Journal Description
Metabolites
Metabolites
is an international, peer-reviewed, open access journal of metabolism and metabolomics, published monthly online by MDPI.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, Embase, CAPlus / SciFinder, and other databases.
- Journal Rank: JCR - Q2 (Biochemistry and Molecular Biology) / CiteScore - Q2 (Endocrinology, Diabetes and Metabolism)
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 13.9 days after submission; acceptance to publication is undertaken in 3.5 days (median values for papers published in this journal in the first half of 2024).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Impact Factor:
3.4 (2023);
5-Year Impact Factor:
4.0 (2023)
Latest Articles
Comparative Metabolic Profiling in Drosophila suzukii by Combined Treatment of Fumigant Phosphine and Low Temperature
Metabolites 2024, 14(10), 526; https://doi.org/10.3390/metabo14100526 (registering DOI) - 28 Sep 2024
Abstract
Background/Objectives: The mechanisms of action of phosphine are diverse and include neurotoxicity, metabolic inhibition, and oxidative stress; however, its efficacy at low temperatures is unclear. Methods: Comparative metabolomics is suitable for investigating the response of the spotted-wing fly Drosophila suzukii to exposure
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Background/Objectives: The mechanisms of action of phosphine are diverse and include neurotoxicity, metabolic inhibition, and oxidative stress; however, its efficacy at low temperatures is unclear. Methods: Comparative metabolomics is suitable for investigating the response of the spotted-wing fly Drosophila suzukii to exposure toward a combination of cold stimuli and fumigant PH3. Results: Under this combined exposure, 52 metabolites exhibiting significant differences in stress were identified and their physiological roles were analyzed in the Drosophila metabolic pathway. Most metabolites were involved in amino acids, TCA cycle, and nucleic acids. In addition, the alteration levels of cell membrane lipids, such as glycerophospholipids, sphingolipids, and glycerolipids, clearly showed changes in the combined treatment compared to PH3 and low temperatures alone. Aconitic acid, a component of the TCA cycle, was completely inhibited by the combined treatment. Conclusions: These results suggest that treatment-specific indicators could be useful biomarkers to indicate the synergistic effects of PH3 and low temperature on energy metabolism.
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(This article belongs to the Section Animal Metabolism)
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Hyperglycosylation as an Indicator of Aging in the Bone Metabolome of Oryzias latipes
by
Remi O. Labeille, Justin Elliott, Hussain Abdulla and Frauke Seemann
Metabolites 2024, 14(10), 525; https://doi.org/10.3390/metabo14100525 - 27 Sep 2024
Abstract
Chronological aging of bone tissues is a multi-faceted process that involves a complex interplay of cellular, biochemical, and molecular mechanisms. Metabolites play a crucial role for bone homeostasis, and a changed metabolome is indicative for bone aging, although bone metabolomics are currently understudied.
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Chronological aging of bone tissues is a multi-faceted process that involves a complex interplay of cellular, biochemical, and molecular mechanisms. Metabolites play a crucial role for bone homeostasis, and a changed metabolome is indicative for bone aging, although bone metabolomics are currently understudied. The vertebral bone metabolome of the model fish Japanese medaka (Oryzias latipes) was employed to identify sex-specific markers of bone aging. 265 and 213 metabolites were differently expressed in 8-month-old vs. 3-month-old female and male fish, respectively. The untargeted metabolomics pathway enrichment analysis indicated a sex-independent increased hyperglycosylation in 8-month-old individuals. The upregulated glycosylation pathways included glycosphingolipids, glycosylphosphatidylinositol anchors, O-glycans, and N-glycans. UDP-sugars and sialic acid were found to be major drivers in regulating glycosylation pathways and metabolic flux. The data indicate a disruption of protein processing at the endoplasmic reticulum and changes in O-glycan biosynthesis. Dysregulation of glycosylation, particularly through the hexosamine biosynthetic pathway, may contribute to bone aging and age-related bone loss. The results warrant further investigation into the functional involvement of increased glycosylation in bone aging. The potential of glycan-based biomarkers as early warning systems for bone aging should be explored and would aid in an advanced understanding of the progression of bone diseases such as osteoporosis.
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(This article belongs to the Special Issue Metabolism and Nutrition in Fish)
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The Effect of Vitamin D Supplementation with or without Calcium on Vitamin D Epimer and Metabolites
by
Salah Gariballa, Ghada S. M. Al-Bluwi and Javed Yasin
Metabolites 2024, 14(10), 524; https://doi.org/10.3390/metabo14100524 - 27 Sep 2024
Abstract
Background: A possible role of vitamin D epimers and metabolites in the measurement and response to treatment of vitamin D has been reported recently. Furthermore, the influence of underlying vitamin D receptor (VDR) genetic polymorphisms which have been linked to diseases such as
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Background: A possible role of vitamin D epimers and metabolites in the measurement and response to treatment of vitamin D has been reported recently. Furthermore, the influence of underlying vitamin D receptor (VDR) genetic polymorphisms which have been linked to diseases such as obesity remains unclear. We therefore aimed to examine the influence of vitamin D3 and calcium supplements on vitamin D epimer and metabolite concentrations in subjects with and those without vitamin D receptor (VDR) gene polymorphisms. Methods: A total of 277 participants who were part of a randomized intervention trial of vitamin D3 and calcium or a placebo for 6 months had clinical and anthropometric assessments. Blood samples were taken for measurements of vitamin D, epimers and metabolites of vitamin D, four vitamin D receptor gene polymorphism SNPs, namely, BsmI, FokI, TaqI, and ApaI, metabolic and inflammatory markers, and related biochemical variables. Repeated-measures analysis of variance was used to assess the between-group difference in cumulative changes in vitamin D epimers and metabolites at 6 months after adjusting for the presence of the 4 VDR genotypes and allele gene polymorphisms. Results: Overall, 277 participants, with a mean (±SD) age of 41 ± 12 and 204 (74%) of whom were female, were included in the study. We found no statistically significant differences in vitamin D metabolites or (epimers) between male and females or younger subjects compared to those over 40 years of age except in 7C4 BL (p < 0.05). There was a statistically significant difference in 1,25(OH)2D3 concentrations between subjects with and those without genotypes AG and the allele G SNP2_Taql VDR gene polymorphism. Vitamin D3 concentrations were also significantly lower in subjects with the CC SNP3_Apal gene polymorphism compared to those without the CC SNP3 gene. No statistically significant effects were seen on vitamin D epimers and metabolites concentration in response to supplements before or after adjusting for the presence of the 4 VDR genotypes and allele gene polymorphisms. Conclusions: The CC SNP3 gene had statistically significant influence on vitamin D3 levels. Vitamin D and/or calcium supplements, however, had no effects on vitamin D epimer and metabolite concentration before or after adjusting for the presence of the 4 VDR genotypes and alleles.
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(This article belongs to the Section Nutrition and Metabolism)
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Bioactive Compound Diversity in a Wide Panel of Sweet Potato (Ipomoea batatas L.) Cultivars: A Resource for Nutritional Food Development
by
Marion Nabot, Cyrielle Garcia, Marc Seguin, Julien Ricci, Catherine Brabet and Fabienne Remize
Metabolites 2024, 14(10), 523; https://doi.org/10.3390/metabo14100523 - 26 Sep 2024
Abstract
Objectives: This study provides an overview of the composition of the raw root flesh of a panel of 22 sweet potato (Ipomoea batatas L.) cultivars, with a focus on bioactive compounds. The large diversity of the proximate and phytochemical compositions observed between
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Objectives: This study provides an overview of the composition of the raw root flesh of a panel of 22 sweet potato (Ipomoea batatas L.) cultivars, with a focus on bioactive compounds. The large diversity of the proximate and phytochemical compositions observed between cultivars and within and between different flesh colors pointed out the importance of composition analysis and not only color choice for the design of foods with nutritional benefits. Methods: The nutritional composition (starch, protein, total dietary fibers) and bioactive compound composition of 22 cultivars from Reunion Island, maintained in the Vatel Biological Resource Center, were investigated. Results: Orange and purple cultivars stood out from white and yellow cultivars for their higher nutritional composition. Purple sweet potatoes were notable for their high contents of anthocyanins (55.7 to 143.4 mg/g dry weight (DW)) and phenolic compounds, in particular chlorogenic acid and ferulic acid, contributing to antioxidant activities, as well as their fiber content (14.1 ± 2.1% DW). Orange cultivars were rich in β-carotene (47.2 ± 0.7 mg/100 g DW) and to a lesser extent α-carotene (4.8 ± 1.2 mg/100 g DW). In contrast, certain white cultivars demonstrated suboptimal nutritional properties, rendering them less relevant even for applications where the lack of coloration in food is desired. Conclusions: Those characteristics enable the selection of sweet potato varieties to design food products ensuring optimal nutritional benefits and culinary versatility.
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(This article belongs to the Special Issue Plants and Plant-Based Foods for Metabolic Disease Prevention)
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Open AccessReview
Metabolite Measurement in Index Substrate Drug Interaction Studies: A Review of the Literature and Recent New Drug Application Reviews
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Jingjing Yu, Nathalie Rioux, Iain Gardner, Katie Owens and Isabelle Ragueneau-Majlessi
Metabolites 2024, 14(10), 522; https://doi.org/10.3390/metabo14100522 - 26 Sep 2024
Abstract
Background/Objectives: Index substrates are used to understand the processes involved in pharmacokinetic (PK) drug–drug interactions (DDIs). The aim of this analysis is to review metabolite measurement in clinical DDI studies, focusing on index substrates for cytochrome P450 (CYP) enzymes, including CYP1A2 (caffeine), CYP2B6
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Background/Objectives: Index substrates are used to understand the processes involved in pharmacokinetic (PK) drug–drug interactions (DDIs). The aim of this analysis is to review metabolite measurement in clinical DDI studies, focusing on index substrates for cytochrome P450 (CYP) enzymes, including CYP1A2 (caffeine), CYP2B6 (bupropion), CYP2C8 (repaglinide), CYP2C9 ((S)-warfarin, flurbiprofen), CYP2C19 (omeprazole), CYP2D6 (desipramine, dextromethorphan, nebivolol), and CYP3A (midazolam, triazolam). Methods: All data used in this evaluation were obtained from the Certara Drug Interaction Database. Clinical index substrate DDI studies with PK data for at least one metabolite, available from literature and recent new drug application reviews, were reviewed. Further, for positive DDI studies, a correlation analysis was performed between changes in plasma exposure of index substrates and their marker metabolites. Results: A total of 3261 individual index DDI studies were available, with 45% measuring at least one metabolite. The occurrence of metabolite measurement in clinical DDI studies varied widely between index substrates and enzymes. Discussion and Conclusions: For substrates such as caffeine, bupropion, omeprazole, and dextromethorphan, the use of the metabolite/parent area under the curve ratio can provide greater sensitivity to DDI or reduce intrasubject variability. In some cases (e.g., omeprazole, repaglinide), the inclusion of metabolite measurement can provide mechanistic insights to understand complex interactions.
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(This article belongs to the Special Issue The Role of Metabolites in Translational and Clinical Pharmacology)
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Struggling to Understand the NEC Spectrum—Could the Integration of Metabolomics, Clinical-Laboratory Data, and Other Emerging Technologies Help Diagnosis?
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Kosmas Sarafidis, Eleni Agakidou, Angeliki Kontou, Charalampos Agakidis and Josef Neu
Metabolites 2024, 14(10), 521; https://doi.org/10.3390/metabo14100521 - 26 Sep 2024
Abstract
Necrotizing enterocolitis (NEC) is the most prevalent and potentially fatal intestinal injury mainly affecting premature infants, with significant long-term consequences for those who survive. This review explores the scale of the problem, highlighting advancements in epidemiology, the understanding of pathophysiology, and improvements in
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Necrotizing enterocolitis (NEC) is the most prevalent and potentially fatal intestinal injury mainly affecting premature infants, with significant long-term consequences for those who survive. This review explores the scale of the problem, highlighting advancements in epidemiology, the understanding of pathophysiology, and improvements in the prediction and diagnosis of this complex, multifactorial, and multifaced disease. Additionally, we focus on the potential role of metabolomics in distinguishing NEC from other conditions, which could allow for an earlier and more accurate classification of intestinal injuries in infants. By integrating metabolomic data with other diagnostic approaches, it is hoped to enhance our ability to predict outcomes and tailor treatments, ultimately improving care for affected infants.
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(This article belongs to the Section Advances in Metabolomics)
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Salicylic Acid and Melatonin Synergy Enhances Boron Toxicity Tolerance via AsA–GSH Cycle and Glyoxalase System Regulation in Fragrant Rice
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Muhammad Imran, Emilie Widemann, Sarfraz Shafiq, Ali Bakhsh, Xiaoyuan Chen and Xiangru Tang
Metabolites 2024, 14(10), 520; https://doi.org/10.3390/metabo14100520 - 26 Sep 2024
Abstract
Background: Boron is an essential micronutrient for plant growth and productivity, yet excessive boron leads to toxicity, posing significant challenges for agriculture. Fragrant rice is popular among consumers, but the impact of boron toxicity on qualitative traits of fragrant rice, especially aroma, remains
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Background: Boron is an essential micronutrient for plant growth and productivity, yet excessive boron leads to toxicity, posing significant challenges for agriculture. Fragrant rice is popular among consumers, but the impact of boron toxicity on qualitative traits of fragrant rice, especially aroma, remains largely unexplored. The individual potentials of melatonin and salicylic acid in reducing boron toxicity are less known, while their synergistic effects and mechanisms in fragrant rice remain unclear. Methods: Thus, this study investigates the combined application of melatonin and salicylic acid on fragrant rice affected by boron toxicity. One-week-old seedlings were subjected to boron (0 and 800 µM) and then treated with melatonin and salicylic acid (0 and 100 µM, for 3 weeks). Results: Boron toxicity significantly impaired photosynthetic pigments, plant growth, and chloroplast integrity while increasing oxidative stress markers such as hydrogen peroxide, malondialdehyde, methylglyoxal, and betaine aldehyde dehydrogenase. Likewise, boron toxicity abridged the precursors involved in the 2-acetyl-1-pyrroline (2-AP) biosynthesis pathway. However, individual as well as combined application of melatonin and salicylic acid ameliorated boron toxicity by strengthening the antioxidant defense mechanisms—including the enzymes involved during the ascorbate–glutathione (AsA–GSH) cycle and glyoxalase system—and substantially improved 2-AP precursors including proline, P5C, Δ1-pyrroline, and GABA levels, thereby restoring the 2-AP content and aroma. These findings deduce that melatonin and salicylic acid synergistically alleviate boron toxicity-induced disruptions on the 2-AP biosynthesis pathway by improving the 2-AP precursors and enzymatic activities, as well as modulating the physio-biochemical processes and antioxidant defense system of fragrant rice plants. Conclusions: The findings of this study have the potential to enhance rice productivity and stress tolerance, offering solutions to improve food security and sustainability in agricultural practices, particularly in regions affected by environmental stressors.
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(This article belongs to the Special Issue Effect of Exogenous or Endogenous Regulatory Factors on Metabolic Responses of Plants to Biotic/Abiotic Stress)
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Non-Nucleoside Lycorine-Based Analogs as Potential DENV/ZIKV NS5 Dual Inhibitors: Structure-Based Virtual Screening and Chemoinformatic Analysis
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Adrián Camilo Rodríguez-Ararat, Yasser Hayek-Orduz, Andrés-Felipe Vásquez, Felipe Sierra-Hurtado, María-Francisca Villegas-Torres, Paola A. Caicedo-Burbano, Luke E. K. Achenie and Andrés Fernando González Barrios
Metabolites 2024, 14(10), 519; https://doi.org/10.3390/metabo14100519 - 26 Sep 2024
Abstract
Dengue (DENV) and Zika (ZIKV) virus continue to pose significant challenges globally due to their widespread prevalence and severe health implications. Given the absence of effective vaccines and specific therapeutics, targeting the highly conserved NS5 RNA-dependent RNA polymerase (RdRp) domain has emerged as
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Dengue (DENV) and Zika (ZIKV) virus continue to pose significant challenges globally due to their widespread prevalence and severe health implications. Given the absence of effective vaccines and specific therapeutics, targeting the highly conserved NS5 RNA-dependent RNA polymerase (RdRp) domain has emerged as a promising strategy. However, limited efforts have been made to develop inhibitors for this crucial target. In this study, we employed an integrated in silico approach utilizing combinatorial chemistry, docking, molecular dynamics simulations, MM/GBSA, and ADMET studies to target the allosteric N-pocket of DENV3-RdRp and ZIKV-RdRp. Using this methodology, we designed lycorine analogs with natural S-enantiomers (LYCS) and R-enantiomers (LYCR) as potential inhibitors of non-structural protein 5 (NS5) in DENV3 and ZIKV. Notably, 12 lycorine analogs displayed a robust binding free energy (<−9.00 kcal/mol), surpassing that of RdRp-ribavirin (<−7.00 kcal/mol) along with promising ADMET score predictions (<4.00), of which (LYCR728-210, LYCS728-210, LYCR728-212, LYCS505-214) displayed binding properties to both DENV3 and ZIKV targets. Our research highlights the potential of non-nucleoside lycorine-based analogs with different enantiomers that may present different or even completely opposite metabolic, toxicological, and pharmacological profiles as promising candidates for inhibiting NS5-RdRp in ZIKV and DENV3, paving the way for further exploration for the development of effective antiviral agents.
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(This article belongs to the Section Pharmacology and Drug Metabolism)
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Association of Firmicutes/Bacteroidetes Ratio with Body Mass Index in Korean Type 2 Diabetes Mellitus Patients
by
Kainat Ahmed, Ha-Neul Choi, Sung-Rae Cho and Jung-Eun Yim
Metabolites 2024, 14(10), 518; https://doi.org/10.3390/metabo14100518 - 26 Sep 2024
Abstract
Background: The gut microbiome, which is the collection of microorganisms living in the gastrointestinal tract, has been shown to play a significant role in the development of metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM). Studies have found that the
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Background: The gut microbiome, which is the collection of microorganisms living in the gastrointestinal tract, has been shown to play a significant role in the development of metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM). Studies have found that the ratio of Firmicutes to Bacteroidetes (F/B) is higher in obese individuals compared to lean individuals and tends to decrease with weight loss. However, the relationship between the F/B ratio and T2DM in Korean individuals, with or without obesity, is not fully understood. Objective: The objective of this study is to compare the F/B ratios and metabolic profiles of lean and obese Korean individuals with T2DM. Methods: In this study, 36 individuals with type 2 diabetes mellitus (T2DM) were recruited and classified into four groups (I, II, III, and IV) based on their body mass index (BMI). Group I had a BMI of less than 23.0, group II had a BMI between 23.0 and 24.9, group III had a BMI between 25.0 and 29.9, and group IV had a BMI of 30 kg/m2 or greater. Fecal samples were collected from all participants and sent to Chunlab Inc. (located in Seoul, Republic of Korea) for analysis. The changes in the major microbial phyla within the samples were investigated using quantitative real-time PCR. The collected data were then statistically analyzed using the SPSS program. Results: The levels of triglycerides and alanine transaminase in group I were significantly lower than in the other three groups. The amount of Actinobacteria in group IV was the highest among all four groups. The ratio of Firmicutes to Bacteroidetes increased as BMI increased, and this ratio was positively correlated with AST activity. Conclusions: Our study showed that there is a correlation between the degree of obesity in individuals with diabetes and their gut microbiome. Additionally, the ratio of Firmicutes to Bacteroidetes (F/B ratio) may play a role in the metabolic effects of fatty liver disease, as it may contribute to obesity.
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(This article belongs to the Special Issue Targeting Microbiota and Metabolites for Prevention and Treatment of Human Diseases)
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Ultra-High-Performance Liquid Chromatography–High-Definition Mass Spectrometry-Based Metabolomics to Reveal the Potential Anti-Arthritic Effects of Illicium verum in Cultured Fibroblast-like Synoviocytes Derived from Rheumatoid Arthritis
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Mingzhen Qin, Lu Chen, Xiaoli Hou, Wuwei Wu, Yu Liu, Yu Pan, Mengli Zhang, Zhien Tan and Danna Huang
Metabolites 2024, 14(10), 517; https://doi.org/10.3390/metabo14100517 - 25 Sep 2024
Abstract
Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. The fruits of Illicium verum, which is a medicinal and edible resource, have been shown to have anti-inflammatory properties. Methods: In this study, we investigated the effects of I. verum extracts (IVEs)
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Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. The fruits of Illicium verum, which is a medicinal and edible resource, have been shown to have anti-inflammatory properties. Methods: In this study, we investigated the effects of I. verum extracts (IVEs) on human RA fibroblasts-like synoviocytes (RA-FLS) by using a sensitive and selective ultra-high-performance liquid chromatography with high-definition mass spectrometry (UPLC-HDMS) method. We subsequently analyzed the metabolites produced after the incubation of cultured RA-FLS with IVEs. Results: IVEs inhibited the proliferation and suppressed the migration of RA-FLS, and reduced the levels of inflammatory factors including TNF-α and IL-6. Twenty differential metabolites responsible for the effects of IVEs were screened and annotated based on the UPLC-HDMS data by using a cell metabolomics approach. Discussion: Our findings suggest that treating RA-FLS with IVEs can regulate lipid and amino acid metabolism, indicating that this extract has the potential to modify the metabolic pathways that cause inflammation in RA. Conclusions: This might lead to novel therapeutic strategies for managing patients with RA.
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(This article belongs to the Section Plant Metabolism)
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The Causal Effect of Urate Level on Female Infertility: A Mendelian Randomization Study
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Jiawei Sun, Ting Shen, Yining Guan, Yixin Jiang and Xiaoling Xu
Metabolites 2024, 14(10), 516; https://doi.org/10.3390/metabo14100516 - 25 Sep 2024
Abstract
Background/Objective: This study aimed to investigate the causal relationship between urate level and female infertility using Mendelian randomization (MR) analysis. Methods: To identify instrumental variables, we selected independent genetic loci associated with serum urate levels in individuals of European ancestry, utilizing data from
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Background/Objective: This study aimed to investigate the causal relationship between urate level and female infertility using Mendelian randomization (MR) analysis. Methods: To identify instrumental variables, we selected independent genetic loci associated with serum urate levels in individuals of European ancestry, utilizing data from large-scale genome-wide association studies (GWAS). The GWAS dataset included information on serum urate levels from 288,649 CKDGen participants. Female infertility data, including different etiologic classifications, consisted of 13,142 female infertility patients and 107,564 controls. We employed four MR methods, namely inverse variance weighted (IVW), MR-Egger, weighted median, and weighted model, to investigate the causal relationship between urate levels and female infertility. The Cochran Q-test was used to assess heterogeneity among single nucleotide polymorphisms (SNPs), and the MR-Egger intercept test was employed to evaluate the presence of horizontal pleiotropy. Additionally, a “leave-one-out” sensitivity analysis was conducted to examine the influence of individual SNPs on the MR study. Results: The IVW analysis demonstrated that elevated serum urate levels increased the risk of female infertility (odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.07–1.33). Furthermore, serum urate levels were found to be associated with infertility due to cervical, vaginal, or other unknown causes (OR = 1.16, 95% CI: 1.06–1.26), also confirmed by other methods. Heterogeneity among instrumental variables was assessed using Cochran’s Q-test (p < 0.05), so a random-effects IVW approach was employed in the effects model. The MR-Egger intercept test indicated no presence of horizontal pleiotropy. A “leave-one-out” sensitivity analysis was conducted, demonstrating that no individual SNP had a substantial impact on the overall findings. Conclusions: In the European population, the urate level is significantly and causally associated with an increased risk of female infertility.
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(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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Global and Targeted Metabolomics for Revealing Metabolomic Alteration in Niemann-Pick Disease Type C Model Cells
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Masahiro Watanabe, Masamitsu Maekawa, Keitaro Miyoshi, Toshihiro Sato, Yu Sato, Masaki Kumondai, Masayoshi Fukasawa and Nariyasu Mano
Metabolites 2024, 14(10), 515; https://doi.org/10.3390/metabo14100515 - 24 Sep 2024
Abstract
Background: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by a functional deficiency of cholesterol transport proteins. However, the molecular mechanisms and pathophysiology of the disease remain unknown. Methods: In this study, we identified several metabolite characteristics of NPC that may
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Background: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by a functional deficiency of cholesterol transport proteins. However, the molecular mechanisms and pathophysiology of the disease remain unknown. Methods: In this study, we identified several metabolite characteristics of NPC that may fluctuate in a cellular model of the disease, using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Three cell lines, HepG2 cells (wild-type[WT]) and two NPC model HepG2 cell lines in which NPC1 was genetically ablated (knockout [KO]1 and KO2), were used for metabolomic analysis. Data were subjected to enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Results: The enrichment analysis of global metabolomics revealed that 8 pathways in KO1 and 16 pathways in KO2 cells were notably altered. In targeted metabolomics for 15 metabolites, 4 metabolites in KO1 and 10 metabolites in KO2 exhibited statistically significant quantitative changes in KO1 or KO2 relative to WT. Most of the altered metabolites were related to creatinine synthesis and cysteine metabolism pathways. Conclusions: In the future, our objective will be to elucidate the relationship between these metabolic alterations and pathophysiology.
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(This article belongs to the Special Issue Advances in Cellular Metabolism and Regulation)
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Relationship of SOD-1 Activity in Metabolic Syndrome and/or Frailty in Elderly Individuals
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Sylwia Dzięgielewska-Gęsiak, Ewa Wysocka, Edyta Fatyga and Małgorzata Muc-Wierzgoń
Metabolites 2024, 14(9), 514; https://doi.org/10.3390/metabo14090514 - 23 Sep 2024
Abstract
Introduction: Although aging is a natural phenomenon, in recent years it has accelerated. One key factor implicated in the aging process is oxidative stress. Oxidative stress also plays a role in frailty (frail) and metabolic syndrome (MetS). Methods: A total of 66 elderly
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Introduction: Although aging is a natural phenomenon, in recent years it has accelerated. One key factor implicated in the aging process is oxidative stress. Oxidative stress also plays a role in frailty (frail) and metabolic syndrome (MetS). Methods: A total of 66 elderly persons (65 years old and older) with no acute or severe chronic disorders were assessed for waist circumference (WC), arterial blood pressure, glycemia, glycated hemoglobin (HbA1c), plasma lipids, and activity of erythrocyte superoxide dismutase (SOD-1). Patients were classified as NonMetS-Nonfrail (n = 19), NonMetS-frail (n = 20), MetS-Nonfrail (n = 17), or MetS-frail (n = 10). Results: There were no significant differences in superoxide dismutase activity among investigated elderly groups. However, the data suggest that MetS individuals, both frail and nonfrail, have higher risk factors for cardiovascular disease compared to NonMetS individuals. The correlations analyses of SOD-1 and other metabolic indices suggest that SOD-1 levels may be influenced by age, total cholesterol, HDL cholesterol, and fasting glucose levels in certain groups of seniors. Conclusions: Aging is associated with decreased antioxidant enzyme SOD-1 activity with glucose alteration in frailty syndrome as well as with lipids disturbances in metabolic syndrome. These factors provide a nuanced view of how frailty and metabolic syndrome interact with various health parameters, informing both clinical practice and future research directions.
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(This article belongs to the Special Issue Inflammation and Oxidative Stress in Age-Related Metabolic Changes and Disorders)
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Liquid Chromatography/Tandem Mass Spectrometry-Based Simultaneous Analysis of 32 Bile Acids in Plasma and Conventional Biomarker-Integrated Diagnostic Screening Model Development for Hepatocellular Carcinoma
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Minami Yamauchi, Masamitsu Maekawa, Toshihiro Sato, Yu Sato, Masaki Kumondai, Mio Tsuruoka, Jun Inoue, Atsushi Masamune and Nariyasu Mano
Metabolites 2024, 14(9), 513; https://doi.org/10.3390/metabo14090513 - 23 Sep 2024
Abstract
Imaging tests, tumor marker (TM) screening, and biochemical tests provide a definitive diagnosis of hepatocellular carcinoma (HCC). However, some patients with HCC may present TM-negative results, warranting a need for developing more sensitive and accurate screening biomarkers. Various diseases exhibit increased blood levels
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Imaging tests, tumor marker (TM) screening, and biochemical tests provide a definitive diagnosis of hepatocellular carcinoma (HCC). However, some patients with HCC may present TM-negative results, warranting a need for developing more sensitive and accurate screening biomarkers. Various diseases exhibit increased blood levels of bile acids, biosynthesized from cholesterol in the liver, and they have been associated with HCC. Herein, we analyzed plasma bile acids using liquid chromatography/tandem mass spectrometry and integrated them with conventional biomarkers to develop a diagnostic screening model for HCC. Plasma samples were obtained from patients diagnosed with chronic hepatitis, hepatic cirrhosis (HC), and HCC. A QTRAP 6500 mass spectrometer and a Nexera liquid chromatograph with a YMC-Triart C18 analytical column were used. The mobile phase A was a 20 mmol/L ammonium formate solution, and mobile phase B was a methanol/acetonitrile mixture (1:1, v/v) with 20 mmol/L ammonium formate. After determining the concentrations of 32 bile acids, statistical analysis and diagnostic screening model development were performed. Plasma concentrations of bile acids differed between sample groups, with significant differences observed between patients with HC and HCC. By integrating bile acid results with conventional biochemical tests, a potential diagnostic screening model for HCC was successfully developed. Future studies should increase the sample size and analyze the data in detail to verify the diagnostic efficacy of the model.
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(This article belongs to the Topic Cancer Cell Metabolism (2nd Edition))
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Metabolic Predictors of Cardiorespiratory Fitness Responsiveness to Continuous Endurance and High-Intensity Interval Training Programs: The TIMES Study—A Randomized Controlled Trial
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Alex Castro, Antonio Gilberto Ferreira, Aparecida Maria Catai, Matheus Alejandro Bolina Amaral, Claudia Regina Cavaglieri and Mara Patrícia Traina Chacon-Mikahil
Metabolites 2024, 14(9), 512; https://doi.org/10.3390/metabo14090512 - 23 Sep 2024
Abstract
Background/Objectives: Cardiorespiratory fitness (CRF) levels significantly modulate the risk of cardiometabolic diseases, aging, and mortality. Nevertheless, there is a substantial interindividual variability in CRF responsiveness to a given standardized exercise dose despite the type of training. Predicting the responsiveness to regular exercise has
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Background/Objectives: Cardiorespiratory fitness (CRF) levels significantly modulate the risk of cardiometabolic diseases, aging, and mortality. Nevertheless, there is a substantial interindividual variability in CRF responsiveness to a given standardized exercise dose despite the type of training. Predicting the responsiveness to regular exercise has the potential to contribute to personalized exercise medicine applications. This study aimed to identify predictive biomarkers for the classification of CRF responsiveness based on serum and intramuscular metabolic levels before continuous endurance training (ET) or high-intensity interval training (HIIT) programs using a randomized controlled trial. Methods: Forty-three serum and seventy intramuscular (vastus lateralis) metabolites were characterized and quantified via proton nuclear magnetic resonance (1H NMR), and CRF levels (expressed in METs) were measured in 70 sedentary young men (age: 23.7 ± 3.0 years; BMI: 24.8 ± 2.5 kg·m−2), at baseline and post 8 weeks of the ET, HIIT, and control (CO) periods. A multivariate binary logistic regression model was used to classify individuals at baseline as Responders or Non-responders to CRF gains after the training programs. Results: CRF responses ranged from 0.9 to 3.9 METs for ET, 1.1 to 4.7 METs for HIIT, and −0.9 to 0.2 METs for CO. The frequency of Responder/Non-responder individuals between ET (76.7%/23.3%) and HIIT (90.0%/10.0%) programs was similar (p = 0.166). The model based on serum O-acetylcarnitine levels [OR (odds ratio) = 4.72, p = 0.012] classified Responder/Non-responders individuals to changes in CRF regardless of the training program with 78.0% accuracy (p = 0.006), while the intramuscular model based on creatinine levels (OR = 4.53, p = 0.0137) presented 72.3% accuracy (p = 0.028). Conclusions: These results highlight the potential value of serum and intramuscular metabolites as biomarkers for the classification of CRF responsiveness previous to different aerobic training programs.
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(This article belongs to the Special Issue Metabolomic Advances in Promoting Exercise-Induced Metabolic Changes)
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Open AccessArticle
Comprehensive Secondary Metabolite Profiling and Antioxidant Activity of Aqueous and Ethanol Extracts of Neolamarckia cadamba (Roxb.) Bosser Fruits
by
Lin Yang, Liyan Wu, Yongxin Li, Yuhui Yang, Yuting Gu, Jialin Yang, Luzy Zhang and Fanxin Meng
Metabolites 2024, 14(9), 511; https://doi.org/10.3390/metabo14090511 - 21 Sep 2024
Abstract
Background: Neolamarckia cadamba (Rubiaceae) is a well-recognized medicinal plant with recorded therapeutical attributes. However, a thorough assessment of active compounds in its fruits is lacking, limiting their use and valorization in pharmacological industries. Methods: Thus, this study investigated variations in the fruits’ secondary
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Background: Neolamarckia cadamba (Rubiaceae) is a well-recognized medicinal plant with recorded therapeutical attributes. However, a thorough assessment of active compounds in its fruits is lacking, limiting their use and valorization in pharmacological industries. Methods: Thus, this study investigated variations in the fruits’ secondary metabolite (SM) profiles, as well as antioxidant activities in aqueous (WA) and ethanol (ET) extracts. Results: Liquid chromatography–electrospray ionization tandem mass spectrometry identified 541 SMs, of which 14 and 1 (di-O-glucosylquinic acid) were specifically detected in ET and WA, respectively. Phenolic acids (36.97%), flavonoids (28.10%), terpenoids (12.20%), and alkaloids (9.98%) were the dominant SMs. The SM profiles of the fruits in WA and ET were quite different. We revealed 198 differentially extracted (DE) metabolites between WA and ET, including 62 flavonoids, 57 phenolic acids, 45 terpenoids, 14 alkaloids, etc. Most DE flavones (36 out of 40), terpenoids (45 out of 45), and alkaloids (12 out of 14) had higher content in ET. Catechin and its derivatives, procyanidins, and tannins had higher content in WA. ABTS and DPPH assays showed that the antioxidant activity of ET was significantly higher than that of WA. Conclusions: Our findings will facilitate the efficient extraction and evaluation of specific active compounds in N. cadamba.
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(This article belongs to the Section Plant Metabolism)
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Open AccessArticle
Predicting the Association of Metabolites with Both Pathway Categories and Individual Pathways
by
Erik D. Huckvale and Hunter N. B. Moseley
Metabolites 2024, 14(9), 510; https://doi.org/10.3390/metabo14090510 - 21 Sep 2024
Abstract
Metabolism is a network of chemical reactions that sustain cellular life. Parts of this metabolic network are defined as metabolic pathways containing specific biochemical reactions. Products and reactants of these reactions are called metabolites, which are associated with certain human-defined metabolic pathways. Metabolic
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Metabolism is a network of chemical reactions that sustain cellular life. Parts of this metabolic network are defined as metabolic pathways containing specific biochemical reactions. Products and reactants of these reactions are called metabolites, which are associated with certain human-defined metabolic pathways. Metabolic knowledgebases, such as the Kyoto Encyclopedia of Gene and Genomes (KEGG) contain metabolites, reactions, and pathway annotations; however, such resources are incomplete due to current limits of metabolic knowledge. To fill in missing metabolite pathway annotations, past machine learning models showed some success at predicting the KEGG Level 2 pathway category involvement of metabolites based on their chemical structure. Here, we present the first machine learning model to predict metabolite association to more granular KEGG Level 3 metabolic pathways. We used a feature and dataset engineering approach to generate over one million metabolite-pathway entries in the dataset used to train a single binary classifier. This approach produced a mean Matthews correlation coefficient (MCC) of 0.806 ± 0.017 SD across 100 cross-validation iterations. The 172 Level 3 pathways were predicted with an overall MCC of 0.726. Moreover, metabolite association with the 12 Level 2 pathway categories was predicted with an overall MCC of 0.891, representing significant transfer learning from the Level 3 pathway entries. These are the best metabolite pathway prediction results published so far in the field.
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(This article belongs to the Special Issue Machine Learning Applications in Metabolomics Analysis)
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Investigating the Mechanisms of 15-PGDH Inhibitor SW033291 in Improving Type 2 Diabetes Mellitus: Insights from Metabolomics and Transcriptomics
by
Yuanfeng Huang, Mingjie Liang, Yiwen Liao, Zirui Ji, Wanfen Lin, Xiangjin Pu, Lexun Wang and Weixuan Wang
Metabolites 2024, 14(9), 509; https://doi.org/10.3390/metabo14090509 - 20 Sep 2024
Abstract
This study focused on exploring the effects of SW033291, an inhibitor of 15-hydroxyprostaglandin dehydrogenase, on type 2 diabetes mellitus (T2DM) mice from a comprehensive perspective. Studies have demonstrated that SW033291 benefits tissue repair, organ function, and muscle mass in elderly mice. Our recent
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This study focused on exploring the effects of SW033291, an inhibitor of 15-hydroxyprostaglandin dehydrogenase, on type 2 diabetes mellitus (T2DM) mice from a comprehensive perspective. Studies have demonstrated that SW033291 benefits tissue repair, organ function, and muscle mass in elderly mice. Our recent investigation initially reported the beneficial effect of SW033291 on T2DM progression. Herein, we used a T2DM mouse model induced by a high-fat diet and streptozotocin injection. Then, serum and liver metabolomics, as well as liver transcriptomic analyses, were performed to provide a systematic perspective of the SW033291-ameliorated T2DM. The results indicate SW033291 improved T2DM by regulating steroid hormone biosynthesis and linoleic/arachidonic acid metabolism. Furthermore, integrated transcriptomic and metabolomic analyses suggested that key genes and metabolites such as Cyp2c55, Cyp3a11, Cyp21a1, Myc, Gstm1, Gstm3, 9,10-dihydroxyoctadecenoic acid, 11-dehydrocorticosterone, and 12,13-dihydroxy-9Z-octadecenoic acid played crucial roles in these pathways. qPCR analysis validated the significant decreases in the hepatic gene expressions of Cyp2c55, Cyp3a11, Myc, Gstm1, and Gstm3 in the T2DM mice, which were reversed following SW033291 treatment. Meanwhile, the elevated mRNA level of Cyp21a1 in T2DM mice was decreased after SW033291 administration. Taken together, our findings suggest that SW033291 has promising potential in alleviating T2DM and could be a novel therapeutic candidate.
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(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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Understanding the Genetic Landscape of Gestational Diabetes: Insights into the Causes and Consequences of Elevated Glucose Levels in Pregnancy
by
Caroline Brito Nunes, Maria Carolina Borges, Rachel M. Freathy, Deborah A. Lawlor, Elisabeth Qvigstad, David M. Evans and Gunn-Helen Moen
Metabolites 2024, 14(9), 508; https://doi.org/10.3390/metabo14090508 - 20 Sep 2024
Abstract
Background/Objectives: During pregnancy, physiological changes in maternal circulating glucose levels and its metabolism are essential to meet maternal and fetal energy demands. Major changes in glucose metabolism occur throughout pregnancy and consist of higher insulin resistance and a compensatory increase in insulin secretion
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Background/Objectives: During pregnancy, physiological changes in maternal circulating glucose levels and its metabolism are essential to meet maternal and fetal energy demands. Major changes in glucose metabolism occur throughout pregnancy and consist of higher insulin resistance and a compensatory increase in insulin secretion to maintain glucose homeostasis. For some women, this change is insufficient to maintain normoglycemia, leading to gestational diabetes mellitus (GDM), a condition characterized by maternal glucose intolerance and hyperglycaemia first diagnosed during the second or third trimester of pregnancy. GDM is diagnosed in approximately 14.0% of pregnancies globally, and it is often associated with short- and long-term adverse health outcomes in both mothers and offspring. Although recent studies have highlighted the role of genetic determinants in the development of GDM, research in this area is still lacking, hindering the development of prevention and treatment strategies. Methods: In this paper, we review recent advances in the understanding of genetic determinants of GDM and glycaemic traits during pregnancy. Results/Conclusions: Our review highlights the need for further collaborative efforts as well as larger and more diverse genotyped pregnancy cohorts to deepen our understanding of the genetic aetiology of GDM, address research gaps, and further improve diagnostic and treatment strategies.
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(This article belongs to the Special Issue Glucose Metabolism in Pregnancy)
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Rice Varieties Intercropping Induced Soil Metabolic and Microbial Recruiting to Enhance the Rice Blast (Magnaporthe Oryzae) Resistance
by
Xiao-Qiao Zhu, Mei Li, Rong-Ping Li, Wen-Qiang Tang, Yun-Yue Wang, Xiao Fei, Ping He and Guang-Yu Han
Metabolites 2024, 14(9), 507; https://doi.org/10.3390/metabo14090507 - 20 Sep 2024
Abstract
[Background] Intercropping is considered an effective approach to defending rice disease. [Objectives/Methods] This study aimed to explore the resistance mechanism of rice intraspecific intercropping by investigating soil metabolites and their regulation on the rhizosphere soil microbial community using metabolomic and microbiome analyses. [Results]
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[Background] Intercropping is considered an effective approach to defending rice disease. [Objectives/Methods] This study aimed to explore the resistance mechanism of rice intraspecific intercropping by investigating soil metabolites and their regulation on the rhizosphere soil microbial community using metabolomic and microbiome analyses. [Results] The results showed that the panicle blast disease occurrence of the resistant variety Shanyou63 (SY63) and the susceptible variety Huangkenuo (HKN) were both decreased in the intercropping compared to monoculture. Notably, HKN in the intercropping system exhibited significantly decreased disease incidence and increased disease resistance-related enzyme protease activity. KEGG annotation from soil metabolomics analysis revealed that phenylalanine metabolic pathway, phenylalanine, tyrosine, and tryptophan biosynthesis pathway, and fructose and mannose metabolic pathway were the key pathways related to rice disease resistance. Soil microbiome analysis indicated that the bacterial genera Nocardioides, Marmoricola, Luedemannella, and Desulfomonile were significantly enriched in HKN after intercropping, while SY63 experienced a substantial accumulation of Ruminiclostridium and Cellulomonas. Omics-based correlation analysis highlighted that the community assembly of Cellulomonas and Desulfomonile significantly affected the content of the metabolites D-sorbitol, D-mannitol, quinic acid, which further proved that quinic acid had a significantly inhibitory effect on the mycelium growth of Magnaporthe oryzae, and these three metabolites had a significant blast control effect. The optimal rice blast-control efficiency on HKN was 51.72%, and Lijiangxintuanheigu (LTH) was 64.57%. [Conclusions] These findings provide a theoretical basis for rice varieties intercropping and sustainable rice production, emphasizing the novelty of the study in elucidating the underlying mechanisms of intercropping-mediated disease resistance.
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(This article belongs to the Section Microbiology and Ecological Metabolomics)
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