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1.
J Immunol ; 211(6): 981-993, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37493438

RESUMO

Current vaccine efforts to combat SARS-CoV-2 are focused on the whole spike protein administered as mRNA, viral vector, or protein subunit. However, the SARS-CoV-2 receptor-binding domain (RBD) is the immunodominant portion of the spike protein, accounting for 90% of serum neutralizing activity. In this study, we constructed several versions of RBD and together with aluminum hydroxide or DDA (dimethyldioctadecylammonium bromide)/TDB (d-(+)-trehalose 6,6'-dibehenate) adjuvant evaluated immunogenicity in mice. We generated human angiotensin-converting enzyme 2 knock-in mice to evaluate vaccine efficacy in vivo following viral challenge. We found that 1) subdomain (SD)1 was essential for the RBD to elicit maximal immunogenicity; 2) RBDSD1 produced in mammalian HEK cells elicited better immunogenicity than did protein produced in insect or yeast cells; 3) RBDSD1 combined with the CD4 Th1 adjuvant DDA/TDB produced higher neutralizing Ab responses and stronger CD4 T cell responses than did aluminum hydroxide; 4) addition of monomeric human Fc receptor to RBDSD1 (RBDSD1Fc) significantly enhanced immunogenicity and neutralizing Ab titers; 5) the Beta version of RBDSD1Fc provided a broad range of cross-neutralization to multiple antigenic variants of concern, including Omicron; and 6) the Beta version of RBDSD1Fc with DDA/TDB provided complete protection against virus challenge in the knock-in mouse model. Thus, we have identified an optimized RBD-based subunit vaccine suitable for clinical trials.


Assuntos
COVID-19 , Vacinas Virais , Humanos , Animais , Camundongos , SARS-CoV-2 , Vacinas contra COVID-19 , Hidróxido de Alumínio , Glicoproteína da Espícula de Coronavírus , Vacinas de Subunidades Antigênicas , Anticorpos Antivirais , Anticorpos Neutralizantes , Mamíferos
2.
Haematologica ; 107(10): 2454-2465, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35385924

RESUMO

Anemia of cancer (AoC) with its multifactorial etiology and complex pathology is a poor prognostic indicator for cancer patients. One of the main causes of AoC is cancer-associated inflammation that activates mechanisms, commonly observed in anemia of inflammation, whereby functional iron deficiency and iron-restricted erythropoiesis are induced by increased hepcidin levels in response to raised levels of interleukin-6. So far only a few AoC mouse models have been described, and most of them did not fully recapitulate the interplay of anemia, increased hepcidin levels and functional iron deficiency in human patients. To test if the selection and the complexity of AoC mouse models dictates the pathology or if AoC in mice per se develops independently of iron deficiency, we characterized AoC in Trp53floxWapCre mice that spontaneously develop breast cancer. These mice developed AoC associated with high levels of interleukin-6 and iron deficiency. However, hepcidin levels were not increased and hypoferremia coincided with anemia rather than causing it. Instead, an early shift in the commitment of common myeloid progenitors from the erythroid to the myeloid lineage resulted in increased myelopoiesis and in the excessive production of neutrophils that accumulate in necrotic tumor regions. This process could not be prevented by either iron or erythropoietin treatment. Trp53floxWapCre mice are the first mouse model in which erythropoietin-resistant anemia is described and may serve as a disease model to test therapeutic approaches for a subpopulation of human cancer patients with normal or corrected iron levels who do not respond to erythropoietin.


Assuntos
Anemia , Neoplasias da Mama , Eritropoetina , Deficiências de Ferro , Anemia/tratamento farmacológico , Anemia/etiologia , Anemia/patologia , Animais , Neoplasias da Mama/complicações , Eritropoese , Eritropoetina/farmacologia , Eritropoetina/uso terapêutico , Feminino , Hepcidinas/genética , Humanos , Inflamação/complicações , Interleucina-6/genética , Ferro/uso terapêutico , Camundongos
3.
Blood ; 121(26): 5158-66, 2013 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-23667053

RESUMO

Hypoxia is a prominent feature in the maintenance of hematopoietic stem cell (HSC) quiescence and multipotency. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain proteins (PHDs) serve as oxygen sensors and may therefore regulate this system. Here, we describe a mouse line with conditional loss of HIF prolyl hydroxylase 2 (PHD2) in very early hematopoietic precursors that results in self-renewal of multipotent progenitors under steady-state conditions in a HIF1α- and SMAD7-dependent manner. Competitive bone marrow (BM) transplantations show decreased peripheral and central chimerism of PHD2-deficient cells but not of the most primitive progenitors. Conversely, in whole BM transfer, PHD2-deficient HSCs replenish the entire hematopoietic system and display an enhanced self-renewal capacity reliant on HIF1α. Taken together, our results demonstrate that loss of PHD2 controls the maintenance of the HSC compartment under physiological conditions and causes the outcompetition of PHD2-deficient hematopoietic cells by their wild-type counterparts during stress while promoting the self-renewal of very early hematopoietic progenitors.


Assuntos
Células-Tronco Hematopoéticas/citologia , Hipóxia/fisiopatologia , Células-Tronco Multipotentes/citologia , Pró-Colágeno-Prolina Dioxigenase/fisiologia , Estresse Fisiológico , Animais , Transplante de Medula Óssea , Ciclo Celular , Diferenciação Celular , Células-Tronco Hematopoéticas/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia , Prolina Dioxigenases do Fator Induzível por Hipóxia , Integrases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Multipotentes/metabolismo , Proteína Smad7/metabolismo
4.
Blood ; 121(8): 1436-45, 2013 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-23264599

RESUMO

Erythropoiesis must be tightly balanced to guarantee adequate oxygen delivery to all tissues in the body. This process relies predominantly on the hormone erythropoietin (EPO) and its transcription factor hypoxia inducible factor (HIF). Accumulating evidence suggests that oxygen-sensitive prolyl hydroxylases (PHDs) are important regulators of this entire system. Here, we describe a novel mouse line with conditional PHD2 inactivation (cKO P2) in renal EPO producing cells, neurons, and astrocytes that displayed excessive erythrocytosis because of severe overproduction of EPO, exclusively driven by HIF-2α. In contrast, HIF-1α served as a protective factor, ensuring survival of cKO P2 mice with HCT values up to 86%. Using different genetic approaches, we show that simultaneous inactivation of PHD2 and HIF-1α resulted in a drastic PHD3 reduction with consequent overexpression of HIF-2α-related genes, neurodegeneration, and lethality. Taken together, our results demonstrate for the first time that conditional loss of PHD2 in mice leads to HIF-2α-dependent erythrocytosis, whereas HIF-1α protects these mice, providing a platform for developing new treatments of EPO-related disorders, such as anemia.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hematopoese Extramedular/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Policitemia/genética , Pró-Colágeno-Prolina Dioxigenase/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Encéfalo/fisiologia , Células Cultivadas , Eritropoetina/genética , Eritropoetina/metabolismo , Feminino , Fibroblastos/citologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia , Queratinócitos/citologia , Rim/citologia , Rim/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Degeneração Neural/genética , Degeneração Neural/metabolismo , Policitemia/metabolismo , Policitemia/patologia , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Índice de Gravidade de Doença , Trombocitopenia/genética , Trombocitopenia/metabolismo , Trombocitopenia/patologia
5.
Int J Cancer ; 134(4): 849-58, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23913502

RESUMO

The tumor microenvironment plays a pivotal role during cancer development and progression. The balance between suppressive and cytotoxic responses of the tumor immune microenvironment has been shown to have a direct effect on the final outcome in various human and experimental tumors. Recently, we demonstrated that the oxygen sensor HIF-prolyl hydroxylase-2 (PHD2) plays a detrimental role in tumor cells, stimulating systemic growth and metastasis in mice. In our current study, we show that the conditional ablation of PHD2 in the hematopoietic system also leads to reduced tumor volume, intriguingly generated by an imbalance between enhanced cell death and improved proliferation of tumor cells. This effect seems to rely on the overall downregulation of protumoral as well as antitumoral cytokines. Using different genetic approaches, we were able to confine this complex phenotype to the crosstalk of PHD2-deficient myeloid cells and T-lymphocytes. Taken together, our findings reveal a multifaceted role for PHD2 in several hematopoietic lineages during tumor development and might have important implications for the development of tumor therapies in the future.


Assuntos
Carcinoma Pulmonar de Lewis/prevenção & controle , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Prolina Dioxigenases do Fator Induzível por Hipóxia/fisiologia , Melanoma Experimental/prevenção & controle , Células Mieloides/patologia , Linfócitos T/patologia , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Medula Óssea/metabolismo , Medula Óssea/patologia , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/patologia , Movimento Celular , Proliferação de Células , Citocinas/genética , Citocinas/metabolismo , Progressão da Doença , Citometria de Fluxo , Perfilação da Expressão Gênica , Técnicas Imunoenzimáticas , Integrases/metabolismo , Melanoma Experimental/genética , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/imunologia , Células Mieloides/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/imunologia , Linfócitos T/metabolismo
6.
STAR Protoc ; 1(3): 100163, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33377057

RESUMO

We describe a method to silence genes in primary acute myeloid leukemia cells by transducing them with shRNA in lentiviral vectors. The transduction of primary non-adherent cells is particularly challenging. The protocol will aid in performing such experiments and is particularly helpful to prepare cells for in vivo engraftment studies. Use of a special medium supplemented with cytokines preserves the viability of the leukemic stem cells and their ability to engraft the marrow of immune-deficient mice. For complete details on the use and execution of this protocol, please refer to Singh et al. (2020).


Assuntos
Vetores Genéticos/metabolismo , Lentivirus/metabolismo , Leucemia Mieloide Aguda/genética , Transplante de Neoplasias , Transdução Genética , Animais , Humanos , Camundongos , Células Tumorais Cultivadas
7.
Cell Stem Cell ; 26(6): 926-937.e10, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32416059

RESUMO

Leukemic stem cells (LSCs) rely on oxidative metabolism and are differentially sensitive to targeting mitochondrial pathways, which spares normal hematopoietic cells. A subset of mitochondrial proteins is folded in the intermembrane space via the mitochondrial intermembrane assembly (MIA) pathway. We found increased mRNA expression of MIA pathway substrates in acute myeloid leukemia (AML) stem cells. Therefore, we evaluated the effects of inhibiting this pathway in AML. Genetic and chemical inhibition of ALR reduces AML growth and viability, disrupts LSC self-renewal, and induces their differentiation. ALR inhibition preferentially decreases its substrate COX17, a mitochondrial copper chaperone, and knockdown of COX17 phenocopies ALR loss. Inhibiting ALR and COX17 increases mitochondrial copper levels which in turn inhibit S-adenosylhomocysteine hydrolase (SAHH) and lower levels of S-adenosylmethionine (SAM), DNA methylation, and chromatin accessibility to lower LSC viability. These results provide insight into mechanisms through which mitochondrial copper controls epigenetic status and viability of LSCs.


Assuntos
Autorrenovação Celular , Leucemia Mieloide Aguda , Diferenciação Celular , Cobre , Humanos , Células-Tronco Neoplásicas
8.
Stem Cell Reports ; 10(6): 1908-1919, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29754961

RESUMO

The hematopoietic stem cell (HSC) compartment consists of a small pool of cells capable of replenishing all blood cells. Although it is established that the hematopoietic system is assembled as a hierarchical organization under steady-state conditions, emerging evidence suggests that distinct differentiation pathways may exist in response to acute stress. However, it remains unclear how different hematopoietic stem and progenitor cell subpopulations behave under sustained chronic stress. Here, by using adult transgenic mice overexpressing erythropoietin (EPO; Tg6) and a combination of in vivo, in vitro, and deep-sequencing approaches, we found that HSCs respond differentially to chronic erythroid stress compared with their closely related multipotent progenitors (MPPs). Specifically, HSCs exhibit a vastly committed erythroid progenitor profile with enhanced cell division, while MPPs display erythroid and myeloid cell signatures and an accumulation of uncommitted cells. Thus, our results identify HSCs as master regulators of chronic stress erythropoiesis, potentially circumventing the hierarchical differentiation-detour.


Assuntos
Eritropoese , Eritropoetina/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Estresse Fisiológico , Animais , Biologia Computacional/métodos , Células Precursoras Eritroides/citologia , Células Precursoras Eritroides/metabolismo , Perfilação da Expressão Gênica , Camundongos , Camundongos Transgênicos
9.
J Clin Invest ; 127(10): 3624-3639, 2017 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-28846069

RESUMO

Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF- or inflammation-induced stress myelopoiesis. Del-1-induced HSC proliferation and myeloid lineage commitment were mediated by ß3 integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis.


Assuntos
Proteínas de Transporte/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Mielopoese , Nicho de Células-Tronco , Estresse Fisiológico , Animais , Proteínas de Ligação ao Cálcio , Proteínas de Transporte/genética , Moléculas de Adesão Celular , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Células Endoteliais/metabolismo , Humanos , Integrina beta3/genética , Integrina beta3/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Camundongos Knockout
10.
J Bone Miner Res ; 31(10): 1877-1887, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27082941

RESUMO

The main oxygen sensor hypoxia inducible factor (HIF) prolyl hydroxylase 2 (PHD2) is a critical regulator of tissue homeostasis during erythropoiesis, hematopoietic stem cell maintenance, and wound healing. Recent studies point toward a role for the PHD2-erythropoietin (EPO) axis in the modulation of bone remodeling, even though the studies produced conflicting results. Here, we used a number of mouse strains deficient of PHD2 in different cell types to address the role of PHD2 and its downstream targets HIF-1α and HIF-2α in bone remodeling. Mice deficient for PHD2 in several cell lineages, including EPO-producing cells, osteoblasts, and hematopoietic cells (CD68:cre-PHD2f/f ) displayed a severe reduction of bone density at the distal femur as well as the vertebral body due to impaired bone formation but not bone resorption. Importantly, using osteoblast-specific (Osx:cre-PHD2f/f ) and osteoclast-specific PHD2 knock-out mice (Vav:cre- PHD2f/f ), we show that this effect is independent of the loss of PHD2 in osteoblast and osteoclasts. Using different in vivo and in vitro approaches, we show here that this bone phenotype, including the suppression of bone formation, is directly linked to the stabilization of the α-subunit of HIF-2, and possibly to the subsequent moderate induction of serum EPO, which directly influenced the differentiation and mineralization of osteoblast progenitors resulting in lower bone density. Taken together, our data identify the PHD2:HIF-2α:EPO axis as a so far unknown regulator of osteohematology by controlling bone homeostasis. Further, these data suggest that patients treated with PHD inhibitors or EPO should be monitored with respect to their bone status. © 2016 American Society for Bone and Mineral Research.


Assuntos
Reabsorção Óssea/metabolismo , Eritropoetina/biossíntese , Células-Tronco Hematopoéticas/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/deficiência , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Animais , Densidade Óssea/genética , Medula Óssea/metabolismo , Medula Óssea/patologia , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Eritropoetina/genética , Células-Tronco Hematopoéticas/patologia , Camundongos , Camundongos Knockout , Osteoblastos/patologia , Osteoclastos/patologia
13.
Mol Cell Biol ; 33(17): 3426-38, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23798557

RESUMO

Skin wound healing in mammals is a complex, multicellular process that depends on the precise supply of oxygen. Hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2) serves as a crucial oxygen sensor and may therefore play an important role during reepithelialization. Hence, this study was aimed at understanding the role of PHD2 in cutaneous wound healing using different lines of conditionally deficient mice specifically lacking PHD2 in inflammatory, vascular, or epidermal cells. Interestingly, PHD2 deficiency only in keratinocytes and not in myeloid or endothelial cells was found to lead to faster wound closure, which involved enhanced migration of the hyperproliferating epithelium. We demonstrate that this effect relies on the unique expression of ß3-integrin in the keratinocytes around the tip of the migrating tongue in an HIF1α-dependent manner. Furthermore, we show enhanced proliferation of these cells in the stratum basale, which is directly related to their attenuated transforming growth factor ß signaling. Thus, loss of the central oxygen sensor PHD2 in keratinocytes stimulates wound closure by prompting skin epithelial cells to migrate and proliferate. Inhibition of PHD2 could therefore offer novel therapeutic opportunities for the local treatment of cutaneous wounds.


Assuntos
Técnicas de Inativação de Genes , Queratinócitos/metabolismo , Pró-Colágeno-Prolina Dioxigenase/genética , Pele/metabolismo , Cicatrização , Animais , Movimento Celular , Proliferação de Células , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia , Integrina beta3/genética , Queratinócitos/citologia , Masculino , Camundongos , Camundongos Knockout , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Pele/citologia , Fenômenos Fisiológicos da Pele , Fator de Crescimento Transformador beta/metabolismo
14.
High Alt Med Biol ; 13(3): 162-8, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22994515

RESUMO

Hypoxia-mediated regulation of stem cell fate, or reduced oxygen availability, is a prominent feature during mammalian development and under physiological and pathological conditions in adults. Oxygen-sensing is therefore indispensable as it enables the cells to adapt instantaneously to an inappropriate pO(2). This machinery relies primarily on hypoxia inducible factor (HIF). Moreover, a growing body of evidence proposes that different types of stem cells exist in a very hypoxic microenvironment, which may be beneficial for the maintenance of these cells and ensures continuous replenishment of dead or damaged cells in virtually all tissues of the body. Recent reports have shown that HIF is a critical player in these responses. However, a better understanding of the different HIF-related mechanisms is of utmost importance for the improvement of therapeutic strategies for tissue regeneration as well as hematological malignancies.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/metabolismo , Transdução de Sinais , Células-Tronco/metabolismo , Animais , Diferenciação Celular , Células-Tronco Hematopoéticas/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neurais/metabolismo , Oxigênio/metabolismo
15.
Mol Cell Biochem ; 282(1-2): 13-21, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16317507

RESUMO

Copper and zinc act as a cofactor of over 300 mammalian proteins. Both have same electronic configuration therefore they are antagonist at higher individual concentration. The present study was designed with the aim to investigate the mechanisms pertaining to toxic effects of copper on human peripheral blood mononuclear cells (PBMCs) and to evaluate the cytoprotective effect of zinc on copper-induced cytotoxicity. The copper uptake into PBMCs was progressively increased with increasing concentration of metal in the growth medium. However, no significant effect on copper uptake was observed in the presence of zinc. Cell proliferation rate was decreased with increasing copper concentration. Interestingly, the proliferation rate of zinc treated PBMCs remained nearly the same as that of control cells. LD(50) of copper (115 microM) was increased six times (710 microM) in presence of zinc for PBMCs. At higher concentrations of copper (> 100 microM) decrease level of GSH was noticed. Increased levels of metallothionein in PBMCs were observed in response to zinc. DNA fragmentation studies also showed that copper produced DNA fragmentation at LD(50) (115 microM). Subsequently, zinc showed protection against DNA fragmentation caused by copper. Cell structure of PBMCs at LD(50) (115 microM copper) showed membrane bound cystic spaces and mitochondria having disrupted cristae and few myelin figures. In presence of zinc at LD(50) of copper (115 microM) cells showed improvement in mitochondrial structure and membrane bound cystic spaces. Taken together, the results of our study demonstrates that zinc play an important role in prevention of copper toxicity in peripheral blood mononuclear cells.


Assuntos
Cobre/toxicidade , Leucócitos Mononucleares/efeitos dos fármacos , Zinco/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/ultraestrutura , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citoproteção , Fragmentação do DNA/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/ultraestrutura , Metalotioneína/metabolismo , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/ultraestrutura , Partículas Submitocôndricas/efeitos dos fármacos , Partículas Submitocôndricas/ultraestrutura
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