Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.953
Filtrar
1.
Life Sci ; 260: 118077, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32810509

RESUMO

AIMS: Multiple myeloma (MM) is the second hematological plasma cell malignany and sensitive to fingolimod (FTY720), a novel immunosuppressant. Previous study shows FTY720-induced apoptosis and autophagy can cause cell death in MM cells, however, the high death rate cannot fully be explained. The study aims to investigate further mechanism of how FTY720 kills MM cells. MATERIALS AND METHODS: Experiments are performed on 25 human primary cell samples and two MM cell lines by flow cytometry, fluorescence microscopy, and transmission electron microscopy. Expressions of relative factors are tested by qRT-PCR or western blot. KEY FINDINGS: Ferroptosis-specific inhibitors, deferoxamine mesylate (DFOM) and ferropstatin-1 (Fer-1), reverse FTY720-induced cell death in MM cells. Glutathione peroxidase 4 (GPX4) and soluble carrier family 7 member 11 (SLC7A11), key regulators of ferroptosis, are highly expressed in primary MM cells and can be decreased by FTY720 at the mRNA and protein level in MM cells. In addition, FTY720 induces other characteristic changes of ferroptosis. Furthermore, FTY720 can dephosphorylate AMP-activated protein kinase subunit ɑ (AMPKɑ) at the Thr172 site by activating protein phosphatase 2A (PP2A) and reduce the expression of phosphorylated eukaryotic elongation factor 2 (eEF2), finally cause MM cell death. Using LB-100, a PP2A inhibitor, AICAR, an agonist of AMPK, and bafilomycin A1 (Baf-A1), an autophagy inhibitor, we discover that FTY720 induces ferroptosis and autophagy through the PP2A/AMPK pathway, and ferroptosis and autophagy can reinforce each other. SIGNIFICANCE: These results provide a new perspective on the treatment of MM.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Cloridrato de Fingolimode/farmacologia , Mieloma Múltiplo/patologia , Proteína Fosfatase 2/metabolismo , Sistema y+ de Transporte de Aminoácidos/efeitos dos fármacos , Sistema y+ de Transporte de Aminoácidos/fisiologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cicloexilaminas/farmacologia , Desferroxamina/farmacologia , Humanos , Mieloma Múltiplo/tratamento farmacológico , Fenilenodiaminas/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/fisiologia , Transdução de Sinais/efeitos dos fármacos
2.
J Virol ; 94(18)2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32641480

RESUMO

We previously reported that the cellular transcription factor hypoxia-inducible factor 1α (HIF-1α) binds a hypoxia response element (HRE) located within the promoter of Epstein-Barr virus's (EBV's) latent-lytic switch BZLF1 gene, Zp, inducing viral reactivation. In this study, EBV-infected cell lines derived from gastric cancers and Burkitt lymphomas were incubated with HIF-1α-stabilizing drugs: the iron chelator deferoxamine (Desferal [DFO]), a neddylation inhibitor (pevonedistat [MLN-4924]), and a prolyl hydroxylase inhibitor (roxadustat [FG-4592]). DFO and MLN-4924, but not FG-4592, induced accumulation of both lytic EBV proteins and phosphorylated p53 in cell lines that contain a wild-type p53 gene. FG-4592 also failed to activate transcription from Zp in a reporter assay despite inducing accumulation of HIF-1α and transcription from another HRE-containing promoter. Unexpectedly, DFO failed to induce EBV reactivation in cell lines that express mutant or no p53 or when p53 expression was knocked down with short hairpin RNAs (shRNAs). Likewise, HIF-1α failed to activate transcription from Zp when p53 was knocked out by CRISPR-Cas9. Importantly, DFO induced binding of p53 as well as HIF-1α to Zp in chromatin immunoprecipitation (ChIP) assays, but only when the HRE was present. Nutlin-3, a drug known to induce accumulation of phosphorylated p53, synergized with DFO and MLN-4924 in inducing EBV reactivation. Conversely, KU-55933, a drug that inhibits ataxia telangiectasia mutated, thereby preventing p53 phosphorylation, inhibited DFO-induced EBV reactivation. Lastly, activation of Zp transcription by DFO and MLN-4924 mapped to its HRE. Thus, we conclude that induction of BZLF1 gene expression by HIF-1α requires phosphorylated, wild-type p53 as a coactivator, with HIF-1α binding recruiting p53 to Zp.IMPORTANCE EBV, a human herpesvirus, is latently present in most nasopharyngeal carcinomas, Burkitt lymphomas, and some gastric cancers. To develop a lytic-induction therapy for treating patients with EBV-associated cancers, we need a way to efficiently reactivate EBV into lytic replication. EBV's BZLF1 gene product, Zta, usually controls this reactivation switch. We previously showed that HIF-1α binds the BZLF1 gene promoter, inducing Zta synthesis, and HIF-1α-stabilizing drugs can induce EBV reactivation. In this study, we determined which EBV-positive cell lines are reactivated by classes of HIF-1α-stabilizing drugs. We found, unexpectedly, that HIF-1α-stabilizing drugs only induce reactivation when they also induce accumulation of phosphorylated, wild-type p53. Fortunately, p53 phosphorylation can also be provided by drugs such as nutlin-3, leading to synergistic reactivation of EBV. These findings indicate that some HIF-1α-stabilizing drugs may be helpful as part of a lytic-induction therapy for treating patients with EBV-positive malignancies that contain wild-type p53.


Assuntos
Herpesvirus Humano 4/genética , Interações Hospedeiro-Patógeno/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Transativadores/genética , Proteína Supressora de Tumor p53/genética , Linhagem Celular Tumoral , Ciclopentanos/farmacologia , Desferroxamina/farmacologia , Inibidores Enzimáticos/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Regulação da Expressão Gênica , Glicina/análogos & derivados , Glicina/farmacologia , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/crescimento & desenvolvimento , Herpesvirus Humano 4/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/agonistas , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imidazóis/farmacologia , Quelantes de Ferro/farmacologia , Isoquinolinas/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/virologia , Morfolinas/farmacologia , Piperazinas/farmacologia , Inibidores de Prolil-Hidrolase/farmacologia , Regiões Promotoras Genéticas , Ligação Proteica/efeitos dos fármacos , Pirimidinas/farmacologia , Pironas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Elementos de Resposta , Transdução de Sinais , Transativadores/metabolismo , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Ativação Viral/efeitos dos fármacos
4.
Am J Respir Crit Care Med ; 202(7): 983-995, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32515984

RESUMO

Rationale: Endothelial injury may provoke emphysema, but molecular pathways of disease development require further discernment. Emphysematous lungs exhibit decreased expression of HIF-2α (hypoxia-inducible factor-2α)-regulated genes, and tobacco smoke decreases pulmonary HIF-2α concentrations. These findings suggest that decreased HIF-2α expression is important in the development of emphysema.Objectives: The objective of this study was to evaluate the roles of endothelial-cell (EC) HIF-2α in the pathogenesis of emphysema in mice.Methods: Mouse lungs were examined for emphysema after either the loss or the overexpression of EC Hif-2α. In addition, SU5416, a VEGFR2 inhibitor, was used to induce emphysema. Lungs were evaluated for HGF (hepatocyte growth factor), a protein involved in alveolar development and homeostasis. Lungs from patients with emphysema were measured for endothelial HIF-2α expression.Measurements and Main Results: EC Hif-2α deletion resulted in emphysema in association with fewer ECs and pericytes. After SU5416 exposure, EC Hif-2α-knockout mice developed more severe emphysema, whereas EC Hif-2α-overexpressing mice were protected. EC Hif-2α-knockout mice demonstrated lower levels of HGF. Human emphysema lung samples exhibited reduced EC HIF-2α expression.Conclusions: Here, we demonstrate a unique protective role for pulmonary endothelial HIF-2α and how decreased expression of this endogenous factor causes emphysema; its pivotal protective function is suggested by its ability to overcome VEGF antagonism. HIF-2α may maintain alveolar architecture by promoting vascular survival and associated HGF production. In summary, HIF-2α may be a key endogenous factor that prevents the development of emphysema, and its upregulation has the potential to foster lung health in at-risk patients.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células Endoteliais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Pulmão/metabolismo , Enfisema Pulmonar/genética , Inibidores da Angiogênese/toxicidade , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Desferroxamina/farmacologia , Modelos Animais de Doenças , Células Endoteliais/patologia , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Indóis/toxicidade , Quelantes de Ferro/farmacologia , Pulmão/irrigação sanguínea , Pulmão/citologia , Pulmão/efeitos dos fármacos , Camundongos , Camundongos Knockout , Microvasos , Pericitos/metabolismo , Circulação Pulmonar , Doença Pulmonar Obstrutiva Crônica/metabolismo , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/patologia , Pirróis/toxicidade , Fumaça/efeitos adversos
5.
Toxicology ; 440: 152489, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32416107

RESUMO

Busulfan is commonly used for cancer chemotherapy, nevertheless it cause male infertility via damaging the germ cells. Therefore, the underlying mechanism should be explored. In the present study, we demonstrated for the first time that ferroptosis was involved in busulfan-induced oligospermia in mice. Mice were given testicular injection of busulfan on both sides at the dose of 4 mg/kg body weight to establish the model of oligospermia. Four weeks later, the results showed that busulfan-treated mice exhibited decreased sperm concentration and motility, along with features of typical ferroptosis in testis, such as increased malondialdehyde (MDA) content and prostaglandin-endoperoxide synthase (PTGS2) mRNA expression, and decreased NADPH content. Inhibition of ferroptosis by ferrostatin-1 (Fer-1) or deferoxamine (DFO) partially alleviated busulfan-induced oligospermia in mice. Additionally, we also revealed that busulfan treatment induced spermatogenic cells ferroptosis by down-regulating nuclear factor-E2-related factor 2 (Nrf2) and glutathione peroxidase 4 (GPX4) expressions, and decreasing iron efflux through reduction of ferroportin 1 (FPN1) expression. Fer-1 or DFO obviously reversed busulfan-induced ferroptosis by increasing Nrf2, GPX4 and FPN1 expressions. Furthermore, after activation of Nrf2 by sulforaphane, sperm concentration and motility in busulfan-treated mice increased, accompanied by enhanced expressions of GPX4 and FPN1. These findings imply that busulfan-induced ferroptosis might be mediated via inhibition of Nrf2-GPX4 (FPN1) signaling pathway, and highlight that targeting ferroptosis serves as a potential strategy for prevention of busulfan-induced damage and male infertility.


Assuntos
Antineoplásicos Alquilantes/toxicidade , Bussulfano/toxicidade , Ferroptose/efeitos dos fármacos , Oligospermia/induzido quimicamente , Oligospermia/prevenção & controle , Animais , Proteínas de Transporte de Cátions/antagonistas & inibidores , Cicloexilaminas/farmacologia , Ciclo-Oxigenase 2/efeitos dos fármacos , Desferroxamina/farmacologia , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Oligospermia/patologia , Fenilenodiaminas/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , Motilidade Espermática/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/patologia
6.
J Plast Reconstr Aesthet Surg ; 73(9): 1738-1746, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32418841

RESUMO

INTRODUCTION: Diabetes mellitus remains a significant public health problem, consuming over $400 billion every year. While Diabetes itself can be controlled effectively, impaired wound healing still occurs frequently in diabetic patients. Adipose-derived mesenchymal stem cells (ASCs) provide an especially appealing source for diabetic wound cell therapy. With autologous approaches, the functionality of ASCs largely underlie patient-dependent factors. Diabetes is a significant diminishing factor of MSC functionality. Here, we explore a novel strategy to enhance diabetic ASC functionality through deferoxamine (DFO) preconditioning. MATERIAL AND METHODS: Human diabetic ASCs have been preconditioned with 150 µM and 300 µM DFO in vitro and analyzed for regenerative cytokine expression. Murine diabetic ASCs have been preconditioned with 150 µM DFO examined for their in vitro and in vivo vasculogenic capacity in Matrigel assays. Additionally, a diabetic murine wound healing model has been performed to assess the regenerative capacity of preconditioned cells. RESULTS: DFO preconditioning enhances the VEGF expression of human diabetic ASCs through hypoxia-inducible factor upregulation. The use of 150 µM of DFO was an optimal concentration to induce regenerative effects. The vasculogenic potential of preconditioned diabetic ASCs is significantly greater in vitro and in vivo. The enhanced regenerative functionality of DFO preconditioned ASCs was further confirmed in a model of diabetic murine wound healing. CONCLUSION: These results demonstrate that DFO significantly induced the upregulation of hypoxia-inducible factor-1 alpha and VEGF in diabetic ASCs and showed efficacy in the treatment of diabetes-associated deficits of wound healing. The favorable status of DFO as a small molecule drug approved since decades for multiple indications makes this approach highly translatable.


Assuntos
Desferroxamina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Células-Tronco Mesenquimais/metabolismo , Regeneração/efeitos dos fármacos , Adulto , Idoso , Animais , Células Cultivadas , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Pessoa de Meia-Idade , Neovascularização Fisiológica/efeitos dos fármacos , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/efeitos dos fármacos
7.
Sci Rep ; 10(1): 1127, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980706

RESUMO

The response of cancer cells to hypoxic conditions found within the interior of a tumor mass is mediated through the hypoxia inducible factor (HIF) cascade and is thought to promote metastasis. However, given their distant proximity from blood vessels as compared to normoxic cells at the vascularised tumor periphery, it is uncertain if these cells can migrate through the tumor mass to gain access. Hypoxia was simulated by exposure to cobalt chloride or deferoxamine in normal (MCF10A) and cancerous [estrogen receptor (ER)-ve (pII), and ER +ve (YS1.2/ EII)] cells. In this report, HIF1α expression and localization was measured using western blotting, ELISA, and immunofluorescence, cell proliferation by MTT assay, motility and invasion by wound healing, live cell imaging, matrigel and co-culture in chambered slides. We found that the expression and nuclear translocation of HIF1α was significantly elevated by hypoxia, which inhibited cell proliferation, but significantly increased motility of pII cells and their penetration into and through a dense layer of adjacent EII cells, as well as their selective emergence out of a co-culture. These data suggest that endocrine resistant pII cancer cells, having undergone epithelial to mesenchymal transition are able to penetrate through other cell layers, with possible enhancement in response to hypoxia.


Assuntos
Hipóxia Celular , Transição Epitelial-Mesenquimal , Células MCF-7/fisiologia , Membrana Basal , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Cobalto/farmacologia , Técnicas de Cocultura , Desferroxamina/farmacologia , Estrogênios , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células MCF-7/efeitos dos fármacos , Invasividade Neoplásica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias Hormônio-Dependentes , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Receptores Estrogênicos/análise , Sefarose
8.
Am J Physiol Heart Circ Physiol ; 318(3): H508-H518, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31975626

RESUMO

Cigarette smoking is a major risk factor for aortic aneurysm and dissection; however, no causative link between smoking and these aortic disorders has been proven. In the present study, we investigated the mechanism by which cigarette smoke affects vascular wall cells and found that cigarette smoke extract (CSE) induced a novel form of regulated cell death termed ferroptosis in vascular smooth muscle cells (VSMCs). CSE markedly induced cell death in A7r5 cells and primary rat VSMCs, but not in endothelial cells, which was completely inhibited by specific ferroptosis inhibitors [ferrostatin-1 (Fer-1) and Liproxstatin-1] and an iron chelator (deferoxamine). CSE-induced VSMC death was partially inhibited by a GSH precursor (N-acetyl cysteine) and an NADPH oxidase inhibitor [diphenyleneiodonium chloride (DPI)], but not by inhibitors of pan-caspases (Z-VAD), caspase-1 (Z-YVAD), or necroptosis (necrostatin-1). CSE also upregulated IL-1ß, IL-6, TNF-α, matrix metalloproteinase (MMP)-2, MMP-9, and TIMP-1 (tissue inhibitor of metalloproteinase)in A7r5 cells, which was inhibited by Fer-1. Furthermore, CSE induced the upregulation of Ptgs2 mRNA, lipid peroxidation, and intracellular GSH depletion, which are key features of ferroptosis. VSMC ferroptosis was induced by acrolein and methyl vinyl ketone, major constituents of CSE. Furthermore, CSE caused medial VSMC loss in ex vivo aortas. Electron microscopy analysis showed mitochondrial damage and fragmentation in medial VSMCs of CSE-treated aortas. All of these manifestations were partially restored by Fer-1. These findings demonstrate that ferroptosis is responsible for CSE-induced VSMC death and suggest that ferroptosis is a potential therapeutic target for preventing aortic aneurysm and dissection.NEW & NOTEWORTHY Cigarette smoke extract (CSE)-induced cell death in rat vascular smooth muscle cells (VSMCs) was completely inhibited by specific ferroptosis inhibitors and an iron chelator. CSE also induced the upregulation of Ptgs2 mRNA, lipid peroxidation, and intracellular GSH depletion, which are key features of ferroptosis. CSE caused medial VSMC loss in ex vivo aortas. These findings demonstrate that ferroptosis is responsible for CSE-induced VSMC death.


Assuntos
Ferroptose/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fumaça , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Cicloexilaminas/farmacologia , Desferroxamina/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , NADPH Oxidases/metabolismo , Fenilenodiaminas/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Sideróforos/farmacologia , Compostos de Espiro/farmacologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo
9.
PLoS One ; 15(1): e0223814, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31910217

RESUMO

INTRODUCTION: Chimeric antigen receptor (CAR) T-cells have been recently developed and are producing impressive outcomes in patients with hematologic malignancies. However, there is no standardized method for cell trafficking and in vivo CAR T-cell monitoring. We assessed the feasibility of real-time in vivo 89Zr-p-Isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS, DFO) labeled CAR T-cell trafficking using positron emission tomography (PET). RESULTS: The 89Zr-DFO radiolabeling efficiency of Jurkat/CAR and human peripheral blood mononuclear cells (hPBMC)/CAR T-cells was 70%-79%, and cell radiolabeling activity was 98.1-103.6 kBq/106 cells. Cell viability after radiolabeling was >95%. Cell proliferation was not significantly different during the early period after radiolabeling, compared with unlabeled cells; however, the proliferative capacity decreased over time (day 7 after labeling). IL-2 or IFN-γ secretion was not significantly different between unlabeled and labeled CAR T-cells. PET/magnetic resonance imaging in the xenograft model showed that most of the 89Zr-DFO-labeled Jurkat/CAR T-cells were distributed in the lung (24.4% ± 3.4%ID) and liver (22.9% ± 5.6%ID) by one hour after injection. The cells gradually migrated from the lung to the liver and spleen by day 1, and remained stable in these sites until day 7 (on day 7: lung 3.9% ± 0.3%ID, liver 36.4% ± 2.7%ID, spleen 1.4% ± 0.3%ID). No significant accumulation of labeled cells was identified in tumors. A similar pattern was observed in ex vivo biodistributions on day 7 (lung 3.0% ± 1.0%ID, liver 19.8% ± 2.2%ID, spleen 2.3% ± 1.7%ID). 89Zr-DFO-labeled hPBMC/CAR T-cells showed a similar distribution, compared with Jurkat/CAR T-cells, on serial PET images. CAR T cell distribution was cross-confirmed by flow cytometry, Alu polymerase chain reaction, and immunohistochemistry. CONCLUSION: Real-time in vivo cell trafficking is feasible using PET imaging of 89Zr-DFO-labeled CAR T-cells. This can be used to investigate cellular kinetics, initial in vivo biodistribution, and safety profiles in future CAR T-cell development.


Assuntos
Desferroxamina/análogos & derivados , Isotiocianatos/farmacologia , Radioisótopos/farmacologia , Receptores de Antígenos de Linfócitos T/isolamento & purificação , Receptores de Antígenos Quiméricos/isolamento & purificação , Zircônio/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desferroxamina/farmacologia , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/patologia , Humanos , Imunoconjugados/farmacologia , Marcação por Isótopo , Células Jurkat , Leucócitos Mononucleares/química , Leucócitos Mononucleares/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Radioisótopos/química , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/química , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/química , Linfócitos T/imunologia , Distribuição Tecidual
10.
World Neurosurg ; 137: e9-e17, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31518742

RESUMO

BACKGROUND: With little information available on axonal and myelin damage surrounding the contusion, the study of spinal cord injury (SCI) so far has focused on neuronal death. In this study, we investigated the role of iron overload in long-term oligodendroglia death and progressive white matter damage to rats after SCI using the iron chelator, deferoxamine (DFX). METHODS: Female Sprague-Dawley rats received either a contusion at T10 or sham-surgery. The rats were treated with DFX or vehicle. All rats were evaluated in behavioral assessments and then euthanized at different time points. Spinal cords were analyzed by diaminobenzidine-enhanced Perls' staining, non-heme iron measurements, Western blotting, immunohistochemistry, and transmission electron microscopy. RESULTS: Iron accumulation after SCI resulted in the upregulation of transferrin receptor and divalent metal transporter 1, which exacerbated the intracellular iron overload. DFX treatment reduced iron overload-induced delayed oligodendrocyte death (e.g., 21 days: 47.12 ± 10.5 vs. 20.02 ± 9.4 x 103/mm2 in the vehicle-treated group, n = 4, P < 0.05). After SCI, the markers of axonal damage and demyelination were increased in white matter in the vehicle-treated group compared with the DFX-treated group (P < 0.05). CONCLUSIONS: Iron overload plays an important role in progressive white matter damage after SCI. DFX may be an effective treatment for white matter damage after SCI.


Assuntos
Desferroxamina/uso terapêutico , Oligodendroglia/efeitos dos fármacos , Sideróforos/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Substância Branca/efeitos dos fármacos , Animais , Desferroxamina/farmacologia , Modelos Animais de Doenças , Feminino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Ratos , Ratos Sprague-Dawley , Receptores da Transferrina/metabolismo , Sideróforos/farmacologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Substância Branca/metabolismo , Substância Branca/patologia
11.
J Trace Elem Med Biol ; 57: 126406, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31570251

RESUMO

BACKGROUND: Intracellular iron involves in Fenton's reaction-mediated Hydroxyl radical (OH·) generation by reacting with the neurotoxic agent 6-Hydroxydopamine (6-OHDA) autoxidation derivative Hydrogen Peroxide (H2O2). Several studies have been conducted so far on the neuroprotective activities of the iron chelator Deferoxamine (DFO) but little or no clear evidence about the underlying cellular mechanism is available. METHODS: The present study was conducted on Human neuroblastoma cell line SH-SY5Y in the absence or presence of 6-OHDA or H2O2 and / or DFO. Following incubation, cell viability assay, intracellular reactive oxygen species (ROS) determination, flow cytometric quantification of apoptotic cells followed by nuclear staining, intracellular tracking of transfected fusion construct of microtubule-associated protein 1B-light chain with Green fluorescent protein - Red fluorescent protein (LC3B-GFP-RFP reporters) and immunocytochemistry of intracellular Cathepsin protein by confocal microscopy, were conducted. In addition, western blotting was carried out to detect expressions of apoptotic and autophagy related proteins. RESULTS: This study confirmed the neuroprotective potential of DFO by inhibiting 6-OHDA-mediated cell death and ROS generation. Reduced percentage of apoptotic cells and appearance of altered nuclei architecture followed by a reduced expression of cleaved PARP (Poly-ADP-ribose Polymerase) and cleaved Caspase-3 were observed upon DFO treatment against 6-OHDA, and as well as against H2O2 in SH-SY5Y cell lines. Besides, DFO induced the intracellular autophagolysosome formation (red puncta) rather than autophagosome (yellow puncta) only. Thereafter it was observed that DFO restored the expression of intracellular lysosomal protease Cathepsin and reduced the expression of the LC3-II. CONCLUSION: Taken together, this study clearly demonstrated that the anti-Fenton activity of DFO inhibited apoptosis and caused blockade in ALP or autophagy dysfunction in SH-SY5Y cell lines. These outcomes further suggest that DFO provides neuroprotection by inhibiting apoptosis and inducing the progression of Autophagy- lysosomal pathway (ALP).


Assuntos
Desferroxamina/farmacologia , Neuroblastoma/metabolismo , Oxidopamina/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Microscopia de Fluorescência , Espécies Reativas de Oxigênio/metabolismo
12.
J Surg Res ; 246: 419-426, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31630885

RESUMO

BACKGROUND: Deferoxamine (DFX) has been reported to have neuroprotective effect. This study aimed to investigate the neuroprotective effect of DFX and its effect on hypoxia-inducible factor 1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in rats after traumatic brain injury (TBI). MATERIALS AND METHODS: Rats were randomly divided into sham operation, TBI + DFX, and TBI + vehicle groups. The rats in the TBI + DFX group were intraperitoneally injected with DFX 2 and 6 h after injury, thereafter once every 12 h. The rats in the TBI + vehicle group were intraperitoneally injected with saline at the same time points. At 6, 12, 24, and 48 h after TBI, 6 rats in each group were euthanized, and the brains were harvested. The expression of HIF-1α and VEGF in the pericontusional area was detected using real-time polymerase chain reaction and Western blot analysis. TBI-induced apoptosis was investigated using the TdT-mediated dUTP nick-end labeling (TUNEL) method. Three days after TBI, the density of microvessels was examined via immunohistochemical staining. RESULTS: DFX treatment upregulated the expression of HIF-1α and VEGF after TBI. DFX treatment reduced apoptosis and improved the neurobehavioral score after TBI. The density of microvessels was higher in the TBI + DFX group than that in the TBI + vehicle group 3 d after TBI. CONCLUSIONS: DFX can stimulate angiogenesis, inhibit apoptosis, and play a protective role after TBI. The protective effect of DFX may, at least in part, be through upregulating the expression of HIF-1α and its downstream target gene VEGF.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Desferroxamina/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fármacos Neuroprotetores/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/patologia , Desferroxamina/uso terapêutico , Modelos Animais de Doenças , Humanos , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima
13.
J Mycol Med ; 30(1): 100905, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31706700

RESUMO

INTRODUCTION: Iron chelator has previously demonstrated fungicidal effects. This study aimed to investigate the antifungal activity of the iron chelators deferoxamine (DFO) and deferasirox (DSX) against Cryptococcus. MATERIALS AND METHODS: Cryptococcus neoformans and Cryptococcus gattii were used to determine the minimal inhibitory concentrations (MICs) of DFO and DSX, and the fractional inhibitory concentration index (FICI) of DFO and DSX when combined with amphotericin B (AMB). Expression of cryptococcal CFT1, CFT2, and CIR1 genes was determined using real-time polymerase chain reaction (PCR). RESULTS: Neither DFO nor DSX alone showed antifungal activity against Cryptococcus strains. When combined with AMB, the MICs of DFO and DSX decreased from>200µg/mL to 6.25 or 12.5µg/mL. The MIC of AMB decreased one-fold dilution in most strains when combined with iron chelators. The FICI of DFO+AMB and DSX+AMB was 0.5 and 1, respectively. C. neoformans showed significant growth retardation when incubated with a combination of sub-MIC concentrations of AMB and DFO; whereas, C. gattii demonstrated lesser growth retardation in DFO+AMB. No cryptococcal growth retardation was observed when DSX was combined with AMB. When C. neoformans was grown in DFO, the CFT1, CFT2, and CIR1 proteins were expressed 1.7, 2.0, and 0.9 times, respectively. When C. neoformans was grown in DSX, the CFT1, CFT2, and CIR1 genes were expressed 0.5, 0.6, and 0.3 times, respectively. CONCLUSION: Synergistic antifungal activity of combination DFO and AMB was observed in Cryptococcus. Relatively increased CFT1 and CFT2 expression may be associated with the effect of DFO that inhibits the growth of fungi.


Assuntos
Cryptococcus/efeitos dos fármacos , Cryptococcus/crescimento & desenvolvimento , Cryptococcus/genética , Quelantes de Ferro/farmacologia , Ferro/metabolismo , Anfotericina B/farmacologia , Antifúngicos/farmacologia , Criptococose/tratamento farmacológico , Criptococose/microbiologia , Cryptococcus/metabolismo , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/genética , Cryptococcus neoformans/crescimento & desenvolvimento , Cryptococcus neoformans/metabolismo , Deferasirox/farmacologia , Desferroxamina/farmacologia , Sinergismo Farmacológico , Cápsulas Fúngicas/efeitos dos fármacos , Cápsulas Fúngicas/genética , Cápsulas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Humanos , Infecções Fúngicas Invasivas/complicações , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/microbiologia , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/microbiologia , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Testes de Sensibilidade Microbiana , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
14.
Vet Immunol Immunopathol ; 219: 109973, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31765882

RESUMO

Preconditioning with hypoxia or hypoxia-mimetic agents has been tried with mesenchymal stem cells (MSCs) to improve the secretion of anti-inflammatory factors. These preconditioning procedures upregulate hypoxia inducible factor (HIF) 1-alpha leading to the transcription of HIF-dependent tissue protective and anti-inflammatory genes. Due to the limited number of studies exploring the activity of deferoxamine (DFO)-a hypoxia-mimetic agent-in MSCs, we aimed to determine whether DFO can enhance the secretion of anti-inflammatory substances in canine adipose tissue-derived (cAT)-MSCs. Furthermore, we investigated whether this activity of DFO could affect macrophage polarization and activate anti-inflammatory reactions. cAT-MSCs preconditioned with DFO exhibited enhanced secretion of anti-inflammatory factors such as prostaglandin E2 and tumor necrosis factor-α-stimulated gene-6. To evaluate the interaction between DFO preconditioned cAT-MSCs and macrophages, RAW 264.7 cells were co-cultured with cAT-MSCs using the Transwell system, and changes in the expression of factors related to macrophage polarization were analyzed using the quantitative real-time PCR and western blot assays. When RAW 264.7 cells were co-cultured with DFO preconditioned cAT-MSCs, the expression of M1 and M2 markers decreased and increased, respectively, compared to co-culturing with non-preconditioned cAT-MSCs. Thus, cAT-MSCs preconditioned with DFO can more effectively direct and reprogram macrophage polarization into the M2 phase, an anti-inflammatory state.


Assuntos
Tecido Adiposo/citologia , Anti-Inflamatórios/farmacologia , Diferenciação Celular/efeitos dos fármacos , Desferroxamina/farmacologia , Macrófagos/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Cães , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Células RAW 264.7 , Transdução de Sinais
15.
PLoS One ; 14(12): e0227278, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31887216

RESUMO

The iron dependent, programmed cell death, ferroptosis was described first in tumour cells. It showed distinct features from the already known cell death forms such as apoptosis, necrosis and autophagy. The caspase independent cell death could be induced by the depletion of glutathione by erastin or by the inhibition of the lipid peroxide scavenger enzyme GPX4 by RSL3 and it was accompanied by the generation of lipid reactive oxygen species. Recently, ferroptosis-like cell death associated to glutathione depletion, lipid peroxidation and iron dependency could also be induced in plant cells by heat treatment. Unfortunately, the mediators and elements of the ferroptotic pathway have not been described yet. Our present results on Arabidopsis thaliana cell cultures suggest that acrolein, a lipid peroxide-derived reactive carbonyl species, is involved in plant ferroptosis-like cell death. The acrolein induced cell death could be mitigated by the known ferroptosis inhibitors such as Ferrostatin-1, Deferoxamine, α-Tocopherol, and glutathione. At the same time acrolein can be a mediator of ferroptosis-like cell death in plant cells since the known ferroptosis inducer RSL3 induced cell death could be mitigated by the acrolein scavenger carnosine. Finally, on the contrary to the caspase independent ferroptosis in human cells, we found that caspase-like activity can be involved in plant ferroptosis-like cell death.


Assuntos
Acroleína/metabolismo , Arabidopsis/fisiologia , Caspases/metabolismo , Ferroptose/fisiologia , Proteínas de Plantas/metabolismo , Acroleína/antagonistas & inibidores , Arabidopsis/citologia , Arabidopsis/efeitos dos fármacos , Carbolinas/farmacologia , Carnosina/farmacologia , Técnicas de Cultura de Células , Células Cultivadas , Cicloexilaminas/farmacologia , Desferroxamina/farmacologia , Ferroptose/efeitos dos fármacos , Glutationa/metabolismo , Ferro/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Fenilenodiaminas/farmacologia
16.
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi ; 37(10): 722-727, 2019 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-31726500

RESUMO

Objective: To investigate the mechanism of Al (mal) (3)-induced ferroptosis in rat adrenal pheochromocytoma cells (PC12), to explore the effect of deferoxamine (DFO) . Methods: Taken PC12 cells growing at logarithmic phase and divided into 6 groups: control group, 200 µmol/L Al (mal) (3) group, 0.5% DMSO group, 200 µmol/L DFO group, Al (mal) (3)+DMSO group, Al (mal) (3)+DFO group. DMSO and DFO were added to the DMSO group and the Al (mal) (3)+DMSO group, the DFO group and the Al (mal) (3)+DFO group for 2 h, respectively, Al (mal) (3) was then added to the Al (mal) (3) group, Al (mal) (3)+DMSO group, and the Al (mal) (3)+DFO group to a final concentration of 200 µmol/L. The cell viability was detected by CCK8, the morphology and ROS levels of PC12 cells was observed by inverted microscope, the cell proliferation toxicity and intracellular iron ion content were detected by colorimetry, the GSH content and GSH-PX activity were detected by biochemical method. Results: Al (mal) (3) exposure significantly inhibited the growth of PC12 cells and destroyed the cell morphological structure, resulting in increased LDH activity and intracellular iron ion content in PC12 cells, decreased GSH content and GSH-PX activity, increased ROS levels; the combined treatment of Al (mal) (3)+DFO can significantly improve the cell viability of PC12 cells, improved cell morphology, decreased cell LDH activity and intracellular iron ion content (P>0.05), increased GSH content and GSH-PX activity, decreased ROS levels. Conclusion: Al (mal) (3) can induce ferroptosis in PC12 cells, DFO may inhibit ferroptosis by reducing intracellular iron levels and reducing oxidative damage.


Assuntos
Apoptose/efeitos dos fármacos , Desferroxamina/farmacologia , Ferro/análise , Alumínio , Animais , Sobrevivência Celular , Estresse Oxidativo , Células PC12 , Ratos
17.
Acta Biochim Biophys Sin (Shanghai) ; 51(11): 1134-1141, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31650158

RESUMO

The widely used inhalation anesthetic, isoflurane, potentially induces neuronal injury in clinical practice. Previous studies showed multiple forms of cell death that resulted from isoflurane-induced cytotoxicity, but the precise underlying mechanism remains poorly understood. Ferroptosis has recently been identified as a non-apoptotic form of regulated cell death. Here, we found that ferroptosis inhibitors, ferrostatin-1 and deferoxamine mesylate (DFOM), showed great efficiency in maintaining cell viability in SH-SY5Y neuroblastoma cells exposed to a high concentration of isoflurane for 24 h. We also observed that cellular chelatable iron and lipid peroxidation were increased in a concentration-dependent manner in response to isoflurane. In addition, isoflurane upregulated Beclin1 phosphorylation, followed by the formation of a Beclin1-solute carrier family 7 member 11 (SLC7A11) complex, which affected the activity of cystine/glutamate antipoter and further regulated ferroptotic cell death. Accordingly, Beclin1 overexpression aggravated isoflurane-induced cell damage by upregulating ferroptosis. This phenomenon was significantly attenuated by silencing of Beclin1 in SH-SY5Y cells. These findings indicate that Beclin1 may regulate ferroptosis in a manner involving inhibition of glutamate exchange activity of system xc(-), which is implicated in isoflurane-induced toxicity. In particular, when isoflurane is administrated at high concentrations and for an extended duration, ferroptosis is more likely to play a crucial role in isoflurane-induced toxicity.


Assuntos
Proteína Beclina-1/fisiologia , Ferroptose , Ácido Glutâmico/metabolismo , Ferro/metabolismo , Isoflurano/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cicloexilaminas/farmacologia , Desferroxamina/farmacologia , Humanos , Fenilenodiaminas/farmacologia
18.
Plast Reconstr Surg ; 144(4): 619e-629e, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31568298

RESUMO

BACKGROUND: The authors hypothesize that ischemic preconditioning of the recipient site with deferoxamine will increase fat graft survival by enhancing angiogenesis in a rat model. METHODS: Cell viability, tube formation, and mRNA expression were measured in human umbilical vein endothelial cells treated with deferoxamine. A total of 36 rats were then used for an in vivo study. A dose of 100 mg/kg of deferoxamine was injected subcutaneously into the rat scalp every other day for five treatments. On the day after the final injection, the scalp skin was harvested from half the animals to evaluate the effects of deferoxamine on the recipient site. In the remaining animals, inguinal fat tissue was transplanted to the scalp. Eight weeks after transplantation, the grafts were harvested to evaluate the effects of deferoxamine preconditioning on fat graft survival. RESULTS: In human umbilical vein endothelial cells, treatment with a deferoxamine concentration higher than 400 µM decreased cell viability compared with the control (p = 0.002). Treatment with 100 and 200 µM deferoxamine increased endothelial tube formation (p = 0.001) and mRNA levels of angiogenesis-related factors (p = 0.02). Rat scalps treated with deferoxamine exhibited increased capillary neoformation (p = 0.001) and vascular endothelial growth factor protein expression (p = 0.024) compared with controls. Fat graft volume retention, capillary density (p < 0.001), and adipocyte viability (p < 0.001) in the grafted fat increased when the recipient site was preconditioned with deferoxamine. CONCLUSION: This study demonstrated that recipient site preconditioning with deferoxamine increases fat graft survival by inducing vascular endothelial growth factor and neovascularization.


Assuntos
Tecido Adiposo/transplante , Desferroxamina/farmacologia , Sobrevivência de Enxerto/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Precondicionamento Isquêmico/métodos , Neovascularização Fisiológica/efeitos dos fármacos , Fatores de Crescimento do Endotélio Vascular/biossíntese , Fatores de Crescimento do Endotélio Vascular/efeitos dos fármacos , Animais , Humanos , Masculino , Modelos Animais , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular
19.
Int J Mol Sci ; 20(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597263

RESUMO

In our previous study, Deferoxamine (DFO) increased the iron concentration by upregulating the expression levels of TfR1 and DMT1 and exacerbated the migration of triple-negative breast cancer cells. However, the mechanisms of iron distribution and utilization in triple-negative breast cancer cells with a DFO-induced iron deficiency are still unclear. In this study, triple-negative MDA-MB-231 and estrogen receptor (ER)-positive MCF-7 breast cancer cells were used to investigate the mechanisms of iron distribution and utilization with a DFO-induced iron deficiency. We found that the mitochondrial iron concentration was elevated in MDA-MB-231 cells, while it was decreased in MCF-7 cells after DFO treatment. The cellular and mitochondrial reactive oxygen species (ROS) levels increased in both breast cancer cell types under DFO-induced iron-deficient conditions. However, the increased ROS levels had different effects on the different breast cancer cell types: Cell viability was inhibited and apoptosis was enhanced in MCF-7 cells, but cell viability was maintained and cell migration was promoted in MDA-MB-231 cells through the ROS/NF-κB and ROS/TGF-ß signaling pathways. Collectively, this study suggests that under DFO-induced iron-deficient conditions, the increased mitochondrial iron levels in triple-negative MDA-MB-231 breast cancer cells would generate large amounts of ROS to activate the NF-κB and TGF-ß signaling pathways to promote cell migration.


Assuntos
Desferroxamina/farmacologia , Ferro/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Células MCF-7
20.
J Cell Mol Med ; 23(11): 7785-7795, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31517438

RESUMO

The patients with mantle cell lymphoma (MCL) have translocation t(11;14) associated with cyclin D1 overexpression. We observed that iron (an essential cofactor of dioxygenases including prolyl hydroxylases [PHDs]) depletion by deferoxamine blocked MCL cells' proliferation, increased expression of DNA damage marker γH2AX, induced cell cycle arrest and decreased cyclin D1 level. Treatment of MCL cell lines with dimethyloxalylglycine, which blocks dioxygenases involving PHDs by competing with their substrate 2-oxoglutarate, leads to their decreased proliferation and the decrease of cyclin D1 level. We then postulated that loss of EGLN2/PHD1 in MCL cells may lead to down-regulation of cyclin D1 by blocking the degradation of FOXO3A, a cyclin D1 suppressor. However, the CRISPR/Cas9-based loss-of-function of EGLN2/PHD1 did not affect cyclin D1 expression and the loss of FOXO3A did not restore cyclin D1 levels after iron chelation. These data suggest that expression of cyclin D1 in MCL is not controlled by ENGL2/PHD1-FOXO3A pathway and that chelation- and 2-oxoglutarate competition-mediated down-regulation of cyclin D1 in MCL cells is driven by yet unknown mechanism involving iron- and 2-oxoglutarate-dependent dioxygenases other than PHD1. These data support further exploration of the use of iron chelation and 2-oxoglutarate-dependent dioxygenase inhibitors as a novel therapy of MCL.


Assuntos
Ciclina D1/metabolismo , Dioxigenases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Quelantes de Ferro/farmacologia , Ácidos Cetoglutáricos/farmacologia , Linfoma de Célula do Manto/enzimologia , Aminoácidos Dicarboxílicos/farmacologia , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA , Desferroxamina/farmacologia , Dioxigenases/metabolismo , Regulação para Baixo/efeitos dos fármacos , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Humanos , Hidroxilação , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Ferro/deficiência , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...