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1.
EBioMedicine ; 103: 105127, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38677183

RESUMO

BACKGROUND: Obesity drives maladaptive changes in the white adipose tissue (WAT) which can progressively cause insulin resistance, type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated liver disease (MASLD). Obesity-mediated loss of WAT homeostasis can trigger liver steatosis through dysregulated lipid pathways such as those related to polyunsaturated fatty acid (PUFA)-derived oxylipins. However, the exact relationship between oxylipins and metabolic syndrome remains elusive and cross-tissue dynamics of oxylipins are ill-defined. METHODS: We quantified PUFA-related oxylipin species in the omental WAT, liver biopsies and plasma of 88 patients undergoing bariatric surgery (female N = 79) and 9 patients (female N = 4) undergoing upper gastrointestinal surgery, using UPLC-MS/MS. We integrated oxylipin abundance with WAT phenotypes (adipogenesis, adipocyte hypertrophy, macrophage infiltration, type I and VI collagen remodelling) and the severity of MASLD (steatosis, inflammation, fibrosis) quantified in each biopsy. The integrative analysis was subjected to (i) adjustment for known risk factors and, (ii) control for potential drug-effects through UPLC-MS/MS analysis of metformin-treated fat explants ex vivo. FINDINGS: We reveal a generalized down-regulation of cytochrome P450 (CYP)-derived diols during obesity conserved between the WAT and plasma. Notably, epoxide:diol ratio, indicative of soluble epoxide hydrolyse (sEH) activity, increases with WAT inflammation/fibrosis, hepatic steatosis and T2DM. Increased 12,13-EpOME:DiHOME in WAT and liver is a marker of worsening metabolic syndrome in patients with obesity. INTERPRETATION: These findings suggest a dampened sEH activity and a possible role of fatty acid diols during metabolic syndrome in major metabolic organs such as WAT and liver. They also have implications in view of the clinical trials based on sEH inhibition for metabolic syndrome. FUNDING: Wellcome Trust (PS3431_WMIH); Duke-NUS (Intramural Goh Cardiovascular Research Award (Duke-NUS-GCR/2022/0020); National Medical Research Council (OFLCG22may-0011); National Institute of Environmental Health Sciences (Z01 ES025034); NIHR Imperial Biomedical Research Centre.


Assuntos
Tecido Adiposo Branco , Fígado Gorduroso , Obesidade , Oxilipinas , Humanos , Obesidade/metabolismo , Obesidade/complicações , Feminino , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/etiologia , Masculino , Oxilipinas/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Pessoa de Meia-Idade , Adulto , Inflamação/metabolismo , Inflamação/patologia , Fígado/metabolismo , Fígado/patologia , Biomarcadores , Espectrometria de Massas em Tandem
2.
EMBO Rep ; 24(3): e56310, 2023 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-36597777

RESUMO

Macrophages undergo plasma membrane fusion and cell multinucleation to form multinucleated giant cells (MGCs) such as osteoclasts in bone, Langhans giant cells (LGCs) as part of granulomas or foreign-body giant cells (FBGCs) in reaction to exogenous material. How multinucleation per se contributes to functional specialization of mature mononuclear macrophages remains poorly understood in humans. Here, we integrate comparative transcriptomics with functional assays in purified mature mononuclear and multinucleated human osteoclasts, LGCs and FBGCs. Strikingly, in all three types of MGCs, multinucleation causes a pronounced downregulation of macrophage identity. We show enhanced lysosome-mediated intracellular iron homeostasis promoting MGC formation. The transition from mononuclear to multinuclear state is accompanied by cell specialization specific to each polykaryon. Enhanced phagocytic and mitochondrial function associate with FBGCs and osteoclasts, respectively. Moreover, human LGCs preferentially express B7-H3 (CD276) and can form granuloma-like clusters in vitro, suggesting that their multinucleation potentiates T cell activation. These findings demonstrate how cell-cell fusion and multinucleation reset human macrophage identity as part of an advanced maturation step that confers MGC-specific functionality.


Assuntos
Macrófagos , Osteoclastos , Humanos , Macrófagos/metabolismo , Osteoclastos/metabolismo , Osso e Ossos , Células Gigantes , Antígenos B7/metabolismo
3.
Front Immunol ; 13: 926220, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844525

RESUMO

Toll-like receptor 4 (TLR4)-mediated changes in macrophages reshape intracellular lipid pools to coordinate an effective innate immune response. Although this has been previously well-studied in different model systems, it remains incompletely understood in primary human macrophages. Here we report time-dependent lipidomic and transcriptomic responses to lipopolysaccharide (LPS) in primary human macrophages from healthy donors. We grouped the variation of ~200 individual lipid species measured by LC-MS/MS into eight temporal clusters. Among all other lipids, glycosphingolipids (glycoSP) and cholesteryl esters (CE) showed a sharp increase during the resolution phase (between 8h or 16h post LPS). GlycoSP, belonging to the globoside family (Gb3 and Gb4), showed the greatest inter-individual variability among all lipids quantified. Integrative network analysis between GlycoSP/CE levels and genome-wide transcripts, identified Gb4 d18:1/16:0 and CE 20:4 association with subnetworks enriched for T cell receptor signaling (PDCD1, CD86, PTPRC, CD247, IFNG) and DC-SIGN signaling (RAF1, CD209), respectively. Our findings reveal Gb3 and Gb4 globosides as sphingolipids associated with the resolution phase of inflammatory response in human macrophages.


Assuntos
Globosídeos , Lipopolissacarídeos , Macrófagos , Cromatografia Líquida , Humanos , Macrófagos/imunologia , Espectrometria de Massas em Tandem
4.
Br J Pharmacol ; 179(9): 1874-1886, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-33665823

RESUMO

BACKGROUND AND PURPOSE: Cardiac glycosides inhibit Na+ /K+ -ATPase and are used to treat heart failure and arrhythmias. They can induce inflammasome activation and pyroptosis in macrophages, suggesting cytotoxicity, which remains to be elucidated in human tissues. EXPERIMENTAL APPROACH: To determine the cell-type specificity of this cytotoxicity, we used human monocyte-derived macrophages and non-adherent peripheral blood cells from healthy donors, plus omental white adipose tissue, stromal vascular fraction-derived pre-adipocytes and adipocytes from obese patients undergoing bariatric surgery. All these cells/tissues were treated with nanomolar concentrations of ouabain (50, 100, 500 nM) to investigate the level of cytotoxicity and the mechanisms leading to cell death. In white adipose tissue, we investigated ouabain-mediated cytotoxicity by measuring insulin sensitivity, adipose tissue function and extracellular matrix deposition ex vivo. KEY RESULTS: Ouabain induced cell death through pyroptosis and apoptosis, and was more effective in monocyte-derived macrophages compared to non-adherent peripheral blood mononuclear cell populations. This cytotoxicity is dependent on K+ flux, as ouabain causes intracellular depletion of K+ and accumulation of Na+ and Ca2+ . Consistently, the cell death caused by these ion imbalances can be rescued by addition of potassium chloride to human monocyte-derived macrophages. Remarkably, when white adipose tissue explants from obese patients are cultured with nanomolar concentrations of ouabain, this causes depletion of macrophages, down-regulation of type VI collagen levels and amelioration of insulin sensitivity ex vivo. CONCLUSION AND IMPLICATIONS: The use of nanomolar concentration of cardiac glycosides could be an attractive therapeutic treatment for metabolic syndrome, characterized by pathogenic infiltration and activation of macrophages. LINKED ARTICLES: This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.


Assuntos
Glicosídeos Cardíacos , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Glicosídeos Cardíacos/metabolismo , Glicosídeos Cardíacos/farmacologia , Homeostase , Humanos , Leucócitos Mononucleares/metabolismo , Macrófagos/metabolismo , Ouabaína/metabolismo , Ouabaína/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo
5.
J Cell Sci ; 133(22)2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33148611

RESUMO

In response to environmental stimuli, macrophages change their nutrient consumption and undergo an early metabolic adaptation that progressively shapes their polarization state. During the transient, early phase of pro-inflammatory macrophage activation, an increase in tricarboxylic acid (TCA) cycle activity has been reported, but the relative contribution of branched-chain amino acid (BCAA) leucine remains to be determined. Here, we show that glucose but not glutamine is a major contributor of the increase in TCA cycle metabolites during early macrophage activation in humans. We then show that, although uptake of BCAAs is not altered, their transamination by BCAT1 is increased following 8 h lipopolysaccharide (LPS) stimulation. Of note, leucine is not metabolized to integrate into the TCA cycle in basal or stimulated human macrophages. Surprisingly, the pharmacological inhibition of BCAT1 reduced glucose-derived itaconate, α-ketoglutarate and 2-hydroxyglutarate levels without affecting succinate and citrate levels, indicating a partial inhibition of the TCA cycle. This indirect effect is associated with NRF2 (also known as NFE2L2) activation and anti-oxidant responses. These results suggest a moonlighting role of BCAT1 through redox-mediated control of mitochondrial function during early macrophage activation.


Assuntos
Ativação de Macrófagos , Macrófagos , Mitocôndrias , Transaminases , Ciclo do Ácido Cítrico , Humanos , Leucina/metabolismo , Macrófagos/metabolismo , Mitocôndrias/metabolismo , Transaminases/metabolismo
6.
Cell Rep ; 28(2): 498-511.e5, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31291584

RESUMO

Iron is an essential metal that fine-tunes the innate immune response by regulating macrophage function, but an integrative view of transcriptional and metabolic responses to iron perturbation in macrophages is lacking. Here, we induced acute iron chelation in primary human macrophages and measured their transcriptional and metabolic responses. Acute iron deprivation causes an anti-proliferative Warburg transcriptome, characterized by an ATF4-dependent signature. Iron-deprived human macrophages show an inhibition of oxidative phosphorylation and a concomitant increase in glycolysis, a large increase in glucose-derived citrate pools associated with lipid droplet accumulation, and modest levels of itaconate production. LPS polarization increases the itaconate:succinate ratio and decreases pro-inflammatory cytokine production. In rats, acute iron deprivation reduces the severity of macrophage-dependent crescentic glomerulonephritis by limiting glomerular cell proliferation and inducing lipid accumulation in the renal cortex. These results suggest that acute iron deprivation has in vivo protective effects mediated by an anti-inflammatory immunometabolic switch in macrophages.


Assuntos
Inflamação/tratamento farmacológico , Deficiências de Ferro , Animais , Humanos , Macrófagos/metabolismo , Masculino , Ratos
7.
Ann Rheum Dis ; 77(4): 596-601, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29348297

RESUMO

OBJECTIVES: Several common and rare risk variants have been reported for systemic sclerosis (SSc), but the effector cell(s) mediating the function of these genetic variants remains to be elucidated. While innate immune cells have been proposed as the critical targets to interfere with the disease process underlying SSc, no studies have comprehensively established their effector role. Here we investigated the contribution of monocyte-derived macrophages (MDMs) in mediating genetic susceptibility to SSc. METHODS: We carried out RNA sequencing and genome-wide genotyping in MDMs from 57 patients with SSc and 15 controls. Our differential expression and expression quantitative trait locus (eQTL) analysis in SSc was further integrated with epigenetic, expression and eQTL data from skin, monocytes, neutrophils and lymphocytes. RESULTS: We identified 602 genes upregulated and downregulated in SSc macrophages that were significantly enriched for genes previously implicated in SSc susceptibility (P=5×10-4), and 270 cis-regulated genes in MDMs. Among these, GSDMA was reported to carry an SSc risk variant (rs3894194) regulating expression of neighbouring genes in blood. We show that GSDMA is upregulated in SSc MDMs (P=8.4×10-4) but not in the skin, and is a significant eQTL in SSc macrophages and lipopolysaccharide/interferon gamma (IFNγ)-stimulated monocytes. Furthermore, we identify an SSc macrophage transcriptome signature characterised by upregulation of glycolysis, hypoxia and mTOR signalling and a downregulation of IFNγ response pathways. CONCLUSIONS: Our data further establish the link between macrophages and SSc, and suggest that the contribution of the rs3894194 risk variant to SSc susceptibility can be mediated by GSDMA expression in macrophages.


Assuntos
Predisposição Genética para Doença , Macrófagos/citologia , Proteínas de Neoplasias/genética , Escleroderma Sistêmico/genética , Transcriptoma/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Locos de Características Quantitativas/genética , Fatores de Risco , Escleroderma Sistêmico/patologia , Transdução de Sinais/genética , Pele/metabolismo , Adulto Jovem
8.
Genetics ; 206(2): 1139-1151, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28450461

RESUMO

Crescentic glomerulonephritis (Crgn) is a complex disorder where macrophage activity and infiltration are significant effector causes. In previous linkage studies using the uniquely susceptible Wistar Kyoto (WKY) rat strain, we have identified multiple crescentic glomerulonephritis QTL (Crgn) and positionally cloned genes underlying Crgn1 and Crgn2, which accounted for 40% of total variance in glomerular inflammation. Here, we have generated a backcross (BC) population (n = 166) where Crgn1 and Crgn2 were genetically fixed and found significant linkage to glomerular crescents on chromosome 2 (Crgn8, LOD = 3.8). Fine mapping analysis by integration with genome-wide expression QTLs (eQTLs) from the same BC population identified ceruloplasmin (Cp) as a positional eQTL in macrophages but not in serum. Liquid chromatography-tandem mass spectrometry confirmed Cp as a protein QTL in rat macrophages. WKY macrophages overexpress Cp and its downregulation by RNA interference decreases markers of glomerular proinflammatory macrophage activation. Similarly, short incubation with Cp results in a strain-dependent macrophage polarization in the rat. These results suggest that genetically determined Cp levels can alter susceptibility to Crgn through macrophage function and propose a new role for Cp in early macrophage activation.


Assuntos
Ceruloplasmina/genética , Predisposição Genética para Doença , Glomerulonefrite/genética , Animais , Ceruloplasmina/biossíntese , Mapeamento Cromossômico , Regulação da Expressão Gênica , Ligação Genética , Glomerulonefrite/patologia , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Ratos , Ratos Endogâmicos WKY
9.
J Immunol ; 194(10): 4705-4716, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25840911

RESUMO

Epoxygenases belong to the cytochrome P450 family. They generate epoxyeicosatrienoic acids, which are known to have anti-inflammatory effects, but little is known about their role in macrophage function. By high-throughput sequencing of RNA in primary macrophages derived from rodents and humans, we establish the relative expression of epoxygenases in these cells. Zinc-finger nuclease-mediated targeted gene deletion of the major rat macrophage epoxygenase Cyp2j4 (ortholog of human CYP2J2) resulted in reduced epoxyeicosatrienoic acid synthesis. Cyp2j4(-/-) macrophages have relatively increased peroxisome proliferator-activated receptor-γ levels and show a profibrotic transcriptome, displaying overexpression of a specific subset of genes (260 transcripts) primarily involved in extracellular matrix, with fibronectin being the most abundantly expressed transcript. Fibronectin expression is under the control of epoxygenase activity in human and rat primary macrophages. In keeping with the in vitro findings, Cyp2j4(-/-) rats show upregulation of type I collagen following unilateral ureter obstruction of the kidney, and quantitative proteomics analysis (liquid chromatography-tandem mass spectrometry) showed increased renal type I collagen and fibronectin protein abundance resulting from experimentally induced crescentic glomerulonephritis in these rats. Taken together, these results identify the rat epoxygenase Cyp2j4 as a determinant of a profibrotic macrophage transcriptome that could have implications in various inflammatory conditions, depending on macrophage function.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Fibrose/enzimologia , Fibrose/genética , Macrófagos/enzimologia , Animais , Western Blotting , Cromatografia Líquida , Citocromo P-450 CYP2J2 , Família 2 do Citocromo P450 , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Técnicas de Inativação de Genes , Glomerulonefrite/enzimologia , Glomerulonefrite/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Interferência de RNA , Ratos , Ratos Endogâmicos WKY , Reação em Cadeia da Polimerase em Tempo Real , Espectrometria de Massas em Tandem , Transcriptoma
10.
Mol Cell Proteomics ; 14(3): 484-98, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25532521

RESUMO

Macrophage multinucleation (MM) is essential for various biological processes such as osteoclast-mediated bone resorption and multinucleated giant cell-associated inflammatory reactions. Here we study the molecular pathways underlying multinucleation in the rat through an integrative approach combining MS-based quantitative phosphoproteomics (LC-MS/MS) and transcriptome (high-throughput RNA-sequencing) to identify new regulators of MM. We show that a strong metabolic shift toward HIF1-mediated glycolysis occurs at transcriptomic level during MM, together with modifications in phosphorylation of over 50 proteins including several ARF GTPase activators and polyphosphate inositol phosphatases. We use shortest-path analysis to link differential phosphorylation with the transcriptomic reprogramming of macrophages and identify LRRFIP1, SMARCA4, and DNMT1 as novel regulators of MM. We experimentally validate these predictions by showing that knock-down of these latter reduce macrophage multinucleation. These results provide a new framework for the combined analysis of transcriptional and post-translational changes during macrophage multinucleation, prioritizing essential genes, and revealing the sequential events leading to the multinucleation of macrophages.


Assuntos
Núcleo Celular/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA Helicases/metabolismo , Perfilação da Expressão Gênica/métodos , Macrófagos/metabolismo , Proteínas Nucleares/metabolismo , Proteoma/análise , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Animais , Células Cultivadas , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/genética , DNA Helicases/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteínas Nucleares/genética , Fosforilação , Proteínas de Ligação a RNA/genética , Ratos , Ratos Endogâmicos Lew , Ratos Endogâmicos WKY , Análise de Sequência de RNA/métodos , Fatores de Transcrição/genética
11.
Cell Rep ; 8(4): 1210-24, 2014 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-25131209

RESUMO

Macrophages can fuse to form osteoclasts in bone or multinucleate giant cells (MGCs) as part of the immune response. We use a systems genetics approach in rat macrophages to unravel their genetic determinants of multinucleation and investigate their role in both bone homeostasis and inflammatory disease. We identify a trans-regulated gene network associated with macrophage multinucleation and Kcnn4 as being the most significantly trans-regulated gene in the network and induced at the onset of fusion. Kcnn4 is required for osteoclast and MGC formation in rodents and humans. Genetic deletion of Kcnn4 reduces macrophage multinucleation through modulation of Ca(2+) signaling, increases bone mass, and improves clinical outcome in arthritis. Pharmacological blockade of Kcnn4 reduces experimental glomerulonephritis. Our data implicate Kcnn4 in macrophage multinucleation, identifying it as a potential therapeutic target for inhibition of bone resorption and chronic inflammation.


Assuntos
Artrite/metabolismo , Osso e Ossos/metabolismo , Núcleo Celular/fisiologia , Glomerulonefrite/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/fisiologia , Macrófagos/metabolismo , Animais , Artrite/patologia , Reabsorção Óssea/metabolismo , Osso e Ossos/imunologia , Sinalização do Cálcio , Células Cultivadas , Redes Reguladoras de Genes , Glomerulonefrite/imunologia , Homeostase , Humanos , Camundongos Knockout , Ratos Endogâmicos Lew , Ratos Endogâmicos WKY , Receptores Imunológicos/metabolismo
12.
Pathobiology ; 74(5): 301-8, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17890897

RESUMO

OBJECTIVE: We attempted to identify novel genes that induce hypoxic cell death to better understand the molecular mechanisms underlying hypoxia-induced cell death. Through this process the GLTSCR2 gene was found. The purpose of this work was to investigate the role of GLTSCR2 in hypoxic cell death pathways. METHODS: This work focuses on an investigation of roles and mechanisms of GLTSCR2 in hypoxic cell death by means of subtractive hybridization, RT-PCR, Western blot, immunocytochemistry, cell death assay, transient gene overexpression, and determination of mitochondrial membrane potential. RESULTS: We found that GLTSCR2 was transcriptionally suppressed by hypoxia, and ectopic expression of GLTSCR2 sensitized cells to hypoxic injury. Interestingly, while the majority of hypoxia-inducible pro-death proteins signal through mitochondrion-dependent pathways, GLTSCR2-overexpressed cells underwent apoptosis in a mitochondrion- and caspase-independent manner. CONCLUSION: Our data categorizes GLTSCR2 as a proapoptotic protein sensitizing cells to hypoxic injury when overexpressed.


Assuntos
Apoptose/fisiologia , Hipóxia Celular/genética , Mitocôndrias/patologia , Transdução de Sinais/fisiologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Western Blotting , Linhagem Celular , Expressão Gênica , Humanos , Imuno-Histoquímica , Potencial da Membrana Mitocondrial/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
Endocrinology ; 147(3): 1357-64, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16322067

RESUMO

Adrenomedullin (AM) participates in a wide range of physiological and pathological processes including vasorelaxation, angiogenesis, cancer promotion, and apoptosis. Recently, it has been reported that AM protects a variety of cells against oxidative stress induced by stressors such as hypoxia, ischemia/reperfusion, and hydrogen peroxide through the phosphatidylinositol 3-kinase (PI3K)-dependent pathway. However, the molecular mechanisms underlying the pathway of cell survival against hypoxic injury are largely unknown. In an effort to investigate the survival mechanism against hypoxic injury, we studied the effects of AM on cellular levels of reactive oxygen species, well-known mediators of cell death after oxidative stress, and the mechanism involved in the regulation of reactive oxygen species levels. Here, we show that AM increases gamma-glutamate-cysteine ligase (gamma-GCL) activity under both hypoxic and normoxic conditions, resulting in an up-regulation of cellular glutathione levels to more than 2-fold higher than basal expression. In addition, we demonstrate that AM induces concentration-dependent expression of the catalytic subunit of gamma-GCL (gamma-GCLC) at the mRNA and protein levels through the activation of the gamma-GCLC promoter fragment sequence from -597 to -320. However, when treated with the PI3K inhibitors, the effects of AM on gamma-GCLC expression were completely abrogated, suggesting that a PI3K pathway linked AM with the transcriptional activation of the gamma-GCLC promoter. Taken together, our data suggests that AM participates in the regulation of cellular redox status via glutathione synthesis. These results may explain, in part, the mechanism by which AM protects cells against oxidative stress.


Assuntos
Glutamato-Cisteína Ligase/metabolismo , Glutationa/metabolismo , Peptídeos/fisiologia , Adrenomedulina , Apoptose , Western Blotting , Morte Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Deleção de Genes , Humanos , Peróxido de Hidrogênio/farmacologia , Hipóxia , Luciferases/metabolismo , Oxirredução , Estresse Oxidativo , Oxigênio/metabolismo , Peptídeos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Regiões Promotoras Genéticas , Estrutura Terciária de Proteína , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Transcrição Gênica , Ativação Transcricional
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