Literatura académica sobre el tema "Metabolic CD34+ cells"
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Artículos de revistas sobre el tema "Metabolic CD34+ cells":
1
Fadini, G. P. "Circulating CD34+ cells, metabolic syndrome, and cardiovascular risk". European Heart Journal 27, n.º 18 (9 de agosto de 2006): 2247–55. http://dx.doi.org/10.1093/eurheartj/ehl198.
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Kochi, Yu, Yoshikane Kikushige, Toshihiro Miyamoto y Koichi Akashi. "Identification of ASCT1 As a Candidate Molecule Enhancing Antioxidant Activity in Primary Human AML Cells". Blood 128, n.º 22 (2 de diciembre de 2016): 1674. http://dx.doi.org/10.1182/blood.v128.22.1674.1674.
Resumen
Abstract Introduction: Recent studies have shown that the specific alteration of metabolic pathways are involved in the regulation of function of normal hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) in acute myeloid leukemia (AML). However, little is known about the features of metabolic activity in human HSCs and LSCs. To reveal the metabolic pathway alterations in primary AML cells, we performed the comprehensive metabolome analysis by comparing normal human CD34+ hematopoietic stem/progenitor cells (HSPCs)(n=5) and CD34+ primitive AML cells containing LSCs (n=16) using highly sensitive CE-tandem mass spectrometry. Method: Metabolome analysis Metabolites were extracted from primitive CD34+ AML cells (n=16) and normal CD34+ bone marrow cells (n=4) and cord blood cells (n=1). Metabolome analysis was conducted by the C-SCOPE package of HMT using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) for cation analysis, and capillary electrophoresis-tandem mass spectrometry (CE-MS/MS) for anion analysis. 116 metabolites were targeted for analysis in this study. Oxygen consumption rates and extracellular acidification rate O2 consumption rates (OCR) and extracellular acidification rate (ECAR) were measured by the Seahorse XF96 extracellular flux analyzer. Three replicate wells of 400,000 leukemic or normal cells per well were seeded in 96-well XF96 well plates coated with BD Cell-Tak (BD Biosciences) in serum-free unbuffered DMEM. Analyses were performed both at basal conditions and after injection of OLI (1 mg/ml), FCCP (1 mM), Antimycin A (5 mM). Result: We detected 101 metabolites involved in central carbon and energy metabolism. In glucose metabolism, the level of lactate, an end-product of aerobic glycolysis, were lower in CD34+ AML cells than normal HSPCs, whereas the level of pyruvate, a precursor of lactate, was not different. Thus, CD34+ AML cells had a significantly high pyruvate/lactate ratio as compared to normal HSPCs, suggesting that aerobic respiration is preferentially utilized in CD34+ AML cells. To confirm this observation, we directly measured the O2 consumption rate (OCR) and extracellular acidification rate (ECAR) of CD34+ AML cells (n=4) and normal HSPCs (n=5) by XF96 extracellular flux analyzer. OCR reflects the activity of aerobic respiration, whereas ECAR reflects lactate generation and correlates with anaerobic respiration activity. Therefore, OCR/ECAR ratio is a good index for the discrimination of aerobic and anaerobic respiration pattern. We found that the OCR/ECAR ratio of CD34+ primitive AML cells was significantly high as compared to that of HSPCs, suggesting that CD34+ AML cells predominantly utilized aerobic respiration. Although the aerobic respiration resulted in the production of reactive oxygen species (ROS), the intracellular ROS level was not different between CD34+ AML (n=7) cells and normal HSPCs (n=3), suggesting that the antioxidant activity should be strongly enhanced in CD34+ AML cells. Consistent with the observation, we found that CD34+ AML cells had a much higher level of glutathione (GSH), a primary intracellular antioxidant, than normal HSPCs. To clarify the molecular mechanisms how CD34+ primitive AML cells could maintain high GSH level, we analyzed the expression of cysteine transporters, because cysteine uptake is the rate-limiting step of GSH synthesis. In human, three amino acid transporters including ASCT1, ASC1 and xCT are known as cystine/cysteine transporters. Interestingly, ASCT1 was significantly highly expressed in CD34+ AML cells (n=10) as compared to normal CD34+ HSPCs (n=3). Of note, normal CD34+CD38- HSCs completely lacked ASCT1 expression, whereas CD34+CD38-LSCs expressed at a high level, indicating the possibility that the high expression of ASCT1 should be a LSC specific machinery for enhanced GSH synthesis. Thus, human AML cells predominantly utilize aerobic respiration that is supported by a high level of GSH, and AML specific ASCT1 expression presumably contributes to the high level of GSH. These data suggest that ASCT1 should be a promising molecule to specifically target AML stem/progenitor cells. Disclosures Akashi: Celgene: Research Funding; Astellas Pharma: Research Funding; Shionogi & Co., Ltd: Research Funding; Asahi Kasei Pharma Corporation: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Bristol Meyers Squibb: Research Funding; Kyowa Hakko Kirin: Consultancy, Research Funding; Sunitomo Dainippon Pharma: Consultancy.
3
Nakasone, Hideki, Misato Kikuchi, Yu Akahoshi, Koji Kawamura, Miki Sato, Kazuki Yoshimura, Yukiko Misaki et al. "The Expression of CD83 Would be Increased in CD34-Positive Monocytes Detected in Peripheral Blood Mobilized By G-CSF in Humans". Blood 132, Supplement 1 (29 de noviembre de 2018): 2063. http://dx.doi.org/10.1182/blood-2018-99-112084.
Resumen
Abstract [Background] CD34-positive monocytes (CD34+mono) have recently been identified following mobilization by granulocyte-colony stimulating factor (G-CSF), and have been suggested to have a potential to modulate immune functions in animal models. However, the biological feature of CD34+mono in humans still remains unclear. Thus, we explored the difference between CD34+mono, CD34+cells, and monocytes through the analyses of gene expression profiles (GEP). [Methods] CD34+mono (Lin-CD34+CD33+CD14+CD11b+, Figure1), CD34+cells (Lin-CD34+CD33-CD14-CD11b- ), and monocytes (Lin-CD34-CD33+CD14+CD11b+) were directly sorted into tubes from cryopreserved grafts from three healthy donors. After the extraction of total RNA, microarray analyses were performed with GeneChip™ 3' IVT Pico Kit and analyzed according to the algorithm of Transcriptome Analysis Console (Thermo Fisher Scientific). Condition false discovery rate (FDR) F-test was used for filtering genes, and the threshold was <0.0005 for hierarchical clustering without considering fold changes. In addition, enrichment analyses were performed for gene ontology (GO) and pathways by the Kyoto Encyclopedia of Genes and Genomes (KEGG) through Database for Annotation, Visualization and Integrated Discovery (DAVID). The differentially expressed genes with <0.05 of F-test values and 2 or more fold changes in CD34+mono compared with CD34+cells and monocytes were selected for the enrichment analyses. Thereafter, the protein-protein interaction (PPI) network in CD34+mono was constructed through Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), which is a biological database. This study was approved by the institutional review board of Jichi Medical University and all subjects gave their written informed consent for the cryopreservation and analysis of the blood samples in accordance with the Helsinki Declaration. [Results] CD34+mono resembled con-mono in the appearance, although it might look slightly immature. In fact, the number of differential expressed genes was smaller in the pair of CD34+mono vs. monocytes (n=605) compared with the other pair (n=2136), suggesting that CD34+mono might stand nearby monocytes. However, a principle component analysis of GEP demonstrated that CD34+mono would be categorized into an independent cell type entity. In addition, the hierarchical clustering heat map suggested that CD34+mono would have the interim gene expressions between CD34+ cells and monocytes (Figure 2). GO analysis was also performed using the 203 genes which were differentially expressed in CD34+mono compared with CD34+cells and monocytes. The differentially expressed genes seemed to be significantly involved in the "immune system process" of biological process, followed by "locomotion", "metabolic process" and "response to stimulus", because pro-inflammatory genes in CD34+mono like IL6, CCL3, IL8, VEGFA, and IL1A were increased. In addition, PPI analyses indicated that 128 of the 203 differentially expressed genes in CD34+mono had close connections with each other. Especially, IL6, VEGFA, IL8, NFkB1, EGR1, CDKN1A (p21), and CYCS could be considered as a hub gene in CD34+mono. Of them, IL6, IL8, and VEGFA are considered to be pro-inflammatory cytokines. NFkB1, and EGR1 are transcriptional factors, and CDKN1A, and CYCS are considered to regulate cell cycle or apoptosis. Furthermore, simultaneously focusing on the difference in the fold changes of gene expressions between CD34+mono vs. monocytes, CD83 (a membrane protein and immunoglobulin superfamily that regulates antigen presentation) and FOSL1 (a kind of regulators of cell proliferation, differentiation, and transformation) were specifically increased in CD34+mono (Figure3). The increased expression of CD83 strongly suggests antigen presenting cells like mature dendritic cells. CD34+mono might be one of progenitors of dendritic cells, or might have a potential of antigen presentation itself. [Conclusion] In summary, the differentially expressed genes in CD34+mono would be mapped in the immune process, especially against infectious pathogens. In addition, the increased CD83 suggested that CD34+mono might play a role of antigen presentation in the immune response. Further investigations would be necessary to confirm the clinical roles of CD34+mono after transplantation. Disclosures Nakasone: Phizer: Honoraria; Novartis: Honoraria; Kyowa Hakko Kirin: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Kimura:Astellas: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Other: Investigator in the institute; Nippon Kayaku: Honoraria; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria; Takeda: Honoraria. Kako:Takeda Pharmaceutical Company Limited.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Celgene K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Kanda:Eisai: Consultancy, Honoraria, Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Nippon-Shinyaku: Research Funding; Pfizer: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Taisho-Toyama: Research Funding; CSL Behring: Research Funding; Tanabe-Mitsubishi: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Ono: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria.
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Desterke, Christophe, Estelle Balducci, Xavier Fund, Claire Borie, Annelise Bennaceur-Griscelli y Ali G. Turhan. "A Novel Metabolic Transcriptome Identified in Myelodysplastic Syndromes (MDS) Correlates with OMS Classification and Poor Prognosis". Blood 132, Supplement 1 (29 de noviembre de 2018): 5495. http://dx.doi.org/10.1182/blood-2018-99-110678.
Resumen
Abstract Myelodysplastic syndromes (MDS) are clonal malignancies of the hematopoietic stem cell leading to an ineffective hematopoiesis with a complex and poorly understood pathophysiology combining increased apoptosis and propensity to transformation associated with immune dysregulation. Despite a major improvement of the classification of MDS in terms of diagnosis and prognosis according to OMS recommendations, a significant fraction of MDS remains unclassified. In this study, we wished to determine if the integrative analysis of global MDS transcriptome associated with single cell experiments performed on CD34+ hematopoietic progenitors using novel bioinformatics tools could identify novel signaling pathways associated with different subtypes of MDS. This transcriptomic analysis included a large cohort of of MDS patients (n=323) as compared to healthy controls (n=86). We concentrated our analysis in the pathways involved in metabolomics as there was an increase of expression of genes involved in metabolic pathways in MDS transcriptome as compared to hematopoietic progenitors from healthy donors. Metabolic meta-analysis on HP transcriptome (datasets GSE15061 and GSE58831) were subsequently analyzed by creating a software "gene2bcp.sh" (https://github.com/cdesterke/gene2bcp) based on metabolic database "BioCycPathway". Forty two genes involved in metabolism were found to be upregulated in MDS samples (LIMMA algorithm, FDR adjust p-value < 0.05 and fold change > 2 in both dataset). A multivariate model was built by selecting the best 17 genes and in order to validate these findings an independent cohort including 11 healthy donors and 55 MDS patients (pts) were studied. This latter group included 18 patients with refractory anemia (RA), 19 pts with RA with ring sideroblasts (RARS) and 18 pts with RA with excess of blasts (RAEB) (GSE4619). This analysis (fig1A) allowed to predict MDS diagnosis as compared to healthy donors in a robust way (p=0.0013). Similarly with this unique metabolic transcriptome, we could stratified MDS patients correctly according to their OMS classification (p=0.00065). Metabolic transcriptome also clearly identified patients with MDS with cytogenetic abnormalities, in particular MDS with 5q- syndromes as compared to MDS without cytogenetic abnormalities (p=0.0023). We then applied these results to the RNAseq single-cell sequencing with cytometric analysis of a MDS patient with RAEB2 and monosomy 7 (GSE99095). Single cell trajectories were built based on 39 metabolic genes identified from previous meta-analysis. Monocle2 algorithm with metabolic gene profile allowed to discriminate CD34+CD38- from CD34+CD38+ cells after "tSNE" clustering (fig1B). These results were submitted to a pseudotime analysis which allows the analysis of transitional states in cell signaling pathways. Nine transition stages were found with stage 5 enriched in CD34+CD38- and stages 1 and 7 were found enriched in CD34+CD38+ (fig1C), differential test on this metabolic trajectory stratified genes in 6 clusters (gig 1D), with an enriched high expression of ACOT4 (Acyl-CoA Thioesterase 4), EARS2 (Glutamyl-TRNA Synthetase 2), PLD6 (Phospholipase D Family Member 6), PSAT1 (Phosphoserine Aminotransferase 1) in sub-compartment CD34+CD38- of this RAEB2 MDS patient. Overall, we show here for the first time a novel metabolic transcriptome correlating with classical MDS subtypes and prognosis. We describe a primitive metabolic trajectory in single bone marrow cells able to reconstitute the clonal architecture. The genes that we identified could be of use as additional markers of diagnosis and prognosis in future studies. Disclosures No relevant conflicts of interest to declare.
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Perrone, Olivia, Tiziana Coppola, James Bartram, Waseem Nasr, Juying Xu y Marie-Dominique Filippi. "The Effect of SCD-1 Inhibition on Human Hematopoietic Stem Cell Mitochondrial Metabolism, Cell Proliferation, and Differentiation Potential". Blood 142, Supplement 1 (28 de noviembre de 2023): 1308. http://dx.doi.org/10.1182/blood-2023-185260.
Resumen
Hematopoietic stem cells (HSC) give rise to all blood lineages and sustain the production of blood cells throughout life. Due to their inherently high regenerative potential, HSC are used in a variety of clinical settings, including bone marrow transplantation (BMT) directly to cure a variety of hematologic and oncologic disorders often with gene therapy. During regeneration, HSC are activated into cycle. For this, HSC undergo drastic mitochondrial and metabolic remodeling to meet the bioenergetic and biosynthetic needs of activated HSC. A growing body of evidence indicates that HSC sustain injury during activation. This remodeling is important for optimal HSC function but is permanently changed after HSC activating stress. It is thus important to identify the metabolic needs of activated HSC to improve HSC functions for therapeutic purposes. In both murine and human HSC, numerous metabolic enzymes get upregulated during activation, including those involved in de novo lipid synthesis. This metabolism is poorly understood in human HSC. Our overarching question is to understand the metabolic needs of HSC within the human system. Stearoyl-co-A-desaturase 1 (SCD-1), an enzyme responsible for conversion of stearic to oleic acid within the de novo lipid synthesis pathway, is suspected to play a role in metabolic reprogramming after stress. Using CD34+ mobilized human peripheral blood, we analyzed the effect of SCD-1 inhibition on HSC and progenitor proliferation, mitochondrial metabolism, and lineage differentiation potential. Cells were cultured either in vehicle control conditions or with SCD-1 inhibitor (SCDi). Subsequently, cells were counted and analyzed by flow cytometry on Days 4-5 and 10-15. More primitive or stem cell markers were utilized on Days 0 and 5 whereas differentiation markers were utilized on Day 10-15. Both tetramethylrhodamine-ethyl ester dye (TMRE) and MitoSOX reagents were used to assess mitochondrial membrane potential and mitochondrial ROS, respectively. Our results demonstrate that the size of the HSC population generated by SCDi-treated CD34+ cells within 5 days of culture was similar to vehicle treated cells and was composed of similar proportion of CD34+CD38+, CD34+CD38-, and CD38+CD34- cells, indicating that SCD-1 inhibition does not alter HSC expansion under these culture conditions. However, TMRE levels were lower in all HSC populations whereas mitoSOX levels were unchanged by SCD-1 inhibition compared to vehicle. In differentiation conditions, SCDi cultures were composed of a larger proportion of myeloid progenitors and a smaller proportion of erythroid cells after 10-15 days, compared to vehicle-treated cultures. These findings suggest that de novo lipid synthesis is necessary for HSC differentiation but dispensable for proliferation/expansion in vitro. We then used a xenotransplant model to assess the effect of SCDi on HSC regenerative potential in vivo. CD34+ mobilized human peripheral blood cells were cultured for 3 days under conditions that maintain HSC functions in vitro and transplanted into immunodeficient, sublethally irradiated NSG mice. Peripheral blood of xenotransplanted mice was analyzed monthly for human cell chimerism and mature blood lineage potential from 1 to 6 months post-transplant. Bone marrow analysis was performed at the 6 month time point as well, assessing for both HSC markers and lineage markers. Mice that received SCDi-treated cells exhibited human cell chimerism at a level similar to mice that were transplanted with vehicle treated cells, at about 3 to 30%. However, SCDi-treated cells gave rise to a lymphoid-biased graft, in particular T cells, both in the peripheral blood and in the bone marrow of xenotransplanted mice, compared to a more balanced myeloid-lymphoid graft from vehicle treated cells. In conclusion, these findings suggest that de novo lipid synthesis is critically important for HSC lineage fate and balanced differentiation in vitro and in vivo. This is especially clinically relevant as this work may implicate a possible therapeutic target as improving de novo lipid synthesis may aid in patients who suffer from persistent cytopenias after BMT and graft failure.
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Devaraj, Sridevi y Ishwarlal Jialal. "Dysfunctional Endothelial Progenitor Cells in Metabolic Syndrome". Experimental Diabetes Research 2012 (2012): 1–5. http://dx.doi.org/10.1155/2012/585018.
Resumen
The metabolic syndrome (MetS) is highly prevalent and confers an increased risk of diabetes and cardiovascular disease. A key early event in atherosclerosis is endothelial dysfunction. Numerous groups have reported endothelial dysfunction in MetS. However, the measurement of endothelial function is far from optimum. There has been much interest recently in a subtype of progenitor cells, termed endothelial progenitor cells (EPCs), that can circulate, proliferate, and dfferentiate into mature endothelial cells. EPCs can be characterized by the assessment of surface markers, CD34 and vascular endothelial growth factor receptor-2, VEGFR-2 (KDR). The CD34+KDR+phenotype has been demonstrated to be an independent predictor of cardiovascular outcomes. MetS patients without diabetes or cardiovascular diseases have decreased EPC number and functionality as evidenced by decreased numbers of colony forming units, decreased adhesion and migration, and decreased tubule formation. Strategies that have been shown to upregulate and enhance EPC number and functionality include statins, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and peroxisome-proliferator-activating-receptor gamma agonists. Mechanisms by which they affect EPC number and functionality need to be studied. Thus, EPC number and/or functionality could emerge as novel cellular biomarkers of endothelial dysfunction and cardiovascular disease risk in MetS.
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Dalloul, Ali H., Claire Patry, Jean Salamero, Bruno Canque, Fernanda Grassi y Christian Schmitt. "Functional and Phenotypic Analysis of Thymic CD34+CD1a− Progenitor-Derived Dendritic Cells: Predominance of CD1a+ Differentiation Pathway". Journal of Immunology 162, n.º 10 (15 de mayo de 1999): 5821–28. http://dx.doi.org/10.4049/jimmunol.162.10.5821.
Resumen
Abstract Whether thymic dendritic cells (DC) are phenotypically and functionally distinct from the monocyte lineage DC is an important question. Human thymic progenitors differentiate into T, NK, and DC. The latter induce clonal deletion of autoreactive thymocytes and therefore might be different from their monocyte-derived counterparts. The cytokines needed for the differentiation of DC from thymic progenitors were also questioned, particularly the need for GM-CSF. We show that various cytokine combinations with or without GM-CSF generated DC from CD34+CD1a− but not from CD34+CD1a+ thymocytes. CD34+ thymic cells generated far fewer DC than their counterparts from the cord blood. The requirement for IL-7 was strict whereas GM-CSF was dispensable but nonetheless improved the yield of DC. CD14+ monocytic intermediates were not detected in these cultures unless macrophage-CSF (M-CSF) was added. Cultures in M-CSF generated CD14−CD1a+ DC precursors but also CD14+CD1a− cells. When sorted and recultured in GM-CSF, CD14+ cells down-regulated CD14 and up-regulated CD1a. TNF-α accelerated the differentiation of progenitors into DC and augmented MHC class II transport to the membrane, resulting in improved capacity to induce MLR. The trafficking of MHC class II molecules was studied by metabolic labeling and immunoprecipitation. MHC class II molecules were transported to the membrane in association with invariant chain isoforms in CD14+ (monocyte)-derived and in CD1a+ thymic-derived DC but not in monocytes. Thus, thymic progenitors can differentiate into DC along a preferential CD1a+ pathway but have conserved a CD14+ maturation capacity under M-CSF. Finally, CD1a+-derived thymic DC and monocyte-derived DC share very close Ag-processing machinery.
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Nishida, Yuki, Edward Ayoub, Darah Scruggs, Shayaun Khazaei, Faryal Munir, Lauren B. Ostermann, Po Yee Mak et al. "Stem-Cell Enriched Cellular Hierarchy of TP53 Mutant Acute Myeloid Leukemia Is Vulnerable to Targeted Protein Degradation of c-MYC". Blood 142, Supplement 1 (28 de noviembre de 2023): 583. http://dx.doi.org/10.1182/blood-2023-174938.
Resumen
Deregulation of MYC genes occurs in up to 70% of all human cancers and is associated with hallmarks of cancer including mitochondrial and ribosomal biogenesis, cell cycle progression, and metabolic abnormalities. TP53 regulates MYC while MYC suppresses TP53, suggesting counteracting negative feedback loops. Therefore, MYC or its function can be activated when TP53 is not functional. TP53 mutations occur in 30% of relapsed/refractory acute myeloid leukemias (AMLs) patients' survival is dismal, and there are no effective therapies for these patients. Compared to TP53 wild-type (TP53wt), TP53 mutant (TP53mut) AMLs have lower percentages and numbers of leukemia blasts with increased immature CD34+ cells and resistance to chemo- or molecularly targeted therapies. However, the exact cellular hierarchy of TP53mut AML has not been elucidated. We observed significantly increased MYC mRNA levels in (TP53mut), as compared to TP53wt AML, and also increased levels in TP53mut versus TP53wt AML leukemia stem cell (LSC) fractions. This finding was confirmed in a dataset from the Munich Leukemia Laboratory (N = 732). We found significantly upregulated MYC pathways in TP53mut compared to TP53wt AML LSC. We confirmed the increased MYC mRNA levels at the protein level in TP53mut AML by single-cell mass cytometry (CyTOF). To dissect the cellular hierarchy in TP53mut AML, we performed single-cell RNA sequencing of 32 BM samples from healthy donors (N = 3), newly diagnosed, high-risk TP53wt (N = 7) and TP53mut (N = 22) AML patients, with 6,685, 10,687 and 10,687 cells from normal, TP53wt and TP53mut AML bone marrow (BM) cells, respectively. We found highly enriched HSC-like cells and reduced progenitor- and GMP-like cells in TP53mut AML compared to normal BM (NBM) and TP53wt AML samples. We overlayed MYC expression levels on the mapping of cellular components and found higher MYC levels in HSC-like cells in TP53mut AML compared to HSC and HSC-like cells in NBM and TP53wt AML samples, suggesting enrichment of immature HSC-like cells and increased activity of MYC in TP53mut AML LSCs ( Fig. A). To target c-MYC and MYC signaling, we utilized GT19715, the first-in-class cereblon modulator (CELMoD) for c-MYC protein (Nishida, ASH 2022). CyTOF confirmed the presence of much increased c-MYC protein levels in primary CD34+ AML than in CD34+ NBM hematopoietic stem cells (HSCs). Notably, CD34+ AML cells showed much greater sensitivity to GT19715 compared to CD34+ NBM cells. Data suggest on-target activity of GT19715 against c-MYC in LSCs with a therapeutic window between LSCs vs. NBM HSCs. Intriguingly, c-MYC protein levels are higher in CD34+CD38+ than in CD34+CD38- AML cells, suggesting that c-MYC drives the proliferation of AML progenitor cells differentiating from quiescent LSCs. Consequently, CD34+CD38+ AML progenitor cells exhibited greater sensitivity to GT19715 compared to CD34+CD38- LSCs. Using paired, TP53 null HL-60 GT19715-sensitive and -resistant cells generated through chronic exposure to GT19715, we interrogated the impact of GT19715 on metabolic changes. GT19715 induced pronounced reductions in basal and maximal oxygen consumption rates (OCRs) in GT19715-sensitive HL-60 cells. GT19715 reduced both basal, glutamine- and glucose-dependent extracellular acidification rates (ECARs) in GT19715-sensitive cells while no inhibition in OCRs or ECARs was observed in GT19715-resistant cells. GT19715 severely inhibited ECARs even after adding glucose to GT19715-sensitive cells, suggesting irreversible inhibition of glycolysis as one of the mechanisms of action of GT19715. GT19715 profoundly reduced AML blasts in TP53mut AML samples (N = 3) ( Fig. B), and in a very aggressive patient-derived xenograft (PDX) TP53mut AML model established from a patient with TP53 p.Y220C and p.P151A mutations along with MECOM rearrangement and K/NRAS mutations. In humanized Crbn I391V mice, where the Crbn-mediated protein degradation is operational, GT19715 only reduced WBC counts along with minimal body weight loss. GT19715 but did not reduce total mouse BM CD45+ cells, suggesting favorable toxicity profiles of GT19715. In conclusion, TP53mut AML comprised highly enriched LSC populations compared to TP53wt AML and targeting of c-MYC protein is highly effective in TP53mut AML in vitro and in vivo with a therapeutic window between AML LSC and normal hematopoietic cells.
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Rai, Richa, Foramben Patel, Stella Melana, Jonathan Feld, Shyamala C. Navada, Rosalie Odchimar-Reissig, Erin P. Demakos, E. Premkumar Reddy y Lewis R. Silverman. "Rigosertib in Combination with Azacitidine Impacts Metabolic and Differentiation Pathways in the MDS-L Cell Line". Blood 136, Supplement 1 (5 de noviembre de 2020): 35–36. http://dx.doi.org/10.1182/blood-2020-142908.
Resumen
Background Myelodysplastic Syndrome (MDS) is characterized by ineffective clonal hematopoiesis with peripheral blood cytopenias, leading to death from infection or bleeding. Azacitidine (AZA), a hypomethylating agent (HMA) is the standard of care for treatment of MDS patients (pts) with higher-risk MDS [Silverman LR, The Myelodysplastic Syndrome in Cancer Medicine, Editors: R.J. Bast, et al. 2017]. Responses to AZA occur in 50% of pts with significant effects on hematopoiesis ranging from improvement in a single lineage to complete restoration of blood counts and transfusion independence [Silverman LR, et al. Leukemia, 1993]. AZA treatment is associated with global DNA hypomethylation, including human endogenous retroviruses (HEV) which further activates innate immune signaling [Chiappinelli KB,et al. Cell, 2015]. The exact mechanism by which AZA improves hematopoiesis is unknown. AZA improves overall survival of pts, yet despite this, 100% of pts ultimately fail treatment with worsening cytopenias or transformation to leukemia [Silverman LR, et al. B. J Clin Oncol, 2002; Cancer, 2011]. Thus, understanding the mechanism of resistance and identification of targets which can reverse HMA failure and improve hematopoiesis in MDS pts is critical. Our clinical data demonstrate that AZA combined with Rigosertib (RIGO), a novel Ras mimetic that inhibits Ras/Raf signaling [Athuluri-Divakar SK, et al. Cell, 2016], yields a response rate of 54% of pts who were HMA failures [Navada SC, et al. EHA 2019]. The response was associated with significant improvement in hematopoiesis and represents a critical observation in overcoming the epigenetic clinical resistance phenotype. The precise mechanism that leads to reversal of the resistance phenotype is poorly understood. Methods: We investigated the differential protein expression in response to different treatment (AZA, RIGO alone and sequential combinations RIGO/AZA; AZA/RIGO) in vitro in MDS-L cell line by Reverse phase protein array (RPPA). Further, we also studied the functional role of these treatments on differentiation in the cell line by growing cells on semi-solid media as well as by flow cytometry using various stem cell and differentiation markers (CD34, CD38, CD45, CD123). Results: RPPA analysis indicated a discrete responses to treatment in the MDS-L cell line. The response was prominent with differential expression of 43 proteins specifically in MDS-L cells treated with RIGO/AZA that include PIK3R1, AKT1, mTOR, p38 MAPK, PTEN, RPS6KA1 (Fold change (FC) < -2). All of these proteins are downregulated which suggests inhibition of PI3K and mTOR signaling. Proteins belonging to metabolic pathways, including ACC1 and ACLY, were found to be downregulated, whereas proteins related to mitochondrial function and oxidative phosphorylation (OXPHOS) were upregulated (FC > 1.5/< -1.5) in cells treated with RIGO/AZA. In addition, we found that MDS-L cells represented both CD34+CD38+ and CD34+CD38- populations by FACS analysis (Fig 1). AZA increases the percentage of CD34+CD38+, indicative of differentiation, whereas RIGO alone increased the percentage of CD34+CD38- cells, representing a primitive stem cell population (Table in Fig 1). Based on the combination of differentiation markers (illustrated in fig 1), we observed that RIGO alone, and sequenced as combination RIGO/AZA, impacts different progenitors such as granulocyte-macrophage progenitor (GMP), megakaryocyte erythroid progenitor (MEP), and multipotent progenitor (MPP). RIGO/AZA treatment showed a decrease in GMP, while the % of MEP was increased, as compared to other treatments. Moreover, we found a remarkable reduction in the number of colony forming units on differentiation media in response to RIGO (83%) and RIGO/AZA (90%). Conclusions: These data demonstrate that in addition to inhibition of the PI3/AKT/mTOR pathway, the RIGO/AZA combination also impacts metabolic and differentiation pathways of MDS-L cells. RIGO alone appears to promote maintenance of a primitive stem cell population, while the RIGO/AZA sequenced combination appears to push the cells toward a cycling stage with increased expression of genes associated with OXPHOS. In comparison, when treated with RIGO, cells remain in a less differentiated stage. Further studies are underway to determine the effect of metabolic changes on differentiation and maintenance of hematopoietic stem cells. Figure Disclosures Navada: Onconova Therapeutics Inc: Research Funding. Reddy:Onconova Therapeutics Inc: Research Funding. Silverman:Celgene: Research Funding; Medimmune: Research Funding; Onconova Therapeutics Inc: Patents & Royalties, Research Funding.
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Forte, Dorian, Roberto Maria Pellegrino, Francesco Fabbri, Ivan Vannini, Samantha Bruno, Giulia Corradi, Rafael J. Argüello et al. "Circulating Extracellular Vesicles from Acute Myeloid Leukemia Patients Drive Distinct Metabolic Profile of Leukemic Cells and Reveal Crucial Lipidomic Biomarkers". Blood 138, Supplement 1 (5 de noviembre de 2021): 3471. http://dx.doi.org/10.1182/blood-2021-150339.
Resumen
Abstract Background. Extracellular vesicles (EVs) are submicron vesicles released from various cell types including blood cells with pleiotropic effects on cell signalling and metabolism. EV cargos are enriched in nucleic acids, proteins, and lipids that can be delivered to target cells to influence surrounding microenvironment. Thus, EVs represent a powerful tool for liquid biopsy in hematological malignancies including acute myeloid leukemia (AML). AML is an aggressive disease with high relapse rate and less invasive tools are urgently needed to investigate disease (metabolic) dynamics. Accumulating evidence has reported a key role for EVs in shaping the AML bone marrow niche. However, at present, the metabolic function and the lipidomic signature driven by circulating EVs have yet to fully emerge. Methods. Peripheral blood (PB) and bone marrow (BM) were collected from AML patients at diagnosis (n=40) and PB from age/sex-matched healthy donors (HD, n=20). EVs were purified from platelet-poor plasma by size exclusion chromatography and quantified using the NanoSight technology. Immunomagnetically isolated CD34+ cells from umbilical cord blood (CB) or AML patients were characterized by analyzing the hematopoietic stem/progenitor cell (HSPC)-specific cluster of differentiation marker expression, redox metabolic profiling (using CellROX, glutathione detection reagent and MitoTracker) after 24 hours co-culture with EVs. Quantitative lipidomic profiling of circulating EVs was performed by Liquid Chromatography coupled with High-Resolution Mass Spectrometry (LC/HRMS). Seahorse extracellular flux analyses were performed in leukemia cell lines (including KG-1, KASUMI-1, MOLM-13, THP-1 and OCI-AML3). To functionally define the metabolic reprogramming of leukemic cellular components within their microenvironment, leukemic stem cell subsets were assessed by flow cytometry-based SCENITH (Single Cell ENergetic metabolism by profilIng Translation inHibition) method in both whole blood and BM samples (n=4). Results. In our work, plasma-derived EVs from AML patients showed a significant increase in the size and protein amounts compared to HD counterparts. To explore the metabolic perturbation triggered by EVs, we developed a co-culture system with circulating EVs from either HD or AML patients with CB or AML CD34+. We found a reduction in the frequency of AML CD34+ with high ROS levels in the presence of AML EVs without affecting the ROS levels in normal CB CD34+. In parallel, AML EVs increased the frequency of AML CD34+ with both high mitochondrial activity and glutathione, a key antioxidant molecule involved in many metabolic pathways. Similar metabolic profiles were also confirmed in human leukemic cell lines tested. Specifically, Seahorse flux analysis revealed that EVs induced a cell energy phenotype consistent with quiescent and chemoresistant state in human leukemic cell lines, showing a more glycolytic state in MOLM-13. Interestingly, both CD34+ and CD34+/CD38- leukemic fractions from whole blood and BM of the same AML patients were analyzed by SCENITH after co-cultures with HD/AML EVs. Remarkably, PB CD34+/CD38- leukemic fractions were more dependent on mitochondrial activity in the presence of AML EVs, suggesting a metabolic shift triggered by leukemic EV that apparently occur in the leukemic fractions out of the BM niche. In addition, to give insights into lipidomic signatures of EVs as disease biomarkers, we detected a total of 25 (out of 200) independent lipid species significantly different between AML-derived EVs and HD (n=20, respectively). We reported the abundance of both glycerolipid and fatty acids species in AML EVs. Also, through a multivariate statistical analysis of EV lipidomic profile, we revealed that AML EVs were depleted in sphingomyelin classes, a class of lipids that are interconnected to HSC metabolism. Finally, according to the 2017 ELN risk stratification system, we observed the depletion in important modulators of EV release and formation as ether-linked phosphatidylethanolamine and phosphatidylethanolamine species in adverse-risk AML patients. Conclusion. Overall, our study provides the basis for further investigations on the metabolic alterations trigger by EVs within the BM microenvironment and suggests prognostic biomarkers for leukemic patients that might reveal novel metabolic vulnerabilities in AML scenario. Disclosures Cavo: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Curti: Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.
Tesis sobre el tema "Metabolic CD34+ cells":
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Guimarães, Tânia Maria Rocha 1963. "Perfil de expressão de células progenitoras endoteliais circulantes CD45-/ CD34+/KDR+ em mulheres hipertensas na pré-menopausa em comparação com mulheres saudáveis normotensas = Expression profile of circulating endothelial progenitor cells CD45-/ CD34+/KDR+ in hypertensive premenopausal women compared with healthy normotensive women". [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317311.
Resumen
Orientadores: Cristina Pontes Vicente, Patrícia Muniz Mendes Freire de MouraTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: As células progenitoras endoteliais (EPCs) estão envolvidas em neovasculogênese e na manutenção da homeostase vascular, sua deficiência pode ter papel na patogênese da hipertensão. Este estudo teve como objetivo analisar o perfil de expressão das EPCs circulantes e diferentes fatores de risco cardiovascular em mulheres hipertensas, na pré-menopausa, em comparação com mulheres normotensas saudáveis. Realizou-se um estudo caso-controle com 45 mulheres voluntárias, faixa etária de 30 a 50 anos (41 ± 6) no Ambulatório do Pronto Socorro Cardiológico de Pernambuco. As EPCs definidas como CD45-/CD34+/KDR+ foram coletadas em sangue venoso periférico e analisadas por citometria de fluxo. As mulheres foram classificadas como controles (CT) saudáveis normotensas com PAS (pressão arterial sistólica) < 130 mmHg e PAD (pressão arterial diastólica) < 85 mmHg (n=15), com hipertensão primária: a) Leve (HL) PAS=140-159mm Hg e PAD=90-99 mmHg (n=15) e b) Severa (HS) PAS > 180 mmHg e PAD > 110 mmHg (n=15). Os grupos foram entrevistados quanto aos hábitos de fumo, prática de exercícios físicos e Índice de Massa Corporal (IMC), sendo aferido o nível da PA em repouso. Realizou-se análise nos prontuários dos resultados dos exames séricos de colesterol total, lipoproteínas de alta densidade-colesterol (HDL-c), lipoproteínas de baixa densidade-colesterol (LDL-c), triglicerídeos e glicemia de jejum, no mês da coleta das amostras sanguíneas. Os resultados comprovaram redução significativa ao número de EPCs no HL (74%) e HS (88%) versus CT; e redução de 67% no HS versus HL, evidenciando relação inversa entre o número de células e o estágio da hipertensão. O grupo HS apresentou aumento de 49% de células CD45+ demonstrando padrão inflamatório e redução de 61% de CD45-/CD34+. Quanto aos níveis séricos verificou-se: HDL-c [HL (52±7); HS (48±5)]; LDL-c [HL (130±8); HS (143±15)]; triglicerídeos [HL (138±19); HS(153 ±40)]; glicemia de jejum [HL(95±7);HS(121±39)] e IMC [HL(31±4);HS(29±3)]; revelando que 67% das mulheres com hipertensão severa apresentavam síndrome metabólica (SM). O desenvolvimento da hipertensão e da SM foi diretamente correlacionado com a diminuição das EPCs. Portanto, a contagem de EPCs pode ser considerada um marcador biológico adequado para indicar a gravidade do estado hipertensivo em mulheres
Abstract: Endothelial progenitor cells (EPCs) are involved in neovasculogenesis and maintenance of vascular homeostasis and their impairment may have a role in the pathogenesis of hypertension. This study aimed analyzes the expression profile of circulating EPCs and different cardiovascular risk factors in hypertensive premenopausal women compared with healthy normotensive women. A case-control study was conducted enrolling 45 women volunteers, aged from 30- 50 years (41 ± 6) in Ambulatory of the Cardiologic Emergency Hospital of Pernambuco. EPCs numbers were determined by flow cytometry in peripheral blood as the CD45-/CD34+/KDR+ cells. The women were classified as healthy normotensive controls (CT) with SBP (systolic blood pressure) <130 mmHg and DBP (diastolic blood pressure) < 85 mmHg (n=15), and with essential hypertension; a) mild (MH), SBP=140-159 mmHg and DBP=90-99 mmHg (n=15); and b) severe (SH), SBP>180 mmHg and DBP>110 mmHg (n=15). The group were interviewed regarding smoking habits, physical exercise and body mass index (BMI), and measured the level of blood pressure at quiescent. An analysis in records of test results cholesterol, high density lipoprotein-cholesterol (HDL-c), low density lipoprotein-cholesterol (LDL-c), triglycerides and fasting glucose in the month of collection of blood samples. The results found a significant reduction in circulating EPCs numbers in MH (74%) and SH (88%) when compared to the CT and reduction of 67% in SH when compared to MH, an inverse relationship between the number of cells and the stage of hypertension. SH group showed an increase of 49% CD45+ cells demonstrating inflammation and reduction of 61% CD45-/ CD34+ cells. Regarding the biochemical serum was found: HDL-c [MH (52±7); SH (48±5)]; LDL-c [MH (130±8); SH (143±15)]; triglycerides [MH (138±19); SH (153±40)]; fasting glucose [MH (95±7); SH (121±39)] and BMI [MH (31±4); SH (29±3)]; revealing that 67% of women with severe hypertension had metabolic syndrome (MS). Development of hypertension and the parameters related to MS are directly correlated with a decrease of circulating EPCs. Therefore, the EPCs counting may be considered a suitable biological marker to follow up the evolution of the hypertensive state in women
Doutorado
Biologia Celular
Doutora em Biologia Celular e Estrutural
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Refeyton, Alice. "La survie et les adaptations métaboliques des cellules primitives mésenchymateuses et hématopoïétiques en anoxie et anoxie/aglycémie". Electronic Thesis or Diss., Bordeaux, 2024. http://www.theses.fr/2024BORD0028.
Resumen
Les cellules stromales mésenchymateuses (CStroM) comprennent des cellules souches (CS) multipotentes capables de régénérer des tissus lésés par des agressions de type ischémique. Pourtant, une mortalité élevée des CStroM après transplantation est mise en évidence lors de leur prise de greffe. Par conséquent, explorer les stratégies visant à améliorer la viabilité des greffes cellulaires constitue le défi de la thérapie cellulaire. À cette fin, nous avons effectué des analyses fonctionnelles et métaboliques sur deux types de population différents contenant des CS somatiques : des CStroM et une population de cellules partenaires de la niche hématopoïétique, les CD34+.Les cellules CStroM ou CD34+ ont été cultivées dans des conditions d'anoxie (absence d'O2) et de type ischémique (anoxie/aglycémie, absenced'O2 et de glucose, AA) ou à 3% d’O2 correspondant à la concentration physiologique optimale, puis analysées.Les tests fonctionnels révèlent que les cellules CStroM et CD34+ présentent des propriétés de prolifération et de différenciation complètes en anoxie. Les analyses fonctionnelles de cellules individuelles et d'expression génique ont révélé que les CStroM et CD34+ sont non seulement maintenues dans un état d'AA, mais sont celles dans lesquelles les CS, ayant la capacité de prolifération et de différenciation la plus élevée, sont les plus enrichies. L'analyse métabolique multiparamétrique montre que la survie en anoxie est principalement soutenue par la glycolyse et le métabolisme des lipides. En revanche, l'homéostasie énergétique des CStroM dans la condition AA est partiellement assurée par l'activité mitochondriale anaérobie engageant particulièrement les complexes mitochondriaux I, III et l'ubiquinone. De plus, une accumulation importante de succinate dans cette condition pour les deux types de CS a été mise en évidence. Ceci est dû en partie à une inversion de la succinate déshydrogénase, qui à son tour est entraînée par le débordement de fumarate provenant de la dégradation des nucléotides puriques et par une activité de la navette malate-aspartate. Cependant, les principales voies contribuant à l'accumulation de succinate comprennent la stimulation du glucose/pyruvate induit par le glycogène, ainsi que le métabolisme du corps cétonique, des acides aminés et du propanoate qui fournissent du succinyl-CoA converti en succinate. De plus, la survie en ischémie des CStroM est liée au métabolisme des sulfides et à la consommation de H2S, ainsi qu’à une survie améliorée en présence des donneurs de H2S. L’oxydation du H2S médiée par la SQR entraîne le transport réverse des électrons au niveau du complexe mitochondrial I, en utilisant le glutathion comme accepteur d'électrons. L'analyse de l'utilisation des substrats énergétiques a montré que les cellules CD34+ en anoxie semblent utiliser majoritairement les oses simples afin d’alimenter la voie glycolytique et une diminution conséquente du métabolisme mitochondrial en comparaison à la condition à 3% d’O2. En revanche, en AA, les intermédiaires du cycle de Krebs sont utilisés de manière intensive pour fournir les coenzymes NAD/NADH.Nos résultats révèlent une grande flexibilité métabolique des populations de CStroM et CD34+ s'appuyant sur l’enrichissement en CS somatiques détecté en anoxie ou dans la condition mimant l’ischémie. Ainsi, contrairement aux cellules différenciées, les CS somatiques (mésenchymateuses et hématopoïétiques) ont la capacité de survivre dans des conditions d'anoxie et d'aglycémie en utilisant les voies énergétiques conservatrices évolutives existant chez les premiers eucaryotes vivant dans des zones anoxiques enrichies en sulfide. L’exploitation de ce conditionnement ex vivo dans des conditions imitant l’ischémie pourrait constituer une stratégie visant à améliorer la survie des CStroM implantées dans des tissus hypoxiques/ischémiquesMesenchymal stromal cells (MStroC) comprise multipotent stem cells (SC) capable of regenerating tissues damaged by ischemic insults. However, high mortality of MStroC after transplantation is highlighted during their engraftment. Therefore, exploring strategies to improve the viability of cell grafts constitutes the challenge of cell therapy. To this end, we performed functional and metabolic analyzes on two different types of populations containing somatic SC: MStroC and a population of hematopoietic niche partner cells, CD34+.MStroC or CD34+ cells were cultured under conditions of anoxia (absence of O2) and ischemic type (anoxia/aglycemia, absence of O2 and glucose, AA) or at 3% O2 corresponding to the physiological optimal concentration, then analyzed.Functional assays reveal that MStroC and CD34+ cells exhibit complete proliferation and differentiation properties in anoxia. Functional analyzes of single cells and gene expression revealed that MStroC and CD34+ are not only maintained in an AA state, but are those in which SC, having the highest proliferation and differentiation capacity, are the most enriched. Multiparametric metabolic analysis shows that survival in anoxia is mainly supported by glycolysis and lipid metabolism. On the other hand, the energy homeostasis of MStroC in the AA condition is partially ensured by anaerobic mitochondrial activity particularly involving mitochondrial complexes I, III and ubiquinone. Furthermore, a significant accumulation of succinate in this condition for both types of SC was demonstrated. This is due in part to an inversion of succinate dehydrogenase, which in turn is driven by fumarate spillover from purine nucleotide degradation and malate-aspartate shuttle activity. However, major pathways contributing to succinate accumulation include glycogen-induced glucose/pyruvate stimulation, as well as ketone body, amino acid, and propanoate metabolism which provide succinyl-CoA converted to succinate. Furthermore, MStroC ischemia survival is linked to sulfide metabolism and H2S consumption, as well as improved survival in the presence of H2S donors. SQR-mediated H2S oxidation results in reverse electron transport at mitochondrial complex I, using glutathione as an electron acceptor. The analysis of the use of energy substrates showed that CD34+ cells in anoxia seem to mainly use simple sugars in order to fuel the glycolytic pathway and a consequent reduction in mitochondrial metabolism compared to the 3% O2 condition. In contrast, in AA, Krebs cycle intermediates are used intensively to provide the coenzyme NAD/NADH.Our results reveal a great metabolic flexibility of MStroC and CD34+ populations based on the enrichment of somatic SC detected in anoxia or in the condition mimicking ischemia. Thus, unlike differentiated cells, somatic SC (mesenchymal and hematopoietic) have the capacity to survive in conditions of anoxia and aglycemia using the evolutionary conservative energy pathways existing in early eukaryotes living in anoxic zones enriched in sulfide . Exploiting this ex vivo conditioning under conditions mimicking ischemia could constitute a strategy to improve the survival of MStroC implanted in hypoxic/ischemic tissues
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Zancanaro, Krauss Maria Eduarda. "CD4+ T cell metabolism during Trichuris muris infection". Thesis, University of Manchester, 2018. https://www.research.manchester.ac.uk/portal/en/theses/cd4-t-cell-metabolism-during-trichuris-muris-infection(24eb0cc7-db70-46ea-ba49-e4fe3d5a5d03).html.
Resumen
Trichuris trichiura is a gastrointestinal dwelling nematode that infects almost 500 million people worldwide. T. muris occurs naturally in mice and is very closely related the human whipworm, making it a suitable model to dissect the immune response against the parasite. Studies using the Trichuris muris system have identified CD4+ T cells as dictators of the outcome of infection. In wild type mice, infection with a high dose of T. muris eggs leads to resistance and worm expulsion, which are dependent on a Th2 response and the secretion of type 2 cytokines especially interleukin (IL) 13. Chronicity is dependent on a Th1 response and occurs when mice are infected with a low dose of T. muris eggs. It is well established that metabolic changes are essential to promoting T cell activation and effector function. Moreover, during chronic infection the host immune system is continuously exposed to parasite antigen, which represents a metabolic challenge. This thesis has investigated the importance of T cell metabolism during response against T. muris. Data presented here show that low and high dose T. muris infections promote upregulation of the glycolytic pathway in CD4+ T cells. During later stages of chronic infection, CD4+ T cells displayed supressed glycolysis and mitochondrial respiration, and may be due to metabolic modulation imposed by the parasite. Leucine uptake via the amino acid transporter Slc7a5 was previously shown to be required for mTORC1 activation and for T cell effector function. Data presented here show that in early stages following a high dose T. muris infection, mice that lack Slc7a5 in T cells have delayed worm expulsion, impaired production of antibodies, and lower levels of IL-13. Their CD4+ T cells present reduced glycolytic rates when compared to cells from cohoused infected wild type mice. However, at later stages of infection, antibody, IL-13 and glycolytic levels were restored together with worm expulsion. CD4+ T cells from the early stage of infection showed reduced phosphorylation of mTOR, which suggested that impairment of function was mTOR dependent. Indeed, mice lacking mTOR in T cells fail to expel a high dose of parasites. They showed abrogation of IL-13 production, impairment in antibody class switching and their CD4+ T cells failed to upregulate glycolysis. Thus, this thesis shows that mTOR is essential for the proper functioning of T cells during T. muris infection and efficient amino acid transport plays a significant role. Taken together, these data show that metabolic orchestration of T cell function influences the capacity to effectively control helminth infection and that even subtle changes in T cell metabolic control can have a major effect on response phenotype.
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St-Pierre, Jessica. "The role of CD4⁺ Foxp3⁺ naturally-occurring regulatory T cells in the host immune response to Plasmodium chabaudi AS /". Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111941.
Resumen
Naturally-occurring CD4+Foxp3+ regulatory T cells (nTreg) play a central role in maintaining immune self-tolerance as well as modulating immunity towards pathogens. Pathogens may establish chronic infections in immunocompetent hosts by engaging nT reg in order to promote immunosuppression. The goal of the research described here is to test the hypothesis that nTreg modulate protective immunity to malaria, and consequentially affect susceptibility to the parasite. To investigate this question, the functional dynamics of CD4+Foxp3 + nTreg cells were evaluated in mice infected with blood-stage Plasmodium chabaudi AS. Adoptive transfer of nTreg to infected wild-type C57BL/6 (B6) mice or infection of transgenic B6 mice over-expressing Foxp3 resulted in increased parasitemia and reduced survival compared to control mice. Moreover, while resistant B6 mice exhibited decreased splenic nT reg frequencies at day 7 post infection, susceptible A/J mice maintained high numbers of nTreg at this time. Investigation of the effects of nTreg regulation on immune cell function in P. chabaudi AS-infected mice revealed that increased nTreg frequencies led to decreased malaria-specific lymphoproliferation and increased systemic levels of IL-10. Unlike B6 mice, increased splenic nTreg frequencies in infected A/J mice correlated with decreased effector T cell proliferation and IFN-gamma secretion, decreased B cell and NK cell proliferation as well as deficient IFN-gamma secretion by NK cells. Finally, nTreg proliferated within infected sites in both B6 and A/J mice, albeit to a greater extent in susceptible A/J mice. Altogether, these results demonstrate that nTreg suppressed anti-malarial immunity, and in turn promoted parasite growth and persistence.
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Tripmacher, Robert. "Untersuchungen zu Wirkungen einer eingeschränkten Energiesynthese auf Funktionen von humanen Immunzellen". Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2005. http://dx.doi.org/10.18452/15260.
Resumen
Hintergrund: Die Funktion von Immunzellen hängt von einer konstanten und ausreichenden Energieversorgung ab, die über die OXPHOS in den Mitochondrien und die Glykolyse im Zytosol realisiert wird. Die wichtigsten Substrate dafür sind Sauerstoff und Glukose. Fragestellung: Bei schweren Erkrankungen oder in Entzündungsgebieten ist die zelluläre Energieversorgung stark beeinträchtigt, weil in der Mikroumgebung der Zelle Sauerstoff und Nährstoffe inadäquat bereitgestellt werden. Ziel war herauszufinden, ob und wie humane Immunzellen ihre Lebensfähigkeit und funktionellen Aktivitäten unter solchen Umständen aufrechterhalten. Methoden: Humane CD4+ T-Zellen und CD14+ Monozyten wurden durch MACS aus peripherem Blut gesunder Spender isoliert. Die Sauerstoffverbrauchsmessung mittels Clark-Elektrode war Maß der oxidativen Energiebildung, die mit Myxothiazol und Glukoseentzug gehemmt wurde. Die CD3/CD28-stimulierte T-Zell-Proliferation wurde durchflußzytometrisch mittels CFDA SE analysiert. Basierend auf dem Paraformaldehyd-Saponin-Prozedere wurde die Zytokinsynthese ebenfalls am FACS bewertet, nachdem die T-Zellen in Anwesenheit von Brefeldin A mit PMA/Ionomycin stimuliert wurden. Mit einem käuflichen Testsystem (FACS-Technik) wurde die monozytäre Phagozytose untersucht. Die HIF-1alpha-Expression wurde nach PMA-Ionomycin-Stimulation von Myxothiazol-behandelten T-Zellen auf mRNA- und Proteinebene gemessen. Ergebnisse: Bei Glukoseanwesenheit waren alle untersuchten Immunfunktionen trotz vollständig gehemmter OXPHOS unbeeinträchtigt. Erst bei gleichzeitigem Glukoseentzug, der per sé Proliferation und Phagozytose signifikant beeinträchtigte, waren sie signifikant vermindert. Es wird vermutet, daß T-Zellen die Energieverluste mit einem überschießenden Effekt ihres Sauerstoffverbrauchs und stark angetriebener Glykolyse kompensieren. HIF-1alpha ist dabei nicht entscheidend für die Umschaltung auf anaerobe Energiesynthese. Schlußfolgerung: Die Daten quantifizieren die Energieanforderungen der funktionellen Aktivität in hochgereinigten humanen Immunzellfraktionen. Es wurde nachgewiesen, daß sich Immunzellen unerwartet lange an eine massiv beeinträchtigte Energetik adaptieren können und ihre spezifischen Funktionen aufrechterhalten.Background: The function of immune cells is dependent upon a constant and adequate supply of energy. Energy is formed via OXPHOS in the mitochondria and via cytosolic glycolysis. Oxygen and glucose are the main substrates for energy synthesis. Objective: In severe diseases or in inflamed areas cellular energy supply is significantly impaired due to inadequate supply of cellular microenvironment with oxygen and nutrients. The aim of this study was to answer the question, whether and how human immune cells maintain viability and functional activity under these circumstances. Methods: Human CD4+ T cells and CD14+ monocytes were isolated by MACS from peripheral blood of healthy donors. The extent of oxidative energy formation was determined via measurement of oxygen consumption using a Clark type electrode. Energy production was restricted in glucose-free cell culture medium and by gradually inhibited OXPHOS using myxothiazol. T cell proliferation was flow-cytometrically analysed using CFDA SE after stimulation with CD3 and CD28 antibodies. Cytokine synthesis was assessed by flow-cytometrical immunofluorescence and the paraformaldehyde-saponin procedure after stimulation of T cells with PMA/ionomycin in the presence of brefeldin A. Phagocytosis of monocytes was measured using a commercial test system (FACS technique). HIF-1alpha expression was assessed by semiquantitative PCR and immunoblot after the stimulation of myxothiazol treated T cells with PMA/ionomycin. Results: In glucose-containing medium all investigated immune functions were unaffected even under complete suppression of OXPHOS. Only when OXPHOS and glycolysis were simultaneously and almost completely suppressed a significant decrease was found. Glucose deprivation per se caused both a significantly reduced proliferation and phagocytosis. It is supposed, that T cells are able to compensate for an energy deficit by an excess of oxygen consumption and strongly induced glycolysis. However, HIF-1alpha was found to be not crucial for switching to anaerobic energy synthesis. Conclusion: These data quantify the energy requirement of functional activity in highly purified human immune cell fractions. An unexpectedly high adaptive potential of immune cells to maintain specific functions even under massively impaired energetic conditions could be demonstrated.
6
COMPAGNONE, MIRCO. "ΔNp63 controls hyaluronic acid metabolism and signaling in head and neck squamous cell carcinoma". Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2015. http://hdl.handle.net/2108/202937.
Resumen
La famiglia di p53 comprende i tre fattori di trascrizione p53, p63 e p73. Il capostipite della famiglia, p53, è definito il “guardiano del genoma”, grazie alla sua abilità di arrestare il ciclo cellulare in presenza di danno al DNA, consentendone una adeguata riparazione e, nell’eventualità che tale danno non possa essere riparato, promuovere la morte cellulare per apoptosi. p53, dunque, agisce funzionalmente come un classico soppressore di tumore. Infatti, mutazioni con perdita di funzione colpiscono il gene p53 nel 50% circa dei tumori umani. Dopo circa vent’anni di studi intensivi su p53, arrivò, inaspettatamente, la scoperta dei due suoi “parenti” stretti, ad alta omologia di sequenza: p73 e p63. Il gene p63 codifica per le isoforme TAp63, dotate del dominio di trans-attivazione all’N-terminale e, grazie ad un secondo promotore, le isoforme ∆Np63, prive di tale dominio ma, comunque, in grado di trans-attivare i propri geni target attraverso un secondo dominio di trans-attivazione. Inoltre, meccanismi di splicing alternativo all’estremità 3’ terminale, generano isoforme C-terminali. Mentre l’isoforma TA “mima” la funzione oncosoppressiva del parente p53, ∆Np63 mostra una spiccata attività oncogenica, in particolare nei carcinomi a cellule squamose di diversa origine, dove risulta altamente espresso. Infatti, ∆Np63 esibisce una notevole abilità nel regolare la trascrizione di molti geni target coinvolti nelle principali caratteristiche biologiche del tumore, tra le quali crescita, evasione dall’apoptosi, migrazione, invasione ed angiogenesi. Nel seguente studio, sveliamo un nuovo programma trascrizionale orchestrato dall’isoforma oncogenica ∆Np63 e che vede come co-protagostista l’acido ialuronico e la sua attività pro-tumorale. L’acido ialuronico, uno dei maggiori costituenti della matrice extracellulare, si comporta da ligando di specifici recettori di membrana plasmatica, tra i quali il CD44, attivandoli ed “accendendo” pathways coinvolti nella crescita, migrazione, invasione e sopravvivenza cellulare. Come atteso, molti tipi tumorali sfruttano la segnalazione dell’acido ialuronico per promuovere la loro crescita, sopravvivenza ed, in fine, la loro chemioresistenza. In particolare, l’interazione tra l’acido ialuronico e il CD44 favorisce l’attivazione dei recettori tirosina chinasi, tra i quali l’EGFR, e dei loro pathways oncogenici. Inoltre, l’attivazione del CD44 da parte dell’acido ialuronico, promuove l’espressione dei trasportatori ABC ed il conseguente efflusso degli agenti chemioterapici presenti nella cellula. Nel nostro studio, mostriamo la sorprendente abilità di ∆Np63, in cellule tumorali, di regolare positivamente il signaling dell’acido ialuronico, agendo sui livelli dell’acido ialuronico e del suo principale recettore CD44. Infatti, ∆Np63 è in grado di indurre direttamente l’espressione della sintasi 3 dell’acido ialuronico (Has3), coinvolta nella sintesi dell’acido ialuronico e, reprimere quella delle ialuronidasi 1 e 3 (Hyal1 e 3), implicate nella degradazione dell’acido ialuronico, determinando un aumento dei livelli extracellulari di acido ialuronico. Inoltre, ∆Np63 direttamente transattiva il gene CD44, auementandone i livelli proteici. In accordo con tali evidenze in vitro, in diversi datasets di tumori primari di origine squamosa, troviamo che l’espressione di p63 correla positivamente con quella di Has3 e CD44. Conseguentemente, osserviamo un’attivazione dell’EGFR e un aumento dei livelli dei trasportatori ABC, guidati dall’asse ∆Np63/acido ialuronico. Infine, dimostriamo la capacità di ∆Np63 di promuovere la chemioresistenza in maniera dipendente dall’acido ialuronico. Infatti, la deplezione di p63, similmente a quella di Has3 e all’inibizione chimica della sintesi dell’acido ialuronico, riduce la resistenza delle cellule tumorali agli agenti chemioterapici. Inoltre, in data sets di tumori umani, la correlazione positiva tra l’espressione di p63 e Has3 risulta essere un fattore prognostico negativo sulla probabilità di sopravvivenza dei pazienti, suggerendo la crucialità dell’asse p63/acido ialuronico nella tumorigenesi guidata da p63 nei carcinomi squamosi di testa e collo.p63 is a transcription factor belonging to the p53 family. Like other members of the p53 family, the TP63 gene is expressed as multiple isoforms arising by either alternative promoter usage or differential splicing events at the C-terminus. Particularly, the ΔN proteins, although lack the canonical transcriptional activation domain, are endowed with an alternative transactivation domain and promote cancer cell survival and tumor progression in squamous cell carcinomas (SCCs) of different origins. By combining RNA-seq approach with co-expression studies in human primary tumors, we identified and characterized the hyaluronan synthase 3 (Has3), the hyaluronidase 1 and 3 (Hyal1 and 3), and CD44 as novel ∆Np63 regulated genes. Has3 catalyzes the synthesis of hyaluronic acid (HA), while Hyal1 and Hyal3 catalyze the degradation of HA. CD44 is the main signal-transducing HA plasma membrane receptor. We found that in HNSCC cell lines of different origin, ∆Np63 silencing decreased Has3 expression and concomitantly increased the expression of Hyal1 and Hyal3, resulting in the inhibition of the extracellular level of HA. Mechanistically, we found that ∆Np63 directly bound to and activated the promoter of Has3 and, conversely, bound to the promoter and the 3’-terminal region of Hyal3 and 1, respectively, resulting in the repression of gene expression. Accordingly, in several primary squamous tumor datasets, we found that the expression of p63 was positively correlated with that of Has3. HA-mediated signaling is mediated through its interaction with plasma membrane receptors, including primarily CD44. We found that in tumor cells, ∆Np63 silencing decreased CD44 expression and, accordingly, the expression of p63 was positively correlated with that of CD44 in primary squamous tumor data sets. Mechanistically, we found that ∆Np63 directly bound to and activated the promoter of CD44. HA-CD44 interaction is important for mediating chemoresistance by sustaining the full activation of several tyrosine kinase receptors (EGFR, ErbB2 and IGFR) and promoting the expression of ABC drug transporters. We found that ∆Np63, through its action on HA metabolism and CD44 abundance, regulated the tyrosine kinase receptors activation and ABC drug transporter expression, mediating thus, tumor chemoresistance. Notably, in vitro ∆Np63-depletion, similar to Has3 silencing and HA-synthesis inhibition by 4-MU treatment, reduced cancer cell chemoresistance, indicating the ∆Np63 ability to promote chemoresistance in a HA-dependent manner. Moreover, in different human tumors data sets, the positive correlation between p63 and Has3 expression was a negative prognostic factor on HNSCC patient survival, suggesting that the ΔNp63/HA signaling axis is an important determinant of the p63-driven tumorigenesis.
7
Divoux, Jordane. "Etude du métabolisme des lymphocytes T CD4+ Foxp3+ régulateurs à l’homéostasie et dans un contexte inflammatoire". Thesis, Sorbonne université, 2019. https://accesdistant.sorbonne-universite.fr/login?url=http://theses-intra.upmc.fr/modules/resources/download/theses/2019SORUS075.pdf.
Resumen
Les lymphocytes T CD4+ Foxp3+ régulateurs (Treg) participent à la régulation de l’activité du système immunitaire et sont essentiel au maintien de la tolérance immune. Ces cellules sont ainsi bénéfiques lors de pathologies auto-immunes tandis que leur action anti-inflammatoire favorise la croissance tumorale. Comprendre le fonctionnement des Treg constitue donc un axe majeur pour le développement de nouvelles stratégies thérapeutiques applicables à ces deux types de pathologies. Au cours de ce travail, nous nous sommes intéressés au métabolisme des Treg étant donné que les informations disponibles à ce jour font encore l’objet de controverse. A l’inverse des lymphocytes T conventionnels (Tconv), qui utilisent un métabolisme de type anabolique sous le control de mTOR, les Treg sont aujourd’hui considéré comme des cellules présentant un métabolisme de type catabolique favorisé par l’AMPK. Afin de vérifier cette hypothèse, nous avons utilisés des modèles murins de délétion conditionnelle permettant la délétion génique d’AMPK ou mTOR, spécifiquement dans les Treg. L’étude de ces souris a permis de mettre en évidence un rôle jusqu’ici insoupçonné de mTOR dans la stabilité et la migration des Treg ainsi qu’une implication de l’AMPK dans la capacité des Treg à inhiber la réponse anti-tumorale. Ces travaux remettent ainsi en question les considérations actuelles sur le métabolisme des Treg et ouvrent la voie vers une meilleure compréhension du métabolisme de ces cellules à l’homéostasie et en condition pathologiqueCD4+ Foxp3+ regulatory T cells (Treg) are able to control the activity of the immune system and are essential to maintain immune tolerance. These cells are thus beneficial in autoimmune diseases while their anti-inflammatory action promotes tumor growth. Understanding Treg biology is therefore a major axis for the development of new therapeutic strategies applicable to these two types of pathologies. In this work we investigated Treg metabolism as information available to date are still controversial. In contrast to conventional T cells (Tconv), which use anabolic metabolism under the control of mTOR, Treg are today considered as catabolic cells with a metabolism favored by AMPK. In order to test this hypothesis, we used conditional knock out mice allowing gene deletion of AMPK or mTOR, specifically in Treg. The study of these mice highlight an unsuspected role of mTOR in the stability and migration of Treg as well as an involvement of AMPK in the ability of Treg to inhibit anti-tumor response. This work puts in question current considerations on Treg metabolism and opens the way towards a better understanding of the metabolism of these cells at homeostasis and in pathological context
8
Vahlas, Zoï. "Régulation métabolique de l'infection des cellules T CD4 par VIH-1 : vers de nouvelles cibles thérapeutiques". Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTT009.
Resumen
La susceptibilité des lymphocytes T CD4 (LT) à l'infection par VIH-1 est régulée par le métabolisme du glucose et de la glutamine. Cependant, les contributions relatives de ces nutriments à l'infection étaient peu connues lorsque j’ai débuté ma thèse. Au cours de mes travaux, j'ai identifié la glutaminolyse comme une voie majeure alimentant la phosphorylation oxydative (OXPHOS) dans les sous-populations de LT activés naïves et mémoires, et j'ai découvert que l'induction de ce réseau métabolique est nécessaire pour une infection optimale par VIH-1. J’ai constaté qu’en condition limitante en glutamine, l’α-kétoglutarate (α-KG), un intermédiaire du cycle TCA (TriCarboxylic Acid) issu de la glutaminolyse, constitue un facteur clé de l'infection des LT CD4 par VIH-1. L'ajout d’α-KG exogène induit une augmentation rapide du ratio OXPHOS/glycolyse et rend les LT naïfs et mémoires plus susceptibles à l’infection. Par ailleurs, l’inhibition du flux glycolytique du pyruvate vers le lactate induit une augmentation de l'OXPHOS et de l'infection des LT CD4 par VIH-1. En accord avec ces données, les LT CD4 infectés présentent une augmentation de la biomasse et de l'activité mitochondriale en comparaison à leurs homologues non infectés. Ces données identifient l'équilibre OXPHOS/glycolyse aérobie comme un élément clé de l'infection des LT par VIH-1.Afin de mieux appréhender les voies métaboliques régulant l'infection des LT par VIH-1, j'ai développé une approche complémentaire basée sur l’utilisation de shRNA ciblant spécifiquement les transporteurs de nutriments GLUT1, ASCT2 et CAT1, permettant notamment le transport du glucose, glutamine et arginine dans la cellule, respectivement. Ainsi, j’ai observé une diminution de la survie d’environ 80% des cellules shRNA+, témoignant ainsi de l’importance de ces transporteurs lors de l’activation de ces cellules. Cependant, la permissivité des LT CD4 à l’infection par VIH-1 est impactée différemment par la diminution de l’expression des transporteurs de nutriments. Conformément aux données présentées ci-dessus, l’inhibition de GLUT1 n'a pas eu d'impact significatif sur l'infection par VIH-1, tandis que l’inhibition de CAT1 a réduit de manière significative l’OXPHOS ainsi que l'infection par VIH-1 (de 35 %). Il est toutefois surprenant de constater que l’inhibition d’ASCT2 entraîne une augmentation de l'infection de 20 %. Cela était associé à une persistance significativement plus élevée des cellules T naïves dont l’expression d’ASCT2 était inhibée, par rapport aux LT mémoires. Ces données mettent ainsi en évidence l’importance relative de ces 3 transporteurs de nutriments dans la survie des LT naïfs par rapport aux LT mémoires et démontrent leur impact spécifique sur la permissivité de ces populations à l'infection par VIH-1.En conclusion, en utilisant deux approches complémentaires, mes travaux de thèse révèlent l'impact critique de l'état énergétique d'une cellule T CD4 sur sa susceptibilité à l'infection par VIH-1. Mes données mettent en évidence l'importance du métabolisme mitochondrial, avec un environnement riche en intermédiaires du cycle du TCA comme l’α-KG, dans la régulation de la sensibilité des LT à l'infection par VIH-1. En outre, l'expression des transporteurs de nutriments impacte différentiellement la sensibilité des LT naïfs et mémoires à l'infection par VIH-1. Ces études offrent donc de nouvelles perspectives utilisant le métabolisme pour le développement de stratégies thérapeutiques ciblées contre l'infection par VIH-1The susceptibility of CD4 T cells to HIV-1 infection is regulated by glucose and glutamine metabolism, but the relative contributions of these nutrients to infection are not known. During my PhD, I identified glutaminolysis as a major pathway fueling oxidative phosphorylation (OXPHOS) in activated naïve as well as memory CD4 cell subsets, and found that induction of this metabolic network is required for optimal HIV-1 infection. Moreover, we determined that under conditions of attenuated glutaminolysis, the α-ketoglutarate (αKG) TCA (tricarboxylic acid) cycle intermediate is a rate-limiting step in infection; exogenous α-KG directly increased OXPHOS and rendered both naïve and memory CD4 T cells significantly more sensitive to infection. Furthermore, blocking the glycolytic flux of pyruvate to lactate resulted in an increased OXPHOS and a significantly augmented level of HIV-1 infection. In agreement with these data, infected CD4 T cells exhibited increased mitochondrial biomass and respiration as compared to their non-infected counterparts. These data identify the OXPHOS/ aerobic glycolysis balance as a major regulator of HIV-1 infection in CD4 T lymphocytes.In order to gain more insight into the metabolic pathways regulating HIV-1 infection in CD4 T cells, we developed a complementary approach to target upstream processes, specifically altering glucose (GLUT1), glutamine (ASCT2), and arginine (CAT1) transporter expression by lentiviral-mediated delivery of specific shRNAs. Testifying to the importance of these transporters, CD4 T cells with downregulated expression of either GLUT1, ASCT2 or CAT1 were negatively selected, resulting in a loss of approximately 80% of shRNA-transduced cells within 14 days. Notably, the permissivity of CD4 T cells to HIV-1 infection was differentially impacted by inhibition of specific nutrient transporters. Consistent with the data presented above, knockdown of GLUT1 did not significantly impact HIV-1 infection whereas knockdown of CAT1 significantly decreased both OXPHOS as well as HIV-1 infection (by 35%). Surprisingly though, ASCT2 knockdown resulted in a significantly augmented infection, by approximately 20%. Mechanistically, we found that this was associated with a markedly higher persistence of naïve, as compared to memory, T cells with downregulated ASCT2 levels. These data highlight differences in the relative importance of distinct nutrient transporters in the survival of naïve vs memory CD4 T cell subsets and demonstrate their specific impact on the sensitivity of these populations to HIV-1 infection.In conclusion, using two complementary approaches, my PhD research has revealed the critical impact of a CD4 T cell’s energetic state on its susceptibility to HIV-1 infection. My data identify the importance of mitochondrial metabolism, with an environment rich in TCA cycle intermediates such as α-KG, in regulating the susceptibility of CD4 T cells to HIV-1 infection. Furthermore, I find that nutrient transporter expression differentially impacts the sensitivity of naïve and memory CD4 T cells to HIV-1 infection. These studies therefore provide new prospects for the development of targeted metabolic therapeutic strategies against HIV-1 infection
9
Aroua, Nesrine. "Etude in vivo de la chimiorésistance dans les leucémies aigues myéloïdes humaines". Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30369.
Resumen
Les leucémies aigües myéloïdes (LAM) sont les leucémies les plus fréquentes chez l'adulte, caractérisée par l'expansion clonale de myéloblastes immatures. Malgré un taux élevé de rémission complète après chimiothérapie conventionnelle d'induction, le pronostic est mauvais dans les LAM à cause de fréquentes rechutes. Les rechutes sont causées par une population leucémique chimiorésistante (CLR), pouvant être enrichies en cellules souches leucémiques quiescentes (CSL). Cependant, ces hypothèses n'ont jamais été testées directement in vivo. Mon travail de thèse a été initialement consacré à valider cette hypothèse in vivo. Nous avons d'abord développé une approche chimiothérapeutique cliniquement pertinente, en traitant avec de la cytarabine (AraC) des souris préalablement xénogreffées à partir de cellules primaires (PDX) de patients atteints de LAM pour caractériser leurs cellules résiduelles post-AraC. Cette population résiduelle et résistante n'est pas nécessairement enrichie en cellules immatures ou en cellules quiescentes et non plus en cellules initiatrices de leucémie. Les cellules résistantes à la chimiothérapie in vivo ont par contre conservé des mitochondries actives, présentent une oxydation accrue des acides gras et une signature génique spécifique, définissant un statut de phosphorylation oxydative élevé ("OxPHOS High"). Le traitement des lignées cellulaires de LAM "OxPHOS High" a démontré une résistance à la chimiothérapie in vivo contrairement aux lignées cellulaires avec un statut "OxPHOS Low". Cibler le statut "OxPHOS High" induit un changement énergétique vers le statut "Low OxPHOS" et améliore l'effet antileucémique de l'AraC.Dans la deuxième partie de mon doctorat, nous avons identifié l'ecto-nucléoside triphosphate diphosphohydrolase-1 CD39 (ENTPD1) surexprimée dans les CLR in vivo après AraC par analyses transcriptomiques des cellules résistantes in vivo. Par cytométrie en flux (FACS), nous avons confirmé que l'AraC augmente l'expression de CD39 à la surface cellulaire des lignées de LAM in vitro et in vivo ainsi que dans 24 modèles PDX. Nous avons également observé cette augmentation chez 50 patients après 35 jours de chimiothérapie intensive par rapport au diagnostic. Fait intéressant, une expression élevée de CD39 chez les patients atteints de LAM est associée à une mauvaise réponse à l'AraC in vivo. Nous avons en outre démontré que la voie de signalisation en aval de CD39 dépend de l'axe AMPc-PKA et son inhibition par H89 sensibilise les cellules de LAM à l'AraC en inhibant PGC1a, TFAM et la fonction OxPHOS mitochondrial. [...]Acute myeloid leukemia (AML) is the most common adult leukemia characterized by clonal expansion of immature myeloblasts. Despite a high rate of complete remission after conventional front-line induction chemotherapy (e.g. daunorubicin or idarubicin plus cytarabine), the prognosis is very poor in AML. This unfavorable overall survival is caused by frequent relapses due to chemoresistant leukemic cell populations (RLCs) in AML. RLCs are thought to be enriched in quiescent leukemic stem/immature cells (LSCs). However, these hypotheses have never been tested directly in vivo. My PhD work was devoted to validate this hypothesis in vivo. We first developed a clinically relevant chemotherapeutic approach treating patient derived xenografts (PDX) with cytarabine (AraC) to characterize AraC residual cells. AraC-treated AML cells are not necessarily enriched for neither immature cells or quiescent (G0) cells or leukemic initiating cells (LICs). Rather chemotherapy resistant cells in vivo have high levels of reactive oxygen species (ROS), showed increased mitochondrial mass, and retained active mitochondria, consistent with a high oxidative phosphorylation (OxPHOS) status. AraC residual cells exhibited increased fatty acid oxidation and a high OxPHOS gene signature predictive for treatment response in PDX and patients. Treatment of High OxPHOS but not Low OxPHOS human AML cell lines demonstrated chemotherapy resistance in vivo. Targeting mitochondrial metabolism induced an energetic shift toward low OxPHOS status and markedly enhanced antileukemic effects of AraC in AML. In the second part of my PhD study, we identified ecto-nucleoside triphosphate diphosphohydrolase-1 CD39 (ENTPD1) overexpressed in RLCs in vivo after chemotherapy. We confirmed that AraC increased cell surface CD39 expression in AML cell lines in vitro and in vivo as well as in 24 diverse PDX models. We further observed this increase in 50 patients at 35-days post-intensive chemotherapy compared to their respective diagnosis. Interestingly, high CD39 expression on AML patients was associated with a worse response to AraC in vivo. We furthermore demonstrated that CD39 downstream signaling pathway was dependent on cAMP-PKA axis and its inhibition by H89 sensitized AML cells to AraC through the inhibition of PGC1a, TFAM and mitochondrial OxPHOS function.[...]
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Bishop, Kenneth D. "Egr-2 and PD-1 Are Required for Induction and Maintenance of T Cell Anergy: A Dissertation". eScholarship@UMMS, 2005. https://escholarship.umassmed.edu/gsbs_diss/354.
Resumen
The prevalence of diabetes is approaching epidemic proportions worldwide. There is currently no cure for type 1 diabetes, and successful treatment requires constant monitoring of blood sugars and use of exogenous insulin to prevent hyperglycemia. Diabetes will be curable when pancreatic β-islet cells can be transplanted into diabetes patients without requiring long-term immunosuppression. This will require learning more about the induction of functional tolerance, a state that maintains the competence of the immune system to most antigens but protects graft-specific antigens from immune rejection, permitting transplantation. One known mechanism of peripheral tolerance is T cell anergy, a phenotype of hypo-reponsiveness in CD4+ T cells. The focus of this thesis is a description of factors shown to be specific to the induction and maintenance of T cell anergy, whose loss reverses the anergic phenotype, restoring the ability of the cells to proliferate in response to antigen. The first of these is Egr-2, a zinc-finger transcription factor, whose presence is required for the induction of anergy induced in T cell clones by TCR stimulation in the absence of costimulation. Egr-2 is shown to be important to anergy induction but not anergy maintenance. In contrast, a negative costimulation receptor, PD-1, is shown to be necessary for the maintenance of anergy. It is possible that learning more about the genetic factors that orchestrate T cell anergy will prove useful in the development of tolerance-based protocols for organ and tissue transplantation without the use of long-term immunosuppression.
Libros sobre el tema "Metabolic CD34+ cells":
1
Workshop on Mechanisms and Specificity of HIV Entry into Host Cells (1989 San Francisco, Calif.). Mechanisms and specificity of HIV entry into host cells. New York: Plenum Press, 1991.
2
Düzgünes, Nejat. Mechanisms and Specificity of HIV Entry into Host Cells. Springer London, Limited, 2012.
3
Düzgünes, Nejat. Mechanisms and Specificity of HIV Entry into Host Cells. Springer, 1991.
4
Düzgünes, Nejat. Mechanisms and Specificity of HIV Entry into Host Cells. Springer, 2012.
Capítulos de libros sobre el tema "Metabolic CD34+ cells":
1
Matsumoto, Kengo, Ken-ichi Hirano, Shuichi Nozaki, Makoto Nishida, Takeshi Ohya, Mohamed Janabi Yakub, Tohru Funahashi, Shizuya Yamashita y Yuji Matsuzawa. "Expression of CD36 in Cultured Human Aortic Smooth Muscle Cells (HASMCs)". En Lipoprotein Metabolism and Atherogenesis, 272–74. Tokyo: Springer Japan, 2000. http://dx.doi.org/10.1007/978-4-431-68424-4_59.
2
Bossi, Paolo y Erika Stucchi. "Exercise and Nutrition Interventions in Head and Neck Cancer". En Critical Issues in Head and Neck Oncology, 347–54. Cham: Springer International Publishing, 2023. http://dx.doi.org/10.1007/978-3-031-23175-9_21.
Resumen
AbstractOverall Survival (OS) and late quality of life of patients with locally advanced, HPV-negative Head and Neck Squamous Cell Cancer (HNSCC) are not satisfactory. Nutritional status at the beginning of both surgical and non-surgical treatment with curative intent has been linked to OS and quality of life. Weight loss, body-mass index, functional parameters, and biochemical examinations have been associated with the risk of treatment-related adverse events, mortality, quality of life and outcome. Moreover, there is a strong need for effective preventive approaches that could be implemented after completion of curative treatment to reduce recurrences, second tumors and improve quality of life. Aerobic exercise training, which is known to stimulate the immune system, and nutritional interventions represent easy, acceptable and reproducible methods to increase immune and nutritional competence, impacting thus on the aforementioned objectives. Participating in exercise training programs has been well accepted by patients with HNSCC, underlining the feasibility of such an intervention. There are also immunological arguments to promote an adequate physical activity in HNSCC patients. Baseline and after treatment immune competence of HNSCC should be weighted, as it may impact on cancer recurrence and OS. Patients with HNSCC have significantly lower absolute numbers of CD3+, CD4+ and CD8 + T cells than normal controls, and lymphocyte counts, neutrophil/lymphocyte ratio and the prognostic nutritional index (PNI) are associated with prognosis. Aerobic exercise training prevents immune senescence, and therefore may prevent cancer development. The immune system activity is accompanied by an increased rate of metabolism, requiring energy sources, substrates for biosynthesis and regulatory molecules, which are ultimately derived from the diet. Hence, an adequate supply of a wide range of nutrients is essential to support the immune system to function optimally. Therefore, a regular nutritional counselling combined with personalized exercise training is a simple and very cheap way that could improve patient’s nutritional condition and immunological function, and ultimately impact on survival and quality of life. There is a strong need for well conducted clinical trials aimed at evaluating, in homogeneous groups of HNSCC patients, the impact of nutritional interventions (also comprising immunonutrition) and physical exercise. The evaluation of surrogate endpoints like circulating immune cells should also be explored to identify feasible and effective interventions. Integrating these interventions within immunotherapy approaches represents another area deserving further studies.
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Sugano, Ryo, Mariko Harada-Shiba, Noriyasu Nishimura, Yasuko Miyake, Jun An, Dong Xan Hui, Taku Yamamura y Akira Yamamoto. "CD36 Expression in Human Monocytic Leukemia Cell Lines: THP-1 and THP-1 Subtype, Show Different Expressions of Type I and Type II Scavenger Receptors". En Lipoprotein Metabolism and Atherogenesis, 230–32. Tokyo: Springer Japan, 2000. http://dx.doi.org/10.1007/978-4-431-68424-4_49.
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Gordon-Smith, E. C. y Emma C. Morris. "Haemopoietic stem cell transplantation". En Oxford Textbook of Medicine, editado por Chris Hatton y Deborah Hay, 5579–88. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198746690.003.0549.
Resumen
Haemopoietic stem cells (HSCs) give rise to the blood cell lineages and the cells of the immune system, and their transplantation may be an appropriate part of the management of conditions including (1) malignant haematological disorders (e.g. leukaemia, lymphoma, myeloma); (2) bone marrow failure syndromes (e.g. aplastic anaemia); and (3) congenital disorders—(a) haematological (e.g. Fanconi’s anaemia); (b) immunological—inherited immunodeficiency syndromes; and (c) metabolic (e.g. lysosomal storage diseases). Transplantation of HSCs uses either autologous HSCs (patient’s own stem cells) or allogeneic HSCs (harvested from an appropriately matched sibling or unrelated healthy donor). Successful engraftment of allogeneic HSCs depends upon (1) overcoming immune rejection by the recipient; (2) preventing or suppressing graft-versus-host disease (GVHD), in which donor cells mount an immune attack against recipient tissues; and (3) supporting the patient through periods of profound cytopenias and immune deficiency with susceptibility to infection. Identification and sources of HSCs—HSCs are principally identified by expression of the surface antigen CD34. Sources include (1) bone marrow; (2) peripheral blood—following stimulation by cytokines (e.g. granulocyte colony-stimulating factor); and (3) umbilical cord blood.
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Wu, Hongmin y Xiancai Zhong. "Nrf2 as a therapy target for Th17-dependent autoimmune disease". En The Role of NRF2 Transcription Factor [Working Title]. IntechOpen, 2024. http://dx.doi.org/10.5772/intechopen.1005037.
Resumen
Th17 cells are a subset of IL-17-expressing CD4+ T helper cells and play a predominant role in the pathogenesis of autoimmune diseases such as multiple sclerosis and psoriasis. Th17 cells sustain their activation and effector functions primarily through a metabolic profile characterized by high glycolytic and oxidative metabolism. Both glycolysis and OXPHOs can affect cellular redox status, and vice versa. Nrf2, a master regulator of redox homeostasis, plays a pivotal role in oxidative stress regulation and influences immune cell function. This chapter summarizes the recent advances in the understanding of redox regulation in Th17 cells and explores the therapeutic potential of targeting Nrf2 in Th17-dependent autoimmune diseases. Overall, targeting Nrf2 holds considerable promise as a novel therapeutic paradigm for Th17-dependent autoimmune diseases, offering new avenues for precision medicine and improved disease outcomes.
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A. Rakityanskaya, Irina, Tat’jana S. Ryabova, Anastasija A. Kalashnikova, Goar S. Balasaniants, Andrej D. Kaprin, Feliks I. Ershov, Vera V. Kir’janova et al. "Perspective Chapter: The Role of Interferon Gamma in Clinical Medicine". En Interferon - Immune Metabolism [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.105476.
Resumen
Interferon gamma (IFN-γ) is one of the key factors of both innate and adaptive immune response that promotes differentiation of naive CD4+ cells into effector Th1 T cells producing the main mediators of cellular immunity against viral and intracellular bacterial infections, and specific cytotoxic immunity through the interaction of T cells with antigen-presenting cells and macrophage activation. The clinical importance of IFN-γ includes its medical use to treat and prevent various viral and bacterial infections. IFN-γ has a direct antiviral effect on infected cells, activates local infiltrating dendritic cells, macrophages and NK cells, modulates the differentiation and maturation of T and B cells, and enhances inflammation and antiviral functions. Immunoregulatory effect of IFN-γ plays one of the essential roles in the regulation of adaptive immune response in patients with tuberculosis infection and cancer. Producing IFN-γ by T cells increases the efficiency of infiltrated phagocytic cells, by stimulating NO and maintaining local host defense during tuberculosis infection. The direct antitumor effect of IFN-γ revealed in several experimental models has numerous mechanisms for the effect of development. IFN-γ has crucial potential for enhancing any antiviral, antimycobacterial, and specific antitumor therapies.
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Masson, Jesse James Ronald y Clovis Steve Palmer. "Glucose metabolism in CD4 and CD8 T cells". En Molecular Nutrition: Carbohydrates, 129–47. Elsevier, 2019. http://dx.doi.org/10.1016/b978-0-12-849886-6.00016-1.
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Gould, Kathleen L. "Cyclin-dependent protein kinases". En Protein Kinase Functions, 277–302. Oxford University PressOxford, 2000. http://dx.doi.org/10.1093/oso/9780199637713.003.0010.
Resumen
Abstract Cyclin-dependent protein kinases (Cdks) regulate progression through the eukaryotic cell cycle. They are also involved in the regulation of other processes such as gene expression and phosphate metabolism. Cdks are the catalytic subunits of hetero dimeric complexes and they approximate the size of a minimal protein-kinase catalytic domain (∼, 34 kDa). Alone, they lack protein kinase activity. As their name implies, By far the best understood of the Cdks are those that have important roles in cell cycle progression-Cdc2, Cdk2, and Cdk4. Cdks are activated transiently at particular stages of the cell cycle, and their activation or inactivation triggers the next events in the cycle. To ensure the coordination of these events, the activation of each Cdk is strictly regulated in a variety of ways including an elaborate cascade of protein phosphorylation events, interaction with subunits in addition to cyclins, and by regulated proteolysis of the cyclin and other subunits. Due to the wealth of knowledge concern ing Cdks and the limitations of space, it is impossible to include all pertinent information about Cdks in this chapter or to cite all the original references. Numerous recent reviews emphasize various aspects of Cdk function and regulation, and readers will be referred to these where appropriate.
Actas de conferencias sobre el tema "Metabolic CD34+ cells":
1
Shen, Yao-An, Yau-Huei Wei y Yann-Jang Chen. "Abstract 482: High CD44/CD24 expressive cells presented cancer stem cell characteristics and undergo mitochondrial resetting and metabolic shift in nasopharyngeal carcinoma". En Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-482.
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Dimitriu, Gabriel, Vasile lucian Boiculese, Mihaela Moscalu y Cristina gena Dascalu. "GLOBAL SENSITIVITY ANALYSIS APPLIED TO A CANCER IMMUNOTHERAPY MODEL". En eLSE 2019. Carol I National Defence University Publishing House, 2019. http://dx.doi.org/10.12753/2066-026x-19-177.
Resumen
Sensitivity analysis methods have a long history and have been widely applied in different fields, such as environmental modeling, economical modeling for decision making, parameter estimation and control, chemical kinetics, and biological modeling analysis, with metabolic networks, signaling pathways and genetic circuits. Cancer immunotherapy is based on the idea of immune surveillance. Immunotherapy, also named biologic therapy, represents a type of cancer treatment that boosts the body's natural defenses to fight cancer. It uses substances made by the body or in a laboratory to improve or restore immune system function. The aim of this paper is to perform a global sensitivity analysis applied to a mathematical model for the tumor-immune interaction. Global sensitivity analysis quantifies the importance of model inputs and their interactions with respect to model output. It provides an overall view on the influence of inputs on outputs as opposed to a local view of partial derivatives as in local sensitivity analysis. The model under investigation is specialized for autologous dendritic cell transfection therapy. It consists of a system of five nonlinear ordinary differential equations which define the rates of change for the following key immune cell populations: the tumor-specific CD4 T helper cells, the tumor-specific CD8 T cells or CTLs cytotoxic cells, the cancer cells that expose the tumor-associated antigens or TAAs, the mature dendritic cells loaded with the TAAs, and the IL-2 secreted by the tumor-specific CD4 T helper cells and responsible for T cell growth. We show how to globally analyze the sensitivity of this complex system by means of several graphical objects: sensitivity heat map, singular spectrum plot, and parameter sensitivity spectrum.
3
Wang, Haiping y Ping-Chih Ho. "Abstract A223: CD36-mediated metabolic adaptation guides regulatory T-cells in tumors". En Abstracts: Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; September 30 - October 3, 2018; New York, NY. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/2326-6074.cricimteatiaacr18-a223.
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Von Gerichten, Johanna, Annette Holland, Barbara Fielding, Elizabeth Miles y Graham Burdge. "α-Linolenic acid metabolism in human CD3+ T cells favours oxylipin production over polyunsaturated fatty acid synthesis". En 2022 AOCS Annual Meeting & Expo. American Oil Chemists' Society (AOCS), 2022. http://dx.doi.org/10.21748/asgv6871.
Resumen
The essential dietary fatty acid α-linolenic acid (ALA) can be converted into anti-inflammatory 18 carbon oxylipins or into longer chain n€‘3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The partitioning of ALA between these alternative metabolic fates is not understood. To address this, peripheral blood CD3+ T cells from healthy volunteers (18-30 years; n=10) were cultured for 48h, with or without concanavalin A (10µg/ml) in 10% (v/v) pooled donor plasma with low ALA (20 µM) or high ALA (40 µM) concentrations (1:10 [13C]€‘labelled/unlabelled). [13C]ALA metabolites were detected either by GC-isotope ratio mass spectrometry for intracellular PUFA or by LC-MS/MS for oxylipins in cell culture supernatant. The ratio of the labelled metabolites hydroxyoctatrienoic acid ([13C]HOTrE) and dihydroxyoctadecaenoic acid ([13C]DiHODE) to [13C]ALA were 1.8±0.2 / 7.2±1.1 and 0.9±0.2 / 4.3±0.6 for low / high ALA, respectively, compared to the eicosatrienoic acid ([13C]20:3n€‘3) to [13C]ALA ratio of 0.002±0.0001 / 0.02±0.003 in stimulated T cells. Results from unstimulated cells were similar. Furthermore, oxylipins from all PUFA precursors were analysed in the culture supernatant of the T cells. The ratio of oxylipin concentrations in high compared to low ALA cultures was 1.4±0.1 for EPA-derived dihydroxyeicosatetraenoic acid (DiHETE), 5.6±0.9 for DHA-derived dihydroxydocosapentaenoic acid (DiHDPE), 7.9±2.7 for resolvin RvE1 and 2.0±0.3 for resolvin RvD1. The total oxylipin profile was not altered significantly by mitogen stimulation. These findings show that ALA is used primarily by T cells for constitutive production of anti-inflammatory lipid mediators rather than synthesis of longer chain PUFA. Further, ALA addition changes the secreted oxylipins towards a less-inflammatory profile. This has implications for understanding the effects of dietary PUFA on immune function.
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Chmielewski, Jeffrey P., Frances Wheeler, Scott Cramer, Shi Lihong, Joseph Sirintrapun y Steven J. Kridel. "Abstract A33: CD38 and Nampt regulate tumor cell metabolism through modulation of NAD+". En Abstracts: AACR Special Conference: Metabolism and Cancer; June 7-10, 2015; Bellevue, WA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1557-3125.metca15-a33.
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Tamada, Mayumi, Makoto Suematsu y Hideyuki Saya. "Abstract 5424: CD44-mediated glucose metabolism affects ROS level and drug sensitivity in glycolytic cancer cells." En Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-5424.
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Iwata, S., K. Sakata, M. Hajime, M. Zhang, M. Torigoe, N. Ohkubo, S. Nakayamada y Y. Tanaka. "30 Metabolic reprogramming in cd4+cd28-cxcr3intt-bethi cells and its relevance to pathogenesis in patients with sle". En LUPUS 2017 & ACA 2017, (12th International Congress on SLE &, 7th Asian Congress on Autoimmunity). Lupus Foundation of America, 2017. http://dx.doi.org/10.1136/lupus-2017-000215.30.
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Zhou, Gang, Tsadik Habtetsion y Zhi-Chun Ding. "Abstract 1533: CD4+ T cells reprogram tumor metabolism and drive oxidative stress-induced tumor destruction". En Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-1533.
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Zhou, Gang, Tsadik Habetesion y Zhi-Chun Ding. "Abstract A56: Alteration of tumor metabolism by antitumor CD4+ T cells leads to tumor rejection". En Abstracts: AACR Special Conference on Tumor Immunology and Immunotherapy; November 27-30, 2018; Miami Beach, FL. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/2326-6074.tumimm18-a56.
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Evans, William, Jazmine Eccles y William Baldwin. "Changes in Energy Metabolism Induced by PFOS and Dietary Oxylipins". En 2022 AOCS Annual Meeting & Expo. American Oil Chemists' Society (AOCS), 2022. http://dx.doi.org/10.21748/jnpe5541.
Resumen
CYP2B6 is a drug metabolizing cytochrome P450 (CYP) that has anti-obesity properties, but also increases non-alcoholic fatty liver disease (NAFLD) in hCYP2B6-transgenic mice compared to Cyp2b-null mice. hCYP2B6-transgenic mice are also more susceptible to perfluorooctane sulfonic acid (PFOS) toxicity, a lipid-like toxicant used in stains, varnishes and firefighting foams that increase NAFLD. Our recent research demonstrates that CYP2B6 metabolizes dietary polyunsaturated fatty acids into the oxylipins, 9-HODE and 9-HOTre, which are strong peroxisome proliferator activated receptor alpha (PPARa) agonists and weak PPARg agonists. The purpose of our studies is to better understand the mechanisms behind PFOS and oxylipin-mediated hepatic steatosis. To test whether PFOS, 9-HODE or 9-HOTrE alter mitochondrial metabolism, Seahorse Mitostress assays were performed using HepG2 cells treated with 0.2, 1 and 5mM PFOS, 9-HODE and 9-HOTrE for 24 hours (n=5). Both PFOS and 9-HOTrE increased spare respiratory capacity in a concentration-dependent manner with lesser effects by 9-HODE. qPCR was performed following exposure of HepG2 cells to 1 and 5 mM of each compound to investigate changes in gene expression that may explain alterations in mitochondrial respiration or hepatic steatosis. PFOS repressed expression of ANGPTL4, a biomarker of PPARgactivation. 9-HODE induced CD36 and FASN expression, genes involved in fatty acid uptake and synthesis. 9-HOTrE induced SREBF1 and Cpt1a expression, genes involved in sterol synthesis and fatty acid transport into the mitochondria and may partially explain the increase in SRC. Thus, based on current results, PFOS is associated with reduced transport of lipids from the liver and 9-HODE increases lipid uptake; both would increase steatosis through different mechanisms. 9-HOTre may increase metabolism and therefore reduce steatosis.