Yang index both showed a consistent dose–response relationship. Seven dose-sensitive metabolites maintained constant inverse upregulation or downregulation in the four dose groups. Three synchronous modules for the DH1–DH4 full-course network were identified. Glycine, N-acetyl-L-glutamate, and tetrahydrofolate as a new emerging module appeared in DH2/DH3 and enriched in glutamine and glutamate metabolism-related pathways.ConclusionThis study takes the DHI metabolic network as an example to provide a new method for the discovery of multiple targets related to pharmacological effects. Our results show that the three conservative allosteric module nodes, taurine, L-tyrosine, and L-leucine, may be one of the basic mechanisms of DHI in the treatment of cerebral infarction, and the other three new emerging module nodes glyoxylate, L-glutamate, and L-valine may participate in the glutamine and glutamate metabolism pathway to improve the efficacy of DHI.

Impact of Up- and Downregulation of Metabolites and Mitochondrial Content on pH and Color of the Longissimus Muscle from Normal-pH and Dark-Cutting Beef.

Limited knowledge is currently available on the biochemical basis for the development of dark-cutting beef. The objective of this research was to determine the metabolite profile and mitochondrial content differences between normal-pH and dark-cutting beef. A gas chromatography-mass spectrometer-based nontargeted metabolomic approach indicated downregulation of glycolytic metabolites, including glucose-1- and 6-phosphate and upregulation of tricarboxylic substrates such as malic and fumaric acids occurred in dark-cutting beef when compared to normal-pH beef. Neurotransmitters such as 4-aminobutyric acid and succinate semialdehyde were upregulated in dark-cutting beef than normal-pH beef. Immunohistochemistry indicated a more oxidative fiber type in dark-cutting beef than normal-pH beef. In support, the mitochondrial protein and DNA content were greater in dark-cutting beef. This increased mitochondrial content, in part, could influence oxygen consumption and myoglobin oxygenation/appearance of dark-cutting beef. The current results demonstrate that the more tricarboxylic metabolites and mitochondrial content in dark-cutting beef impact muscle pH and color.

Spermine-priming restrained water relations and biochemical deteriorations prompted by water deficit on two soybean cultivars

The outstanding role of spermine in eliciting defense adaptation of soybean to different levels of water deficit (0, -0.1, -0.5 and -1.1 MPa) was investigated by determining the changes in growth, photosynthetic pigments, osmolytes, water relations, and antioxidants. All the studied traits clearly revealed cultivar-dependent variation in response to water deficit where cv. Giza 111 was tolerant and cv. Giza 21 was sensitive. Both cultivars came in agreement that photosynthetic limitation (chlorophylls reduction) was the troubling shot induced by water deficit. Such limitation was reflected on three directions (a) disturbances of water relations (stomatal conductance, transpiration rate, relative water content and water use efficiency), (b) down regulation of metabolites which affect osmotic adjustment and (c) elevated reactive oxygen species (increased hydrogen peroxide) and destruction of membrane stability (increment of electrolyte leakage and lipid peroxidation). The damaging impacts of water deficit on these parameters were obviously coined for sensitive cultivar compared to tolerant one. Although spermine priming did not have apparent stimulatory role on well-watered plants, unequivocal inversion from a state of down regulation to up-regulation was distinct under water stress. In this regard, spermine enhanced pigments, osmolytes accumulation, up-regulated water relations and enhanced membrane stabilization. Furthermore, spermine pre-sowing decreased oxidative stress by lowering hydrogen peroxide via activation of anthocyanins, total antioxidants and phenolic compounds.

Metabolomics study of fatigue in patients with rheumatoid arthritis naïve to biological treatment.

Fatigue occurs in all chronic inflammatory diseases, in cancer, and in some neurological conditions. Patients often regard fatigue as one of their most debilitating problems, but currently there is no established treatment and the mechanisms that lead to and regulate fatigue are incompletely understood. Our objective was to more completely understand the physiology of this phenomenon. Twenty-four patients with rheumatoid arthritis (RA) naïve to treatment with biological drugs were enrolled for the study. Fatigue was measured with a fatigue visual analogue scale (fVAS). Ethylenediaminetetraacetic acid (EDTA) plasma samples were subjected to gas chromatography-time-of-flight mass spectrometry (GC/MS-TOF)-based metabolite profiling. Obtained metabolite data were evaluated by multivariate data analysis with orthogonal projections to latent structures (OPLS) method to pinpoint metabolic changes related to fatigue severity. A significant multivariate OPLS model was obtained between the fVAS scores and the measured metabolic levels. Increasing fatigue scores were associated with a metabolic pattern characterized by down-regulation of metabolites from the urea cycle, fatty acids, tocopherols, aromatic amino acids, and hypoxanthine. Uric acid levels were increased. Apart from fatigue, we found no other disease-related variables that might be responsible for these changes. Our MS-based metabolomic approach demonstrated strong associations between fatigue and several biochemical patterns related to oxidative stress.

Metabolic Differences in Microbial Cell Populations Revealed by Nanophotonic Ionization

Playing (yeast) laser tag: Laser desorption ionization mass spectrometry (LDI-MS) with nanopost arrays (NAPA, see scheme) was shown to quantitatively analyze trace amounts of intracellular metabolites from single cells of Saccharomyces cerevisiae (baker's yeast). The upregulation and downregulation of metabolites because of external stress (such as oxidative stress) are also observed, even at the single-cell level.