Integration of Lipidomics and Transcriptomics Reveals Reprogramming of the Lipid Metabolism and Composition in Clear Cell Renal Cell Carcinoma

Metabolites, Journal Year: 2020, Volume and Issue: 10(12), P. 509 - 509

Published: Dec. 13, 2020

Clear cell renal carcinoma (ccRCC) is fundamentally a metabolic disease. Given the importance of lipids in many cellular processes, this study we delineated lipidomic profile human ccRCC and integrated it with transcriptomic data to connect variations cancer lipid metabolism gene expression changes. Untargeted analysis was performed on 20 paired normal tissues, using LC-MS GC-MS. Different classes were altered compared tissue. Among long chain fatty acids (LCFAs), significant accumulations polyunsaturated (PUFAs) found. Integrated showed that acid desaturation elongation pathways enriched neoplastic Consistent these findings, observed increased stearoyl-CoA desaturase (SCD1) FA elongase 2 5 ccRCC. Primary cells treated small molecule SCD1 inhibitor (A939572) proliferated at slower rate than untreated cells. In addition, after cisplatin treatment, death tumor A939572 significantly greater conclusion, our findings delineate signature inhibition reduced proliferation sensitivity, suggesting pathway can be involved chemotherapy resistance.

Language: Английский

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Maternal consumption of artificially sweetened beverages during pregnancy is associated with infant gut microbiota and metabolic modifications and increased infant body mass index

Gut Microbes, Journal Year: 2020, Volume and Issue: 13(1)

Published: Dec. 31, 2020

Artificial sweetener consumption by pregnant women has been associated with an increased risk of infant obesity, but the underlying mechanisms are unknown. We aimed to determine if maternal artificially sweetened beverages (ASB) during pregnancy is modifications gut bacterial community composition and function first year life, whether these alterations linked body mass index (BMI) at one age. studied 100 infants from prospective Canadian CHILD Cohort Study, selected based on ASB (50 non-consumers 50 daily consumers). BMI was higher among ASB-exposed infants. Infant stool (16S rRNA gene sequencing) urine (untargeted metabolomics) were acquired in early (3-4 months) late (12 infancy. identified four microbiome clusters, which two recapitulated maturation trajectory communities immature (Cluster 1) mature 4) deviated this (Clusters 2 3). Maternal did not differ between community-level shifts taxonomy structure depletion several Bacteroides sp. Cluster 2. In complete dataset, succinate spermidine levels 3 months infants, positively one-year-old. Overall, gestational exposure microbiota 2, BMI. Gestational spermidine. Succinate found mediate 29% effect one-year-old, revealing a potential role metabolite weight consumption. As we face unprecedented rise childhood future studies should evaluate causal relationships (a modifiable exposure), metabolites, metabolism, composition.

Language: Английский

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Hepatocyte-Specific Loss of PPARγ Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver

Cellular and Molecular Gastroenterology and Hepatology, Journal Year: 2021, Volume and Issue: 11(5), P. 1291 - 1311

Published: Jan. 1, 2021

Background & AimsNonalcoholic steatohepatitis (NASH) is commonly observed in patients with type 2 diabetes, and thiazolidinediones (TZD) are considered a potential therapy for NASH. Although TZD increase insulin sensitivity partially reduce steatosis alanine aminotransferase, the efficacy of on resolving liver pathology limited. In fact, may activate peroxisome proliferator-activated receptor gamma (PPARγ) hepatocytes promote steatosis. Therefore, we assessed role that hepatocyte-specific PPARγ plays development NASH, how it alters therapeutic effects mice diet-induced NASH.MethodsHepatocyte-specific expression was knocked out adult before after NASH induced high fat, cholesterol, fructose (HFCF) diet.ResultsHFCF diet increased hepatocytes, rosiglitazone further activated HFCF-fed vivo vitro. Hepatocyte-specific loss reduced progression HFCF-induced male benefits derived from extrahepatic tissues non-parenchymal cells. RNAseq metabolomics indicated HFCF promoted inflammation fibrogenesis hepatocyte PPARγ–dependent manner associated dysregulation hepatic metabolism. Specifically, positive regulation methionine metabolism, could NASH.ConclusionsBecause negative effect inhibition mechanisms by endogenous represent novel strategy increases efficiency therapies NAFLD. Nonalcoholic diet. Because

Language: Английский

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Selenium Deficiency Dysregulates One-Carbon Metabolism in Nutritional Muscular Dystrophy of Chicks

Journal of Nutrition, Journal Year: 2022, Volume and Issue: 153(1), P. 47 - 55

Published: Dec. 20, 2022

Language: Английский

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Cell energy metabolism and bone formation

Bone Reports, Journal Year: 2022, Volume and Issue: 16, P. 101594 - 101594

Published: May 27, 2022

Energy metabolism plays an important role in cell and tissue ability to effectively function, maintain homeostasis, perform repair. Yet, the of energy skeletal tissues general bone, particular, remains understudied. We, here, review aspects relevant bone tissue, such as: i) availability substrates oxygen; ii) regulatory mechanisms most active e.g. HIF BMP; iii) crosstalk bioenergetics with other functions, proliferation differentiation; iv) glycolysis mitochondrial oxidative phosphorylation osteogenic lineage; v) significant changes observed aging pathologies. In addition, we available methods study on a subcellular, cellular, live animal levels.

Language: Английский

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Excess S-adenosylmethionine inhibits methylation via catabolism to adenine

Communications Biology, Journal Year: 2022, Volume and Issue: 5(1)

Published: April 5, 2022

The global dietary supplement market is valued at over USD 100 billion. One popular supplement, S-adenosylmethionine, marketed to improve joints, liver health and emotional well-being in the US since 1999, has been a prescription drug Europe treat depression arthritis 1975, but recent studies questioned its efficacy. In our body, S-adenosylmethionine critical for methylation of nucleic acids, proteins many other targets. marketing SAM implies that more better it would stimulate methylations health. Previously, we have shown reactions regulate biological rhythms organisms. Here, using assess effects exogenous reveal excess disrupts and, rather than promoting methylation, catabolized adenine methylthioadenosine, toxic inhibitors. These findings further understanding methyl metabolism question safety as supplement.

Language: Английский

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Blockage of glycolysis by targeting PFKFB3 suppresses the development of infantile hemangioma

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Feb. 6, 2023

Abstract Background Infantile hemangioma (IH) is the most common tumor among infants, but exact pathogenesis of IH largely unknown. Our previous study revealed that glucose metabolism may play an important role in and inhibition glycolytic key enzyme phosphofructokinase-1 suppresses angiogenesis IH. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) a metabolic converts fructose-6-bisphosphate to fructose-2,6-bisphosphate (F-2,6-BP), which potent allosteric activator rate-limiting phosphofructokinase-1. This was performed explore PFKFB3 Methods Microarray analysis screen differentially expressed genes (DEGs) between proliferating involuting tissues. expression examined by western blot immunohistochemistry analyses. Cell migration, apoptosis tube formation were analyzed. Metabolic analyses investigate effect PFK15. Mouse models established examine vivo. Results identified as one significant DEGs more highly tissues hemangioma-derived endothelial cells (HemECs) than human umbilical vein cells, respectively. PFK15 suppressed HemEC mainly affecting metabolite decreasing flux. Moreover, inhibited migration induced via activation pathway. Treatment with combination propranolol had synergistic inhibitory on HemECs. knockdown markedly angiogenesis. Mechanistically, PI3K-Akt signaling pathway apoptotic cell death. More importantly, suppression or shPFKFB3 led reduced growth Conclusions findings suggest can suppress induce apoptosis. Thus, targeting be novel therapeutic strategy for

Language: Английский

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Can Small Molecules Provide Clues on Disease Progression in Cerebrospinal Fluid from Mild Cognitive Impairment and Alzheimer’s Disease Patients?

Environmental Science & Technology, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 19, 2024

Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease, which currently diagnosed via clinical symptoms nonspecific biomarkers (such as Aβ

Language: Английский

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Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction‐associated steatotic liver disease

The Journal of Pathology, Journal Year: 2024, Volume and Issue: unknown

Published: July 18, 2024

Abstract Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a chronic condition that often progresses to more advanced stages, such as metabolic steatohepatitis (MASH). MASH characterized by inflammation and hepatocellular ballooning, in addition hepatic steatosis. Despite the relatively high incidence of population its potential detrimental effects on human health, this still not fully understood from pathophysiological perspective. Deregulation polyamine levels has been detected various pathological conditions, including neurodegenerative diseases, inflammation, cancer. However, role pathway disorders MASLD explored. In study, we measured expression ornithine decarboxylase (ODC1), rate‐limiting enzyme responsible for production putrescine, preclinical model well biopsies patients with obesity undergoing bariatric surgery. Our findings reveal ODC1 but spermidine nor spermine, are elevated tissue both diet‐induced mice biopsy‐proven compared control without MASH, respectively. Furthermore, found putrescine were positively associated higher aspartate aminotransferase concentrations serum an increased SAF score (steatosis, activity, fibrosis). Additionally, vitro assays using HepG2 cells, demonstrate exacerbate cellular response palmitic acid, leading decreased cell viability release CK‐18. results support association between progression MASLD, which could have translational relevance understanding onset disease. © 2024 The Pathological Society Great Britain Ireland.

Language: Английский

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Deciphering Colorectal Cancer–Hepatocyte Interactions: A Multiomics Platform for Interrogation of Metabolic Crosstalk in the Liver–Tumor Microenvironment

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 1976 - 1976

Published: Feb. 25, 2025

Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to adapt and exploit their microenvironment for sustained growth. The liver common site metastasis, but the interactions between hepatocytes remain poorly understood. In context these play crucial role in promoting survival progression. This study leverages multiomics coverage via liquid chromatography high-resolution, high-mass-accuracy mass spectrometry-based untargeted metabolomics, 13C-stable isotope tracing, RNA sequencing uncover metabolic impact co-localized primary colon adenocarcinoma cell line, SW480, using 2D co-culture model. profiling revealed disrupted Warburg metabolism with an 80% decrease glucose consumption 94% lactate production by hepatocyte-SW480 co-cultures relative SW480 control cultures. Decreased was coupled alterations glutamine ketone body metabolism, suggesting possible fuel switch upon co-culturing. Further, integrated analysis indicates that disruptions pathways, including nucleoside biosynthesis, amino acids, TCA cycle, correlate altered transcriptional profiles highlight importance redox homeostasis adaptation. Finally, findings were replicated three-dimensional microtissue organoids. Taken together, studies support bioinformatic approach crosstalk discovery potential therapeutic targets preclinical models microenvironment.

Language: Английский

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