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1.
Arterioscler Thromb Vasc Biol ; 37(10): 1840-1848, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28798141

RESUMO

OBJECTIVE: Despite the early promising results of 18F-fluorodeoxyglucose positron emission tomography for assessment of vessel wall inflammation, its accuracy in prospective identification of vulnerable plaques has remained limited. Additionally, previous studies have indicated that 18F-fluorodeoxyglucose uptake alone may not allow for accurate identification of specific macrophage activation states. We aimed to determine whether combined measurement of glucose and glutamine accumulation-the 2 most important bioenergetic substrates for macrophages-improves the distinction of macrophage inflammatory states and can be utilized to image atherosclerosis. APPROACH AND RESULTS: Murine peritoneal macrophages (MΦ) were activated ex vivo into proinflammatory states with either lipopolysaccharide (MΦLPS) or interferon-γ+tumor necrosis factor-α (MΦIFN-γ+TNF-α). An alternative polarization phenotype was induced with interleukin-4 (MΦIL-4). The pronounced increase in 2-deoxyglucose uptake distinguishes MΦLPS from MΦIFN-γ+TNF-α, MΦIL-4, and unstimulated macrophages (MΦ0). Despite having comparable levels of 2-deoxyglucose accumulation, MΦIL-4 can be distinguished from both MΦIFN-γ+TNF-α and MΦ0 based on the enhanced glutamine accumulation, which was associated with increased expression of a glutamine transporter, Slc1a5. Ex vivo autoradiography experiments demonstrated distinct and heterogenous patterns of 18F-fluorodeoxyglucose and 14C-glutamine accumulation in atherosclerotic lesions of low-density lipoprotein receptor-null mice fed a high-fat diet. CONCLUSIONS: Combined assessment of glutamine and 2-deoxyglucose accumulation improves the ex vivo identification of macrophage activation states. Combined ex vivo metabolic imaging demonstrates heterogenous and distinct patterns of substrate accumulation in atherosclerotic lesions. Further studies are required to define the in vivo significance of glutamine uptake in atherosclerosis and its potential application in identification of vulnerable plaques.


Assuntos
Aterosclerose/diagnóstico por imagem , Desoxiglucose/metabolismo , Fluordesoxiglucose F18 , Glutamina/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Animais , Aorta/diagnóstico por imagem , Aorta/metabolismo , Aterosclerose/metabolismo , Autorradiografia , Camundongos , Placa Aterosclerótica/metabolismo
2.
Radiology ; 283(1): 87-97, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27849433

RESUMO

Purpose To determine the divergence of immunometabolic phenotypes of macrophages stimulated with macrophage colony-stimulating factor (M-CSF) and granulocyte-M-CSF (GM-CSF) and its implications for fluorine 18 (18F) fluorodeoxyglucose (FDG) imaging of atherosclerosis. Materials and Methods This study was approved by the animal care committee. Uptake of 2-deoxyglucose and various indexes of oxidative and glycolytic metabolism were evaluated in nonactivated murine peritoneal macrophages (MΦ0) and macrophages stimulated with M-CSF (MΦM-CSF) or GM-CSF (MΦGM-CSF). Intracellular glucose flux was measured by using stable isotope tracing of glycolytic and tricyclic acid intermediary metabolites. 18F-FDG uptake was evaluated in murine atherosclerotic aortas after stimulation with M-CSF or GM-CSF by using quantitative autoradiography. Results Despite inducing distinct activation states, GM-CSF and M-CSF stimulated progressive but similar levels of increased 2-deoxyglucose uptake in macrophages that reached up to sixfold compared with MΦ0. The expression of glucose transporters, oxidative metabolism, and mitochondrial biogenesis were induced to similar levels in MΦM-CSF and MΦGM-CSF. Unexpectedly, there was a 1.7-fold increase in extracellular acidification rate, a 1.4-fold increase in lactate production, and overexpression of several critical glycolytic enzymes in MΦM-CSF compared with MΦGM-CSF with associated increased glucose flux through glycolytic pathway. Quantitative autoradiography demonstrated a 1.6-fold induction of 18F-FDG uptake in murine atherosclerotic plaques by both M-CSF and GM-CSF. Conclusion The proinflammatory and inflammation-resolving activation states of macrophages induced by GM-CSF and M-CSF in either cell culture or atherosclerotic plaques may not be distinguishable by the assessment of glucose uptake. © RSNA, 2016 Online supplemental material is available for this article.


Assuntos
Fluordesoxiglucose F18 , Glucose/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Inflamação/diagnóstico por imagem , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/metabolismo , Tomografia por Emissão de Pósitrons , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Inflamação/metabolismo , Camundongos , Compostos Radiofarmacêuticos
3.
Proc Natl Acad Sci U S A ; 109(30): 12052-7, 2012 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-22778398

RESUMO

Cellular senescence is widely believed to play a key role in tumor suppression, but the molecular pathways that regulate senescence are only incompletely understood. By using a secretome proteomics approach, we identified insulin-like growth factor binding protein 3 (IGFBP3) as a secreted mediator of breast cancer senescence upon chemotherapeutic drug treatment. The senescence-inducing activity of IGFBP3 is inhibited by tissue-type plasminogen activator-mediated proteolysis, which is counteracted by plasminogen activator inhibitor 1 (PAI-1), another secreted mediator of senescence. We demonstrate that IGFBP3 is a critical downstream target of PAI-1-induced senescence. These results suggest a role for an extracellular cascade of secreted proteins in the regulation of cellular senescence.


Assuntos
Senescência Celular/fisiologia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Neoplasias/tratamento farmacológico , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Proteólise/efeitos dos fármacos , Estresse Fisiológico/fisiologia , Ativador de Plasminogênio Tecidual/farmacologia , Análise de Variância , Linhagem Celular Tumoral , Meios de Cultura/química , Primers do DNA/genética , Doxorrubicina/farmacologia , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Humanos , Immunoblotting , Imuno-Histoquímica , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Proteômica/métodos , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ativador de Plasminogênio Tecidual/metabolismo , Células Tumorais Cultivadas , beta-Galactosidase
4.
Arch Biochem Biophys ; 518(2): 103-10, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22234250

RESUMO

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor is associated with renal carcinoma, hemangioblastoma and pheochromocytoma. The VHL protein is a component of a ubiquitin ligase complex that ubiquitinates and degrades hypoxia inducible factor-α (HIF-α). Degradation of HIF-α by VHL is proposed to suppress tumorigenesis and tumor angiogenesis. Several lines of evidence also suggest important roles for HIF-independent VHL functions in tumor suppression and other biological processes. Using GST-VHL pull-down experiment and mass spectrometry, we detected an interaction between VHL and heterochromatin protein 1 (HP1). We identified a conserved HP1-binding motif (PXVXL) in the ß domain of VHL, which is disrupted in a renal carcinoma-associated P81S mutant. We show that the VHL P81S mutant displays reduced binding to HP1, yet retains the ability to interact with elongin B, elongin C, and cullin 2 and is fully capable of degrading HIF-α. We also demonstrate that HP1 increases the chromatin association of VHL. These results suggest a role for the VHL-HP1 interaction in VHL chromatin targeting.


Assuntos
Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/metabolismo , Proteólise , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Motivos de Aminoácidos , Substituição de Aminoácidos , Animais , Linhagem Celular , Cromatina/genética , Homólogo 5 da Proteína Cromobox , Proteínas Cromossômicas não Histona/genética , Proteínas Culina/genética , Proteínas Culina/metabolismo , Elonguina , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Renais/genética , Camundongos , Mutação de Sentido Incorreto , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ubiquitinação/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética
5.
Sci Total Environ ; 833: 155059, 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35395314

RESUMO

Over the course of the COVID-19 pandemic, variants of SARS-CoV-2 have emerged that are more contagious and more likely to cause breakthrough infections. Targeted amplicon sequencing approach is a gold standard for identification and analysis of variants. However, when applied to environmental samples such as wastewater, it remains unclear how sensitive this method is for detecting variant-associated mutations in environmental samples. Here we directly compare a targeted amplicon sequencing approach (using ARTIC v3; hereafter referred to as sequencing) with RT-ddPCR quantification for the detection of five mutations that are characteristic of variants of concern (VoCs) in wastewater samples. In total, 547 wastewater samples were analyzed using both methods in parallel. When we observed positive mutation detections by RT-ddPCR, 42.6% of the detection events were missed by sequencing, due to negative detection or the limited read coverage at the mutation position. Further, when sequencing reported negative or depth-limited mutation detections, 26.7% of those events were instead positive detections by RT-ddPCR, highlighting the relatively poor sensitivity of sequencing. No or weak associations were observed between quantitative measurements of target mutations determined by RT-ddPCR and sequencing. These findings caution the use of quantitative measurements of SARS-CoV-2 variants in wastewater samples determined solely based on sequencing.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Mutação , Pandemias , SARS-CoV-2/genética , Águas Residuárias
6.
J Proteome Res ; 10(11): 5175-82, 2011 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-21942715

RESUMO

The von Hippel-Lindau (VHL) tumor suppressor gene encodes a component of a ubiquitin ligase complex containing elongin B, elongin C, cullin 2, and Rbx1, which acts as a negative regulator of hypoxia inducible factor (HIF). VHL ubiquitinates and degrades the alpha subunits of HIF, and this is proposed to suppress tumorigenesis and tumor angiogenesis. Several lines of evidence also suggest important roles for HIF-independent VHL functions in the maintenance of primary cilium, extracellular matrix formation, and tumor suppression. We undertook a series of proteomic analyses to gain a comprehensive picture of the VHL-interacting proteins. We found that the ARF tumor suppressor interacts with VHL30, a longer VHL isoform, but not with VHL19, a shorter VHL isoform. ARF was found to release VHL30 from the E3 ligase complex, promoting the binding of VHL30 to a protein arginine methyltransferase, PRMT3. Our analysis of the VHL19 interactome also uncovered that VHL19 displays an affinity to collagens and their biosynthesis enzymes.


Assuntos
Mapeamento de Interação de Proteínas , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína Supressora de Tumor p14ARF/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Arginina/metabolismo , Linhagem Celular Tumoral , Colágeno/biossíntese , Colágeno/metabolismo , Proteínas Culina/metabolismo , Elonguina , Células HEK293 , Humanos , Metilação , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/metabolismo , Ligação Proteica , Isoformas de Proteínas/metabolismo , Proteômica , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Complexos Ubiquitina-Proteína Ligase/metabolismo
7.
Appl Environ Microbiol ; 74(1): 73-9, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17981934

RESUMO

Treponema denticola, a periodontal pathogen, has recently been shown to exhibit properties of a facultative anaerobic spirochete, in contrast to its previous recognition as an obligate anaerobic bacterium. In this study, the capacity and possible mechanism of T. denticola survival and growth under aerobic conditions were investigated. Factors detrimental to the growth of T. denticola ATCC 33405, such as oxygen concentration and hydrogen sulfide (H(2)S) levels as well as the enzyme activities of gamma-glutamyltransferase, cysteinylglycinase, and cystalysin associated with the cells were monitored. The results demonstrated that T. denticola grew only at deeper levels of broth (>or=3 ml in a 10-ml tube), high inoculation ratios (>or=20% of culture in medium), and short cultivation times (

Assuntos
Oxigênio/metabolismo , Treponema denticola/crescimento & desenvolvimento , Treponema denticola/metabolismo , Aerobiose , Anaerobiose , Antibacterianos/metabolismo , Meios de Cultura/química , Cistationina gama-Liase/metabolismo , Dipeptidases/metabolismo , Sulfeto de Hidrogênio/metabolismo , Fatores de Tempo , gama-Glutamiltransferase/metabolismo
8.
PLoS One ; 6(2): e16975, 2011 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-21386990

RESUMO

BACKGROUND: The von Hippel-Lindau (VHL) tumor suppressor gene encodes a component of a ubiquitin ligase complex, which is best understood as a negative regulator of hypoxia inducible factor (HIF). VHL ubiquitinates and degrades the α subunits of HIF, and this is proposed to suppress tumorigenesis and tumor angiogenesis. However, several lines of evidence suggest that there are unidentified substrates or targets for VHL that play important roles in tumor suppression. METHODOLOGY/PRINCIPAL FINDINGS: Employing quantitative proteomics, we developed an approach to systematically identify the substrates of ubiquitin ligases and using this method, we identified the Myb-binding protein p160 as a novel substrate of VHL. CONCLUSIONS/SIGNIFICANCE: A major barrier to understanding the functions of ubiquitin ligases has been the difficulty in pinpointing their ubiquitination substrates. The quantitative proteomics approach we devised for the identification of VHL substrates will be widely applicable to other ubiquitin ligases.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas Nucleares/metabolismo , Proteômica , Proteína Supressora de Tumor Von Hippel-Lindau/fisiologia , Animais , Células 3T3 BALB , Células Cultivadas , Proteínas de Ligação a DNA , Desferroxamina/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Marcação por Isótopo/métodos , Leupeptinas/farmacologia , Camundongos , Modelos Biológicos , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteômica/métodos , Proteínas de Ligação a RNA , Sideróforos/farmacologia , Fatores de Transcrição , Ubiquitina-Proteína Ligases/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
9.
J Immunotoxicol ; 8(4): 346-58, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22017689

RESUMO

Estriol (E(3)), an endogenous estrogen predominantly produced during human pregnancy, has been suggested to play an important role in modulating the immune system function during pregnancy. The present study sought to investigate the ability of E(3) to alter splenocyte functions in non-immunized naïve BALB/c female mice and also in mice injected with complete Freund's adjuvant (CFA), and the effect of E(3) was compared with that of 17ß-estradiol (E(2)). When mice were injected with CFA, their spleen weight index (i.e., wet organ wet/whole body weight) was increased by ~ 300%, but co-administration of E(3) almost completely suppressed splenomegaly. E(3) also reduced cytokine production and reduced ERK and p38 activation in both splenocytes and peritoneal exudate cells from CFA-treated animals. In comparison, while E(2) had a similar but slightly weaker effect than E(3) in reducing splenomegaly, it had a rather different effect from E(3) on cytokine production and ERK activation in splenocytes and peritoneal exudate cells from CFA-treated mice. Under naïve immunological conditions, E(3) and E(2) had very similar effects on splenocyte functions. Both of them transiently increased the percentages of splenic CD4(+) and CD8(+) cells. They also increased the proliferation of splenocytes ex vivo, and stimulated production of interferon-γ and interleukin-2. Altogether, these data show that E(3) and E(2) have different effects on splenocyte functions when the animals are under experimentally induced inflammatory conditions.


Assuntos
Estradiol/farmacologia , Estriol/farmacologia , Estrogênios/farmacologia , Adjuvante de Freund/farmacologia , Baço/efeitos dos fármacos , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Antagonismo de Drogas , Feminino , Interferon gama/metabolismo , Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Tamanho do Órgão/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Esplenomegalia/induzido quimicamente
10.
Stem Cells Dev ; 19(7): 1095-107, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19737070

RESUMO

The difficulty in long-term expansion of mesenchymal stem cells (MSCs) using standard culture systems without the loss of their stem cell properties suggests that a critical feature of their microenvironment necessary for retention of stem cell properties is absent in these culture systems. We report here the reconstitution of a native extracellular matrix (ECM) made by human marrow cells ex vivo, which consists of at least collagen types I and III, fibronectin, small leucine-rich proteoglycans such as biglycan and decorin, and major components of basement membrane such as the large molecular weight proteoglycan perlecan and laminin. Expansion of human MSCs on this ECM strongly promoted their proliferation, retained their stem cell properties with a low level of reactive oxygen species (ROS), and substantially increased their response to BMP-2. The quality of the expanded cells following each passage was further tested by an in vivo transplantation assay. The results showed that MSCs expanded on the ECM for multiple passages still retained the same capacity for skeletogenesis. In contrast, the bone formation capacity of cells expanded on plastic was dramatically diminished after 6-7 passages. These findings suggest that the marrow stromal cell-derived ECM is a promising matrix for expanding largescale highly functional MSCs for eventualuse in stem cell-based therapy. Moreover, this system should also be invaluable for establishment of a unique tissue-specific ECM, which will facilitate control of the fate of MSCs for therapeutic applications.


Assuntos
Células da Medula Óssea/fisiologia , Técnicas de Cultura de Células/métodos , Matriz Extracelular/metabolismo , Células-Tronco Mesenquimais/fisiologia , Animais , Células da Medula Óssea/citologia , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Células Cultivadas , Matriz Extracelular/química , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Humanos , Sialoproteína de Ligação à Integrina , Células-Tronco Mesenquimais/citologia , Análise em Microsséries , Osteocalcina/genética , Osteocalcina/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sialoglicoproteínas/genética , Sialoglicoproteínas/metabolismo , Telomerase/metabolismo
12.
J Biol Chem ; 283(28): 19351-8, 2008 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-18482986

RESUMO

The metabolism of glutathione by the periodontal pathogen Treponema denticola produces hydrogen sulfide, which may play a role in the host tissue destruction seen in periodontitis. H2S production in this organism has been proposed to occur via a three enzyme pathway, gamma-glutamyltransferase, cysteinylglycinase (CGase), and cystalysin. In this study, we describe the purification and characterization of T. denticola CGase. Standard approaches were used to purify a 52-kDa CGase activity from T. denticola, and high pressure liquid chromatography electrospray ionization tandem mass spectrometry analysis of this molecule showed that it matches the amino acid sequence of a predicted 52-kDa protein in the T. denticola genome data base. A recombinant version of this protein was overexpressed in and purified from Escherichia coli and shown to catalyze the hydrolysis of cysteinylglycine (Cys-Gly) with the same kinetics as the native protein. Surprisingly, because sequence homology indicates that this protein is a member of a family of metalloproteases called M17 leucine aminopeptidases, the preferred substrate for the T. denticola protein is Cys-Gly (k cat/Km of 8.2 microm(-1) min(-1)) not l-Leu-p-NA (k cat/Km of 1.1 microm(-1) min(-1)). The activity of CGase for Cys-Gly is optimum at pH 7.3 and is enhanced by Mn2+, Co2+, or Mg2+ but not by Zn2+ or Ca2+. Importantly, in combination with the two other previously purified T. denticola enzymes, gamma-glutamyltransferase and cystalysin, CGase mediates the in vitro degradation of glutathione into the expected end products, including H2S. These results prove that T. denticola contains the entire three-step pathway to produce H2S from glutathione, which may be important for pathogenesis.


Assuntos
Proteínas de Bactérias/metabolismo , Dipeptidases/metabolismo , Glutationa/biossíntese , Leucil Aminopeptidase/metabolismo , Treponema denticola/enzimologia , Sequência de Aminoácidos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Cromatografia Líquida de Alta Pressão , Dipeptidases/química , Dipeptidases/genética , Dipeptídeos/química , Dipeptídeos/genética , Dipeptídeos/metabolismo , Escherichia coli/genética , Genoma Bacteriano/fisiologia , Sulfeto de Hidrogênio/metabolismo , Hidrólise , Leucil Aminopeptidase/química , Leucil Aminopeptidase/genética , Periodontite/enzimologia , Periodontite/genética , Periodontite/microbiologia , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Treponema denticola/genética , Treponema denticola/patogenicidade , gama-Glutamiltransferase/química , gama-Glutamiltransferase/genética , gama-Glutamiltransferase/metabolismo
13.
Cell Biol Int ; 28(4): 323-5, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15109990

RESUMO

GDNF plays an important role in the survival and differentiation of primary dopaminergic neurons, but it requires multiple factors for its entire range of activities. This study investigated the effects of GDNF and its cofactors on the development of bFGF-responsive neural progenitor cells (NPCs), mesencephalic and cortical progenitor cells (MP and CP). Various factors were found to have significant inductive effects on the survival and maintenance of these cells in late developmental stages. MP had greater potential than CP to differentiate into dopaminergic neurons. Treatment of NPCs with GDNF and its cofactors enhanced MAP-2 and TH expression, particularly the latter. These findings suggest that NPCs, particularly MP, could develop into more specific neurons if the appropriate factors were applied during the final cell fate specification. They might thus become beneficial sources of donor cells in the treatment of neurological disorders.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fatores de Crescimento Neural/farmacologia , Neurônios/metabolismo , Células-Tronco/citologia , Animais , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Dopamina/metabolismo , Fator 2 de Crescimento de Fibroblastos/farmacologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Mesencéfalo/citologia , Mesencéfalo/metabolismo , Neurônios/efeitos dos fármacos , Fosfoproteínas Fosfatases/metabolismo , Ratos , Células-Tronco/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
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