Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

Metabolomic analysis reveals macrophage metabolic reprogramming and polarization under different nutritional cues

Tue, 21/05/2024 - 12:00
Clin Chim Acta. 2024 May 19:119735. doi: 10.1016/j.cca.2024.119735. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Obesity-induced chronic inflammation and metabolic abnormalities are highly relevant to the functional dysregulation of macrophages, especially under obese conditions. Hyperglycemia and hyperlipidemia, central to obesity, directly alter macrophage activity. However, the impacts of different nutritional cues on the intricate metabolic networks in macrophages remain unclear.MATERIALS AND METHODS: In this study, we employed metabolomic approaches to examine the metabolic responses of macrophages to high glucose, high fat and their coexistence, aiming to delineate the molecular mechanisms of nutritional factors on macrophage activation and obesity-related diseases from a metabolic perspective.RESULTS: Our findings revealed that different nutritional conditions could reprogram key metabolism in macrophages. Additionally, we identified a metabolite derived from macrophages, Long-Chain Phosphatidylcholine (LPC), which exerts beneficial effects on obese mice. It ameliorates the obesity phenotype and improves glucose metabolism profiles. This discovery suggests that LPC has a significant therapeutic potential in the context of obesity-induced metabolic dysfunctions. Our study unveils the metabolic phenotype of macrophages in high-fat and high-sugar environments and uncovers a macrophage-derived metabolite that significantly ameliorates the obesity phenotype.CONCLUSION: This finding reveals a potential dialogue mechanism between macrophages and adipocytes, shedding light on the complex interplay of immune and metabolic systems in obesity. This discovery not only enhances our understanding of obesity's underlying mechanisms but also opens up new avenues for therapeutic interventions targeting macrophage-adipocyte interactions.PMID:38772523 | DOI:10.1016/j.cca.2024.119735

Gut microbiota and serum metabolite signatures along the colorectal adenoma-carcinoma sequence: Implications for early detection and intervention

Tue, 21/05/2024 - 12:00
Clin Chim Acta. 2024 May 19:119732. doi: 10.1016/j.cca.2024.119732. Online ahead of print.ABSTRACTAIM: Our study focuses on the microbial and metabolomic profile changes during the adenoma stage, as adenomas can be considered potential precursors to colorectal cancer through the adenoma-carcinoma sequence. Identifying possible intervention targets at this stage may aid in preventing the progression of colorectal adenoma (CRA) to malignant lesions. Furthermore, we evaluate the efficacy of combined microbial and metabolite biomarkers in detecting CRA.METHODS: Fecal metagenomic and serum metabolomic analyses were performed for the discovery of alterations of gut microbiome and metabolites in CRA patients (n = 26), Colorectal cancer (CRC) patients (n = 19), Familial Adenomatous Polyposis (FAP) patients (n = 10), and healthy controls (n = 20). Finally, analyzing the associations between gut microbes and metabolites was performed by a Receiver Operating Characteristic (ROC) curve.RESULTS: Our analysis present that CRA patients differ significantly in gut microflora and serum metabolites compared with healthy controls, especially for Lachnospiraceae and Parasutterella. Its main metabolite, butyric acid, concentrations were raised in CRA patients compared with the healthy controls, indicating its role as a promoter of colorectal tumorigenesis. α-Linolenic acid and lysophosphatidylcholine represented the other healthy metabolite for CRA. Combining five microbial and five metabolite biomarkers, we differentiated CRA from CRC with an Area Under the Curve (AUC) of 0.85 out of this performance vastly superior to the specificity recorded by traditional markers CEA and CA199 in such differentiation of these conditions.CONCLUSIONS: The study underlines significant microbial and metabolic alterations in CRA with a novel insight into screening and early intervention of its tumorigenesis.PMID:38772522 | DOI:10.1016/j.cca.2024.119732

Polystyrene nanoplastics exacerbate aflatoxin B1-induced hepatic injuries by modulating the gut-liver axis

Tue, 21/05/2024 - 12:00
Sci Total Environ. 2024 May 19:173285. doi: 10.1016/j.scitotenv.2024.173285. Online ahead of print.ABSTRACTDietary pollution of Aflatoxin B1 (AFB1) poses a great threat to global food safety, which can result in serious hepatic injuries. Following the widespread use of plastic tableware, co-exposure to microplastics and AFB1 has dramatically increased. However, whether microplastics could exert synergistic effects with AFB1 and amplify its hepatotoxicity, and the underlying mechanisms are still unelucidated. Here, mice were orally exposed to 100 nm polystyrene nanoplastics (NPs) and AFB1 to investigate the influences of NPs on AFB1-induced hepatic injuries. We found that exposure to only NPs or AFB1 resulted in colonic inflammation and the impairment of the intestinal barrier, which was exacerbated by combined exposure to NPs and AFB1. Meanwhile, co-exposure to NPs exacerbated AFB1-induced dysbiosis of gut microbiota and remodeling of the fecal metabolome. Moreover, NPs and AFB1 co-exposure exhibited higher levels of systemic inflammatory factors compared to AFB1 exposure. Additionally, NPs co-exposure further exacerbated AFB1-induced hepatic fibrosis and inflammation, which could be associated with the overactivation of the TLR4/MyD88/NF-κB pathway. Notably, Spearman's correlation analysis revealed that the exacerbation of NPs co-exposure was closely associated with microbial dysbiosis. Furthermore, microbiota from NPs-exposed mice (NPsFMT) partly reproduced the exacerbation of NPs on AFB1-induced systemic and hepatic inflammation, but not fibrosis. In summary, our findings indicate that gut microbiota could be involved in the exacerbation of NPs on AFB1-induced hepatic injuries, highlighting the health risks of NPs.PMID:38772488 | DOI:10.1016/j.scitotenv.2024.173285

Combined analysis of Polygonum cuspidatum transcriptome and metabolome revealed that PcMYB62, a transcription factor, responds to methyl jasmonate and inhibits resveratrol biosynthesis

Tue, 21/05/2024 - 12:00
Int J Biol Macromol. 2024 May 19:132450. doi: 10.1016/j.ijbiomac.2024.132450. Online ahead of print.ABSTRACTA comparative transcriptomic and metabolomic analysis of Polygonum cuspidatum leaves treated with MeJA was carried out to investigate the regulatory mechanisms of its active compounds. A total of 692 metabolites and 77,198 unigenes were obtained, including 200 differentially accumulated metabolites and 6819 differentially expressed genes. We screened potential regulatory transcription factors involved in resveratrol and flavonoids biosynthesis, and successfully identified an MYB transcription factor, PcMYB62, which could significantly decrease the resveratrol content in P. cuspidatum leaves when over-expressed. PcMYB62 could directly bind to the MBS motifs in the promoter region of stilbene synthase (PcSTS) gene and repress its expression. Besides, PcMYB62 could also repress PcSTS expression and resveratrol biosynthesis in transgenic Arabidopsis thaliana. Our results provide abundant candidate genes for further investigation, and the new finding of the inhibitory role of PcMYB62 on the resveratrol biosynthesis could also potentially be used in metabolic engineering of resveratrol in P. cuspidatum.PMID:38772462 | DOI:10.1016/j.ijbiomac.2024.132450

Genome-wide identification and examination of the wheat glycosyltransferase family 43 regulation during Fusarium graminearum infection

Tue, 21/05/2024 - 12:00
Int J Biol Macromol. 2024 May 19:132475. doi: 10.1016/j.ijbiomac.2024.132475. Online ahead of print.ABSTRACTIn Arabidopsis and rice, the glycosyltransferase (GT) 43 family is involved in xylan synthesis. However, there have been limited reports on the study of the TaGT43 family in wheat. In this study, 28 TaGT43 family members were identified in wheat (Triticum aestivum L.) and clustered into three major groups based on the similarity of amino acid sequences. The results of the TaGT43 family's conserved motif and gene structure analyses agree with this result. Collinearity analysis revealed segmental duplications mainly promoted TaGT43 family expansion. cis-Acting element analysis revealed that the TaGT43 genes were involved in the light response, phytohormone response, abiotic/biotic stress response, and growth and development. The TaGT43 family showed a tissue-specific expression pattern, primarily expressed in roots and stems. Besides, the transcriptional and expression levels of multiple TaGT43 genes were upregulated during the infection of F. graminearum. According to metabolomics studies, F. graminearum infection affected the phenylpropanoid biosynthesis pathway in wheat, a critical factor in cell wall construction. Furthermore, GO enrichment analysis indicated that the TaGT43 genes play a significant role in cell wall organization. Based on these results, it may be concluded that the TaGT43 family mediates cell wall organization in response to F. graminearum infection.PMID:38772456 | DOI:10.1016/j.ijbiomac.2024.132475

Unveiling novel metabolic alterations in postmenopausal osteoporosis and type 2 diabetes mellitus through NMR-based metabolomics: A pioneering approach for identifying early diagnostic markers

Tue, 21/05/2024 - 12:00
J Proteomics. 2024 May 19:105200. doi: 10.1016/j.jprot.2024.105200. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Postmenopausal osteoporosis (PMO) and type 2 diabetes mellitus (T2DM) frequently coexist in postmenopausal women. The study aimed to explore metabolic variations linked to these circumstances and their simultaneous presence through proton nuclear magnetic resonance metabolomics (1H NMR).MATERIALS AND METHODS: Serum samples from 80 postmenopausal women, including 20 PMO individuals, 20 T2DM, 20 T2DM + PMO, and 20 healthy postmenopausal women, were analyzed using 1H NMR spectroscopy.RESULTS: Our study revealed significant metabolic profile differences among the four groups. Notably, the T2DM + PMO group showed elevated levels of alanine, pyruvate, glutamate, lactate, and aspartate, indicating their involvement in lipid metabolism, energy, and amino acids. Importantly, our multivariate statistical analysis identified a metabolite set that accurately distinguished the groups, suggesting its potential as an early diagnostic marker.CONCLUSION: The 1H NMR metabolomics approach uncovered metabolic biomarkers intricately linked to postmenopausal osteoporosis (PMO), type 2 diabetes mellitus (T2DM), and their concurrent presence. Among these biomarkers, alanine emerged as a pivotal player, showing its significant role in the metabolic landscape associated with PMO and T2DM. These findings shed light on the pathophysiological mechanisms underlying these conditions and underscore alanine's potential as a diagnostic biomarker.PMID:38772440 | DOI:10.1016/j.jprot.2024.105200

Oncogenic fatty acid oxidation senses circadian disruption in sleep-deficiency-enhanced tumorigenesis

Tue, 21/05/2024 - 12:00
Cell Metab. 2024 May 14:S1550-4131(24)00138-4. doi: 10.1016/j.cmet.2024.04.018. Online ahead of print.ABSTRACTCircadian disruption predicts poor cancer prognosis, yet how circadian disruption is sensed in sleep-deficiency (SD)-enhanced tumorigenesis remains obscure. Here, we show fatty acid oxidation (FAO) as a circadian sensor relaying from clock disruption to oncogenic metabolic signal in SD-enhanced lung tumorigenesis. Both unbiased transcriptomic and metabolomic analyses reveal that FAO senses SD-induced circadian disruption, as illustrated by continuously increased palmitoyl-coenzyme A (PA-CoA) catalyzed by long-chain fatty acyl-CoA synthetase 1 (ACSL1). Mechanistically, SD-dysregulated CLOCK hypertransactivates ACSL1 to produce PA-CoA, which facilitates CLOCK-Cys194 S-palmitoylation in a ZDHHC5-dependent manner. This positive transcription-palmitoylation feedback loop prevents ubiquitin-proteasomal degradation of CLOCK, causing FAO-sensed circadian disruption to maintain SD-enhanced cancer stemness. Intriguingly, timed β-endorphin resets rhythmic Clock and Acsl1 expression to alleviate SD-enhanced tumorigenesis. Sleep quality and serum β-endorphin are negatively associated with both cancer development and CLOCK/ACSL1 expression in patients with cancer, suggesting dawn-supplemented β-endorphin as a potential chronotherapeutic strategy for SD-related cancer.PMID:38772364 | DOI:10.1016/j.cmet.2024.04.018

The tricarboxylic acid cycle is inhibited under acute stress from carbonate alkalinity in the gills of Eriocheir sinensis

Tue, 21/05/2024 - 12:00
Comp Biochem Physiol Part D Genomics Proteomics. 2024 May 16;51:101245. doi: 10.1016/j.cbd.2024.101245. Online ahead of print.ABSTRACTOwing to population growth and environmental pollution, freshwater aquaculture has been rapidly shrinking in recent years. Aquaculture in saline-alkaline waters is a crucial strategy to meet the increasing demand for aquatic products. The Chinese mitten crab is an important economic food in China, but the molecular mechanism by which it tolerates carbonate alkalinity (CA) in water remains unclear. Here, we found that enzyme activities of the tricarboxylic acid (TCA) cycle in the gills, such as citrate synthase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase, were markedly reduced under CA stress induced by 40 mM NaHCO3. Secondly, the TCA cycle in the gills is inhibited under acute CA stress, according to proteomic and metabolomic analyses. The expressions of six enzymes, namely aconitate hydratase, isocitrate dehydrogenase, 2-oxoglutarate dehydrogenase, dihydrolipoyl dehydrogenase, succinate-CoA ligase, and malate dehydrogenase, were downregulated, resulting in the accumulation of phosphoenolpyruvic acid, citric acid, cis-aconitate, and α-ketoglutaric acid. Finally, we testified that if the TCA cycle is disturbed by malonate, the survival rate increases in CA water. To our knowledge, this is the first study to show that the TCA cycle in the gills is inhibited under CA stress. Overall, the results provide new insights into the molecular mechanism of tolerance to saline-alkaline water in crabs, which helped us expand the area for freshwater aquaculture and comprehensively understand the physiological characteristics of crab migration.PMID:38772315 | DOI:10.1016/j.cbd.2024.101245

Untargeted foodomics for authenticating the organic farming of water spinach (Ipomoea aquatica)

Tue, 21/05/2024 - 12:00
Food Chem. 2024 May 6;453:139545. doi: 10.1016/j.foodchem.2024.139545. Online ahead of print.ABSTRACTThis study aimed to conduct a comprehensive analysis of the primary and secondary metabolites of water spinach (Ipomoea aquatica) using hydrophilic interaction liquid chromatography coupled with Orbitrap high-resolution mass spectrometry (HILIC-Orbitrap-HRMS). Certified samples from two cultivars, Green stem water spinach (G) and White stem water spinach (W) cultivated using organic and conventional farming methods, were collected from the Hong Kong market. Multivariate analysis was used to differentiate water spinach of different cultivars and farming methods. We identified 12 metabolites to distinguish between G and W, 26 metabolites to identify G from organic farming and 8 metabolites to identify W from organic farming. Then, two metabolites, isorhamnetin and jasmonic acid, have been proposed to serve as biomarkers for organic farming (in both G and W). Our foodomics findings provide useful tools for improving the crop performance of water spinach under abiotic/biotic stressesand authentication of organic produce.PMID:38772304 | DOI:10.1016/j.foodchem.2024.139545

Nicotine promotes Staphylococcus aureus-induced osteomyelitis by activating the Nrf2/Slc7a11 signaling axis

Tue, 21/05/2024 - 12:00
Int Immunopharmacol. 2024 May 20;135:112223. doi: 10.1016/j.intimp.2024.112223. Online ahead of print.ABSTRACTAlthough smoking is a significant risk factor for osteomyelitis, there is limited experimental evidence that nicotine, a key tobacco constituent, is associated with this condition, leaving its mechanistic implications uncharacterized. This study revealed that nicotine promotes Staphylococcus aureus-induced osteomyelitis by increasing Nrf2 and Slc7a11 expression in vivo and in vitro. Inhibition of Slc7a11 using Erastin augmented bacterial phagocytosis/killing capabilities and fortified antimicrobial responses in an osteomyelitis model. Moreover, untargeted metabolomic analysis demonstrated that Erastin mitigated the effects of nicotine on S. aureus-induced osteomyelitis by altering glutamate/glutathione metabolism. These findings suggest that nicotine aggravates S. aureus-induced osteomyelitis by activating the Nrf2/Slc7a11 signaling pathway and that Slc7a11 inhibition can counteract the detrimental health effects of nicotine.PMID:38772295 | DOI:10.1016/j.intimp.2024.112223

Schauerella fraxinea gen. nov., sp. nov., a bacterial species that colonises ash trees tolerant to dieback caused by Hymenoscyphus fraxineus

Tue, 21/05/2024 - 12:00
Syst Appl Microbiol. 2024 May 12;47(4):126516. doi: 10.1016/j.syapm.2024.126516. Online ahead of print.ABSTRACTThe tolerance of ash trees against the pathogen Hymenoscyphus fraxineus seems to be associated with the occurrence of specific microbial taxa on leaves. A group of bacterial isolates, primarily identified on tolerant trees, was investigated with regard to their taxonomic classification and their potential to suppress the ash dieback pathogen. Examination of OGRI values revealed a separate species position. A phylogenomic analysis, based on orthologous and marker genes, indicated a separate genus position along with the species Achromobacter aestuarii. Furthermore, analysis of the ratio of average nucleotide identities and genome alignment fractions demonstrated genomic dissimilarities typically observed for inter-genera comparisons within this family. As a result of these investigations, the strains are considered to represent a separate species within a new genus, for which the name Schauerella fraxinea gen. nov., sp. nov. is proposed, with the type strain B3P038T (=LMG 33092 T = DSM 115926 T). Additionally, a reclassification of the species Achromobacter aestuarii as Schauerella aestuarii comb. nov. is proposed. In a co-cultivation assay, the strains were able to inhibit the growth of a H. fraxineus strain. Accordingly, a functional analysis of the genome of S. fraxinea B3P038T revealed genes mediating the production of antifungal substances. This potential, combined with the prevalent presence in the phyllosphere of tolerant ash trees, makes this group interesting for an inoculation experiment with the aim of controlling the pathogen in an integrative approach. For future field trials, a strain-specific qPCR system was developed to establish an efficient method for monitoring the inoculation success.PMID:38772267 | DOI:10.1016/j.syapm.2024.126516

A multiomics approach reveals evidence for phenylbutyrate as a potential treatment for combined D,L-2- hydroxyglutaric aciduria

Tue, 21/05/2024 - 12:00
Mol Genet Metab. 2024 May 15;142(3):108495. doi: 10.1016/j.ymgme.2024.108495. Online ahead of print.ABSTRACTPURPOSE: To identify therapies for combined D, L-2-hydroxyglutaric aciduria (C-2HGA), a rare genetic disorder caused by recessive variants in the SLC25A1 gene.METHODS: Patients C-2HGA were identified and diagnosed by whole exome sequencing and biochemical genetic testing. Patient derived fibroblasts were then treated with phenylbutyrate and the functional effects assessed by metabolomics and RNA-sequencing.RESULTS: In this study, we demonstrated that C-2HGA patient derived fibroblasts exhibited impaired cellular bioenergetics. Moreover, Fibroblasts form one patient exhibited worsened cellular bioenergetics when supplemented with citrate. We hypothesized that treating patient cells with phenylbutyrate (PB), an FDA approved pharmaceutical drug that conjugates glutamine for renal excretion, would reduce mitochondrial 2-ketoglutarate, thereby leading to improved cellular bioenergetics. Metabolomic and RNA-seq analyses of PB-treated fibroblasts demonstrated a significant decrease in intracellular 2-ketoglutarate, 2-hydroxyglutarate, and in levels of mRNA coding for citrate synthase and isocitrate dehydrogenase. Consistent with the known action of PB, an increased level of phenylacetylglutamine in patient cells was consistent with the drug acting as 2-ketoglutarate sink.CONCLUSION: Our pre-clinical studies suggest that citrate supplementation has the possibility exacerbating energy metabolism in this condition. However, improvement in cellular bioenergetics suggests phenylbutyrate might have interventional utility for this rare disease.PMID:38772223 | DOI:10.1016/j.ymgme.2024.108495

New analytical methods focusing on polar metabolite analysis in mass spectrometry and NMR-based metabolomics

Tue, 21/05/2024 - 12:00
Curr Opin Chem Biol. 2024 May 20;80:102466. doi: 10.1016/j.cbpa.2024.102466. Online ahead of print.ABSTRACTFollowing in the footsteps of genomics and proteomics, metabolomics has revolutionised the way we investigate and understand biological systems. Rapid development in the last 25 years has been driven largely by technical innovations in mass spectrometry and nuclear magnetic resonance spectroscopy. However, despite the modest size of metabolomes relative to proteomes and genomes, methodological capabilities for robust, comprehensive metabolite analysis remain a major challenge. Therefore, development of new methods and techniques remains vital for progress in the field. Here, we review developments in LC-MS, GC-MS and NMR methods in the last few years that have enhanced quantitative and comprehensive metabolome coverage, highlighting the techniques involved, their technical capabilities, relative performance, and potential impact.PMID:38772215 | DOI:10.1016/j.cbpa.2024.102466

Association of serum metal levels with type 2 diabetes: A prospective cohort and mediating effects of metabolites analysis in Chinese population

Tue, 21/05/2024 - 12:00
Ecotoxicol Environ Saf. 2024 May 20;279:116470. doi: 10.1016/j.ecoenv.2024.116470. Online ahead of print.ABSTRACTSeveral studies have suggested an association between exposure to various metals and the onset of type 2 diabetes (T2D). However, the results vary across different studies. We aimed to investigate the associations between serum metal concentrations and the risk of developing T2D among 8734 participants using a prospective cohort study design. We utilized inductively coupled plasmamass spectrometry (ICP-MS) to assess the serum concentrations of 27 metals. Cox regression was applied to calculate the hazard ratios (HRs) for the associations between serum metal concentrations on the risk of developing T2D. Additionally, 196 incident T2D cases and 208 healthy control participants were randomly selected for serum metabolite measurement using an untargeted metabolomics approach to evaluate the mediating role of serum metabolite in the relationship between serum metal concentrations and the risk of developing T2D with a nested casecontrol study design. In the cohort study, after Bonferroni correction, the serum concentrations of zinc (Zn), mercury (Hg), and thallium (Tl) were positively associated with the risk of developing T2D, whereas the serum concentrations of manganese (Mn), molybdenum (Mo), barium (Ba), lutetium (Lu), and lead (Pb) were negatively associated with the risk of developing T2D. After adding these eight metals, the predictive ability increased significantly compared with that of the traditional clinical model (AUC: 0.791 vs. 0.772, P=8.85×10-5). In the nested casecontrol study, a machine learning analysis revealed that the serum concentrations of 14 out of 1579 detected metabolites were associated with the risk of developing T2D. According to generalized linear regression models, 7 of these metabolites were significantly associated with the serum concentrations of the identified metals. The mediation analysis showed that two metabolites (2-methyl-1,2-dihydrophthalazin-1-one and mestranol) mediated 46.81% and 58.70%, respectively, of the association between the serum Pb concentration and the risk of developing T2D. Our study suggested that serum Mn, Zn, Mo, Ba, Lu, Hg, Tl, and Pb were associated with T2D risk. Two metabolites mediated the associations between the serum Pb concentration and the risk of developing T2D.PMID:38772147 | DOI:10.1016/j.ecoenv.2024.116470

Chronic exposure to tris(1,3-dichloro-2-propyl) phosphate: Effects on intestinal microbiota and serum metabolism in rats

Tue, 21/05/2024 - 12:00
Ecotoxicol Environ Saf. 2024 May 20;279:116469. doi: 10.1016/j.ecoenv.2024.116469. Online ahead of print.ABSTRACTTris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used organophosphate ester that can adversely affect animal or human health. The intestinal microbiota is critical to human health. High-dose exposure to TDCIPP can markedly affect the intestinal ecosystem of mice, but the effects of long-term exposure to lower concentrations of TDCIPP on the intestinal flora and body metabolism remain unclear. In this study, TDCIPP was administered to Sprague-Dawley rats by gavage at a dose of 13.3 mg/kg bw/day for 90 days. TDCIPP increased the relative weight of the kidneys (P = 0.017), but had no effect on the relative weight of the heart, liver, spleen, lungs, testes, and ovaries (P > 0.05). 16 S rRNA gene sequencing revealed that long-term TDCIPP exposure affected the diversity, relative abundance, and functions of rat gut microbes. The serum metabolomics of the rats showed that TDCIPP can disrupt the serum metabolic profiles, result in the up-regulation of 26 metabolites and down-regulation of 3 metabolites, and affect multiple metabolic pathways in rat sera. In addition, the disturbed genera and metabolites were correlated. The functions of some disturbed gut microbes were consistent with the affected metabolic pathways in the sera, and these metabolic pathways were all associated with kidney disease, suggesting that TDCIPP may cause kidney injury in rats by affecting the intestinal flora and serum metabolism.PMID:38772141 | DOI:10.1016/j.ecoenv.2024.116469

Mechanism of cytochrome P450s mediated interference with glutathione and amino acid metabolisms from halogenated PAHs exposure

Tue, 21/05/2024 - 12:00
J Hazard Mater. 2024 May 11;473:134589. doi: 10.1016/j.jhazmat.2024.134589. Online ahead of print.ABSTRACTEpidemiological evidence indicates that exposure to halogenated polycyclic aromatic hydrocarbons (HPAHs) is associated with many adverse effects. However, the mechanisms of metabolic disorder of HPAHs remains limited. Herein, effects of pyrene (Pyr), and its halogenated derivatives (1-chloropyrene (1-Cl-Pyr), 1-bromopyrene (1-Br-Pyr)) on endogenous metabolic pathways were investigated, in human hepatoma (HepG2) and HepG2-derived cell lines expressing various human cytochrome P450s (CYPs). Non-targeted metabolomics results suggested that 1-Br-Pyr and Pyr exposure (625 nM) induced disruption in glutathione and riboflavin metabolism which associated with redox imbalance, through abnormal accumulation of oxidized glutathione, mediated by bioactivation of CYP2E1. Conversely, CYP2C9-mediated 1-Cl-Pyr significantly interfered with glutathione metabolism intermediates, including glycine, L-glutamic acid and pyroglutamic acid. Notably, CYP1A1-mediated Pyr-induced perturbation of amino acid metabolism which associated with nutrition and glycolipid metabolism, resulting in significant upregulation of most amino acids, whereas halogenated derivatives mediated by CYP1A2 substantially downregulated amino acids. In conclusion, this study suggested that Pyr and its halogenated derivatives exert potent effects on endogenous metabolism disruption under the action of various exogenous metabolic enzymes (CYPs). Thus, new evidence was provided to toxicological mechanisms of HPAHs, and reveals potential health risks of HPAHs in inducing diseases caused by redox and amino acid imbalances.PMID:38772114 | DOI:10.1016/j.jhazmat.2024.134589

Suppression of OsSAUR2 gene expression immobilizes soil arsenic bioavailability by modulating root exudation and rhizosphere microbial assembly in rice

Tue, 21/05/2024 - 12:00
J Hazard Mater. 2024 May 11;473:134587. doi: 10.1016/j.jhazmat.2024.134587. Online ahead of print.ABSTRACTOne of the factors influencing the behavior of arsenic (As) in environment is microbial-mediated As transformation. However, the detailed regulatory role of gene expression on the changes of root exudation, rhizosphere microorganisms, and soil As occurrence forms remains unclear. In this study, we evidence that loss-of-function of OsSAUR2 gene, a member of the SMALL AUXIN-UP RNA family in rice, results in significantly higher As uptake in roots but greatly lower As accumulation in grains via affecting the expression of OsLsi1, OsLsi2 in roots and OsABCC1 in stems. Further, the alteration of OsSAUR2 expression extensively affects the metabolomic of root exudation, and thereby leading to the variations in the composition of rhizosphere microbial communities in rice. The microbial community in the rhizosphere of Ossaur2 plants strongly immobilizes the occurrence forms of As in soil. Interestingly, Homovanillic acid (HA) and 3-Coumaric acid (CA), two differential metabolites screened from root exudation, can facilitate soil iron reduction, enhance As bioavailability, and stimulate As uptake and accumulation in rice. These findings add our further understanding in the relationship of OsSAUR2 expression with the release of root exudation and rhizosphere microbial assembly under As stress in rice, and provide potential rice genetic resources and root exudation in phytoremediation of As-contaminated paddy soil.PMID:38772107 | DOI:10.1016/j.jhazmat.2024.134587

Bisphenol S exposed changes in intestinal microflora and metabolomics of freshwater crayfish, Procambarus clarkii

Tue, 21/05/2024 - 12:00
Aquat Toxicol. 2024 May 17;272:106957. doi: 10.1016/j.aquatox.2024.106957. Online ahead of print.ABSTRACTBisphenol S (BPS), a typical endocrine-disrupting chemical (EDC), can cause hepatopancreas damage and intestinal flora disturbance. Comprehensive studies on the mechanisms of acute toxicity in crustaceans are lacking. In this study, 16S rRNA and liquid chromatography were used to investigate intestinal microbiota and metabolites of freshwater crayfish (Procambarus clarkii). In this study, freshwater crayfish were exposed to BPS (10 µg/L and 100 µg/L). The results showed a significant decrease in catalase (CAT) and superoxide dismutase (SOD) activities after exposure to BPS, which inhibited the Nrf2-Keap1 signaling pathway and induced oxidative stress toxicity in freshwater crayfish. In addition, BPS exposure induced the structural changes of intestinal microbial in the freshwater crayfish, showing different patterns of effects. The number of potentially pathogenic bacteria increased, such as Citrobacter, Hafnia-Obesumbacterium, and RsaHf231. A total of 128 different metabolites were analyzed by LC-MS/MS. The inositol and leukotriene (LT) contents in the hepatopancreas of freshwater crayfish were significantly decreased after 10 µg/L BPS exposure, which in turn led to the accumulation of lipids causing hepatopancreas damage. In conclusion, when the concentration of BPS in the water environment exceeded 10 µg/L, the freshwater crayfish intestinal microbiota was dysbiosis and the hepatopancreas metabolism was disturbed.PMID:38772067 | DOI:10.1016/j.aquatox.2024.106957

Metabolic self-feeding in HBV-associated hepatocarcinoma centered on feedback between circulation lipids and the cellular MAPK/mTOR axis

Tue, 21/05/2024 - 12:00
Cell Commun Signal. 2024 May 21;22(1):280. doi: 10.1186/s12964-024-01619-5.ABSTRACTINTRODUCTION: Hepatitis B Virus (HBV) is widely recognized as a "metabolic virus" that disrupts hepatic metabolic homeostasis, rendering it one of the foremost risk factors for hepatocellular carcinoma (HCC). Except for antiviral therapy, the fundamental principles underlying HBV- and HBV+ HCC have remained unchanged, limiting HCC treatment options.OBJECTIVES: In this study, we aim to identify the distinctive metabolic profile of HBV-associated HCC, with the promise of identifying novel metabolic targets that confer survival advantages and ultimately impede cancer progression.METHODS: We employed a comprehensive methodology to evaluate metabolic alterations systematically. Initially, we analyzed transcriptomic and proteomic data obtained from a public database, subsequently validating these findings within our test cohort at both the proteomic and transcriptomic levels. Additionally, we conducted a comprehensive analysis of tissue metabolomics profiles, lipidomics, and the activity of the MAPK and AKT signaling pathway to corroborate the abovementioned changes.RESULTS: Our multi-omics approach revealed distinct metabolic dysfunctions associated with HBV-associated HCC. Specifically, we observed upregulated steroid hormone biosynthesis, primary bile acid metabolism, and sphingolipid metabolism in HBV-associated HCC patients' serum. Notably, metabolites involved in primary bile acid and sphingolipids can activate the MAPK/mTOR pathway. Tissue metabolomics and lipidomics analyses further validated the serum metabolic alterations, particularly alterations in lipid composition and accumulation of unsaturated fatty acids.CONCLUSION: Our findings emphasize the pivotal role of HBV in HCC metabolism, elucidating the activation of a unique MAPK/mTOR signaling axis by primary bile acids and sphingolipids. Moreover, the hyperactive MAPK/mTOR signaling axis transduction leads to significant reprogramming in lipid metabolism within HCC cells, further triggering the activation of the MAPK/mTOR pathway in turn, thereby establishing a self-feeding circle driven by primary bile acids and sphingolipids.PMID:38773448 | DOI:10.1186/s12964-024-01619-5

Study on the causes of changes in colour during Hibiscus syriacus flowering based on transcriptome and metabolome analyses

Tue, 21/05/2024 - 12:00
BMC Plant Biol. 2024 May 21;24(1):431. doi: 10.1186/s12870-024-05142-0.ABSTRACTBACKGROUND: The flower colour of H. syriacus 'Qiansiban' transitions from fuchsia to pink-purple and finally to pale purple, thereby enhancing the ornamental value of the cultivars. However, the molecular mechanism underlying this change in flower colour in H. syriacus has not been elucidated. In this study, the transcriptomic data of H. syriacus 'Qiansiban' at five developmental stages were analysed to investigate the impact of flavonoid components on flower colour variation. Additionally, five cDNA libraries were constructed from H. syriacus 'Qiansiban' during critical blooming stages, and the transcriptomes were sequenced to investigate the molecular mechanisms underlying changes in flower colouration.RESULTS: High-performance liquid chromatography‒mass spectrometry detected five anthocyanins in H. syriacus 'Qiansiban', with malvaccin-3-O-glucoside being the predominant compound in the flowers of H. syriacus at different stages, followed by petunigenin-3-O-glucoside. The levels of these five anthocyanins exhibited gradual declines throughout the flowering process. In terms of the composition and profile of flavonoids and flavonols, a total of seven flavonoids were identified: quercetin-3-glucoside, luteolin-7-O-glucoside, Santianol-7-O-glucoside, kaempferol-O-hexosyl-C-hexarbonoside, apigenin-C-diglucoside, luteolin-3,7-diglucoside, and apigenin-7-O-rutinoside. A total of 2,702 DEGs were identified based on the selected reference genome. Based on the enrichment analysis of differentially expressed genes, we identified 9 structural genes (PAL, CHS, FLS, DRF, ANS, CHI, F3H, F3'5'H, and UFGT) and 7 transcription factors (3 MYB, 4 bHLH) associated with flavonoid biosynthesis. The qRT‒PCR results were in good agreement with the high-throughput sequencing data.CONCLUSION: This study will establish a fundamental basis for elucidating the mechanisms underlying alterations in the flower pigmentation of H. syriacus.PMID:38773421 | DOI:10.1186/s12870-024-05142-0

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