PubMed

ACS Infect Dis. 2023 Feb 10. doi: 10.1021/acsinfecdis.2c00567. Online ahead of print.ABSTRACTAchieving cellular uptake is a central challenge for novel antibiotics targeting Gram-negative bacterial pathogens. One strategy is to hijack the bacterial iron transport system by siderophore-antibiotic conjugates that are actively imported into the cell. This was realized with the MECAM-ampicillin conjugate LP-600 we recently reported that was highly active against E. coli. In the present study, we investigate a paradoxical regrowth of E. coli upon treatment of LP-600 at concentrations 16-32 times above the minimum inhibitory concentration (MIC). The phenomenon, coined "Eagle-effect" in other systems, was not due to resistance formation, and it occurred for the siderophore conjugate but not for free ampicillin. To investigate the molecular imprint of the Eagle effect, a combined transcriptome and untargeted metabolome analysis was conducted. LP-600 induced the expression of genes involved in iron acquisition, SOS response, and the e14 prophage upon regrowth conditions. The Eagle effect was diminished in the presence of sulbactam, which we ascribe to a putative synergistic antibiotic action but not to β-lactamase inhibition. The study highlights the relevance of the Eagle effect for siderophore conjugates. Through the first systematic -omics investigations, it also demonstrates that the Eagle effect manifests not only in a paradoxical growth but also in unique gene expression and metabolite profiles.PMID:36763039 | DOI:10.1021/acsinfecdis.2c00567

Arthritis Rheumatol. 2023 Feb 10. doi: 10.1002/art.42470. Online ahead of print.ABSTRACTOBJECTIVE: Many patients with acromegaly, a hormonal disorder with excessive growth hormone (GH), report pain in joints. The objective of this study is to characterize the joint pathology of mice with over-expression of either bovine GH (bGH) or a GH receptor antagonist (GHa). We also investigate the effect of GH on regulation of chondrocyte cellular metabolism.METHODS: Knee joints from mice over-expressing bGH or GHa and WT were histologically and μCT analyzed for OA pathologies. Additionally, cartilage from bGH mice was used for metabolomics. Mouse primary chondrocytes from WT or bGH mice with or without Pegvisomant (Peg) treatment were used for Q-PCR and Seahorse Respirometry analysis.RESULTS: Both male and female bGH mice at ~13 months had increased knee joint degeneration, which is characterized by loss of cartilage structure, expansion of hypertrophic chondrocytes, synovitis, and subchondral plate thinning. The joint pathologies were also demonstrated by significantly higher OARSI and Mankin scores in bGH compared with WT mice. Metabolomics revealed changes of a wide range of metabolic pathways in bGH mice including beta-alanine metabolism, tryptophan metabolism, lysine degradation, and ascorbate and aldarate metabolism. Also, bGH chondrocytes upregulated fatty acid oxidation (FAO) and increased expression of Col10a. Joints of GHa mice are remarkably protected from developing age-associated joint degeneration with smooth articular joint surface.CONCLUSIONS: These studies uncover that an excessive amount of GH promotes joint degeneration in mice, whereas antagonizing GH action through a GHa protects mice from OA development, which is associated with chondrocyte metabolic dysfunction and hypertrophic changes.PMID:36762426 | DOI:10.1002/art.42470

Front Chem. 2023 Jan 25;11:1129717. doi: 10.3389/fchem.2023.1129717. eCollection 2023.ABSTRACTMetabolites are closely intertwined genotypes that can provide clear information about the final phenotype. The high-throughput analysis platform used to identify candidate metabolites and describe their contributions can help to quickly detect metabolic characteristics from large spectral data, which may lead to peak data preprocessing, statistical analysis and functional interpretation. Developing a comprehensive strategy for discovering and verifying bioactive metabolites can provide a large number of new functional biomarkers, and then more closely reveal their functional changes, which has relevant biological significance for disease diagnosis and prognosis treatment.PMID:36762198 | PMC:PMC9905695 | DOI:10.3389/fchem.2023.1129717

Front Pharmacol. 2023 Jan 24;14:1133685. doi: 10.3389/fphar.2023.1133685. eCollection 2023.ABSTRACTBackground: Methicillin-resistant Staphylococcus aureus (MRSA) has now become a major nosocomial pathogen bacteria and resistant to many antibiotics. Therefore, Development of novel approaches to combat the disease is especially important. The present study aimed to provide a novel approach involving the use of nucleotide-mediated metabolic reprogramming to tackle intractable methicillin-resistant S. aureus (MRSA) infections. Objective: This study aims to explore the bacterial effects and mechanism of uracil and gentamicin in S. aureus. Methods: Antibiotic bactericidal assays was used to determine the synergistic bactericidal effect of uracil and gentamicin. How did uracil regulate bacterial metabolism including the tricarboxylic acid (TCA) cycle by GC-MS-based metabolomics. Next, genes and activity of key enzymes in the TCA cycle, PMF, and intracellular aminoglycosides were measured. Finally, bacterial respiration, reactive oxygen species (ROS), and ATP levels were also assayed in this study. Results: In the present study, we found that uracil could synergize with aminoglycosides to kill MRSA (USA300) by 400-fold. Reprogramming metabolomics displayed uracil reprogrammed bacterial metabolism, especially enhanced the TCA cycle to elevate NADH production and proton motive force, thereby promoting the uptake of antibiotics. Furthermore, uracil increased cellular respiration and ATP production, resulting the generation of ROS. Thus, the combined activity of uracil and antibiotics induced bacterial death. Inhibition of the TCA cycle or ROS production could attenuate bactericidal efficiency. Moreover, uracil exhibited bactericidal activity in cooperation with aminoglycosides against other pathogenic bacteria. In a mouse mode of MRSA infection, the combination of gentamicin and uracil increased the survival rate of infected mice. Conclusion: Our results suggest that uracil enhances the activity of bactericidal antibiotics to kill Gram-positive bacteria by modulating bacterial metabolism.PMID:36762116 | PMC:PMC9902350 | DOI:10.3389/fphar.2023.1133685

Front Pharmacol. 2023 Jan 25;14:1113213. doi: 10.3389/fphar.2023.1113213. eCollection 2023.ABSTRACTIntroduction: Epimedium, a traditional Chinese medicine (TCM) commonly used in ancient and modern China, is one of the traditional Chinese medicines clinically used to treat kidney yang deficiency syndrome (KYDS). There are differences in the efficacy of Epimedium before and after processing, and the effect of warming the kidney and enhancing yang is significantly enhanced after heating with suet oil. However, the active compounds, corresponding targets, metabolic pathways, and synergistic mechanism of frying Epimedium in suet oil to promote yang, remain unclear. Methods: Herein, a strategy based on comprehensive GC-TOF/MS metabolomics and network pharmacology analysis was used to construct an "active compounds-targets-metabolic pathways" network to identify the active compounds, targets and metabolic pathways involved. Subsequently, the targets in kidney tissue were further validated by real-time quantitative polymerase chain reaction (RT-qPCR). Histopathological analysis with physical and biochemical parameters were performed. Results: Fifteen biomarkers from urine and plasma, involving five known metabolic pathways related to kidney yang deficiency were screened. The network pharmacology results showed 37 active compounds (13 from Epimedium and 24 from suet oil), 159 targets, and 267 pathways with significant correlation. Importantly, integrated metabolomics and network pharmacologic analysis revealed 13 active compounds (nine from Epimedium and four from suet oil), 7 corresponding targets (ALDH2, ARG2, GSTA3, GSTM1, GSTM2, HPGDS, and NOS2), two metabolic pathways (glutathione metabolism, arginine and proline metabolism), and two biomarkers (Ornithine and 5-Oxoproline) associated with improved kidney yang deficiency by Epimedium fried with suet oil. Discussion: These finds may elucidate the underlying mechanism of yang enhancement via kidney warming effects. Our study indicated that the mechanism of action mainly involved oxidative stress and amino acid metabolism. Here, we demonstrated the novel strategies of integrating metabolomics and network pharmacology in exploring of the mechanisms of traditional Chinese medicines.PMID:36762111 | PMC:PMC9905240 | DOI:10.3389/fphar.2023.1113213

Front Microbiol. 2023 Jan 24;13:1047121. doi: 10.3389/fmicb.2022.1047121. eCollection 2022.ABSTRACTAIM: The treatment of Alzheimer's disease (AD) is still a worldwide problem due to the unclear pathogenesis and lack of effective therapeutic targets. In recent years, metabolomic and gut microbiome changes in patients with AD have received increasing attention, and the microbiome-gut-brain (MGB) axis has been proposed as a new hypothesis for its etiology. Considering that electroacupuncture (EA) efficiently moderates cognitive deficits in AD and its mechanisms remain poorly understood, especially regarding its effects on the gut microbiota, we performed urinary metabolomic and microbial community profiling on EA-treated AD model mice, presenilin 1/2 conditional double knockout (PS cDKO) mice, to observe the effect of EA treatment on the gut microbiota in AD and find the connection between affected gut microbiota and metabolites.MATERIALS AND METHODS: After 30 days of EA treatment, the recognition memory ability of PS cDKO mice was evaluated by the Y maze and the novel object recognition task. Urinary metabolomic profiling was conducted with the untargeted GC-MS method, and 16S rRNA sequence analysis was applied to analyze the microbial community. In addition, the association between differential urinary metabolites and gut microbiota was clarified by Spearman's correlation coefficient analysis.KEY FINDINGS: In addition to reversed cognitive deficits, the urinary metabolome and gut microbiota of PS cDKO mice were altered as a result of EA treatment. Notably, the increased level of isovalerylglycine and the decreased levels of glycine and threonic acid in the urine of PS cDKO mice were reversed by EA treatment, which is involved in glyoxylate and dicarboxylate metabolism, as well as glycine, serine, and threonine metabolism. In addition to significantly enhancing the diversity and richness of the microbial community, EA treatment significantly increased the abundance of the genus Mucispirillum, while displaying no remarkable effect on the other major altered gut microbiota in PS cDKO mice, norank_f_Muribaculaceae, Lactobacillus, and Lachnospiraceae_NK4A136 group. There was a significant correlation between differential urinary metabolites and differential gut microbiota.SIGNIFICANCE: Electroacupuncture alleviates cognitive deficits in AD by modulating gut microbiota and metabolites. Mucispirillum might play an important role in the underlying mechanism of EA treatment. Our study provides a reference for future treatment of AD from the MGB axis.PMID:36762099 | PMC:PMC9904445 | DOI:10.3389/fmicb.2022.1047121

Front Cell Infect Microbiol. 2023 Jan 25;13:1112148. doi: 10.3389/fcimb.2023.1112148. eCollection 2023.ABSTRACTAs the most common type of stroke, ischemic stroke, also known as cerebral infarction (CI), with its high mortality and disability rate, has placed a huge burden on social economy and public health. Treatment methods for CI mainly include thrombectomy, thrombolysis, drug therapy, and so on. However, these treatments have certain timeliness and different side effects. In recent years, the gut-brain axis has become a hot topic, and its role in nervous system diseases has been confirmed by increasing evidences. The intestinal microbiota, as an important part of the gut-brain axis, has a non-negligible impact on the progression of CI through mechanisms such as inflammatory response and damage-associated molecular patterns, and changes in the composition of intestinal microbiota can also serve as the basis for predicting CI. At the same time, the diagnosis of CI requires more high-throughput techniques, and the analysis method of metabolomics just fits this demand. This paper reviewed the changes of intestinal microbiota in patients within CI and the effects of the intestinal microbiota on the course of CI, and summarized the therapeutic methods of the intervention with the intestinal microbiota. Furthermore, metabolic changes of CI patients were also discussed to reveal the molecular characteristics of CI and to elucidate the potential pathologic pathway of its interference.PMID:36761896 | PMC:PMC9905239 | DOI:10.3389/fcimb.2023.1112148

Heliyon. 2023 Jan 24;9(2):e13219. doi: 10.1016/j.heliyon.2023.e13219. eCollection 2023 Feb.ABSTRACTThe ubiquitin-specific chaperone AAA-ATPase Cdc48 and its orthologs p97/valosin-containing protein (VCP) in mammals play crucial roles in regulating numerous intracellular pathways via segregase activity, which separates polyubiquitinated targets from membranes or binding partners. Interestingly, high-throughput experiments show that a vast number of metabolic enzymes are modified with ubiquitin. Therefore, Cdc48 may regulate metabolic pathways, for example by acting on the polyubiquitin chains of metabolic enzymes; however, the role of Cdc48 in metabolic regulation remains largely unknown. To begin to analyze the role of Cdc48 in metabolic regulation in yeast, we performed a metabolomics analysis of temperature-sensitive cdc48-3 mutant cells. We found that the amount of metabolites in the glycolytic pathway was altered. Moreover, the pool of nucleotides, as well as the levels of metabolites involved in the tricarboxylic acid cycle and oxidative phosphorylation, increased, whereas the pool of amino acids decreased. These results suggest the involvement of Cdc48 in metabolic regulation in yeast. In addition, because of the roles of p97/VCP in regulating multiple cellular pathways, its inhibition is being considered as a promising anticancer drug target. We propose that the metabolomics study of Cdc48-deficient yeast will be useful as a complement to p97/VCP-related pathological and therapeutic studies.PMID:36761826 | PMC:PMC9905943 | DOI:10.1016/j.heliyon.2023.e13219

Front Immunol. 2023 Jan 24;14:1067602. doi: 10.3389/fimmu.2023.1067602. eCollection 2023.ABSTRACTINTRODUCTION: Children born by cesarean section (CS) are at a greater risk of inflammatory bowel disease (IBD). However, the mechanisms underlying the association are not yet well understood. Herein, we investigated the impact of CS delivery on colonic inflammation and mechanisms underlying these effects in offspring.METHODS: CS mice model and dextran sulfate sodium (DSS)-induced colitis model were constructed and used to analyze the impact of CS on the development of colitis. Colonic tight junction markers and epithelium differentiation markers were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Levels of zonulin in serum were detected by enzyme-linked immunosorbent assay (ELISA). Immune cells in colon were analyzed by flow cytometry. Metabolic profiling between human vaginal delivery (VD) and CS AF were analyzed by using mass spectrometry. Transcriptome changes between VD AF- and CS AF-treated human intestine epithelial cells were analyzed by RNA-sequencing. A multi-omics approach that integrated transcriptomics with metabolomics to identify the pathways underlying colonic inflammation associated with delivery modes. Then, the identified pathways were confirmed by immunoblotting and ELISA.RESULTS: Mice pups delivered by CS exhibited a defective intestinal homeostasis manifested by decreased expression of tight junction markers of ZO-1 and Occludin in the colons, increased levels of zonulin in serum and dysregulated expression of intestinal epithelium differentiation markers of Lysozyme, Mucin2, and Dipeptidyl peptidase-4. CS pups were more susceptible to DSS-induced colitis compared to VD pups. The proportion of macrophage, dendritic cells (DCs), and natural killer cells (NKs) in the colons were altered in an age-dependent manner compared with pups born naturally. The metabolites in AF differed between CS and VD cases, and the CS AF-induced differentially expressed genes (DEGs) were significantly enriched in pathways underlying IBD. Signal transducer and activator of transcription 3 (STAT3) signaling was downregulated in NCM460 intestinal epithelial cells by CS AF compared to VD AF and in colon of CS pups compared to VD pups. Deficiency in metabolites like vitamin D2 glucosiduronate in CS AF may attribute to the risk of inflammatory intestine through STAT3 signaling.CONCLUSION: Our study provides a novel insight into the underlying mechanisms of CS-associated intestinal inflammation and potential prevention strategies.PMID:36761749 | PMC:PMC9903135 | DOI:10.3389/fimmu.2023.1067602

Front Public Health. 2023 Jan 25;10:899638. doi: 10.3389/fpubh.2022.899638. eCollection 2022.ABSTRACTOccupational exposure to potentially toxic elements (PTEs) is a concerning reality of informal workers engaged in the jewelry production chain that can lead to adverse health effects. In this study, untargeted proteomic and metabolomic analyses were employed to assess the impact of these exposures on informal workers' exposome in Limeira city, São Paulo state, Brazil. PTE levels (Cr, Mn, Ni, Cu, Zn, As, Cd, Sn, Sb, Hg, and Pb) were determined in blood, proteomic analyses were performed for saliva samples (n = 26), and metabolomic analyses in plasma (n = 145) using ultra-high performance liquid chromatography (UHPLC) coupled with quadrupole-time-of-flight (Q-TOF) mass spectrometry. Blood PTE levels of workers, controls, and their family members were determined by inductively coupled plasma-mass spectrometry (ICP-MS). High concentration levels of Sn and Cu were detected in welders' blood (p < 0.001). Statistical analyses were performed using MetaboAnalyst 4.0. The results showed that 26 proteins were upregulated, and 14 proteins downregulated on the welder group, and thirty of these proteins were also correlated with blood Pb, Cu, Sb, and Sn blood levels in the welder group (p < 0.05). Using gene ontology analysis of these 40 proteins revealed the biological processes related to the upregulated proteins were translational initiation, SRP-dependent co-translational protein targeting to membrane, and viral transcription. A Metabolome-Wide Association Study (MWAS) was performed to search for associations between blood metabolites and exposure groups. A pathway enrichment analysis of significant features from the MWAS was then conducted with Mummichog. A total of 73 metabolomic compounds and 40 proteins up or down-regulated in welders were used to perform a multi-omics analysis, disclosing seven metabolic pathways potentially disturbed by the informal work: valine leucine and isoleucine biosynthesis, valine leucine and isoleucine degradation, arginine and proline metabolism, ABC transporters, central carbon metabolism in cancer, arachidonic acid metabolism and cysteine and methionine metabolism. The majority of the proteins found to be statistically up or downregulated in welders also correlated with at least one blood PTE level, providing insights into the biological responses to PTE exposures in the informal work exposure scenario. These findings shed new light on the effects of occupational activity on workers' exposome, underscoring the harmful effects of PTE.PMID:36761330 | PMC:PMC9905639 | DOI:10.3389/fpubh.2022.899638

Front Nutr. 2023 Jan 25;10:1118923. doi: 10.3389/fnut.2023.1118923. eCollection 2023.ABSTRACTOBJECTIVE: In this study, the structure of Pleurotus eryngii polysaccharides (PEPs) was characterized, and the mechanism of PEP on obesity and hyperlipidemia induced by high-fat diet was evaluated by metabonomic analysis.METHODS: The structure of PEPs were characterized by monosaccharide composition, Fourier transform infrared spectroscopy and thermogravimetry. In animal experiments, H&E staining was used to observe the morphological difference of epididymal adipose tissue of mice in each group. Ultrahigh performance liquid chromatography (UHPLC)-(QE) HFX -mass spectrometry (MS) was used to analyze the difference of metabolites in serum of mice in each group and the related metabolic pathways.RESULTS: The PEPs contained nine monosaccharides: 1.05% fucose, 0.30% arabinose, 17.94% galactose, 53.49% glucose, 1.24% xylose, 23.32% mannose, 1.30% ribose, 0.21%galacturonic acid, and 1.17% glucuronic acid. The PEPs began to degrade at 251°C (T0), while the maximum thermal degradation rate temperature (Tm) appeared at 300°C. The results histopathological observation demonstrated that the PEPs had signifificant hypolipidemic activities. After PEPs intervention, the metabolic profile of mice changed significantly. A total of 29 different metabolites were selected as adjunctive therapy to PEPs, for treatment of obesity and hyperlipidemia-related complications caused by a high-fat diet. These metabolites include amino acids, unsaturated fatty acids, choline, glycerol phospholipids, and other endogenous compounds, which can prevent and treat obesity and hyperlipidemia caused by a high-fat diet by regulating amino acid metabolism, fatty acid metabolism, and changes in metabolic pathways such as that involved in the citric cycle (TCA cycle).CONCLUSIONS: The presented results indicate that PEPs treatment can alleviate the obesity and hyperlipidemia caused by a high-fat diet and, thus, may be used as a functional food adjuvant, providing a theoretical basis and technical guidance for the prevention and treatment of high-fat diet-induced obesity and hyperlipidemia.PMID:36761225 | PMC:PMC9905146 | DOI:10.3389/fnut.2023.1118923

Front Endocrinol (Lausanne). 2023 Jan 24;14:1107162. doi: 10.3389/fendo.2023.1107162. eCollection 2023.ABSTRACTPURPOSE: Type 1 diabetes is characterized by elevated blood glucose levels, which negatively impacts multiple organs and tissues throughout the body, and its prevalence is on the rise. Prior reports primarily investigated the serum and urine specimen from diabetic patients. However, only a few studies examined the overall metabolic profile of diabetic animals or patients. The current systemic investigation will benefit the knowledge of STZ-based type 1 diabetes pathogenesis.METHODS: Male SD rats were arbitrarily separated into control and streptozotocin (STZ)-treated diabetic rats (n = 7). The experimental rats received 50mg/kg STZ intraperitoneal injection daily for 2 consecutive days. Following 6 weeks, metabolites were assessed via gas chromatography-mass spectrometry (GC-MS), and multivariate analysis was employed to screen for differentially expressed (DE) metabolites between the induced diabetic and normal rats.RESULTS: We identified 18, 30, 6, 24, 34, 27, 27 and 12 DE metabolites in the serum, heart, liver, kidney, cortex, renal lipid, hippocampus, and brown fat tissues of STZ-treated diabetic rats, compared to control rats. Based on our analysis, the largest differences were observed in the amino acids (AAs), B-group vitamin, and purine profiles. Using the metabolic pathway analysis, we screened 13 metabolic pathways related to the STZ-exposed diabetes pathogenesis. These pathways were primarily AA metabolism, followed by organic acids, sugars, and lipid metabolism.CONCLUSION: Based on our GC-MS analysis, we identified potential metabolic alterations within the STZ-exposed diabetic rats, which may aid in the understanding of diabetes pathogenesis.PMID:36761194 | PMC:PMC9902650 | DOI:10.3389/fendo.2023.1107162

Front Plant Sci. 2023 Jan 25;14:1124046. doi: 10.3389/fpls.2023.1124046. eCollection 2023.ABSTRACTVitis adenoclada is a wild grape unique to China. It exhibits well resistance to heat, humidity, fungal disease, drought, and soil infertility. Here, we report the high-quality, chromosome-level genome assembly of GH6 (V. adenoclada). The 498.27 Mb genome contained 221.78 Mb of transposable elements, 28,660 protein-coding genes, and 481.44 Mb of sequences associated with 19 chromosomes. GH6 shares a common ancestor with PN40024 (Vitis vinifera) from approximately 4.26-9.01 million years ago, whose divergence occurred later than Vitis rotundifolia and Vitis riparia. Widely-targeted metabolome and transcriptome analysis revealed that the profiles and metabolism of phenolic compounds in V. adenoclada varieties significantly were differed from other grape varieties. Specifically, V. adenoclada varieties were rich in phenolic acids and flavonols, whereas the flavan-3-ol and anthocyanin content was lower compared with other varieties that have V. vinifera consanguinity in this study. In addition, ferulic acid and stilbenes content were associated with higher expressions of COMT and STSs in V. adenoclada varieties. Furthermore, MYB2, MYB73-1, and MYB73-2 were presumably responsible for the high expression level of COMT in V. adenoclada berries. MYB12 (MYBF1) was positively correlated with PAL, CHS, FLS and UFGT.Meanwhile, MYB4 and MYBC2-L1 may inhibit the synthesis of flavan-3-ols and anthocyanins in two V. adenoclada varieties (YN2 and GH6). The publication of the V. adenoclada grape genome provides a molecular foundation for further revealing its flavor and quality characteristics, is also important for identifying favorable genes of the East Asian species for future breeding.PMID:36760645 | PMC:PMC9907855 | DOI:10.3389/fpls.2023.1124046

Front Plant Sci. 2023 Jan 24;14:1060242. doi: 10.3389/fpls.2023.1060242. eCollection 2023.ABSTRACTDendrobium officinale is an orchid with medicinal and nutritional properties that has received increasing attention because of its health benefits; however, there is limited information about the metabolic basis of these properties. In this report, secondary metabolites and the antioxidant activity of D. officinale stem samples from three provenances were analyzed, using a UHPLC-QqQ-MS/MS-based metabolomics approach. In total, 411 metabolites were identified including 8 categories such as flavonoids and phenolic acids, 136 of which were differential metabolites. These differentially accumulated metabolites (DAMs) were mainly enriched in secondary metabolic pathways such as flavone, flavonol, tropane, piperidine, pyridine, isoquinoline alkaloid biosynthesis and tyrosine metabolism. The metabolomic profiling suggested that the quantity and content of flavonoid compounds accounted for the highest proportion of total metabolites. Hierarchical cluster analysis (HCA) showed that the marker metabolites of D. officinale from the three provenances were mainly flavonoids, alkaloids and phenolic acids. Correlation analysis identified that 48 differential metabolites showed a significant positive correlation with antioxidant capacity (r ³ 0.8 and p < 0.0092), and flavonoids were the main factors affecting the different antioxidant activities. It is worth noting that quercetin-3-O-sophoroside-7-O-rhamnoside and dihydropinosylvin methyl ether might be the main compounds causing the differences in antioxidant capacity of Yunnan provenance (YN), Zhejiang provenance (ZJ), and Guizhou provenance (GZ). These finding provides valuable information for screening varieties, quality control and product development of D. officinale.PMID:36760636 | PMC:PMC9902878 | DOI:10.3389/fpls.2023.1060242

Evid Based Complement Alternat Med. 2023 Jan 31;2023:2139634. doi: 10.1155/2023/2139634. eCollection 2023.ABSTRACTRadish seed (RS), the dried ripe seed of Raphanus sativus L., is widely used in traditional Chinese medicine (TCM) to reduce blood pressure. However, the molecular and pharmacological mechanisms underlying its therapeutic effects are still unclear. In this study, we analyzed the effects of RS in a rat model of prehypertension and assessed the mechanistic basis by integrating transcriptomics and metabolomics. RS administration significantly reduced blood pressure in prehypertensive male Wistar rats, negatively regulated endothelin-1, increased nitric oxide levels, and reduced the exfoliation of endothelium cells. In vitro vascular ring experiments further confirmed the effects of RS on vascular endothelial cells. Furthermore, we identified 65 differentially expressed genes (DEGs; P adj < 0.05 and fold change (FC) > 2) and 52 metabolites (VIP > 1, P < 0.05 and FC ≥ 2 or ≤0.5) in the RS intervention group using RNA-seq and UPLC-MS/MS, respectively. A network of the DEGs and the metabolites was constructed,q which indicated that RS regulates purine metabolism, linoleic acid metabolism, arachidonic acid metabolism, circadian rhythm, and phosphatidylinositol signaling pathway, and its target genes are Pik3c2a, Hspa8, Dnaja1, Arntl, Ugt1a1, Dbp, Rasd1, and Aldh1a3. Thus, the antihypertensive effects of RS can be attributed to its ability to improve vascular endothelial dysfunction by targeting multiple genes and pathways. Our findings provide new insights into the pathological mechanisms underlying prehypertension, along with novel targets for the prevention and treatment of hypertension.PMID:36760467 | PMC:PMC9904934 | DOI:10.1155/2023/2139634

BMC Plant Biol. 2023 Feb 9;23(1):85. doi: 10.1186/s12870-023-04094-1.ABSTRACTCold temperatures can be detrimental to crop survival and productivity. Breeding progress can be improved by understanding the molecular basis of low temperature tolerance. We investigated the key routes and critical metabolites related to low temperature resistance in cold-tolerant and -sensitive common bean cultivars 120 and 093, respectively. Many potential genes and metabolites implicated in major metabolic pathways during the chilling stress response were identified through transcriptomics and metabolomics research. Under chilling stress, the expression of many genes involved in lipid, amino acid, and flavonoid metabolism, as well as metabolite accumulation increased in the two bean types. Malondialdehyde (MDA) content was lower in 120 than in 093. Regarding amino acid metabolism, 120 had a higher concentration of acidic amino acids than 093, whereas 093 had a higher concentration of basic amino acids. Methionine accumulation was clearly higher in 120 than in 093. In addition, 120 had a higher concentration of many types of flavonoids than 093. Flavonoids, methionine and malondialdehyde could be used as biomarkers of plant chilling injury. Transcriptome analysis of hormone metabolism revealed considerably greater, expression of abscisic acid (ABA), gibberellin (GA), and jasmonic acid (JA) in 093 than in 120 during chilling stress, indicating that hormone regulation modes in 093 and 120 were different. Thus, chilling stress tolerance is different between 093 and 120 possibly due to transcriptional and metabolic regulation.PMID:36759761 | DOI:10.1186/s12870-023-04094-1

Nat Microbiol. 2023 Feb 9. doi: 10.1038/s41564-023-01327-9. Online ahead of print.ABSTRACTBehaviours such as chemotaxis can facilitate metabolic exchanges between phytoplankton and heterotrophic bacteria, which ultimately regulate oceanic productivity and biogeochemistry. However, numerically dominant picophytoplankton have been considered too small to be detected by chemotactic bacteria, implying that cell-cell interactions might not be possible between some of the most abundant organisms in the ocean. Here we examined how bacterial behaviour influences metabolic exchanges at the single-cell level between the ubiquitous picophytoplankton Synechococcus and the heterotrophic bacterium Marinobacter adhaerens, using bacterial mutants deficient in motility and chemotaxis. Stable-isotope tracking revealed that chemotaxis increased nitrogen and carbon uptake of both partners by up to 4.4-fold. A mathematical model following thousands of cells confirmed that short periods of exposure to small but nutrient-rich microenvironments surrounding Synechococcus cells provide a considerable competitive advantage to chemotactic bacteria. These findings reveal that transient interactions mediated by chemotaxis can underpin metabolic relationships among the ocean's most abundant microorganisms.PMID:36759754 | DOI:10.1038/s41564-023-01327-9

Nat Commun. 2023 Feb 9;14(1):709. doi: 10.1038/s41467-023-36148-1.ABSTRACTAdipocyte-derived extracellular vesicles (AdEVs) are membranous nanoparticles that convey communication from adipose tissue to other organs. Here, to delineate their role as messengers with glucoregulatory nature, we paired fluorescence AdEV-tracing and SILAC-labeling with (phospho)proteomics, and revealed that AdEVs transfer functional insulinotropic protein cargo into pancreatic β-cells. Upon transfer, AdEV proteins were subjects for phosphorylation, augmented insulinotropic GPCR/cAMP/PKA signaling by increasing total protein abundances and phosphosite dynamics, and ultimately enhanced 1st-phase glucose-stimulated insulin secretion (GSIS) in murine islets. Notably, insulinotropic effects were restricted to AdEVs isolated from obese and insulin resistant, but not lean mice, which was consistent with differential protein loads and AdEV luminal morphologies. Likewise, in vivo pre-treatment with AdEVs from obese but not lean mice amplified insulin secretion and glucose tolerance in mice. This data suggests that secreted AdEVs can inform pancreatic β-cells about insulin resistance in adipose tissue in order to amplify GSIS in times of increased insulin demand.PMID:36759608 | DOI:10.1038/s41467-023-36148-1

Sci Rep. 2023 Feb 9;13(1):2374. doi: 10.1038/s41598-022-26377-7.ABSTRACTThe underlying mechanisms linking physical activity to better health are not fully understood. Here we examined the associations between physical activity and small circulatory molecules, the metabolome, to highlight relevant biological pathways. We examined plasma metabolites associated with self-reported physical activity among 2217 participants from the Airwave Health Monitoring Study. Metabolic profiling was conducted using the mass spectrometry-based Metabolon platform (LC/GC-MS), measuring 828 known metabolites. We replicated our findings in an independent subset of the study (n = 2971) using untargeted LC-MS. Mendelian randomisation was carried out to investigate potential causal associations between physical activity, body mass index, and metabolites. Higher vigorous physical activity was associated (P < 0.05/828 = 6.03 × 10-5) with circulatory levels of 28 metabolites adjusted for age, sex and body mass index. The association was inverse for glutamate and diacylglycerol lipids, and direct for 3-4-hydroxyphenyllactate, phenyl lactate (PLA), alpha-hydroxy isovalerate, tiglylcarnitine, alpha-hydroxyisocaproate, 2-hydroxy-3-methylvalerate, isobutyrylcarnitine, imidazole lactate, methionine sulfone, indole lactate, plasmalogen lipids, pristanate and fumarate. In the replication panel, we found 23 untargeted LC-MS features annotated to the identified metabolites, for which we found nominal associations with the same direction of effect for three features annotated to 1-(1-enyl-palmitoyl)-2-oleoyl-GPC (P-16:0/18:1), 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2), 1-stearoyl-2-dihomo-linolenoyl-GPC (18:0/20:3n3 or 6). Using Mendelian randomisation, we showed a potential causal relationship between body mass index and three identified metabolites. Circulatory metabolites are associated with physical activity and may play a role in mediating its health effects.PMID:36759570 | DOI:10.1038/s41598-022-26377-7

Life Sci Alliance. 2023 Feb 9;6(5):e202201702. doi: 10.26508/lsa.202201702. Print 2023 May.ABSTRACTThe role of dietary tannin in inflammatory bowel disease (IBD) is still not clear. Therefore, we aim to study the effect of TA in the progression of IBD. Dextran sulphate sodium (DSS)-induced model was used to mimic IBD. Metagenomics and metabolomics were performed to study the alteration of intestinal microbiota and metabolites. NCM460 and THP-1 cells were used for in vitro study. The amount of TA was associated with the outcomes of DSS-induced IBD as evidenced by in vivo and in vitro studies. Metabolomic and metagenomic analyses revealed that TA-induced enrichment of microbial metabolite gallic acid (GA) was responsible for the action of TA. Mechanistically, protective dose of GA promoted colonic mucus secretion to suppress bacterial infection and that it ameliorated DSS-induced epithelial damage by inhibiting p53 signaling, whereas toxic dose of GA directly caused epithelial damage by promoting cell cycle arrest. Therapeutic experiment showed protective dose of GA-promoted recovery of DSS-induced colonic inflammation. The role of tannase-containing bacteria can be transformed under different conditions in IBD progression.PMID:36759174 | DOI:10.26508/lsa.202201702