Amino acid metabolism in tumour-bearing mice.
Ontology highlight
ABSTRACT:
SUBMITTER: Rivera S
PROVIDER: S-EPMC1148723 | biostudies-other | 1988 Jan
REPOSITORIES: biostudies-other
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Project description:During starvation for 72 h, tumour-bearing rats showed accelerated ketonaemia and marked ketonuria. Total blood [ketone bodies] were 8.53 mM and 3.34 mM in tumour-bearing and control (non-tumour-bearing) rats respectively (P less than 0.001). The [3-hydroxybutyrate]/[acetoacetate] ratio was 1.3 in the tumour-bearing rats, compared with 3.2 in the controls at 72 h (P less than 0.001). Blood [glucose] and hepatic [glycogen] were lower at the start of starvation in tumour-bearing rats, whereas plasma [non-esterified fatty acids] were not increased above those in the control rats during starvation. After functional hepatectomy, blood [acetoacetate], but not [3-hydroxybutyrate], decreased rapidly in tumour-bearing rats, whereas both ketone bodies decreased, and at a slower rate, in the control rats. Blood [glucose] decreased more rapidly in the hepatectomized control rats. Hepatocytes prepared from 72 h-starved tumour-bearing and control rats showed similar rates of ketogenesis from palmitate, and the distribution of [1-14C] palmitate between oxidation (ketone bodies and CO2) and esterification was also unaffected by tumour-bearing, as was the rate of gluconeogenesis from lactate. The carcinoma itself showed rapid rates of glycolysis and a poor ability to metabolize ketone bodies in vitro. The results are consistent with the peripheral, normal, tissues in tumour-bearing rats having increased ketone-body and decreased glucose metabolic turnover rates.
| S-EPMC1153051 | biostudies-other
Project description:BackgroundRecent studies have emphasised the important role of amino acids in cancer metabolism. Cold physical plasma is an evolving technology employed to target tumour cells by introducing reactive oxygen species (ROS). However, limited understanding is available on the role of metabolic reprogramming in tumour cells fostering or reducing plasma-induced cancer cell death.MethodsThe utilisation and impact of major metabolic substrates of fatty acid, amino acid and TCA pathways were investigated in several tumour cell lines following plasma exposure by qPCR, immunoblotting and cell death analysis.ResultsMetabolic substrates were utilised in Panc-1 and HeLa but not in OVCAR3 and SK-MEL-28 cells following plasma treatment. Among the key genes governing these pathways, ASCT2 and SLC3A2 were consistently upregulated in Panc-1, Miapaca2GR, HeLa and MeWo cells. siRNA-mediated knockdown of ASCT2, glutamine depletion and pharmacological inhibition with V9302 sensitised HeLa cells to the plasma-induced cell death. Exogenous supplementation of glutamine, valine or tyrosine led to improved metabolism and viability of tumour cells following plasma treatment.ConclusionThese data suggest the amino acid influx driving metabolic reprogramming in tumour cells exposed to physical plasma, governing the extent of cell death. This pathway could be targeted in combination with existing anti-tumour agents.
| S-EPMC8144554 | biostudies-literature
Project description:The gut microbiota has been proposed as an environmental factor that promotes the progression of metabolic diseases. Here, we investigated how the gut microbiota modulates the global metabolic differences in duodenum, jejunum, ileum, colon, liver, and two white adipose tissue depots obtained from conventionally raised (CONV-R) and germ-free (GF) mice using gene expression data and tissue-specific genome-scale metabolic models (GEMs). We created a generic mouse metabolic reaction (MMR) GEM, reconstructed 28 tissue-specific GEMs based on proteomics data, and manually curated GEMs for small intestine, colon, liver, and adipose tissues. We used these functional models to determine the global metabolic differences between CONV-R and GF mice. Based on gene expression data, we found that the gut microbiota affects the host amino acid (AA) metabolism, which leads to modifications in glutathione metabolism. To validate our predictions, we measured the level of AAs and N-acetylated AAs in the hepatic portal vein of CONV-R and GF mice. Finally, we simulated the metabolic differences between the small intestine of the CONV-R and GF mice accounting for the content of the diet and relative gene expression differences. Our analyses revealed that the gut microbiota influences host amino acid and glutathione metabolism in mice.
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Project description:The ruthenium-catalyzed ring-opening polymerization (ROMP) of 1-cyclobutenecarbonyl glycine methyl ester provides translationally invariant, head-to-tail ordered polymers. This polybutadiene backbone contains (within the limits of detection) only E-trisubstituted olefins, and it has no stereocenters that would serve as a source of structural ambiguities. Characterization of the polymer products indicates that they have polydispersities ranging from 1.2 to 1.6 and suggests that they are the products of a "living" polymerization. 1-Cyclobutenecarboxamide-derived ROMP polymers are excellent prospects for applications that require stereoregular chains functionalized with polar ligands.
| S-EPMC2562595 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the third leading cause of the cancer-related death in the world. Human amniotic mesenchymal stem cells (hAMSCs) have been characterized with a pluripotency, low immunogenicity and no tumorigenicity. Especially, the immunosuppressive and anti-inflammatory effects of hAMSCs make them suitable for treating HCC. Here, we reported that hAMSCs administrated by intravenous injection significantly inhibited HCC through suppressing cell proliferation and inducing cell apoptosis in tumour-bearing mice with Hepg2 cells. Cell tracking experiments with GFP-labelled hAMSCs showed that the stem cells possessed the ability of migrating to the tumorigenic sites for suppressing tumour growth. Importantly, both hAMSCs and the conditional media (hAMSC-CM) have the similar antitumour effects in vitro, suggesting that hAMSCs-derived cytokines might be involved in their antitumour effects. Antibody array assay showed that hAMSCs highly expressed dickkopf-3 (DKK-3), dickkopf-1 (DKK-1) and insulin-like growth factor-binding protein 3 (IGFBP-3). Furthermore, the antitumour effects of hAMSCs were further confirmed by applications of the antibodies or the specific siRNAs of DKK-3, DKK-1 and IGFBP-3 in vitro. Mechanically, hAMSCs-derived DKK-3, DKK-1 and IGFBP-3 markedly inhibited cell proliferation and promoted apoptosis of Hepg2 cells through suppressing the Wnt/β-catenin signalling pathway and IGF-1R-mediated PI3K/AKT signalling pathway, respectively. Taken together, our study demonstrated that hAMSCs possess significant antitumour effects in vivo and in vitro and might provide a novel strategy for HCC treatment clinically.
| S-EPMC7521292 | biostudies-literature
Project description:BackgroundBreast cancer is a major health burden for women, worldwide. Lifestyle-related risk factors, such as obesity and being overweight, have reached epidemic proportions and contributes to the development of breast cancer. Doxorubicin (DXR) is a chemotherapeutic drug commonly used to treat breast cancer, and although effective, may cause toxicity to other organs. The mechanisms and effects of DXR on hepatic tissue, and the contributing role of obesity, in breast cancer patients are poorly understood. The aim of this study was therefore to investigate the effects of DXR on hepatic tissue in an obese tumour-bearing mouse model.MethodsA diet-induced obesity (DIO) mouse model was established, where seventy-four three-week-old female C57BL6 mice were divided into two main groups, namely the high fat diet (containing 60% kcal fat) and standard diet (containing 10% kcal fat) groups. After eight weeks on their respective diets, the DIO phenotype was established, and the mice were further divided into tumour and non-tumour groups. Mice were subcutaneously inoculated with E0771 triple negative breast cancer cells in the fourth mammary gland and received three doses of 4 mg/kg DXR (cumulative dosage of 12 mg/kg) or vehicle treatments via intraperitoneal injection. The expression levels of markers involved in apoptosis and alanine aminotransferase (ALT) were compared by means of western blotting. To assess the pathology and morphology of hepatic tissue, haematoxylin and eosin staining was performed. The presence of fibrosis and lipid accumulation in hepatic tissues were assessed with Masson's trichrome and Oil Red O staining, respectively.ResultsMicroscopic examination of liver tissues showed significant changes in the high fat diet tumour-bearing mice treated with DXR, consisting of macrovesicular steatosis, hepatocyte ballooning and lobular inflammation, compared to the standard diet tumour-bearing mice treated with DXR and the control group (standard diet mice). These changes are the hallmarks of non-alcoholic fatty liver disease, associated with obesity.ConclusionThe histopathological findings indicated that DXR caused significant hepatic parenchymal injury in the obese tumour-bearing mice. Hepatotoxicity is aggravated in obesity as an underlying co-morbidity. It has been shown that obesity is associated with poor clinical outcomes in patients receiving neo-adjuvant chemotherapy treatment regimens.
| S-EPMC9710042 | biostudies-literature
Project description:To accurately detect and quantify low abundant transcripts no represented in current EST databases we generated an RNA-seq dataset based on RNA isolated from Petunia hybrida corolla tissue harvested at 8 PM at two developmental stages, day -1 (bud) and day 2 postanthesis (the tissues containing the lowest and highest levels of phenylalanine, respectively). Total RNA samples were obtained from corollas of at least eight wild-type petunia flowers per biological replicate at the two developmental stages using an RNeasy plant mini kit from Qiagen.
2015-09-09 | E-GEOD-70948 | biostudies-arrayexpress
Project description:Obligate intracellular pathogens have coevolved with their host, leading to clever strategies to access nutrients, to combat the host's immune response, and to establish a safe niche for intracellular replication. The host, on the other hand, has also developed ways to restrict the replication of invaders by limiting access to nutrients required for pathogen survival. In this review, we describe the recent advancements in both computational methods and high-throughput -omics techniques that have been used to study and interrogate metabolic functions in the context of intracellular parasitism. Specifically, we cover the current knowledge on the presence of amino acid biosynthesis and uptake within the Apicomplexa phylum, focusing on human-infecting pathogens: Toxoplasma gondii and Plasmodium falciparum. Given the complex multi-host lifecycle of these pathogens, we hypothesize that amino acids are made, rather than acquired, depending on the host niche. We summarize the stage specificities of enzymes revealed through transcriptomics data, the relevance of amino acids for parasite pathogenesis in vivo, and the role of their transporters. Targeting one or more of these pathways may lead to a deeper understanding of the specific contributions of biosynthesis versus acquisition of amino acids and to design better intervention strategies against the apicomplexan parasites.
| S-EPMC7909243 | biostudies-literature
Project description:Cancer immunosuppression involves cellular pathways appropriated by tumors to escape immune surveillance but are normally required for tissue homeostasis and repair, self-tolerance, and successful transplantation. Among these pathways, enzymes that degrade tryptophan and arginine are thought to suppress activated T cells in the tumor microenvironment and are therefore attractive drug targets. However, how amino acid metabolism controls the development and progression of cancer has remained elusive, since commonly used implantable tumor models may not faithfully recapitulate the complex cellular and biochemical interactions within tumor microenvironments. To address this, we generated a novel, penetrant autochthonous model of neuroblastoma to accurately quantify tumor growth non-invasively and simultaneously genetically manipulate the enzymes that mediate tryptophan and arginine metabolism, and the cells that express them. We established that tumor development and growth were dependent on infiltrating CCR2+ bone marrow-derived myeloid cells but independent of Stat6-dependent ‘M2’ macrophages. Macrophages can modulate CD4+ T cell activation, proliferation, and differentiation by consuming amino acids and forcing the T cells to remain in the G1 phase of the cell cycle. Indeed, we found that CD4+ T cells deprived of arginine increased Foxp3 expression and adopted a unique regulatory-like phenotype. Notably, depletion of CD4+ T cells like CCR2+ macrophages, virtually eliminated tumor formation. When rare tumors did form in CD4-depleted mice, they contained Foxp3+ CD8 T cells, suggesting regulatory T cell activity is a fundamental requirement for tumor development. When we ablated macrophage arginase 1 (Arg1), an enzyme that locally consumes arginine, in the tumor-prone background, almost no tumors were observed. Therefore, Arg1 and arginine metabolism form a pro-tumor pathway. We extended these findings to two pathways of programmed myeloid tryptophan metabolism (IDO1, IDO2, IL4i1). Like Arg1, expression of these enzymes was confined to myeloid cells in humans and mice, and each enzyme was independently essential for tumor formation and growth. The protective effects of genetic ablation of each myeloid amino acid pathways uniformly occurred early in tumor formation, arguing that a network of immune cells controlled by myeloid amino acid metabolism and CD4+ T cells is important for the origins of a pro-tumor environment. Our results establish an unappreciated potency of macrophage amino acid metabolism in promoting malignancy, and suggest that these pathways can be disabled by targeting of myeloid amino acid metabolism. OVA-specific CD4+ T cells were stimulated with peptide in the presence of APCs (CD3-depleted splenocytes) either in control complete RPMI-1640 (containing 10% dialyzed FBS) or in RPMI-1640 (containing 10% dialyzed FBS) containing 1% of the normal arginine levels (12uM) to characterize the effects of limited arginine availability on gene expression.
2021-10-13 | GSE126024 | GEO
Project description:BackgroundCancer cachexia occurs in approximately 80% of cancer patients and is a key contributor to cancer-related death. The mechanisms controlling development of tumour-induced muscle wasting are not fully elucidated. Specifically, the progression and development of cancer cachexia are underexplored. Therefore, we examined skeletal muscle protein turnover throughout the development of cancer cachexia in tumour-bearing mice.MethodsLewis lung carcinoma (LLC) was injected into the hind flank of C57BL6/J mice at 8 weeks age with tumour allowed to develop for 1, 2, 3, or 4 weeks and compared with PBS injected control. Muscle size was measured by cross-sectional area analysis of haematoxylin and eosin stained tibialis anterior muscle. 2 H2 O was used to assess protein synthesis throughout the development of cancer cachexia. Immunoblot and RT-qPCR were used to measure regulators of protein turnover. TUNEL staining was utilized to measure apoptotic nuclei. LLC conditioned media (LCM) treatment of C2C12 myotubes was used to analyse cancer cachexia in vitro.ResultsMuscle cross-sectional area decreased ~40% 4 weeks following tumour implantation. Myogenic signalling was suppressed in tumour-bearing mice as soon as 1 week following tumour implantation, including lower mRNA contents of Pax7, MyoD, CyclinD1, and Myogenin, when compared with control animals. AchRδ and AchRε mRNA contents were down-regulated by ~50% 3 weeks following tumour implantation. Mixed fractional synthesis rate protein synthesis was ~40% lower in 4 week tumour-bearing mice when compared with PBS controls. Protein ubiquitination was elevated by ~50% 4 weeks after tumour implantation. Moreover, there was an increase in autophagy machinery after 4 weeks of tumour growth. Finally, ERK and p38 MAPK phosphorylations were fourfold and threefold greater than control muscle 4 weeks following tumour implantation, respectively. Inhibition of p38 MAPK, but not ERK MAPK, in vitro partially rescued LCM-induced loss of myotube diameter.ConclusionsOur findings work towards understanding the pathophysiological signalling in skeletal muscle in the initial development of cancer cachexia. Shortly following the onset of the tumour-bearing state alterations in myogenic regulatory factors are apparent, suggesting early onset alterations in the capacity for myogenic induction. Cancer cachexia presents with a combination of a loss of protein synthesis and increased markers of protein breakdown, specifically in the ubiquitin-proteasome system. Also, p38 MAPK may be a potential therapeutic target to combat cancer cachexia via a p38-FOX01-atrogene-ubiquitin-proteasome mechanism.
| S-EPMC6204589 | biostudies-literature