PubMed

Pediatr Nephrol. 2023 Jan 17. doi: 10.1007/s00467-022-05872-z. Online ahead of print.ABSTRACTRecent insights in allorecognition and graft rejection mechanisms revealed a more complex picture than originally considered, involving multiple pathways of both adaptive and innate immune response, supplied by efficient inflammatory synergies. Current pillars of transplant monitoring are serum creatinine, proteinuria, and drug blood levels, which are considered as traditional markers, due to consolidated experience, low cost, and widespread availability. The most diffuse immunological biomarkers are donor-specific antibodies, which are included in routine post-transplant monitoring in many centers, although with some reproducibility issues and interpretation difficulties. Confirmed abnormalities in these traditional biomarkers raise the suspicion for rejection and guide the indication for graft biopsy, which is still considered the gold standard for rejection monitoring. Rapidly evolving new "omic" technologies have led to the identification of several novel biomarkers, which may change the landscape of transplant monitoring should their potential be confirmed. Among them, urinary chemokines and measurement of cell-free DNA of donor origin are perhaps the most promising. However, at the moment, these approaches remain highly expensive and cost-prohibitive in most settings, with limited clinical applicability; approachable costs upon technology investments would speed their integration. In addition, transcriptomics, metabolomics, proteomics, and the study of blood and urinary extracellular vesicles have the potential for early identification of subclinical rejection with high sensitivity and specificity, good reproducibility, and for gaining predictive value in an affordable cost setting. In the near future, information derived from these new biomarkers is expected to integrate traditional tools in routine use, allowing identification of rejection prior to clinical manifestations and timely therapeutic intervention. This review will discuss traditional, novel, and invasive and non-invasive biomarkers, underlining their strengths, limitations, and present or future applications in children.PMID:36648536 | DOI:10.1007/s00467-022-05872-z

Glycobiology. 2023 Jan 16:cwad003. doi: 10.1093/glycob/cwad003. Online ahead of print.ABSTRACTIn epithelial cancers, truncated O-glycans, such as the Thomson-nouveau antigen (Tn) and its sialylated form (STn), are up-regulated on the cell surface and associated with poor prognosis and immunological escape. Recent studies have shown that these carbohydrate epitopes facilitate cancer development and can be targeted therapeutically; however, the mechanism underpinning their expression remains unclear. To identify genes directly influencing the expression of cancer-associated O-glycans, we conducted an unbiased, positive-selection, whole genome CRISPR knockout-screen using monoclonal antibodies against Tn and STn. We show that knockout of the Zn2+-transporter SLC39A9 (ZIP9), alongside the well-described targets C1GALT1 (C1GalT1) and its molecular chaperone, C1GALT1C1 (COSMC), results in surface-expression of cancer-associated O-glycans. No other gene perturbations were found to reliably induce O-glycan truncation. We furthermore show that ZIP9 knockout affects N-linked glycosylation, resulting in up-regulation of oligo-mannose, hybrid-type, and α2,6-sialylated structures as well as down-regulation of tri- and tetra-antennary structures. Finally, we demonstrate that accumulation of Zn2+ in the secretory pathway coincides with cell-surface presentation of truncated O-glycans in cancer tissue, and that over-expression of COSMC mitigates such changes. Collectively, the findings show that dysregulation of ZIP9 and Zn2+ induces cancer-like glycosylation on the cell surface by affecting the glycosylation machinery.PMID:36648436 | DOI:10.1093/glycob/cwad003

Am J Physiol Lung Cell Mol Physiol. 2023 Jan 17. doi: 10.1152/ajplung.00278.2022. Online ahead of print.ABSTRACTUsing latent class analysis (LCA) of clinical and protein biomarkers, researchers have identified two phenotypes of the acute respiratory distress syndrome (ARDS) with divergent clinical trajectories and treatment responses. We investigated whether plasma metabolites differed amongst patients with LCA-derived hyperinflammatory and hypoinflammatory ARDS, and tested the prognostic utility of adding metabolic clusters to LCA phenotypes. We analyzed data from 93 ARDS patients with sepsis enrolled in a multi-center prospective cohort of critically ill patients, comparing 970 metabolites between the two LCA-derived phenotypes. 188 metabolites were differentially abundant between the two LCA-derived phenotypes. After adjusting for age, sex, confounding medications, and comorbid liver and kidney disease, 82 metabolites remained significantly different. Hyperinflammatory ARDS patients had reduced circulating lipids but high levels of pyruvate, lactate, and malate. Metabolic cluster and LCA-derived phenotypes were each significantly and independently associated with survival. Hyperinflammatory ARDS patients may be experiencing a glycolytic shift leading to dysregulated lipid metabolism. Metabolic profiling offers prognostic information beyond what is captured by LCA phenotypes alone. Deeper biologic profiling may identify key differences in pathogenesis among patients with ARDS and lead to novel targeted therapies.PMID:36648136 | DOI:10.1152/ajplung.00278.2022

Neural Plast. 2023 Jan 7;2023:1455634. doi: 10.1155/2023/1455634. eCollection 2023.ABSTRACTDepression is a highly prevalent and heterogeneous disorder that requires new strategies to overcome depression. In this study, we aimed to investigate whether leonurine modulated hippocampal nerve regeneration in chronic and unpredictable mild stress (CUMS) rats through the SHH/GLI signaling pathway and restoring gut microbiota and microbial metabolic homeostasis. The CUMS rat model was constructed and treated with leonurine. The body weight of rats was recorded, and a series of tests were performed. Western blot was utilized to measure the expression of BDNF and 5-HT in the hippocampus. Then the expression of SHH, GLI, PTCH, and SMO were measured by qRT-PCR and western blot. The colocalization of BrdU+DCX and BrdU+NeuN was evaluated by IF. 16S rDNA high-throughput sequencing was applied to detect the composition and distribution of gut microbiota. The differential metabolites were analyzed by untargeted metabolomics. The correlation between gut microbiota and microbial metabolites was analyzed by Pearson correlation coefficient. After CUMS modeling, the body weight of rats was decreased, and the expression of BDNF and 5-HT were decreased, while the body weight was recovered, and the expression of BDNF and 5-HT were increased after leonurine treatment. Leonurine reversed the reduction in the colocalization of BrdU+DCX and BrdU+NeuN and the reduction in the levels of SHH, GLI, PTCH, and SMO induced by CUMS modeling. Leonurine also restored gut microbiota and microbial metabolites homeostasis in CUMS rats. Furthermore, Prevotellaceae_Ga6A1_group was negatively correlated with 3-Oxocholic acid, nutriacholic acid, and cholic acid. Collectively, leonurine regulated hippocampal nerve regeneration in CUMS rats by activating the SHH/GLI signaling pathway and restoring gut microbiota and microbial metabolic homeostasis.PMID:36647544 | PMC:PMC9840550 | DOI:10.1155/2023/1455634

PeerJ. 2023 Jan 11;11:e14658. doi: 10.7717/peerj.14658. eCollection 2023.ABSTRACTBacterial wilt is a soil-borne disease that represents ubiquitous threat to Solanaceae crops. The whole-root transcriptomes and metabolomes of bacterial wilt-resistant eggplant were studied to understand the response of eggplant to bacterial wilt. A total of 2,896 differentially expressed genes and 63 differences in metabolites were identified after inoculation with Ralstonia solanacearum. Further analysis showed that the biosynthesis pathways for phytohormones, phenylpropanoids, and flavonoids were altered in eggplant after inoculation with R. solanacearum. The results of metabolomes also showed that phytohormones played a key role in eggplant response to bacterial wilt. Integrated analyses of the transcriptomic and metabolic datasets indicated that jasmonic acid (JA) content and gene involved in the JA signaling pathway increased in response to bacterial wilt. These findings remarkably improve our understanding of the mechanisms of induced defense response in eggplant and will provide insights intothe development of disease-resistant varieties of eggplant.PMID:36647448 | PMC:PMC9840387 | DOI:10.7717/peerj.14658

Oxid Med Cell Longev. 2023 Jan 7;2023:4202861. doi: 10.1155/2023/4202861. eCollection 2023.ABSTRACTHerb-induced liver injury (HILI) is gradually increasing, and Psoraleae Fructus (PF) has been reported to induce hepatotoxicity. However, its underlying toxicity mechanism has been only poorly revealed. In this paper, we attempted to explore the liver injury and mechanism caused by Psoraleae Fructus ethanol extract (PFE). First, we administered PFE to mice for 4 weeks and evaluated their serum liver function indices. H&E staining was performed to observe the pathological changes of the livers. Oil red O staining was used to visualize hepatic lipids. Serum-untargeted metabolomics and liver proteomics were used to explore the mechanism of PF hepatotoxicity, and transmission electron microscopy was determined to assess mitochondria and western blot to determine potential target proteins expression. The results showed that PFE caused abnormal liver biochemical indicators and liver tissue injury in mice, and there was substantial fat accumulation in liver tissue in this group. Furthermore, metabolomic analysis showed that PFE changed bile acid synthesis, lipid metabolism, etc., and eight metabolites, including linoleic acid, which could be used as potential biomarkers of PFE hepatotoxicity. Proteomic analysis revealed that differential proteins were clustered in the mitochondrial transmembrane transport, the long-chain fatty acid metabolic process and purine ribonucleotide metabolic process. Multiomics analysis showed that eight pathways were enriched in both metabolomics and proteomics, such as bile secretion, unsaturated fatty acid biosynthesis, and linoleic acid metabolism. The downregulation of SLC27A5, CPT1A, NDUFB5, and COX6A1 and upregulation of cytochrome C and ABCC3 expressions also confirmed the impaired fatty acid oxidative catabolism. Altogether, this study revealed that PFE induced hepatotoxicity by damaging mitochondria, reducing fatty acid β-oxidation levels, and inhibiting fatty acids ingested by bile acids.PMID:36647431 | PMC:PMC9840557 | DOI:10.1155/2023/4202861

Mol Nutr Food Res. 2023 Jan 16:e2200432. doi: 10.1002/mnfr.202200432. Online ahead of print.ABSTRACTSCOPE: High red and processed meat consumption is associated with several adverse outcomes such as colorectal cancer and overall global mortality. However, the underlying mechanisms remain debated and need to be elucidated.METHODS AND RESULTS: Urinary untargeted LC-MS metabolomics data from 240 subjects from the French cohort NutriNet-Santé were analysed. Individuals were matched and divided into 3 groups according to their consumption of red and processed meat: high red and processed meat consumers, non-red and processed meat consumers and an at random group. Results were supported by a preclinical experiment where rats were fed either a high red meat or a control diet. Microbiota derived metabolites, in particular indoxyl sulfate and cinnamoylglycine, were found impacted by the high red meat diet in both studies, suggesting a modification of microbiota by the high red/processed meat diet. Rat microbiota sequencing analysis strengthened this observation. Although not evidenced in the human study, rat mercapturic acid profile concomitantly revealed an increased lipid peroxidation induced by high red meat diet.CONCLUSION: Novel microbiota metabolites were identified as red meat consumption potential biomarkers, suggesting a deleterious effect, which could partly explain the adverse effects associated with high red and processed meat consumption. This article is protected by copyright. All rights reserved.PMID:36647294 | DOI:10.1002/mnfr.202200432

Mass Spectrom Rev. 2023 Jan 16:e21824. doi: 10.1002/mas.21824. Online ahead of print.ABSTRACTBiological processes unfold across broad spatial and temporal dimensions, and measurement of the underlying molecular world is essential to their understanding. Interdisciplinary efforts advanced mass spectrometry (MS) into a tour de force for assessing virtually all levels of the molecular architecture, some in exquisite detection sensitivity and scalability in space-time. In this review, we offer vignettes of milestones in technology innovations that ushered sample collection and processing, chemical separation, ionization, and 'omics analyses to progressively finer resolutions in the realms of tissue biopsies and limited cell populations, single cells, and subcellular organelles. Also highlighted are methodologies that empowered the acquisition and analysis of multidimensional MS data sets to reveal proteomes, peptidomes, and metabolomes in ever-deepening coverage in these limited and dynamic specimens. In pursuit of richer knowledge of biological processes, we discuss efforts pioneering the integration of orthogonal approaches from molecular and functional studies, both within and beyond MS. With established and emerging community-wide efforts ensuring scientific rigor and reproducibility, spatiotemporal MS emerged as an exciting and powerful resource to study biological systems in space-time.PMID:36647247 | DOI:10.1002/mas.21824

Microb Cell Fact. 2023 Jan 16;22(1):11. doi: 10.1186/s12934-022-02013-x.ABSTRACTMacroscopic fungi, mainly higher basidiomycetes and some ascomycetes, are considered medicinal mushrooms and have long been used in different areas due to their pharmaceutically/nutritionally valuable bioactive compounds. However, the low production of these bioactive metabolites considerably limits the utilization of medicinal mushrooms both in commerce and clinical trials. As a result, many attempts, ranging from conventional methods to novel approaches, have been made to improve their production. The novel strategies include conducting omics investigations, constructing genome-scale metabolic models, and metabolic engineering. So far, genomics and the combined use of different omics studies are the most utilized omics analyses in medicinal mushroom research (both with 31% contribution), while metabolomics (with 4% contribution) is the least. This article is the first attempt for reviewing omics investigations in medicinal mushrooms with the ultimate aim of bioactive compound overproduction. In this regard, the role of these studies and systems biology in elucidating biosynthetic pathways of bioactive compounds and their contribution to metabolic engineering will be highlighted. Also, limitations of omics investigations and strategies for overcoming them will be provided in order to facilitate the overproduction of valuable bioactive metabolites in these valuable organisms.PMID:36647087 | DOI:10.1186/s12934-022-02013-x

Nat Metab. 2023 Jan 16. doi: 10.1038/s42255-022-00705-7. Online ahead of print.NO ABSTRACTPMID:36646753 | DOI:10.1038/s42255-022-00705-7

Nat Commun. 2023 Jan 16;14(1):228. doi: 10.1038/s41467-023-35861-1.ABSTRACTThe interplay between western diet and gut microbiota drives the development of non-alcoholic fatty liver disease and its progression to non-alcoholic steatohepatitis. However, the specific microbial and metabolic mediators contributing to non-alcoholic steatohepatitis remain to be identified. Here, a choline-low high-fat and high-sugar diet, representing a typical western diet, named CL-HFS, successfully induces male mouse non-alcoholic steatohepatitis with some features of the human disease, such as hepatic inflammation, steatosis, and fibrosis. Metataxonomic and metabolomic studies identify Blautia producta and 2-oleoylglycerol as clinically relevant bacterial and metabolic mediators contributing to CL-HFS-induced non-alcoholic steatohepatitis. In vivo studies validate that both Blautia producta and 2-oleoylglycerol promote liver inflammation and hepatic fibrosis in normal diet- or CL-HFS-fed mice. Cellular and molecular studies reveal that the GPR119/TAK1/NF-κB/TGF-β1 signaling pathway mediates 2-oleoylglycerol-induced macrophage priming and subsequent hepatic stellate cell activation. These findings advance our understanding of non-alcoholic steatohepatitis pathogenesis and provide targets for developing microbiome/metabolite-based therapeutic strategies against non-alcoholic steatohepatitis.PMID:36646715 | DOI:10.1038/s41467-023-35861-1

Nutr Metab Cardiovasc Dis. 2022 Dec 17:S0939-4753(22)00498-7. doi: 10.1016/j.numecd.2022.12.011. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: The association between the metabolic syndrome (MetS) and plasminogen activator inhibitor-1 (PAI-1) has been well established in cross-sectional studies. It is less clear whether this translates into decreased clot lysis rates and very little information is available on non-European populations. Little is known regarding prospective associations and whether clot lysis progressively worsens in MetS individuals over time. We determined the prospective association of MetS with PAI-1 activity (PAI-1act) and clot lysis time (CLT) over a 10-year period.METHODS AND RESULTS: As many as 2010 African men and women aged ≥30 years were stratified according to MetS status and number of MetS criteria (0-5). We also determined the contribution of the PAI-1 4G/5G polymorphism to these associations and identified which MetS criteria had the strongest associations with PAI-1act and CLT. Both PAI-1act and CLT remained consistently elevated in individuals with MetS throughout the 10-year period. PAI-1act and CLT did not increase more over time in MetS individuals than in controls. The 4G/5G genotype did not influence the association of PAI-1act or clot lysis with MetS. Increased waist circumference, increased triglycerides and decreased HDL-C were the main predictors of PAI-1act and CLT.CONCLUSIONS: Black South Africans with MetS had increased PAI-1act and longer CLTs than individuals without MetS. The inhibited clot lysis in MetS did, however, not deteriorate over time compared to controls. Of the MetS criteria, obesity and altered lipids were the main predictors of PAI-1act and CLT and are thus potential targets for prevention strategies to decrease thrombotic risk.PMID:36646603 | DOI:10.1016/j.numecd.2022.12.011

Environ Pollut. 2023 Jan 13:121081. doi: 10.1016/j.envpol.2023.121081. Online ahead of print.ABSTRACTMicroplastics (MPs) are a global threat to the environment, and plant uptake of MP particles (≤0.2 μm) is a particular cause for concern. However, physiological and molecular mechanisms underlying MP-induced growth inhibition need to be clarified. Towards this goal, we conducted a hydroponic experiment to investigate the accumulation of MPs, changes in physiology, gene expression, and metabolites in lettuce from a series of concentrations of fluorescence-labelled polystyrene MPs (0, 10, 20, 30, 40, 50 mg L-1, ∼0.2 μm). Our results showed that MPs accumulated in the lettuce root tips and leaf veins, resulting in the hypertonic injury of lettuce, and the down-regulation of genes related to ion homeostasis. Stress-related genes were up-regulated, and sphingolipid metabolism increased in response to MP additions, causing increased biosynthesis of ascorbic acid, terpenoid, and flavonoids in root exudates. Our findings provide a molecular-scale perspective on the response of leafy vegetables to MP-stress at a range of concentrations. This enables more comprehensive evaluation of the risks of MPs to human health and the ecological environment.PMID:36646407 | DOI:10.1016/j.envpol.2023.121081

Environ Pollut. 2023 Jan 13:121071. doi: 10.1016/j.envpol.2023.121071. Online ahead of print.ABSTRACTToxic effects of exposure to microplastics (MPs) on living organisms and humans have attracted global concern. However, most previous studies exposed animals to only one type of MP (mainly polystyrene) to assess the health risk of MPs for animals. Therefore, we conducted a laboratory gavage experiment on rats based on the types and concentration of MPs to which humans are exposed in their daily life. The purpose of this study is to use Sprague-Dawley (SD) rat models to assess the potential health risks in mammals from co-exposure to various MPs. In the present study, SD rats were exposed to 12 mg/kg bw/day mixed-MPs (containing 10 types of MPs) for 42 days, and then examined the alteration of gut microbes and serum metabolites. The results showed that 6 gut microbes at the family level (f_Muribaculaceae, f_Oscillospiraceae, f_Bacteroidaceae, f_Neisseriaceae, f_Prevotellaceae, and f_Veillonellaceae) were significantly perturbed (t-test, p < 0.05) in rats after MP exposure. After MP intervention, 47 metabolites significantly regulated in SD rat serum, mainly including lipids and lipid-like molecules (e.g., fatty acids), organic acids and derivatives (e.g., phosphoric acids), and isoflavonoids (e.g., daidzein). These findings contribute to assessing the health risks of various MP co-exposure in mammals in the actual environment and provide a novel insight into the toxicity mechanism of MPs.PMID:36646405 | DOI:10.1016/j.envpol.2023.121071

Clin Immunol. 2023 Jan 13:109230. doi: 10.1016/j.clim.2023.109230. Online ahead of print.ABSTRACTBACKGROUND: Checkpoint inhibitor pneumonitis (CIP) is a potentially fatal adverse event resulting from immunotherapy in patients with malignant tumors. However, the pathogenesis of CIP remains poorly understood.METHODS: We collected bronchoalveolar lavage fluid (BALF) from cohorts of patients with CIP, new-onset lung cancer (LC), and idiopathic pulmonary fibrosis (IPF). Non-targeted metabolomics analysis was conducted to analyze metabolic signatures. Flow cytometry was used to evaluate immune cell subsets.RESULTS: Lymphocytes were predominant in the BALF of patients with CIP. A total of 903 metabolites were identified, among which lipid compounds were the most abundant. In a comparison between patients with CIP and LC, enrichment analysis of the altered metabolites showed suppressed amino sugar metabolism, and spermidine and spermine biosynthesis in the CIP group. Metabolism of alpha linolenic acid, linoleic acid, and their fatty acid derivatives was enriched in the CIP group relative to the IPF group. The twelve metabolites found to be enriched in the CIP group were positively correlated with the proportion of CD8+ T cells. One cluster of BALF metabolites, 57.14% of which were lipid molecules, was inversely correlated with the proportion of natural killer cells.CONCLUSIONS: In this study, the metabolomic landscape of BALF in patients with CIP was determined. We elucidated suppressed tumor metabolic signatures, enhanced pulmonary inflammatory signaling, and the characteristics of responsible immune cells, which helps to understand the pathogenesis of CIP.PMID:36646189 | DOI:10.1016/j.clim.2023.109230

Neuroendocrinology. 2023 Jan 16. doi: 10.1159/000529146. Online ahead of print.ABSTRACTIntroduction The present study aimed to prove the metyrapone short test in a day clinic to be suitable for examining the integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with suspected secondary and tertiary adrenal insufficiency and to identify novel effector molecules in acute stress response. Methods 44 patients were prospectively enrolled. Based on stimulated 11-deoxycortisol levels, patients were divided into a physiological (11-deoxycortisol ≥70 µg/l) and a pathological (11-deoxycortisol <70 µg/l) response group. Clinical follow-up examination was performed for validation. Ultra-performance-liquid-chromatography-tandem-mass-spectrometry and a Fourier-transform-ion-cyclotron-resonance-mass-spectrometry were used for targeted and untargeted steroid metabolomics. Results At baseline, lower levels of cortisone (42 vs. 50 nmol/l, p=0.048) and 17-OH-progesterone (0.6 vs. 1.2 nmol/l, p=0.041) were noted in the pathological response group. After metyrapone administration, the pathological response group exhibited significantly lower 11-deoxycortisol (39.0 vs. 94.2 µg/l, p<0.001) and ACTH (49 vs. 113 pg/ml, p<0.001) concentrations as well as altered upstream metabolites. Untargeted metabolomics identified a total of 76 metabolites to be significantly up- or downregulated by metyrapone. A significant increase of the bile acid glycochenodeoxycholic acid (GCDC, p<0.01) was detected in both groups with an even stronger increase in the physiological response group. After a mean follow-up of 17.2 months, an 11-deoxycortisol cut-off of 70 µg/l showed a high diagnostic performance (sensitivity 100%, specificity 96%). Conclusion The metyrapone short test is safe and feasible in a day clinic setting. The alterations of the bile acid GCDC indicate that the liver might be involved in the acute stress response of the HPA axis.PMID:36646062 | DOI:10.1159/000529146

Rapid Commun Mass Spectrom. 2023 Jan 16:e9473. doi: 10.1002/rcm.9473. Online ahead of print.ABSTRACTRATIONALE: Anemarrhenae Rhizoma (AR) has been a often used traditional Chinese medicine (TCM) for a long time. Its salt processing is one of the most common application forms. Modern pharmacological research showed that the salt-processed product has significantly enhanced various pharmacological activities. However, the pharmacodynamic material basis of this change had not been yet known. The aim of this study was to develop a strategy to screen pharmacodynamic substances in AR and salt-processed Anemarrhenae Rhizoma (SAR).METHODS: An integrated strategy combined plant metabolomics with molecular docking technology was established to screen pharmacodynamic substances. The plant metabolomics analysis was performed to select the chemical markers between AR and SAR. Then, molecular docking technology was applied to explore the relationship between chemical markers and diabetes targets (α-glucosidase). Finally, potential quality control markers were screened.RESULTS: As a result, there were significant differences in the quantification of 9 steroidal saponins between AR and SAR. The results of plant metabolomics showed that a quite clear discrimination including 29 chemical markers between AR and SAR. Taking the hypoglycemic activity into consideration, 16 steroidal saponins were selected as the potential quality markers.CONCLUSION: The developed method not only supplied an optional solution to search for pharmacophores in AR and SAR, but also provided a foundation for the study of the differential components and pharmacodynamics in different processed products of TCM.PMID:36645740 | DOI:10.1002/rcm.9473

Metabolomics. 2023 Jan 16;19(2):6. doi: 10.1007/s11306-022-01968-7.ABSTRACTINTRODUCTION: Lipid metabolism participates in various biological processes such as proliferation, apoptosis, migration, invasion, and maintenance of membrane homeostasis of prostate tumor cells. Bufadienolides, the active ingredients of Chansu, show a robust anti-proliferative effect against prostate cancer cells in vitro, but whether bufadienolides could regulate the lipid metabolism in prostate cancer has not been evaluated.OBJECTIVES: Our study explored the regulatory effects of bufadienolides on lipid metabolism in human prostate carcinoma cells (PC-3).METHODS: Untargeted lipidomics and transcriptomics were combined to study the effect of different bufadienolides interventions on lipid and gene changes of PC-3 cells. The key genes related to lipid metabolism and prostate cancer development were verified by qPCR and western blotting.RESULTS: Lipidomic analysis showed that the active bufadienolides significantly downregulated the content of long-chain lipids of PC-3 cells. Based on transcriptomic and qPCR analyses, many genes related to lipid metabolism were significantly regulated by active bufadienolides, such as ELOVL6, CYP2E1, GAL3ST1, CERS1, PLA2G10, PLD1, SPTLC3, and GPX2. Bioinformatics analysis of the Cancer Genome Atlas database and literature retrieval showed that elongation of very long-chain fatty acids protein 6 (ELOVL6) and phospholipase D1 (PLD1) might be important regulatory genes. Western blot analysis revealed that active bufadienolides could downregulate PLD1 protein levels which might promote anti-prostate cancer effect.CONCLUSIONS: All these findings support that bufadienolides might induce lipid metabolic remodeling by regulating long-chain lipids synthesis and phospholipid hydrolysis to achieve an anti-prostate cancer effect, and PLD1 would probably be the key protein.PMID:36645548 | DOI:10.1007/s11306-022-01968-7

J Sci Food Agric. 2023 Jan 16. doi: 10.1002/jsfa.12457. Online ahead of print.ABSTRACTBACKGROUND: Tilapia skin collagen hydrolysates (TSCHs) are the product of enzymatic hydrolysis of collagen, which is mainly extracted from tilapia skin. The components of TSCHs have recently been reported play a preventive role in dextran sulphate sodium (DSS)-induced ulcerative colitis (UC). However, it has not been illustrated whether TSCHs can prevent against DSS-induced UC via the gut microbiota and its derived metabolites.RESULTS: TSCHs are mainly composed of amino acids, which have similar characteristics to collagen, with most having a molecular weight below 5 kDa. In a mouse model of UC, TSCHs had no toxic effect at a dose of 60 g kg-1 and could reduce body weight changes, colon length, histopathological changes and score, and the level of the serum inflammatory cytokine interleukin (IL)-6. Concurrently, 16S rRNA sequencing showed that TSCHs significantly reduced the abundance of Bacteroidetes and Proteobacteria at the phylum level and norank_f__Muribaculaceae and Escherichia-Shigella at the genus level, while they increased the abundance of Firmicutes at the phylum level and Lachnoclostridium, Allobaculum, Enterorhabdus, and unclassified__f__Ruminococcaceae at the genus level. Target metabolomic analysis showed that TSCHs elevated the concentration of total acid, acetic acid, propanoic acid, and butanoic acid, but reduced isovaleric acid concentrations. Moreover, Pearson correlation analysis revealed that Allobaculum, unclassified_Ruminococcaceae, and Enterorhabdus were positively correlated with acetic acid and butyric acid, but not Escherichia-Shigella.CONCLUSION: These findings suggest that TSCHs can prevent UC by modulating gut microbial and microbiota-derived metabolites. This article is protected by copyright. All rights reserved.PMID:36645331 | DOI:10.1002/jsfa.12457

J Am Heart Assoc. 2023 Jan 16:e026885. doi: 10.1161/JAHA.122.026885. Online ahead of print.ABSTRACTBackground The study aimed to show the relationship between a large number of circulating metabolites and subsequent cardiovascular disease (CVD) and subclinical markers of CVD in the general population. Methods and Results In 2278 individuals free from CVD in the EpiHealth study (aged 45-75 years, mean age 61 years, 50% women), 790 annotated nonxenobiotic metabolites were measured by mass spectroscopy (Metabolon). The same metabolites were measured in the PIVUS (Prospective Investigation of Vasculature in Uppsala Seniors) study (n=603, all aged 80 years, 50% women), in which cardiac and carotid artery pathologies were evaluated by ultrasound. During a median follow-up of 8.6 years, 107 individuals experienced a CVD (fatal or nonfatal myocardial infarction, stroke, or heart failure) in EpiHealth. Using a false discovery rate of 0.05 for age- and sex-adjusted analyses and P<0.05 for adjustment for traditional CVD risk factors, 37 metabolites were significantly related to incident CVD. These metabolites belonged to multiple biochemical classes, such as amino acids, lipids, and nucleotides. Top findings were dimethylglycine and N-acetylmethionine. A lasso selection of 5 metabolites improved discrimination when added on top of traditional CVD risk factors (+4.0%, P=0.0054). Thirty-five of the 37 metabolites were related to subclinical markers of CVD evaluated in the PIVUS study. The metabolite 1-carboxyethyltyrosine was associated with left atrial diameter as well as inversely related to both ejection fraction and the echogenicity of the carotid artery. Conclusions Several metabolites were discovered to be associated with future CVD, as well as with subclinical markers of CVD. A selection of metabolites improved discrimination when added on top of CVD risk factors.PMID:36645074 | DOI:10.1161/JAHA.122.026885