PubMed

Clin Transl Med. 2024 Jun;14(6):e1727. doi: 10.1002/ctm2.1727.ABSTRACTBACKGROUND: The liver is anatomically divided into eight segments based on the distribution of Glisson's triad. However, the molecular mechanisms underlying each segment and its association with hepatocellular carcinoma (HCC) heterogeneity are not well understood. In this study, our objective is to conduct a comprehensive multiomics profiling of the segmentation atlas in order to investigate potential subtypes and therapeutic approaches for HCC.METHODS: A high throughput liquid chromatography-tandem mass spectrometer strategy was employed to comprehensively analyse proteome, lipidome and metabolome data, with a focus on segment-resolved multiomics profiling. To classify HCC subtypes, the obtained data with normal reference profiling were integrated. Additionally, potential therapeutic targets for HCC were identified using immunohistochemistry assays. The effectiveness of these targets were further validated through patient-derived organoid (PDO) assays.RESULTS: A multiomics profiling of 8536 high-confidence proteins, 1029 polar metabolites and 3381 nonredundant lipids was performed to analyse the segmentation atlas of HCC. The analysis of the data revealed that in normal adjacent tissues, the left lobe was primarily involved in energy metabolism, while the right lobe was associated with small molecule metabolism. Based on the normal reference atlas, HCC patients with segment-resolved classification were divided into three subtypes. The C1 subtype showed enrichment in ribosome biogenesis, the C2 subtype exhibited an intermediate phenotype, while the C3 subtype was closely associated with neutrophil degranulation. Furthermore, using the PDO assay, exportin 1 (XPO1) and 5-lipoxygenase (ALOX5) were identified as potential targets for the C1 and C3 subtypes, respectively.CONCLUSION: Our extensive analysis of the segmentation atlas in multiomics profiling defines molecular subtypes of HCC and uncovers potential therapeutic strategies that have the potential to enhance the prognosis of HCC.PMID:38804617 | DOI:10.1002/ctm2.1727

Heliyon. 2024 May 10;10(10):e30868. doi: 10.1016/j.heliyon.2024.e30868. eCollection 2024 May 30.ABSTRACTLicorice is a well-known Chinese medicinal plant that is widely used to treat multiple diseases and process food; however, wild licorice is now facing depletion. Therefore, there is an urgent need to identify and protect licorice germplasm diversity. In this study, metabolomic and transcriptomic analyses were conducted to investigate the biodiversity and potential medicinal value of the rare wild Glycyrrhiza squamulose. A total of 182 differentially accumulated metabolites and 395 differentially expressed genes were identified by comparing Glycyrrhiza uralensis and Glycyrrhiza squamulose. The molecular weights of the chemical component of G. squamulose were comparable with those of G. uralensis, suggesting that G. squamulose may have medicinal value. Differentially accumulated metabolites (DAMs), mainly flavonoids such as kaempferol-3-O-galactoside, kaempferol-3-O-(6"malonyl) glucoside, and hispidulin-7-O-glucoside, showed potential vitality in G. squamulose. Comparative transcriptomics with G. uralensis showed that among the 395 differentially expressed genes (DEGs), 69 were enriched in the isoflavonoid biosynthesis pathway. Multiomics analysis showed that the distinction in flavonoid biosynthesis between G. squamulose and G. uralensis was strongly associated with the expression levels of IF7GT and CYP93C. In addition to identifying similarities and differences between G. squamulose and G. uralensis, this study provides a theoretical basis to protect and investigate rare species such as G. squamulose.PMID:38803917 | PMC:PMC11128877 | DOI:10.1016/j.heliyon.2024.e30868

Heliyon. 2024 May 14;10(10):e31149. doi: 10.1016/j.heliyon.2024.e31149. eCollection 2024 May 30.ABSTRACTThe reserve of glycogen is essential for embryonic development. In oviparous fish, egg is an isolated system after egg laying with all the required energy deposits by their mothers. However, the key regulated factor mediates the storage of maternal glycogen reserve which support for embryogenesis in the offspring is largely unknown. Glycogen synthase (GYS) is a central enzyme for glycogen synthesis. In our previous study, we generated a gys1 knockout zebrafish line, showed an embryonic developmental defect in F3 generation. In this study, firstly we determined that the gys1 was maternal origin by backcrossing the F2 mutant with wildtype lines. PAS staining and glycogen content measurement showed that glycogen reserve was reduced both in ovaries and embryos in the mutant group compared to wildtypes. Free glucose measurement analysis showed a 50 % of reduction in gys1 mutant embryos compared to wildtype embryos at 24 hpf; showed an approximal 50 % of reduction in gys1 mutant adults compared to wildtypes. Microinjection of 2-NBDG in embryos and comparison of fluorescent signal demonstrated that glucose uptake ability was decreased in the mutant embryos, indicating an impaired glucose metabolism. Untargeted metabolomics analysis then was employed and revealed that key modified metabolites enriched into vitamin B pathway, carbohydrate and unsaturated fatty acid pathways. These results demonstrated that gys1 played a role on glycogen metabolism, involved into the maternal glycogen reserve which essentially contribute to embryonic development.PMID:38803914 | PMC:PMC11128933 | DOI:10.1016/j.heliyon.2024.e31149

Food Chem X. 2024 May 14;22:101460. doi: 10.1016/j.fochx.2024.101460. eCollection 2024 Jun 30.ABSTRACTThe effects of irradiation on pork quality characteristics were investigated by combining sensory experiments, pork color, TBARS, volatile components, and differential metabolites. Pork irradiated at a dose of 1 kGy received the highest sensory scores, whereas pork irradiated at doses of 3 and 5 kGy obtained lower sensory scores, particularly with regard to odor. Irradiation makes pork more ruddy and promotes fat oxidation, leading to increased a* and TBARS values. The main volatile substances in irradiated pork were hydrocarbons, aldehydes, and alcohols, and hexanal, heptanal, and valeric acid were considered as important substances responsible for the generation of radiation-induced off-flavors. 65 differential metabolites were identified. l-pyroglutamic acid, l-glutamate, l-proline, fumarate acids, betaine, and l-anserine were considered as the main substances contributing to the differences in pork quality. In addition, metabolic pathways such as arginine biosynthesis, alanine, aspartate and glutamate metabolism were found to be considerably affected by irradiation.PMID:38803672 | PMC:PMC11129168 | DOI:10.1016/j.fochx.2024.101460

Front Plant Sci. 2024 May 13;15:1378707. doi: 10.3389/fpls.2024.1378707. eCollection 2024.ABSTRACTINTRODUCTION: This study used Bacillus amyloliquefaciens DGL1 isolated from the arid sandy land of the Qinghai-Tibetan Plateau as the research strain and investigated the effects of DGL1 on the biomass, physiology, and metabolites of Medicago sativa under different intensities of drought stress to provide a high-quality bacterial source and a theoretical basis for the research and development of biological fertilizer suitable for arid areas.METHODS: The exopolysaccharides (EPS), 1-Aminocyclopropane-1-carboxylate deaminase (ACC), and phosphorus solubilizing capacity of DGL1 were determined. The effects of a DGL1 suspension on alfalfa biomass, physiological indexes, degree of peroxidation of cell membranes, and activity of antioxidant enzymes were determined after irrigating roots under drought stress. The effects on soil physicochemical properties were also evaluated, and metabolomics analysis was performed to explore the effect of DGL1 on the metabolites of alfalfa under drought stress.RESULTS: Strain DGL1 produced extracellular polysaccharide EPS and ACC deaminase and was capable of phosphorus solubilization. Treatment with DGL1 increased the biomass of alfalfa under different degrees of drought stress, significantly increased the activities of alfalfa antioxidant enzymes Super Oxide Dismutase (SOD), Peroxidase (POD), and catalase (CAT), reduced the content of MDA and H2O2, and increased the content of quick-acting phosphorus, quick-acting potassium, ammonium nitrogen, and nitrate nitrogen in the soil, thus improving soil fertility. Through metabolomics analysis, DGL1 was shown to affect amino acid metabolic pathways, such as arginine, leucine, glutamate, and tyrosine, as well as the levels of energy-providing polysaccharides and lipids, in alfalfa under 15% PEG-6000 drought stress, enhancing alfalfa's capacity to resist drought stress.DISCUSSION: Strain DGL1 enhances the drought suitability of alfalfa and has the potential for dryland development as a biological agent.PMID:38803604 | PMC:PMC11128672 | DOI:10.3389/fpls.2024.1378707

Front Nutr. 2024 May 13;11:1379390. doi: 10.3389/fnut.2024.1379390. eCollection 2024.ABSTRACTINTRODUCTION: The branched-chain amino acids (BCAAs) are essential to mammalian growth and development but aberrantly elevated in obesity and diabetes. Each BCAA has an independent and specific physio-biochemical effect on the host. However, the exact molecular mechanism of the detrimental effect of valine on metabolic health remains largely unknown.METHODS AND RESULTS: This study showed that for lean mice treated with valine, the hepatic lipid metabolism and adipogenesis were enhanced, and the villus height and crypt depth of the ileum were significantly increased. Transcriptome profiling on white and brown adipose tissues revealed that valine disturbed multiple signaling pathways (e.g., inflammation and fatty acid metabolism). Integrative cecal metagenome and metabolome analyses found that abundances of Bacteroidetes decreased, but Proteobacteria and Helicobacter increased, respectively; and 87 differential metabolites were enriched in several molecular pathways (e.g., inflammation and lipid and bile acid metabolism). Furthermore, abundances of two metabolites (stercobilin and 3-IAA), proteins (AMPK/pAMPK and SCD1), and inflammation and adipogenesis-related genes were validated.DISCUSSION: Valine treatment affects the intestinal microbiota and metabolite compositions, induces gut inflammation, and aggravates hepatic lipid deposition and adipogenesis. Our findings provide novel insights into and resources for further exploring the molecular mechanism and biological function of valine on lipid metabolism.PMID:38803448 | PMC:PMC11128663 | DOI:10.3389/fnut.2024.1379390

Front Mol Biosci. 2024 May 13;11:1250413. doi: 10.3389/fmolb.2024.1250413. eCollection 2024.ABSTRACTNutrition during the perinatal period is an essential component of health and one that can severely impact the correct development of a human being and its overall condition, in all the subsequent stages of life. The availability of several compounds, mainly macronutrients and micronutrients, plays a key role in the balanced nutrition of both mother and baby and is a process with direct relation to the gut microbiome. Thus, we hereby refer to the set of small molecules derived from gut microbiome metabolism as the gut metabolome. These continuous processes occurring in the gut of a gestating or lactating mother related to microbial communities and nutrients, can be revealed by metabolomics. In this study, we explore for the first time the gut metabolome of pregnant and lactating women, from our region of Antioquia-Colombia, applying untargeted metabolomics by LC-QTOF-MS, and molecular networking. Regarding the gut metabolome composition of the cohort, we found, key metabolites that can be used as biomarkers of microbiome function, overall metabolic health, dietary intake, pharmacology, and lifestyle. In our cohort, pregnant women evidenced a significantly higher abundance of prostaglandins, alkaloids, corticosteroids, organosilicons, and natural toxins, while in lactating women, lipids stand out. Our results suggest that unveiling the metabolic phenotype of the gut microbiome of an individual, by untargeted metabolomics, allows a broad visualization of the chemical space present in this important niche and enables the recognition of influential indicators of the host's health status and habits, especially of women during this significant perinatal period. This study constitutes the first evidence of the use of untargeted LC-QTOF-MS coupled with molecular networking analysis, of the gut microbiome in a Colombian cohort and establishes a methodology for finding relative abundances of key metabolites, with potential use in nutritional and physiological state assessments, for future personalized health and nutrition practices.PMID:38803424 | PMC:PMC11128665 | DOI:10.3389/fmolb.2024.1250413

Front Microbiol. 2024 May 13;15:1336278. doi: 10.3389/fmicb.2024.1336278. eCollection 2024.ABSTRACTINTRODUCTION: The aim of this study was to investigate the effects of diets on the composition and function of rumen microbiome and metabolites in Sanhe heifers.METHODS: Metagenomic and metabolomic analyses were performed using rumen fluid samples collected from Sanhe heifers (n = 20) with similar body weights and ages from grass-fed and grain-fed systems.RESULTS: The grain-fed group exhibited more intensive rumen fermentation than the grass-fed group. However, the grass-fed group exhibited carbohydrate metabolism and methane production higher than that of the grain-fed group; these increases were observed as a higher abundance of various bacterial phyla (Firmicutes, Bacteroidetes, Actinobacteria, Lentisphaerae, and Verrucomicrobia), families (Lachnospiraceae, Eubacteriaceae, and Eggerthellaceae), and the archaeal family Methanobacteriaceae. A comparison of genes encoding carbohydrate-active enzymes, using Kyoto Encyclopedia of Genes and Genome profiles, revealed noteworthy differences in the functions of rumen microbiota; these differences were largely dependent on the feeding system.CONCLUSION: These results could help manipulate and regulate feed efficiency in Sanhe cattle.PMID:38803375 | PMC:PMC11128563 | DOI:10.3389/fmicb.2024.1336278

Front Microbiol. 2024 May 13;15:1394880. doi: 10.3389/fmicb.2024.1394880. eCollection 2024.ABSTRACTINTRODUCTION: Higher alcohols are volatile compounds produced during alcoholic fermentation that affect the quality and safety of the final product. This study used a correlation analysis of transcriptomics and metabolomics to study the impact of the initial addition of SO2 (30, 60, and 90 mg/L) on the synthesis of higher alcohols in Saccharomyces cerevisiae EC1118a and to identify key genes and metabolic pathways involved in their metabolism.METHODS: Transcriptomics and metabolomics correlation analyses were performed and differentially expressed genes (DEGs) and differential metabolites were identified. Single-gene knockouts for targeting genes of important pathways were generated to study the roles of key genes involved in the regulation of higher alcohol production.RESULTS: We found that, as the SO2 concentration increased, the production of total higher alcohols showed an overall trend of first increasing and then decreasing. Multi-omics correlation analysis revealed that the addition of SO2 affected carbon metabolism (ko01200), pyruvate metabolism (ko00620), glycolysis/gluconeogenesis (ko00010), the pentose phosphate pathway (ko00030), and other metabolic pathways, thereby changing the precursor substances. The availability of SO2 indirectly affects the formation of higher alcohols. In addition, excessive SO2 affected the growth of the strain, leading to the emergence of a lag phase. We screened the ten most likely genes and constructed recombinant strains to evaluate the impact of each gene on the formation of higher alcohols. The results showed that ADH4, SER33, and GDH2 are important genes of alcohol metabolism in S. cerevisiae. The isoamyl alcohol content of the EC1118a-ADH4 strain decreased by 21.003%; The isobutanol content of the EC1118a-SER33 strain was reduced by 71.346%; and the 2-phenylethanol content of EC1118a-GDH2 strain was reduced by 25.198%.CONCLUSION: This study lays a theoretical foundation for investigating the mechanism of initial addition of SO2 in the synthesis of higher alcohols in S. cerevisiae, uncovering DEGs and key metabolic pathways related to the synthesis of higher alcohols, and provides guidance for regulating these mechanisms.PMID:38803372 | PMC:PMC11128613 | DOI:10.3389/fmicb.2024.1394880

J Agric Food Chem. 2024 May 28. doi: 10.1021/acs.jafc.4c01312. Online ahead of print.ABSTRACTCereal grains play an important role in human health as a source of macro- and micronutrients, besides phytochemicals. The metabolite diversity was investigated in cereal crops and their milling fractions by untargeted metabolomics ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) of 69 samples: 7 species (barley, oat, pearl millet, rye, sorghum, triticale, and wheat), 23 genotypes, and 4 milling fractions (husk, bran, flour, and wholegrain). Samples were also analyzed by in vitro antioxidant activity. UHPLC-MS/MS signals were processed using XCMS, and metabolite annotation was based on SIRIUS and GNPS libraries. Bran and husk showed the highest antioxidant capacity and phenolic content/diversity. The major metabolite classes were phenolic acids, flavonoids, fatty acyls, and organic acids. Sorghum, millet, barley, and oats showed distinct metabolite profiles, especially related to the bran fraction. Molecular networking and chemometrics provided a comprehensive insight into the metabolic profiling of cereal crops, unveiling the potential of coproducts and super cereals such as sorghum and millet as sources of polyphenols.PMID:38803291 | DOI:10.1021/acs.jafc.4c01312

Cell Prolif. 2024 May 27:e13663. doi: 10.1111/cpr.13663. Online ahead of print.ABSTRACTMacrophage pyroptosis is of key importance to host defence against pathogen infections and may participate in the progression and recovery of periodontitis. However, the role of pyroptotic macrophages in regulating periodontal ligament stem cells (PDLSCs), the main cell source for periodontium renewal, remains unclear. First, we found that macrophage pyroptosis were enriched in gingiva tissues from periodontitis patients compared with those of healthy people through immunofluorescence. Then the effects of pyroptotic macrophages on the PDLSC osteogenic differentiation were investigated in a conditioned medium (CM)-based coculture system in vitro. CM derived from pyroptotic macrophages inhibited the osteogenic differentiation-related gene and protein levels, ALP activity and mineralized nodule formation of PDLSCs. The osteogenic inhibition of CM was alleviated when pyroptosis was inhibited by VX765. Further, untargeted metabolomics showed that glutamate limitation may be the underlying mechanism. However, exogenous glutamate supplementation aggravated the CM-inhibited osteogenic differentiation of PDLSCs. Moreover, CM increased extracellular glutamate and decreased intracellular glutamate levels of PDLSCs, and enhanced the gene and protein expression levels of system xc - (a cystine/glutamate antiporter). After adding cystine to CM-based incubation, the compromised osteogenic potency of PDLSCs was rescued. Our data suggest that macrophage pyroptosis is related to the inflammatory lesions of periodontitis. Either pharmacological inhibition of macrophage pyroptosis or nutritional supplements to PDLSCs, can rescue the compromised osteogenic potency caused by pyroptotic macrophages.PMID:38803043 | DOI:10.1111/cpr.13663

J Pineal Res. 2024 May;76(4):e12964. doi: 10.1111/jpi.12964.ABSTRACTCircadian disruption such as shift work, jet lag, has gradually become a global health issue and is closely associated with various metabolic disorders. The influence and mechanism of circadian disruption on renal injury in chronic kidney disease (CKD) remains inadequately understood. Here, we evaluated the impact of environmental light disruption on the progression of chronic renal injury in CKD mice. By using two abnormal light exposure models to induce circadian disruption, we found that circadian disruption induced by weekly light/dark cycle reversal (LDDL) significantly exacerbated renal dysfunction, accelerated renal injury, and promoted renal fibrosis in mice with 5/6 nephrectomy and unilateral ureteral obstruction (UUO). Mechanistically, RNA-seq analysis revealed significant immune and metabolic disorder in the LDDL-conditioned CKD kidneys. Consistently, renal content of ATP was decreased and ROS production was increased in the kidney tissues of the LDDL-challenged CKD mice. Untargeted metabolomics revealed a significant buildup of lipids in the kidney affected by LDDL. Notably, the level of β-NMN, a crucial intermediate in the NAD+ pathway, was found to be particularly reduced. Moreover, we demonstrated that both β-NMN and melatonin administration could significantly rescue the light-disruption associated kidney dysfunction. In conclusion, environmental circadian disruption may exacerbate chronic kidney injury by facilitating inflammatory responses and disturbing metabolic homeostasis. β-NMN and melatonin treatments may hold potential as promising approaches for preventing and treating light-disruption associated CKD.PMID:38803014 | DOI:10.1111/jpi.12964

Anim Microbiome. 2024 May 27;6(1):30. doi: 10.1186/s42523-024-00314-7.ABSTRACTBACKGROUND: Metritis is a prevalent uterine disease that affects the welfare, fertility, and survival of dairy cows. The uterine microbiome from cows that develop metritis and those that remain healthy do not differ from calving until 2 days postpartum, after which there is a dysbiosis of the uterine microbiome characterized by a shift towards opportunistic pathogens such as Fusobacteriota and Bacteroidota. Whether these opportunistic pathogens proliferate and overtake the uterine commensals could be determined by the type of substrates present in the uterus. The objective of this study was to integrate uterine microbiome and metabolome data to advance the understanding of the uterine environment in dairy cows that develop metritis. Holstein cows (n = 104) had uterine fluid collected at calving and at the day of metritis diagnosis. Cows with metritis (n = 52) were paired with cows without metritis (n = 52) based on days after calving. First, the uterine microbiome and metabolome were evaluated individually, and then integrated using network analyses.RESULTS: The uterine microbiome did not differ at calving but differed on the day of metritis diagnosis between cows with and without metritis. The uterine metabolome differed both at calving and on the day of metritis diagnosis between cows that did and did not develop metritis. Omics integration was performed between 6 significant bacteria genera and 153 significant metabolites on the day of metritis diagnosis. Integration was not performed at calving because there were no significant differences in the uterine microbiome. A total of 3 bacteria genera (i.e. Fusobacterium, Porphyromonas, and Bacteroides) were strongly correlated with 49 metabolites on the day of metritis diagnosis. Seven of the significant metabolites at calving were among the 49 metabolites strongly correlated with opportunistic pathogenic bacteria on the day of metritis diagnosis. The main metabolites have been associated with attenuation of biofilm formation by commensal bacteria, opportunistic pathogenic bacteria overgrowth, tissue damage and inflammation, immune evasion, and immune dysregulation.CONCLUSIONS: The data integration presented herein helps advance the understanding of the uterine environment in dairy cows with metritis. The identified metabolites may provide a competitive advantage to the main uterine pathogens Fusobacterium, Porphyromonas and Bacteroides, and may be promising targets for future interventions aiming to reduce opportunistic pathogenic bacteria growth in the uterus.PMID:38802977 | DOI:10.1186/s42523-024-00314-7

Genome Med. 2024 May 28;16(1):69. doi: 10.1186/s13073-024-01322-7.ABSTRACTBACKGROUND: The role of metabolism in the variation of age at menarche (AAM) and age at natural menopause (ANM) in the female population is not entirely known. We aimed to investigate the causal role of circulating metabolites in AAM and ANM using Mendelian randomization (MR).METHODS: We combined MR with genetic colocalization to investigate potential causal associations between 658 metabolites and AAM and between 684 metabolites and ANM. We extracted genetic instruments for our exposures from four genome-wide association studies (GWAS) on circulating metabolites and queried the effects of these variants on the outcomes in two large GWAS from the ReproGen consortium. Additionally, we assessed the mediating role of the body mass index (BMI) in these associations, identified metabolic pathways implicated in AAM and ANM, and sought validation for selected metabolites in the Avon Longitudinal Study of Parents and Children (ALSPAC).RESULTS: Our analysis identified 10 candidate metabolites for AAM, but none of them colocalized with AAM. For ANM, 76 metabolites were prioritized (FDR-adjusted MR P-value ≤ 0.05), with 17 colocalizing, primarily in the glycerophosphocholines class, including the omega-3 fatty acid and phosphatidylcholine (PC) categories. Pathway analyses and validation in ALSPAC mothers also highlighted the role of omega and polyunsaturated fatty acids levels in delaying age at menopause.CONCLUSIONS: Our study suggests that metabolites from the glycerophosphocholine and fatty acid families play a causal role in the timing of both menarche and menopause. This underscores the significance of specific metabolic pathways in the biology of female reproductive longevity.PMID:38802955 | DOI:10.1186/s13073-024-01322-7

BMC Cancer. 2024 May 27;24(1):644. doi: 10.1186/s12885-024-12321-7.ABSTRACTBACKGROUND: Understanding the metabolic changes in colorectal cancer (CRC) and exploring potential diagnostic biomarkers is crucial for elucidating its pathogenesis and reducing mortality. Cancer cells are typically derived from cancer tissues and can be easily obtained and cultured. Systematic studies on CRC cells at different stages are still lacking. Additionally, there is a need to validate our previous findings from human serum.METHODS: Ultrahigh-performance liquid chromatography tandem high-resolution mass spectrometry (UHPLC-HRMS)-based metabolomics and lipidomics were employed to comprehensively measure metabolites and lipids in CRC cells at four different stages and serum samples from normal control (NR) and CRC subjects. Univariate and multivariate statistical analyses were applied to select the differential metabolites and lipids between groups. Biomarkers with good diagnostic efficacy for CRC that existed in both cells and serum were screened by the receiver operating characteristic curve (ROC) analysis. Furthermore, potential biomarkers were validated using metabolite standards.RESULTS: Metabolite and lipid profiles differed significantly among CRC cells at stages A, B, C, and D. Dysregulation of glycerophospholipid (GPL), fatty acid (FA), and amino acid (AA) metabolism played a crucial role in the CRC progression, particularly GPL metabolism dominated by phosphatidylcholine (PC). A total of 46 differential metabolites and 29 differential lipids common to the four stages of CRC cells were discovered. Eight metabolites showed the same trends in CRC cells and serum from CRC patients compared to the control groups. Among them, palmitoylcarnitine and sphingosine could serve as potential biomarkers with the values of area under the curve (AUC) more than 0.80 in the serum and cells. Their panel exhibited excellent performance in discriminating CRC cells at different stages from normal cells (AUC = 1.00).CONCLUSIONS: To our knowledge, this is the first research to attempt to validate the results of metabolism studies of serum from CRC patients using cell models. The metabolic disorders of PC, FA, and AA were closely related to the tumorigenesis of CRC, with PC being the more critical factor. The panel composed of palmitoylcarnitine and sphingosine may act as a potential biomarker for the diagnosis of CRC, aiding in its prevention.PMID:38802800 | DOI:10.1186/s12885-024-12321-7

J Biomed Sci. 2024 May 28;31(1):55. doi: 10.1186/s12929-024-01044-3.ABSTRACTBACKGROUND: Radioresistance is a key clinical constraint on the efficacy of radiotherapy in lung cancer patients. REV1 DNA directed polymerase (REV1) plays an important role in repairing DNA damage and maintaining genomic stability. However, its role in the resistance to radiotherapy in lung cancer is not clear. This study aims to clarify the role of REV1 in lung cancer radioresistance, identify the intrinsic mechanisms involved, and provide a theoretical basis for the clinical translation of this new target for lung cancer treatment.METHODS: The effect of targeting REV1 on the radiosensitivity was verified by in vivo and in vitro experiments. RNA sequencing (RNA-seq) combined with nontargeted metabolomics analysis was used to explore the downstream targets of REV1. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify the content of specific amino acids. The coimmunoprecipitation (co-IP) and GST pull-down assays were used to validate the interaction between proteins. A ubiquitination library screening system was constructed to investigate the regulatory proteins upstream of REV1.RESULTS: Targeting REV1 could enhance the radiosensitivity in vivo, while this effect was not obvious in vitro. RNA sequencing combined with nontargeted metabolomics revealed that the difference result was related to metabolism, and that the expression of glycine, serine, and threonine (Gly/Ser/Thr) metabolism signaling pathways was downregulated following REV1 knockdown. LC-MS/MS demonstrated that REV1 knockdown results in reduced levels of these three amino acids and that cystathionine γ-lyase (CTH) was the key to its function. REV1 enhances the interaction of CTH with the E3 ubiquitin ligase Rad18 and promotes ubiquitination degradation of CTH by Rad18. Screening of the ubiquitination compound library revealed that the ubiquitin-specific peptidase 9 X-linked (USP9X) is the upstream regulatory protein of REV1 by the ubiquitin-proteasome system, which remodels the intracellular Gly/Ser/Thr metabolism.CONCLUSION: USP9X mediates the deubiquitination of REV1, and aberrantly expressed REV1 acts as a scaffolding protein to assist Rad18 in interacting with CTH, promoting the ubiquitination and degradation of CTH and inducing remodeling of the Gly/Ser/Thr metabolism, which leads to radioresistance. A novel inhibitor of REV1, JH-RE-06, was shown to enhance lung cancer cell radiosensitivity, with good prospects for clinical translation.PMID:38802791 | DOI:10.1186/s12929-024-01044-3

BMC Plant Biol. 2024 May 27;24(1):463. doi: 10.1186/s12870-024-04945-5.ABSTRACTBACKGROUND: Fusarium graminearum and Fusarium avenaceum are two of the most important causal agents of Fusarium head blight (FHB) of wheat. They can produce mycotoxins that accumulate in infected wheat heads, including deoxynivalenol (DON) and enniatins (ENNs), produced by F. graminearum and F. avenaceum, respectively. While the role of DON as a virulence factor in F. graminearum toward wheat is well known, ENNs in F. avenaceum has been poorly explored. Results obtained to-date indicate that ENNs may confer an advantage to F. avenaceum only on particular hosts.RESULTS: In this study, with the use of ENN-producing and ENN non-producing F. avenaceum strains, the role of ENNs on F. avenaceum virulence was investigated on the root, stem base and head of common wheat, and compared with the role of DON, using DON-producing and DON non-producing F. graminearum strains. The DON-producing F. graminearum strain showed a significantly higher ability to cause symptoms and colonise each of the tested tissues than the non-producing strain. On the other hand, the ability to produce ENNs increased initial symptoms of the disease and fungal biomass accumulation, measured by qPCR, only in wheat heads, and not in roots or stem bases. LC-MS/MS analysis was used to confirm the presence of ENNs and DON in the different strains, and results, both in vitro and in wheat heads, were consistent with the genetics of each strain.CONCLUSION: While the key role of DON on F. graminearum virulence towards three different wheat tissues was noticeable, ENNs seemed to have a role only in influencing F. avenaceum virulence on common wheat heads probably due to an initial delay in the appearance of symptoms.PMID:38802782 | DOI:10.1186/s12870-024-04945-5

Physiol Plant. 2024 May-Jun;176(3):e14365. doi: 10.1111/ppl.14365.ABSTRACTLavender plantation is globally expanded due to the increasing demand of its essential oil and its popularity as an ornamental species. However, lavender plantations, and consequently essential oil industries, are threatened by more frequent and severe drought episodes in a globally changing climate. Still little is known about the changes in the general metabolome, which provides the precursors of essential oil production, by extended drought events. Prolonged drought fundamentally results in yield losses and changing essential oil composition. In the present study, the general metabolome of a main cultivated lavender species (Lavandula angustifolia Mill.) in response to water deprivation (WD) and re-watering was analyzed to identify the metabolomics responses. We found prolonged WD resulted in significant accumulations of glucose, 1,6-anhydro-β-D-glucose, sucrose, melezitose and raffinose, but declines of allulose, β-D-allose, altrose, fructose and D-cellobiose accompanied by decreased organic acids abundances. Amino acids and aromatic compounds of p-coumaric acid, hydrocaffeic acid and caffeic acid significantly accumulated at prolonged WD, whereas aromatics of cis-ferulic acid, taxifolin and two fatty acids (i.e., palmitic acid and stearic acid) significantly decreased. Prolonged WD also resulted in decreased abundances of polyols, particularly myo-inositol, galactinol and arabitol. The altered metabolite profiles by prolonged WD were mostly not recovered after re-watering, except for branched-chain amino acids, proline, serine and threonine. Our study illustrates the complex changes of leaf primary and secondary metabolic processes of L. angustifolia by drought events and highlights the potential impact of these precursors of essential oil production on the lavender industry.PMID:38802725 | DOI:10.1111/ppl.14365

Int J Legal Med. 2024 May 28. doi: 10.1007/s00414-024-03258-4. Online ahead of print.ABSTRACTIn forensic practice, determining the postmortem submersion interval (PMSI) and cause-of-death of cadavers in aquatic ecosystems has always been challenging task. Traditional approaches are not yet able to address these issues effectively and adequately. Our previous study proposed novel models to predict the PMSI and cause-of-death based on metabolites of blood from rats immersed in freshwater. However, with the advance of putrefaction, it is hardly to obtain blood samples beyond 3 days postmortem. To further assess the feasibility of PMSI estimation and drowning diagnosis in the later postmortem phase, gastrocnemius, the more degradation-resistant tissue, was collected from drowned rats and postmortem submersion model in freshwater immediately after death, and at 1 day, 3 days, 5 days, 7 days, and 10 days postmortem respectively. Then the samples were analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to investigate the dynamic changes of the metabolites. A total of 924 metabolites were identified. Similar chronological changes of gastrocnemius metabolites were observed in the drowning and postmortem submersion groups. The difference in metabolic profiles between drowning and postmortem submersion groups was only evident in the initial 1 day postmortem, which was faded as the PMSI extension. Nineteen metabolites representing temporally-dynamic patterns were selected as biomarkers for PMSI estimation. A regression model was built based on these biomarkers with random forest algorithm, which yielded a mean absolute error (± SE) of 5.856 (± 1.296) h on validation samples from an independent experiment. These findings added to our knowledge of chronological changes in muscle metabolites from submerged vertebrate remains during decomposition, which provided a new perspective for PMSI estimation.PMID:38802694 | DOI:10.1007/s00414-024-03258-4

Sci Rep. 2024 May 27;14(1):12143. doi: 10.1038/s41598-024-62966-4.ABSTRACTMicroglia are natural immune cells in the central nervous system, and the activation of microglia is accompanied by a reprogramming of glucose metabolism. In our study, we investigated the role of long non-coding RNA taurine-upregulated gene 1 (TUG1) in regulating microglial glucose metabolism reprogramming and activation. BV2 cells were treated with Lipopolysaccharides (LPS)/Interferon-γ (IFN-γ) to establish a microglial activation model. The glycolysis inhibitor 2-Deoxy-D-glucose (2-DG) was used as a control. The expression levels of TUG1 mRNA and proinflammatory cytokines such as Interleukin-1β (IL-1β), Interleukin -6, and Tumor Necrosis Factor-α mRNA and anti-inflammatory cytokines such as IL-4, Arginase 1(Arg1), CD206, and Ym1 were detected by RT-qPCR. TUG1 was silenced using TUG1 siRNA and knocked out using CRISPR/Cas9. The mRNA and protein expression levels of key enzymes involved in glucose metabolism, such as Hexokinase2, Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Lactate dehydrogenase, Glucose 6 phosphate dehydrogenase, and Pyruvate dehydrogenase (PDH), were determined by RT-qPCR and Western blotting. The glycolytic rate of microglial cells was measured using Seahorse. Differential metabolites were determined by metabolomics, and pathway enrichment was performed using these differential metabolites. Our findings revealed that the expression of TUG1 was elevated in proinflammatory-activated microglia and positively correlated with the levels of inflammatory factors. The expression of anti-inflammatory cytokines such as IL-4, Arg1, CD206, and Ym1 were decreased when induced with LPS/IFN-γ. However, this decrease was reversed by the treatment with 2-DG. Silencing of GAPDH led to an increase in the expression of TUG1 and inflammatory factors. TUG1 knockout (TUG1KO) inhibited the expression of glycolytic key enzymes and promoted the expression of oxidative phosphorylation key enzymes, shifting the metabolic profile of activated microglia from glycolysis to oxidative phosphorylation. Additionally, TUG1KO reduced the accumulation of metabolites, facilitating the restoration of the tricarboxylic acid cycle and enhancing oxidative phosphorylation in microglia. Furthermore, the downregulation of TUG1 was found to reduce the expression of both proinflammatory and anti-inflammatory cytokines under normal conditions. Interestingly, when induced with LPS/IFN-γ, TUG1 downregulation showed a potentially beneficial effect on microglia in terms of inflammation. Downregulation of TUG1 expression inhibits glycolysis and facilitates the shift of microglial glucose metabolism from glycolysis to oxidative phosphorylation, promoting their transformation towards an anti-inflammatory phenotype and exerting anti-inflammatory effects in BV2.PMID:38802677 | DOI:10.1038/s41598-024-62966-4