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1.
J Exp Med ; 216(9): 2038-2056, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31217193

RESUMO

Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-ß and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients' iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I and/or III IFN-mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature.

2.
Development ; 145(5)2018 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-29440304

RESUMO

The entire lung epithelium arises from SRY box 9 (SOX9)-expressing progenitors that form the respiratory tree and differentiate into airway and alveolar cells. Despite progress in understanding their initial specification within the embryonic foregut, how these progenitors are subsequently maintained is less clear. Using inducible, progenitor-specific genetic mosaic mouse models, we showed that ß-catenin (CTNNB1) maintains lung progenitors by promoting a hierarchical lung progenitor gene signature, suppressing gastrointestinal (GI) genes, and regulating NK2 homeobox 1 (NKX2.1) and SRY box 2 (SOX2) in a developmental stage-dependent manner. At the early, but not later, stage post-lung specification, CTNNB1 cell-autonomously maintained normal NKX2.1 expression levels and suppressed ectopic SOX2 expression. Genetic epistasis analyses revealed that CTNNB1 is required for fibroblast growth factor (Fgf)/Kirsten rat sarcoma viral oncogene homolog (Kras)-mediated promotion of the progenitors. In silico screening of Eurexpress and translating ribosome affinity purification (TRAP)-RNAseq identified a progenitor gene signature, a subset of which depends on CTNNB1. Wnt signaling also maintained NKX2.1 expression and suppressed GI genes in cultured human lung progenitors derived from embryonic stem cells.


Assuntos
Linhagem da Célula/genética , Células-Tronco Embrionárias/metabolismo , Células Epiteliais/citologia , Pulmão/embriologia , Mucosa Respiratória/citologia , Mucosa Respiratória/embriologia , beta Catenina/fisiologia , Animais , Células Cultivadas , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/fisiologia , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Pulmão/citologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Knockout , Gravidez , Mucosa Respiratória/metabolismo , Transcriptoma , beta Catenina/genética
3.
Sci Adv ; 3(8): e1700521, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28875163

RESUMO

End-stage lung disease is the third leading cause of death worldwide, accounting for 400,000 deaths per year in the United States alone. To reduce the morbidity and mortality associated with lung disease, new therapeutic strategies aimed at promoting lung repair and increasing the number of donor lungs available for transplantation are being explored. Because of the extreme complexity of this organ, previous attempts at bioengineering functional lungs from fully decellularized or synthetic scaffolds lacking functional vasculature have been largely unsuccessful. An intact vascular network is critical not only for maintaining the blood-gas barrier and allowing for proper graft function but also for supporting the regenerative cells. We therefore developed an airway-specific approach to removing the pulmonary epithelium, while maintaining the viability and function of the vascular endothelium, using a rat model. The resulting vascularized lung grafts supported the attachment and growth of human adult pulmonary cells and stem cell-derived lung-specified epithelial cells. We propose that de-epithelialization of the lung with preservation of intact vasculature could facilitate cell therapy of pulmonary epithelium and enable bioengineering of functional lungs for transplantation.

4.
Science ; 348(6233): 448-53, 2015 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-25814066

RESUMO

Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient's dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity.


Assuntos
Heterozigoto , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/imunologia , Fator Regulador 7 de Interferon/genética , Interferon Tipo I/biossíntese , Síndrome do Desconforto Respiratório do Adulto/imunologia , Criança , Células Dendríticas/imunologia , Feminino , Fibroblastos/imunologia , Genes Recessivos , Humanos , Células-Tronco Pluripotentes Induzidas/imunologia , Influenza Humana/complicações , Influenza Humana/genética , Interferon Tipo I/genética , Leucócitos/imunologia , Pulmão/imunologia , Mutação , Síndrome do Desconforto Respiratório do Adulto/genética , Síndrome do Desconforto Respiratório do Adulto/virologia , Mucosa Respiratória/imunologia
5.
Nat Protoc ; 10(3): 413-25, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25654758

RESUMO

Lung and airway epithelial cells generated in vitro from human pluripotent stem cells (hPSCs) have applications in regenerative medicine, modeling of lung disease, drug screening and studies of human lung development. Here we describe a strategy for directed differentiation of hPSCs into developmental lung progenitors, and their subsequent differentiation into predominantly distal lung epithelial cells. The protocol entails four stages that recapitulate lung development, and it takes ∼50 d. First, definitive endoderm (DE) is induced in the presence of high concentrations of activin A. Subsequently, lung-biased anterior foregut endoderm (AFE) is specified by sequential inhibition of bone morphogenetic protein (BMP), transforming growth factor-ß (TGF-ß) and Wnt signaling. AFE is then ventralized by applying Wnt, BMP, fibroblast growth factor (FGF) and retinoic acid (RA) signaling to obtain lung and airway progenitors. Finally, these are further differentiated into more mature epithelial cells types using Wnt, FGF, cAMP and glucocorticoid agonism. This protocol is conducted in defined conditions, it does not involve genetic manipulation of the cells and it results in cultures in which the majority of the cells express markers of various lung and airway epithelial cells, with a predominance of cells identifiable as functional type II alveolar epithelial cells.


Assuntos
Diferenciação Celular/fisiologia , Células Epiteliais/citologia , Células-Tronco Pluripotentes/citologia , Sistema Respiratório/citologia , Células-Tronco/citologia , Engenharia Tecidual/métodos , Humanos , Técnicas In Vitro/métodos
6.
Nat Biotechnol ; 32(1): 84-91, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24291815

RESUMO

The ability to generate lung and airway epithelial cells from human pluripotent stem cells (hPSCs) would have applications in regenerative medicine, modeling of lung disease, drug screening and studies of human lung development. We have established, based on developmental paradigms, a highly efficient method for directed differentiation of hPSCs into lung and airway epithelial cells. Long-term differentiation of hPSCs in vivo and in vitro yielded basal, goblet, Clara, ciliated, type I and type II alveolar epithelial cells. The type II alveolar epithelial cells were capable of surfactant protein-B uptake and stimulated surfactant release, providing evidence of specific function. Inhibiting or removing retinoic acid, Wnt and BMP-agonists to signaling pathways critical for early lung development in the mouse-recapitulated defects in corresponding genetic mouse knockouts. As this protocol generates most cell types of the respiratory system, it may be useful for deriving patient-specific therapeutic cells.


Assuntos
Diferenciação Celular/genética , Linhagem da Célula/genética , Células-Tronco Pluripotentes Induzidas/citologia , Pulmão/citologia , Animais , Diferenciação Celular/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Camundongos Knockout , Precursores de Proteínas/metabolismo , Proteolipídeos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tretinoína/administração & dosagem
7.
Int J Cancer ; 132(1): 19-28, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22644783

RESUMO

Human small airway epithelial cells (SAECs) immortalized with human telomerase reverse transcriptase were exposed to either a single or multiple doses of α-particles. Irradiated cells showed a dose-dependent cytotoxicity and progressive neoplastic transformation phenotype. These included an increase in saturation density of growth, a greater resistance to N-phosphonoacetyl-L-aspartate, faster anchorage-independent growth, reinforced cell invasion and c-Myc expression. In addition, the transformed cells formed progressively growing tumors upon inoculation into athymic nude mice. Specifically, α-irradiation induced damage to both mitochondrial DNA (mtDNA) and mitochondrial functions in transformed cells as evidenced by increased mtDNA copy number and common deletion, decreased oxidative phosphorylation activity as measured by cytochrome C oxidase (COX) activity and oxygen consumption. There was a linear correlation between mtDNA copy number, common deletion, COX activity and cellular transformation represented by soft agar colony formation and c-Myc expression. These results suggest that mitochondria are associated with neoplastic transformation of SAEC cells induced by α-particles, and that the oncogenesis process may depend not only on the genomes inside the nucleus, but also on the mitochondrial DNA outside the nucleus.


Assuntos
Partículas alfa , Transformação Celular Neoplásica/efeitos da radiação , Células Epiteliais/efeitos da radiação , Mitocôndrias/fisiologia , Mitocôndrias/efeitos da radiação , Animais , Asparagina/análogos & derivados , Asparagina/farmacologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Células Cultivadas , DNA Mitocondrial/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Masculino , Camundongos , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Organofosfonatos/farmacologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo
8.
Bioessays ; 35(3): 261-70, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23175215

RESUMO

We review recent progress in the stem cell biology of the respiratory system, and discuss its scientific and translational ramifications. Several studies have defined novel stem cells in postnatal lung and airways and implicated their roles in tissue homeostasis and repair. In addition, significant advances in the generation of respiratory epithelium from pluripotent stem cells (PSCs) now provide a novel and powerful platform for understanding lung development, modeling pulmonary diseases, and implementing drug screening. Finally, breakthroughs have been made in the generation of decellularized lung matrices that can serve as a scaffold for repopulation with respiratory cells derived from either postnatal or PSCs. These studies are a critical step forward towards the still distant goal of stem cell-based regenerative medicine for diseases of lung and airways.


Assuntos
Diferenciação Celular , Células Epiteliais/citologia , Epitélio/crescimento & desenvolvimento , Sistema Respiratório/citologia , Células-Tronco/citologia , Animais , Humanos
9.
Environ Health Perspect ; 120(6): 840-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22398240

RESUMO

BACKGROUND: The incidence of asbestos-induced human cancers is increasing worldwide, and considerable evidence suggests that reactive oxygen species (ROS) are important mediators of these diseases. Our previous studies suggested that mitochondria might be involved in the initiation of oxidative stress in asbestos-exposed mammalian cells. OBJECTIVE: We investigated whether mitochondria are a potential cytoplasmic target of asbestos using a mitochondrial DNA-depleted (ρ(0)) human small airway epithelial (SAE) cell model: ρ(0) SAE cells lack the capacity to produce mitochondrial ROS. METHODS: We examined nuclear DNA damage, micronuclei (MN), intracellular ROS production, and the expression of inflammation-related nuclear genes in both parental and ρ(0) SAE cells in response to asbestos treatment. RESULTS: Asbestos induced a dose-dependent increase in nuclear DNA oxidative damage and MN in SAE cells. Furthermore, there was a significant increase in intracellular oxidant production and activation of genes involved in nuclear factor κB and proinflammatory signaling pathways in SAE cells. In contrast, the effects of asbestos were minimal in ρ(0) SAE cells. CONCLUSIONS: Mitochondria are a major cytoplasmic target of asbestos. Asbestos may initiate mitochondria-associated ROS, which mediate asbestos-induced nuclear mutagenic events and inflammatory signaling pathways in exposed cells. These data provide new insights into the molecular mechanisms of asbestos-induced genotoxicity.


Assuntos
Asbestos/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Análise de Variância , Dano ao DNA , Desoxiguanosina/análogos & derivados , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Imunofluorescência , Perfilação da Expressão Gênica , Humanos , Testes para Micronúcleos , Microscopia de Fluorescência , Mitocôndrias/metabolismo , Sistema Respiratório/citologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
10.
J Toxicol Environ Health B Crit Rev ; 14(1-4): 179-245, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21534089

RESUMO

The cellular and molecular mechanisms of how asbestos fibers induce cancers and other diseases are not well understood. Both serpentine and amphibole asbestos fibers have been shown to induce oxidative stress, inflammatory responses, cellular toxicity and tissue injuries, genetic changes, and epigenetic alterations in target cells in vitro and tissues in vivo. Most of these mechanisms are believe to be shared by both fiber-induced cancers and noncancerous diseases. This article summarizes the findings from existing literature with a focus on genetic changes, specifically, mutagenicity of asbestos fibers. Thus far, experimental evidence suggesting the involvement of mutagenesis in asbestos carcinogenicity is more convincing than asbestos-induced fibrotic diseases. The potential contributions of mutagenicity to asbestos-induced diseases, with an emphasis on carcinogenicity, are reviewed from five aspects: (1) whether there is a mutagenic mode of action (MOA) in fiber-induced carcinogenesis; (2) mutagenicity/carcinogenicity at low dose; (3) biological activities that contribute to mutagenicity and impact of target tissue/cell type; (4) health endpoints with or without mutagenicity as a key event; and finally, (5) determinant factors of toxicity in mutagenicity. At the end of this review, a consensus statement of what is known, what is believed to be factual but requires confirmation, and existing data gaps, as well as future research needs and directions, is provided.


Assuntos
Asbestos/toxicidade , Carcinógenos Ambientais/toxicidade , Fibras Minerais/toxicidade , Neoplasias/induzido quimicamente , Animais , Asbestos/administração & dosagem , Asbestos/química , Asbestose/metabolismo , Carcinógenos Ambientais/administração & dosagem , Carcinógenos Ambientais/química , Fenômenos Químicos , Dano ao DNA , Humanos , Fibras Minerais/análise , Mitose/efeitos dos fármacos , Mutação/efeitos dos fármacos , Neoplasias/metabolismo , Doenças Pleurais/induzido quimicamente , Doenças Pleurais/metabolismo
11.
J Cell Biochem ; 112(2): 463-75, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21268068

RESUMO

Melanoma is the most lethal form of human skin cancer. However, only limited chemotherapy is currently available for the metastatic stage of the disease. Since chemotherapy, radiation and sodium arsenite treatment operate mainly through induction of the intrinsic mitochondrial pathway, a strongly decreased mitochondrial function in metastatic melanoma cells, could be responsible for low efficacy of the conventional therapy of melanoma. Another feature of metastatic melanoma cells is their proinflammatory phenotype, linked to endogenous expression of the inflammatory cytokines, such as TNFα IL6 and IL8, their receptors, and constitutive NF-κB- and STAT3-dependent gene expression, including cyclooxygenase-2 (PTGS2/COX2). In the present study, we treated melanoma cells with immunological (monoclonal antibody against TNFα or IL6), pharmacological (small molecular inhibitors of IKKß-NF-κB and JAK2-STAT3) or genetic (specific RNAi for COX-2) agents that suppressed the inflammatory response in combination with induction of apoptosis via TRAIL. As a result of these combined treatments, exogenous TRAIL via interactions with TRAIL-R2/R1 strongly increased levels of apoptosis in resistant melanoma cells. The present study provides new understanding of the regulation of TRAIL-mediated apoptosis in melanoma and will serve as the foundation for the potential development of a novel approach for a therapy of resistant melanomas.


Assuntos
Apoptose/efeitos dos fármacos , Melanoma/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Western Blotting , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , NF-kappa B/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Reação em Cadeia da Polimerase , Fator de Transcrição STAT3/metabolismo
12.
J Toxicol Environ Health A ; 72(5): 301-4, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19184745

RESUMO

One of the long-term objectives of the research in our laboratory was to determine whether mitochondrial DNA (mtDNA) mutations were generated in cell lines exposed to a variety of known mutagens. Many of these mutagens are known to increase oxidative stress in the cell, and one potential outcome of this would be an increased incidence of point mutations in mtDNA. Recently, there has been some controversy regarding the validity of point mutations in the regulatory region of mtDNA as a predictive or causative marker for carcinogenesis. Studies were undertaken to assess whether nuclear mutagens such as arsenic (As), asbestos, and ultraviolet (UV) and gamma-radiation, induced both heteroplasmic and homoplasmic point mutations in mtDNA. A direct sequencing approach was used to reduce the occurrence of experimental errors and cross-checked all base changes with databases of known polymorphisms. Our results showed that, while base changes did occur, there was no marked difference between the number of changes in treated and untreated cells. Furthermore, in human lymphocyte samples from subjects exposed to As, most of these base changes were previously reported. Interestingly, there was an increase in the number of transversions (purine ( pyrimidine) in smokers from a human population study, but as with the findings in cell culture samples, there was no difference in the total number of base changes. Data suggest that only a change in the number of rare transversions would be indicative of an increase in point mutations in mtDNA after exposure to mutagens.


Assuntos
DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/efeitos da radiação , Poluentes Ambientais/toxicidade , Raios gama , Regulação da Expressão Gênica/efeitos dos fármacos , Mutagênicos/toxicidade , Raios Ultravioleta , Animais , Arsênico/toxicidade , Asbestos/toxicidade , Células CHO , Carcinógenos/toxicidade , Linhagem Celular , Cricetinae , Cricetulus , Dano ao DNA , Exposição Ambiental/efeitos adversos , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/efeitos da radiação , Mutação/genética , Espécies Reativas de Oxigênio , Fumar/genética
13.
Exp Cell Res ; 314(5): 1163-76, 2008 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-18222423

RESUMO

Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-kappaB that control the expression of antiapoptotic genes, including cFLIP and Bcl-xL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-kappaB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while gamma-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by gamma-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Melanoma/patologia , Estilbenos/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/efeitos dos fármacos , Antineoplásicos Fitogênicos , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Linhagem Celular Tumoral , Regulação da Expressão Gênica/imunologia , Humanos , Melanoma/tratamento farmacológico , NF-kappa B/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Resveratrol , Fator de Transcrição STAT3/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/análise
14.
Cancer Res ; 67(11): 5239-47, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17545603

RESUMO

Arsenic is a well-established human carcinogen that is chronically consumed in drinking water by millions of people worldwide. Recent evidence has suggested that arsenic is a genotoxic carcinogen. Furthermore, we have shown that mitochondria mediate the mutagenic effects of arsenic in mammalian cells, as arsenic did not induce nuclear mutations in mitochondrial DNA (mtDNA)-depleted cells. Using the human-hamster hybrid A(L) cells, we show here that arsenic alters mitochondrial function by decreasing cytochrome c oxidase function and oxygen consumption but increasing citrate synthase function. These alterations correlated with depletion in mtDNA copy number and increase in large heteroplasmic mtDNA deletions. In addition, mtDNA isolated periodically from cultures treated continuously with arsenic did not consistently display the same deletion pattern, indicating that the mitochondrial genome was subjected to repeated and continuous damage. These data support the theory that the mitochondria, and particularly mtDNA, are important targets of the mutagenic effects of arsenic in mammalian cells.


Assuntos
Arsênico/toxicidade , Dano ao DNA , DNA Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Animais , Cricetinae , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Relação Dose-Resposta a Droga , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Humanos , Células Híbridas , Mitocôndrias/genética , Mitocôndrias/metabolismo , Testes de Mutagenicidade , Oxirredução , Consumo de Oxigênio/efeitos dos fármacos
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