PubMed

Int J Mol Sci. 2024 Sep 30;25(19):10574. doi: 10.3390/ijms251910574.ABSTRACTLaccase, a copper-containing oxidoreductase, has close links with secondary metabolite biosynthesis in plants. Its activity can affect the synthesis and accumulation of secondary metabolites, thereby influencing plant growth, development, and stress resistance. This study aims to identify the grape laccases (VviLAC) gene family members in grape (Vitis vinifera L.) and explore the transcriptional regulatory network in berry development. Here, 115 VviLACs were identified and divided into seven (Type I-VII) classes. These were distributed on 17 chromosomes and out of 47 VviLACs on chromosome 18, 34 (72.34%) were involved in tandem duplication events. VviLAC1, VviLAC2, VviLAC3, and VviLAC62 were highly expressed before fruit color development, while VviLAC4, VviLAC12, VviLAC16, VviLAC18, VviLAC20, VviLAC53, VviLAC60 and VviLAC105 were highly expressed after fruit color transformation. Notably, VviLAC105 showed a significant positive correlation with important metabolites including resveratrol, resveratrol dimer, and peonidin-3-glucoside. Analysis of the transcriptional regulatory network predicted that the 12 different transcription factors target VviLACs genes. Specifically, WRKY and ERF were identified as potential transcriptional regulatory factors for VviLAC105, while Dof and MYB were identified as potential transcriptional regulatory factors for VviLAC51. This study identifies and provides basic information on the grape LAC gene family members and, in combination with transcriptome and metabolome data, predicts the upstream transcriptional regulatory network of VviLACs.PMID:39408902 | DOI:10.3390/ijms251910574

Int J Mol Sci. 2024 Sep 30;25(19):10544. doi: 10.3390/ijms251910544.ABSTRACTAs a part of the important species that form coral reef ecosystems, stony corals have become a potential source of pharmacologically active lead compounds for an increasing number of compounds with novel chemical structures and strong biological activity. In this study, the secondary metabolites and biological activities are reported for Aspergillus terreus C21-1, an epiphytic fungus acquired from Porites pukoensis collected from Xuwen Coral Reef Nature Reserve, China. This strain was cultured in potato dextrose broth (PDB) media and rice media with different salinities based on the OSMAC strategy. The mycelial morphology and high-performance thin layer chromatographic (HPTLC) fingerprints of the fermentation extracts together with bioautography were recorded. Furthermore, an untargeted metabolomics study was performed using principal component analysis (PCA), orthogonal projection to latent structure discriminant analysis (O-PLSDA), and feature-based molecular networking (FBMN) to analyze their secondary metabolite variations. The comprehensive results revealed that the metabolite expression in A. terreus C21-1 differed significantly between liquid and solid media. The metabolites produced in liquid medium were more diverse but less numerous compared to those in solid medium. Meanwhile, the mycelial morphology underwent significant changes with increasing salinity under PDB cultivation conditions, especially in PDB with 10% salinity. Untargeted metabolomics revealed significant differences between PDB with 10% salinity and other media, as well as between liquid and solid media. FBMN analysis indicated that alkaloids, which might be produced under high salt stress, contributed largely to the differences. The biological activities results showed that six groups of crude extracts exhibited acetylcholinesterase (AChE) inhibitory activities, along with 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging and antibacterial activities. The results of this study showed that the increase in salinity favored the production of unique alkaloid compounds by A. terreus C21-1.PMID:39408873 | DOI:10.3390/ijms251910544

Int J Mol Sci. 2024 Sep 28;25(19):10467. doi: 10.3390/ijms251910467.ABSTRACTThe complex biology of the microbiome was elucidated once the genomics era began. The proteogenomic approach analyzes and integrates genetic makeup (genomics) and microbial communities' expressed proteins (proteomics). Therefore, researchers gained insights into gene expression, protein functions, and metabolic pathways, understanding microbial dynamics and behavior, interactions with host cells, and responses to environmental stimuli. In this context, our work aims to bring together data regarding the application of genomics, proteomics, and bioinformatics in microbiome research and to provide new perspectives for applying microbiota modulation in clinical practice with maximum efficiency. This review also synthesizes data from the literature, shedding light on the potential biomarkers and therapeutic targets for various diseases influenced by the microbiome.PMID:39408795 | DOI:10.3390/ijms251910467

Int J Mol Sci. 2024 Sep 27;25(19):10456. doi: 10.3390/ijms251910456.ABSTRACTAlkaline water is toxic to cultured aquatic animals that frequently live in pH-neutral freshwater. Overfishing and habitat destruction have contributed to the decline in the wild sturgeon population; consequently, the domestic hybrid sturgeon has become an increasingly important commercial species in China. Hybrid sturgeons are widely cultured in alkaline water, but little is known about the effects of alkalinity stress on hybrid sturgeon liver tissues. We exposed hybrid sturgeons to four alkaline concentrations (3.14 ± 0.02 mmol/L, 7.57 ± 0.08 mmol/L, 11.78 ± 0.24 mmol/L and 15.46 ± 0.48 mmol/L). Histopathology, biochemical index assessment, gene expression level detection and metabolomics analysis were used to investigate the negative effects on liver functions following exposure to NaHCO3. Livers exposed to alkaline stress exhibited severe tissue injury and clear apoptotic characteristics. With increased exposure concentrations, the hepatic superoxide dismutase, catalase, glutathione peroxidase and alkaline phosphatase activities significantly decreased in a dose-dependent manner. NaHCO3 exposure up-regulated the transcriptional levels of apoptosis/ferroptosis-related genes in livers. Similarly, the expression trends of interleukin-1β and heat shock protein genes also increased in high-alkalinity environments. However, the expression levels of complement protein 3 significantly decreased (p < 0.05). Hepatic untargeted metabolomics revealed the alteration conditions of various metabolites associated with the antioxidant response, the ferroptosis process and amino acid metabolism (such as beta-alanine metabolism; alanine, aspartate and glutamate metabolism; and glycine, serine and threonine metabolism). These data provided evidence that NaHCO3 impaired immune functions and the integrity of hybrid sturgeon liver tissues by mediating oxidative-stress-mediated apoptosis and ferroptosis. Our results shed light on the breeding welfare of domestic hybrid sturgeons and promote the economic development of fisheries in China.PMID:39408786 | DOI:10.3390/ijms251910456

Int J Mol Sci. 2024 Sep 27;25(19):10440. doi: 10.3390/ijms251910440.ABSTRACTChinese cabbage (Brassica rapa L. ssp. pekinensis) ranks among the most cultivated and consumed vegetables in China. A major threat to its production is Plasmodiophora brassicae, which causes large root tumors, obstructing nutrient and water absorption and resulting in plant withering. This study used a widely targeted metabolome technique to identify resistance-related metabolites in resistant (DH40R) and susceptible (DH199S) Chinese cabbage varieties after inoculation with P. brassicae. This study analyzed disease-related metabolites during different periods, identifying 257 metabolites linked to resistance, enriched in the phenylpropanoid biosynthesis pathway, and 248 metabolites linked to susceptibility, enriched in the arachidonic acid metabolism pathway. Key metabolites and genes in the phenylpropanoid pathway were upregulated at 5 days post-inoculation (DPI), suggesting their role in disease resistance. In the arachidonic acid pathway, linoleic acid and gamma-linolenic acid were upregulated at 5 and 22 DPI in resistant plants, while arachidonic acid was upregulated at 22 DPI in susceptible plants, leading to the conclusion that arachidonic acid may be a response substance in susceptible plants after inoculation. Many genes enriched in these pathways were differentially expressed in DH40R and DH199S. The research provided insights into the defense mechanisms of Chinese cabbage against P. brassicae through combined metabolome and transcriptome analysis.PMID:39408769 | DOI:10.3390/ijms251910440

Int J Mol Sci. 2024 Sep 27;25(19):10430. doi: 10.3390/ijms251910430.ABSTRACTWheat is the most widely grown crop in the world; its production is severely disrupted by increasing water deficit. Plant roots play a crucial role in the uptake of water and perception and transduction of water deficit signals. In the past decade, the mechanisms of drought tolerance have been frequently reported; however, the transcriptome and metabolome regulatory network of root responses to water stress has not been fully understood in wheat. In this study, the global transcriptomic and metabolomics profiles were employed to investigate the mechanisms of roots responding to water stresses using the drought-tolerant (DT) and drought-susceptible (DS) wheat genotypes. The results showed that compared with the control group, wheat roots exposed to polyethylene glycol (PEG) had 25941 differentially expressed genes (DEGs) and more upregulated genes were found in DT (8610) than DS (7141). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the DEGs of the drought-tolerant genotype were preferably enriched in the flavonoid biosynthetic process, anthocyanin biosynthesis and suberin biosynthesis. The integrated analysis of the transcriptome and metabolome showed that in DT, the KEGG pathways, including flavonoid biosynthesis and arginine and proline metabolism, were shared by differentially accumulated metabolites (DAMs) and DEGs at 6 h after treatment (HAT) and pathways including alanine, aspartate, glutamate metabolism and carbon metabolism were shared at 48 HAT, while in DS, the KEGG pathways shared by DAMs and DEGs only included arginine and proline metabolism at 6 HAT and the biosynthesis of amino acids at 48 HAT. Our results suggest that the drought-tolerant genotype may relieve the drought stress by producing more ROS scavengers, osmoprotectants, energy and larger roots. Interestingly, hormone signaling plays an important role in promoting the development of larger roots and a higher capability to absorb and transport water in drought-tolerant genotypes.PMID:39408761 | DOI:10.3390/ijms251910430

Int J Mol Sci. 2024 Sep 27;25(19):10428. doi: 10.3390/ijms251910428.ABSTRACTGlioblastoma (GBM) is a deadly brain cancer. The prognosis of GBM patients has marginally improved over the last three decades. The response of GBMs to initial treatment is inevitably followed by relapse. Thus, there is an urgent need to identify and develop new therapeutics to target this cancer and improve both patient outcomes and long-term survival. Metabolic reprogramming is considered one of the hallmarks of cancers. However, cell-based studies fail to accurately recapitulate the in vivo tumour microenvironment that influences metabolic signalling and rewiring. Against this backdrop, we conducted global, untargeted metabolomics analysis of the G7 and R24 GBM 2D monolayers and 3D spheroid cultures under identical cell culture conditions. Our studies revealed that the levels of multiple metabolites associated with the vitamin B6 pathway were significantly altered in 3D spheroids compared to the 2D monolayer cultures. Importantly, we show that pharmacological intervention with hydralazine, a small molecule that reduces vitamin B6 levels, resulted in the cell death of 3D GBM spheroid cultures. Thus, our study shows that inhibition of the vitamin B6 pathway is a novel therapeutic strategy for the development of targeted therapies in GBMs.PMID:39408757 | DOI:10.3390/ijms251910428

Int J Mol Sci. 2024 Sep 27;25(19):10398. doi: 10.3390/ijms251910398.ABSTRACTTo reveal the effect of sucrose concentration on the production of secondary metabolites, a metabolome and transcriptome joint analysis was carried out using callus induced from grape variety Mio Red cambial meristematic cells. We identified 559 metabolites-mainly flavonoids, phenolic acids, and stilbenoids-as differential content metabolites (fold change ≥2 or ≤0.5) in at least one pairwise comparison of treatments with 7.5, 15, or 30 g/L sucrose in the growing media for 15 or 30 days (d). Resveratrol, viniferin, and amurensin contents were highest at 15 d of subculture; piceid, ampelopsin, and pterostilbene had higher contents at 30 d. A transcriptome analysis identified 1310 and 498 (at 15 d) and 1696 and 2211 (at 30 d) differentially expressed genes (DEGs; log2(fold change) ≥ 1, p < 0.05) in 7.5 vs. 15 g/L and 15 vs. 30 g/L sucrose treatments, respectively. In phenylpropane and isoflavone pathways, DEGs encoding cinnamic acid 4-hydroxylase, chalcone synthase, chalcone isomerase, and flavanone 3-hydroxylase were more highly expressed at 15 d than at 30 d, while other DEGs showed different regulation patterns corresponding to sucrose concentrations and cultivation times. For all three sucrose concentrations, the stilbene synthase (STS) gene exhibited significantly higher expression at 15 vs. 30 d, while two resveratrol O-methyltransferase (ROMT) genes related to pterostilbene synthesis showed significantly higher expression at 30 vs. 15 d. In addition, a total of 481 DEGs were annotated as transcription factors in pairwise comparisons; an integrative analysis suggested MYB59, WRKY20, and MADS8 as potential regulators responding to sucrose levels in flavonoid and stilbene biosynthesis in grape callus. Our results provide valuable information for high-efficiency production of flavonoids and stilbenes using grape callus.PMID:39408726 | DOI:10.3390/ijms251910398

Int J Mol Sci. 2024 Sep 26;25(19):10385. doi: 10.3390/ijms251910385.ABSTRACTLinoleic acid (LA), the primary ω-6 polyunsaturated fatty acid (PUFA) found in the epidermis, plays a crucial role in preserving the integrity of the skin's water permeability barrier. Additionally, vegetable oils rich in LA have been shown to notably mitigate ultraviolet (UV) radiation-induced effects, including the production of reactive oxygen species (ROS), cellular damage, and skin photoaging. These beneficial effects are primarily ascribed to the LA in these oils. Nonetheless, the precise mechanisms through which LA confers protection against damage induced by exposure to UVB radiation remain unclear. This study aimed to examine whether LA can restore redox and metabolic equilibria and to assess its influence on the inflammatory response triggered by UVB radiation in keratinocytes. Flow cytometry analysis unveiled the capacity of LA to diminish UVB-induced ROS levels in HaCaT cells. GC/MS-based metabolomics highlighted significant metabolic changes, especially in carbohydrate, amino acid, and glutathione (GSH) metabolism, with LA restoring depleted GSH levels post-UVB exposure. LA also upregulated PI3K/Akt-dependent GCLC and GSS expression while downregulating COX-2 expression. These results suggest that LA induces metabolic reprogramming, protecting against UVB-induced oxidative damage by enhancing GSH biosynthesis via PI3K/Akt signaling. Moreover, it suppresses UVB-induced COX-2 expression in HaCaT cells, making LA treatment a promising strategy against UVB-induced oxidative and inflammatory damage.PMID:39408715 | DOI:10.3390/ijms251910385

Int J Mol Sci. 2024 Sep 26;25(19):10355. doi: 10.3390/ijms251910355.ABSTRACTOncidium hybridum Lodd. is an important ornamental flower that is used as both a cut flower and a potted plant around the world; additionally, its pseudobulbs serve as essential carriers for floral organs and flower development. The NAM gene family is crucial for managing responses to various stresses as well as regulating growth in plants. However, the mechanisms by which NAM genes regulate the development of pseudobulbs remain unclear. In this study, a total of 144 NAM genes harboring complete structural domains were identified in O. hybridum. The 144 NAM genes were systematically classified into 14 distinct subfamilies via phylogenetic analysis. Delving deeper into the conserved motifs revealed that motifs 1-6 exhibited remarkable conservation, while motifs 7-10 presented in a few NAM genes only. Notably, NAM genes sharing identical specific motifs were classified into the same subfamily, indicating functional relatedness. Furthermore, the examination of occurrences of gene duplication indicated that the NAM genes display 16 pairs of tandem duplications along with five pairs of segmental duplications, suggesting their role in genetic diversity and potential adaptive evolution. By conducting a correlation analysis integrating transcriptomics and metabolomics at four stages of pseudobulb development, we found that OhNAM023, OhNAM030, OhNAM007, OhNAM019, OhNAM083, OhNAM047, OhNAM089, and OhNAM025 exhibited significant relationships with the endogenous plant hormones jasmonates (JAs), hinting at their potential involvement in hormonal signaling. Additionally, OhNAM089, OhNAM025, OhNAM119, OhNAM055, and OhNAM136 showed strong links with abscisic acid (ABA) and abscisic acid glucose ester (ABA-GE), suggesting the possible regulatory function of these NAM genes in plant growth and stress responses. The 144 NAM genes identified in this study provide a basis for subsequent research and contribute to elucidating the intricate molecular mechanisms of NAM genes in Oncidium and potentially in other species.PMID:39408686 | DOI:10.3390/ijms251910355

Int J Mol Sci. 2024 Sep 26;25(19):10333. doi: 10.3390/ijms251910333.ABSTRACTEctopic pregnancy (EP) is the leading cause of maternal morbidity and mortality in the first trimester. Using an untargeted metabolomic approach, we sought to identify putative plasma biomarkers using tandem liquid chromatography-mass spectrometry for the detection of tubal EP. This case-control study included the prospective recruitment of 50 tubal EP cases and 50 early intrauterine pregnancy controls. To avoid over-fitting, logistic regression models were developed in a randomly selected discovery group (30 cases vs. 30 controls) and validated in the test group (20 cases vs. 20 controls). In total, 585 mass spectral features were detected, of which 221 molecular features were significantly altered in EP plasma (p < 0.05). Molecular networking and metabolite identification was employed using the Global Natural Products Social Molecular Networking (GNPS) database, which identified 97 metabolites at a high confidence level. Top significant metabolites include subclasses of sphingolipids, carnitines, glycerophosphocholines, and tryptophan metabolism. The top regression model, consisting of D-erythro-sphingosine and oleoyl-carnitine, was validated in a test group and achieved an area under receiving operating curve (AUC) (95% CI) = 0.962 (0.910-1) with a sensitivity of 100% and specificity of 95.9%. Metabolite alterations indicate alterations related to inflammation and abnormal placentation in EP. The validation of these metabolite biomarkers in the future could potentially result in improved early diagnosis.PMID:39408663 | DOI:10.3390/ijms251910333

Int J Mol Sci. 2024 Sep 25;25(19):10312. doi: 10.3390/ijms251910312.ABSTRACTPlants generate a range of physiological and molecular responses to sustain their growth and development when suffering heat stress. Avocado is a type of tropical fruit tree with high economic value. Most avocado cultivars delete, wither, or even die when exposed to heat stress for a long time, which seriously restricts the introduction and cultivation of avocados. In this study, samples of a heat-intolerant variety ('Hass') were treated under heat stress, and the transcriptomics and metabolomics were analyzed, with the expectation of providing information on the variety improvement and domestication of avocados. The differentially expressed genes identified using transcriptome analysis mainly involved metabolic pathways such as plant hormone signal transduction, plant-pathogen interaction, and protein processing in the endoplasmic reticulum. Combined transcriptome and metabolome analysis indicated that the down-regulation of Hass.g03.10206 and Hass.g03.10205 in heat shock-like proteins may result in the reduced Trehalose and Sinapoyl aldehyde content. Metabolomics analysis results indicated that the decrease in Trehalose and Sinapoyl aldehyde content may be an important factor for heat intolerance. These results provide important clues for understanding the physiological mechanisms of adaptation to heat stress in avocados.PMID:39408642 | DOI:10.3390/ijms251910312

Int J Mol Sci. 2024 Sep 25;25(19):10310. doi: 10.3390/ijms251910310.ABSTRACTThe swnN gene in the endophytic fungus Alternaria oxytropis OW 7.8 isolated from Oxytropis glabra was identified, and the gene knockout mutant ΔswnN was first constructed in this study. Compared with A. oxytropis OW 7.8, the ΔswnN mutant exhibited altered colony and mycelia morphology, slower growth rate, and no swainsonine (SW) in mycelia. SW was detected in the gene function complementation strain ΔswnN/swnN, indicating that the function of the swnN gene promoted SW biosynthesis. Six differentially expressed genes (DEGs) closely associated with SW synthesis were identified by transcriptomic analysis of A. oxytropis OW 7.8 and ΔswnN, with P5CR, swnR, swnK, swnH2, and swnH1 down-regulating, and sac up-regulating. The expression levels of the six genes were consistent with the transcriptomic analysis results. Five differential metabolites (DEMs) closely associated with SW synthesis were identified by metabolomic analysis, with L-glutamate, α-ketoglutaric acid, and L-proline up-regulating, and phosphatidic acid (PA) and 2-aminoadipic acid down-regulating. The SW biosynthetic pathways in A. oxytropis OW 7.8 were predicted and refined. The results lay the foundation for in-depth elucidation of molecular mechanisms and the SW synthesis pathway in fungi. They are also of importance for the prevention of locoism in livestock, the control and utilization of locoweeds, and the protection and sustainable development of grassland ecosystems.PMID:39408639 | DOI:10.3390/ijms251910310

Int J Mol Sci. 2024 Sep 24;25(19):10279. doi: 10.3390/ijms251910279.ABSTRACTDuring a heart attack, ischemia causes losses of billions of cells; this is especially concerning given the minimal regenerative capability of cardiomyocytes (CMs). Heart remuscularization utilizing stem cells has improved cardiac outcomes despite little cell engraftment, thereby shifting focus to cell-free therapies. Consequently, we chose induced pluripotent stem cells (iPSCs) given their pluripotent nature, efficacy in previous studies, and easy obtainability from minimally invasive techniques. Nonetheless, using iPSC secretome-based therapies for treating injured CMs in a clinical setting is ill-understood. We hypothesized that the iPSC secretome, regardless of donor health, would improve cardiovascular outcomes in the CM model of ischemia-reperfusion (IR) injury. Episomal-generated iPSCs from healthy and dilated cardiomyopathy (DCM) donors, passaged 6-10 times, underwent 24 h incubation in serum-free media. Protein content of the secretome was analyzed by mass spectroscopy and used to treat AC16 immortalized CMs during 5 h reperfusion following 24 h of hypoxia. IPSC-derived secretome content, independent of donor health status, had elevated expression of proteins involved in cell survival pathways. In IR conditions, iPSC-derived secretome increased cell survival as measured by metabolic activity (p < 0.05), cell viability (p < 0.001), and maladaptive cellular remodelling (p = 0.052). Healthy donor-derived secretome contained increased expression of proteins related to calcium contractility compared to DCM donors. Congruently, only healthy donor-derived secretomes improved CM intracellular calcium concentrations (p < 0.01). Heretofore, secretome studies mainly investigated differences relating to cell type rather than donor health. Our work suggests that healthy donors provide more efficacious iPSC-derived secretome compared to DCM donors in the context of IR injury in human CMs. These findings illustrate that the regenerative potential of the iPSC secretome varies due to donor-specific differences.PMID:39408608 | DOI:10.3390/ijms251910279

Int J Mol Sci. 2024 Sep 24;25(19):10266. doi: 10.3390/ijms251910266.ABSTRACTSchizophrenia (SCH) is a major mental illness that causes impaired cognitive function and long-term disability, so the requirements for reliable biomarkers for early diagnosis and therapy of SCH are essential. The objective of this work was an untargeted lipidomic study of serum samples from a Serbian cohort including 30 schizophrenia (SCH) patients and 31 non-psychiatric control (C) individuals by applying liquid chromatography (LC) coupled with high-resolution mass spectrometry (HRMS) and chemometric analyses. Principal component analysis (PCA) of all samples indicated no clear separation between SCH and C groups but indicated clear gender separation in the C group. Multivariate statistical analyses (PCA and orthogonal partial least squares discriminant analysis (OPLS-DA)) of gender-differentiated SCH and C groups established forty-nine differential lipids in the differentiation of male SCH (SCH-M) patients and male controls (C-M), while sixty putative biomarkers were identified in the differentiation of female SCH patients (SCH-F) and female controls (C-F). Lipidomic study of gender-differentiated groups, between SCH-M and C-M and between SCH-F and C-F groups, confirmed that lipids metabolism was altered and the content of the majority of the most affected lipid classes, glycerophospholipids (GP), sphingolipids (SP), glycerolipids (GL) and fatty acids (FA), was decreased compared to controls. From differential lipid metabolites with higher content in both SCH-M and SCH-F patients groups compared to their non-psychiatric controls, there were four common lipid molecules: ceramides Cer 34:2, and Cer 34:1, lysophosphatidylcholine LPC 16:0 and triacylglycerol TG 48:2. Significant alteration of lipids metabolism confirmed the importance of metabolic pathways in the pathogenesis of schizophrenia.PMID:39408605 | DOI:10.3390/ijms251910266

Int J Mol Sci. 2024 Sep 24;25(19):10261. doi: 10.3390/ijms251910261.ABSTRACTFlavonoids are pharmacologically active compounds in flowers of Chrysanthemum morifolium 'Boju' (C. morifolium); however, the molecular regulatory network governing flower development remains largely elusive. Flower samples were collected at four stages, namely budding (BD), bud breaking (BB), early blooming (EB), and full blooming (FB), for omics analysis. We revealed distinct transcriptional regulation patterns at these four stages of the flower from the perspective of differentially expressed unigenes (DEGs). There are 152 DEGs shared among the three comparative groups (BD vs. BB, BB vs EB, EB vs FB), wherein the expression of 44 DEGs (including AtADT6, MDL3, and ROMT) continues to be upregulated, and 85 DEGs (including CYP81E, TPS-Cin-1, and TPS-Cin-2) showed persistent downregulation with flower development. Flavonoid-targeted metabolomics identified 118 differentially abundant metabolites (DAMs) in the FB group compared to the BD stage; the top three upregulated and downregulated metabolites are Cyanidin-3-O-(6″-O-malonyl)glucoside-5-O-glucoside, Luteolin-7-O-(6″-caffeoyl)rhamnoside, Kaempferol-3-O-(6″-p-coumaroyl)glucoside and Chrysoeriol-6,8-di-C-glucoside-7-O-glucoside, Kaempferol, Kaempferol-3,7-O-dirhamnoside, respectively. These DAMs were predominantly enriched in "flavonoid biosynthesis", "isoflavonoid biosynthesis", and "flavone and flavonol biosynthesis" pathways. AtADT6, MDL3, ROMT, CYP81E, TPS-Cin-1, and TPS-Cin-2 were correlated with kaempferol. Our findings provide a new idea for interfering with flavonoid production, especially kaempferol, in flowers.PMID:39408589 | DOI:10.3390/ijms251910261

Int J Mol Sci. 2024 Sep 24;25(19):10252. doi: 10.3390/ijms251910252.ABSTRACTThe incorporation of multi-omics data methodologies facilitates the concurrent examination of proteins, metabolites, and genes associated with inflammation, thereby leveraging multi-dimensional biological data to achieve a comprehensive understanding of the complexities involved in the progression of inflammation. Inspired by ensemble learning principles, we implemented ID normalization preprocessing, categorical sampling homogenization, and pathway enrichment across each sample matrix derived from multi-omics datasets available in the literature, directing our focus on inflammation-related targets within lipopolysaccharide (LPS)-stimulated RAW264.7 cells towards β-alanine metabolism. Additionally, through the use of LPS-treated RAW264.7 cells, we tentatively validated the anti-inflammatory properties of the metabolite Ureidopropionic acid, originating from β-alanine metabolism, by evaluating cell viability, nitric oxide production levels, and mRNA expression of inflammatory biomarkers. In conclusion, our research represents the first instance of an integrated analysis of multi-omics datasets pertaining to LPS-stimulated RAW264.7 cells as documented in the literature, underscoring the pivotal role of β-alanine metabolism in cellular inflammation and successfully identifying Ureidopropionic acid as a novel anti-inflammatory compound. Moreover, the findings from database predictions and molecular docking studies indicated that the inflammatory-related pathways and proteins may serve as potential mechanistic targets for Ureidopropionic acid.PMID:39408583 | DOI:10.3390/ijms251910252

Nutrients. 2024 Sep 26;16(19):3250. doi: 10.3390/nu16193250.ABSTRACTOBJECTIVES: This study examined the effect of a 4-week unsweetened cranberry beverage (CRAN) (317 mg polyphenols) versus placebo beverage (PLAC) ingestion (240 mL/day) on moderating exercise-induced changes in innate immunity.METHODS: Participants included 25 male and female non-elite cyclists. A randomized, placebo-controlled, double-blind crossover design was used with two 4-week supplementation periods and a 2-week washout period. Supplementation periods were followed by an intensive 2.25 h cycling bout. Six blood samples were collected before and after supplementation (in an overnight fasted state) and at 0 h, 1.5 h, 3 h, and 24 h post-exercise. Stool and urine samples were collected pre- and post-supplementation. Outcome measures included serum creatine kinase, myoglobin, and cortisol, complete blood counts, plasma untargeted proteomics, plasma-targeted oxylipins, untargeted urine metabolomics, and stool microbiome composition via whole genome shotgun (WGS) sequencing.RESULTS: Urine CRAN-linked metabolites increased significantly after supplementation, but no trial differences in alpha or beta microbiota diversity were found in the stool samples. The 2.25 h cycling bout caused significant increases in plasma arachidonic acid (ARA) and 53 oxylipins (FDR q-value < 0.05). The patterns of increase for ARA, four oxylipins generated from ARA-cytochrome P-450 (CYP) (5,6-, 8,9-, 11,12-, and 14,15-diHETrEs), two oxylipins from linoleic acid (LA) and CYP (9,10-DiHOME, 12,13-DiHOME), and two oxylipins generated from LA and lipoxygenase (LOX) (9-HODE, 13-HODE) were slightly but significantly higher for the CRAN versus PLAC trial (all interaction effects, p < 0.05). The untargeted proteomics analysis showed that two protein clusters differed significantly between the CRAN and PLAC trials, with CRAN-related elevations in proteins related to innate immune activation and reduced levels of proteins related to the regulation of the complement cascade, platelet activation, and binding and uptake of ligands by scavenger receptors. No trial differences were found for cortisol and muscle damage biomarkers.CONCLUSIONS: CRAN versus PLAC juice resulted in a significant increase in CRAN-related metabolites but no differences in the gut microbiome. CRAN supplementation was associated with a transient and modest but significant post-exercise elevation in selected oxylipins and proteins associated with the innate immune system.PMID:39408218 | DOI:10.3390/nu16193250

J Clin Med. 2024 Oct 8;13(19):5983. doi: 10.3390/jcm13195983.ABSTRACTBackground: kidney transplant recipients are exposed to multiple pathogenic pathways that may alter short and long-term allograft survival. Metabolomic profiling is useful for detecting potential biomarkers of kidney disease with a predictive capacity. This field is still under development in kidney transplantation and metabolome analysis is faced with analytical challenges. We performed a cross-sectional study including stable kidney transplant patients and aimed to search for relevant associations between baseline plasmatic and urinary metabolites and relevant outcomes over a follow-up period of 3 years. Methods: we performed a cross-sectional study including 72 stable kidney transplant patients with stored plasmatic and urinary samples at the baseline evaluation which were there analyzed by nuclear magnetic resonance in order to quantify and describe metabolites. We performed a 3-year follow-up and searched for relevant associations between renal failure outcomes and baseline metabolites. Between-group comparisons were made after classification by observed estimated glomerular filtration rate slope during the follow-up: positive slope and negative slope. Results: The mean estimated GFR (glomerular filtration rate) was higher at baseline in the patients who exhibited a negative slope during the follow-up (63.4 mL/min/1.73 m2 vs. 55.8 mL/min/1.73 m2, p = 0,019). After log transformation and division by urinary creatinine, urinary dimethylamine (3.63 vs. 3.16, p = 0.027), hippuric acid (7.33 vs. 6.29, p = 0.041), and acetone (1.88 vs. 1, p = 0.023) exhibited higher concentrations in patients with a negative GFR slope when compared to patients with a positive GFR slope. By computing a linear regression, a significant low-strength regression equation between the log 2 transformed plasmatic level of glycine and the estimated glomerular filtration rate was found (F (1,70) = 5.15, p = 0.026), with an R2 of 0.069. Several metabolites were correlated positively with hand grip strength (plasmatic tyrosine with r = 0.336 and p = 0.005 and plasmatic leucine with r = 0.371 and p = 0.002). Other urinary metabolites were found to be correlated negatively with hand grip strength (dimethylamine with r = -0.250 and p = 0.04, citric acid with r = -0.296 and p = 0.014, formic acid with r = -0.349 and p = 0.004, and glycine with r = -0.306 and p = 0.01). Conclusions: some metabolites had different concentrations compared to kidney transplant patients with negative and positive slopes, and significant correlations were found between hand grip strength and urinary and plasmatic metabolites.PMID:39408043 | DOI:10.3390/jcm13195983

J Clin Med. 2024 Sep 25;13(19):5697. doi: 10.3390/jcm13195697.ABSTRACTBackground: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by distinctive physical, cognitive, and behavioral manifestations, coupled with profound alterations in appetite regulation, leading to severe obesity and metabolic dysregulation. These clinical features arise from disruptions in neurodevelopment and neuroendocrine regulation, yet the molecular intricacies of PWS remain incompletely understood. Methods: This study aimed to comprehensively profile circulating neuromodulatory factors in the serum of 53 subjects with PWS and 34 patients with non-syndromic obesity, utilizing a proximity extension assay with the Olink Target 96 neuro-exploratory and neurology panels. The ANOVA p-values were adjusted for multiple testing using the Benjamani-Hochberg method. Protein-protein interaction networks were generated in STRING V.12. Corrplots were calculated with R4.2.2 by using the Hmisc, Performance Analytics, and Corrplot packages Results: Our investigation explored the potential genetic underpinnings of the circulating protein signature observed in PWS, revealing intricate connections between genes in the PWS critical region and the identified circulating proteins associated with impaired oxytocin, NAD metabolism, and sex-related neuromuscular impairment involving, CD38, KYNU, NPM1, NMNAT1, WFIKKN1, and GDF-8/MSTN. The downregulation of CD38 in individuals with PWS (p < 0.01) indicates dysregulation of oxytocin release, implicating pathways associated with NAD metabolism in which KYNU and NMNAT1 are involved and significantly downregulated in PWS (p < 0.01 and p < 0.05, respectively). Sex-related differences in the circulatory levels of WFIKKN1 and GDF-8/MSTN (p < 0.05) were also observed. Conclusions: This study highlights potential circulating protein biomarkers associated with impaired oxytocin, NAD metabolism, and sex-related neuromuscular impairment in PWS individuals with potential clinical implications.PMID:39407757 | DOI:10.3390/jcm13195697