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1.
J Neuroinflammation ; 20(1): 200, 2023 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-37660072

RESUMO

BACKGROUND: Peripheral nerve injury to dorsal root ganglion (DRG) neurons develops intractable neuropathic pain via induction of neuroinflammation. However, neuropathic pain is rare in the early life of rodents. Here, we aimed to identify a novel therapeutic target for neuropathic pain in adults by comprehensively analyzing the difference of gene expression changes between infant and adult rats after nerve injury. METHODS: A neuropathic pain model was produced in neonatal and young adult rats by spared nerve injury. Nerve injury-induced gene expression changes in the dorsal root ganglion (DRG) were examined using RNA sequencing. Thymic stromal lymphopoietin (TSLP) and its siRNA were intrathecally injected. T cells were examined using immunofluorescence and were reduced by systemic administration of FTY720. RESULTS: Differences in changes in the transcriptome in injured DRG between infant and adult rats were most associated with immunological functions. Notably, TSLP was markedly upregulated in DRG neurons in adult rats, but not in infant rats. TSLP caused mechanical allodynia in adult rats, whereas TSLP knockdown suppressed the development of neuropathic pain. TSLP promoted the infiltration of T cells into the injured DRG and organized the expressions of multiple factors that regulate T cells. Accordingly, TSLP caused mechanical allodynia through T cells in the DRG. CONCLUSION: This study demonstrated that TSLP is causally involved in the development of neuropathic pain through T cell recruitment.


Assuntos
Neuralgia , Linfopoietina do Estroma do Timo , Ratos , Animais , Gânglios Espinais , Hiperalgesia/etiologia , Linfócitos T , Citocinas , Neurônios
2.
Int J Mol Sci ; 24(15)2023 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-37569481

RESUMO

Lipid accumulation in the liver due to chronic alcohol consumption (CAC) is crucial in the development of alcohol liver disease (ALD). It is promoted by the NADH/NAD ratio increase via alcohol dehydrogenase (ADH)-dependent alcohol metabolism and lipogenesis increase via peroxisome proliferator-activated receptor γ (PPARγ) in the liver. The transcriptional activity of PPARγ on lipogenic genes is inhibited by S-nitrosylation but activated by denitrosylation via S-nitrosoglutathione reductase (GSNOR), an enzyme identical to ADH3. Besides ADH1, ADH3 also participates in alcohol metabolism. Therefore, we investigated the specific contribution of ADH3 to ALD onset. ADH3-knockout (Adh3-/-) and wild-type (WT) mice were administered a 10% ethanol solution for 12 months. Adh3-/- exhibited no significant pathological changes in the liver, whereas WT exhibited marked hepatic lipid accumulation (p < 0.005) with increased serum transaminase levels. Adh3-/- exhibited no death during CAC, whereas WT exhibited a 40% death. Liver ADH3 mRNA levels were elevated by CAC in WT (p < 0.01). The alcohol elimination rate measured after injecting 4 g/kg ethanol was not significantly different between two strains, although the rate was increased in both strains by CAC. Thus, ADH3 plays a key role in the ALD onset, likely by acting as GSNOR.


Assuntos
Hepatopatias Alcoólicas , Oxirredutases , Animais , Camundongos , Álcool Desidrogenase/genética , Álcool Desidrogenase/metabolismo , Etanol/metabolismo , Lipídeos , Fígado/metabolismo , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/metabolismo , Oxirredutases/metabolismo , PPAR gama/metabolismo
3.
Alcohol Alcohol ; 55(1): 11-19, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31825074

RESUMO

AIMS: It is still unclear which enzymes contribute to the adaptive enhancement of alcohol metabolism by chronic alcohol consumption (CAC). ADH1 (Class I) has the lowest Km for ethanol and the highest sensitivity for 4-methylpyrazole (4MP) among ADH isozymes, while ADH3 (Class III) has the highest Km and the lowest sensitivity. We investigated how these two major ADHs relate to the adaptive enhancement of alcohol metabolism. METHODS: Male mice with different ADH genotypes (WT, Adh1-/- and Adh3-/-) were subjected to CAC experiment using a 10% ethanol solution for 1 month. Alcohol elimination rate (AER) was measured after ethanol injection at a 4.0 g/kg dose. 4MP-sensitive and -insensitive AERs were measured by the simultaneous administration of 4MP at a dose of 0.5 mmol/kg in order to estimate ADH1 and non-ADH1 pathways. RESULTS: AER was enhanced by CAC in all ADH genotypes, especially more than twofold in Adh1-/- mice, with increasing ADH1 and/or ADH3 liver contents, but not CYP2E1 content. 4MP-sensitive AER was also increased by CAC in WT and Adh3-/- strains, which was greater in Adh3-/- than in WT mice. The sensitive AER was increased even in Adh1-/- mice probably due to the increase in ADH3, which is semi-sensitive for 4MP. 4MP-insensitive AER was also increased in WT and Adh1-/- by CAC, but not in Adh3-/- mice. CONCLUSION: ADH1 contributes to the enhancement of alcohol metabolism by CAC, particularly in the absence of ADH3. ADH3 also contributes to the enhancement as a non-ADH1 pathway, especially in the absence of ADH1.


Assuntos
Álcool Desidrogenase/fisiologia , Eliminação Renal/fisiologia , Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Etanol/metabolismo , Fomepizol/farmacologia , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos , Eliminação Renal/efeitos dos fármacos
4.
J Cell Mol Med ; 23(10): 7043-7053, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31424157

RESUMO

Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD), a primary cause of mortality in patients with RA, has limited treatment options. A previously established RA model in D1CC transgenic mice aberrantly expressed major histocompatibility complex class II genes in joints, developing collagen II-induced polyarthritis and anti-cyclic citrullinated peptide antibodies and interstitial pneumonitis, similar to those in humans. Molecular hydrogen (H2 ) is an efficient antioxidant that permeates cell membranes and alleviates the reactive oxygen species-induced injury implicated in RA pathogenesis. We used D1CC mice to analyse chronic lung fibrosis development and evaluate H2 treatment effects. We injected D1CC mice with type II collagen and supplied them with H2 -rich or control water until analysis. Increased serum surfactant protein D values and lung densities images were observed 10 months after injection. Inflammation was patchy within the perilymphatic stromal area, with increased 8-hydroxy-2'-deoxyguanosine-positive cell numbers and tumour necrosis factor-α, BAX, transforming growth factor-ß, interleukin-6 and soluble collagen levels in the lungs. Inflammatory and fibrotic changes developed diffusely within the perilymphatic stromal area, as observed in humans. H2 treatment decreased these effects in the lungs. Thus, this model is valuable for studying the effects of H2 treatment and chronic interstitial pneumonia pathophysiology in humans. H2 appears to protect against RA-ILD by alleviating oxidative stress.


Assuntos
Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Hidrogênio/uso terapêutico , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/tratamento farmacológico , Animais , Artrite Reumatoide/sangue , Artrite Reumatoide/patologia , Bovinos , Colágeno Tipo II/administração & dosagem , Citocinas/metabolismo , Modelos Animais de Doenças , Hidrogênio/farmacologia , Pulmão/patologia , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/patologia , Masculino , Camundongos , Camundongos Transgênicos , Estresse Oxidativo/efeitos dos fármacos , Proteína D Associada a Surfactante Pulmonar/sangue , Proteína X Associada a bcl-2/metabolismo
5.
J Gastroenterol Hepatol ; 33(11): 1912-1919, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29663519

RESUMO

BACKGROUND AND AIM: Alcohol dehydrogenases (ADHs) 1 and 3 are responsible for systemic alcohol metabolism. The current study investigated the contribution of liver ADH1 and ADH3 to the metabolic pharmacokinetics of chronic alcohol consumption (CAC). METHODS: The 9-week-old male mice of different ADH genotypes (wild-type [WT], Adh1-/- , and Adh3-/- ) were administered with 10% ethanol solution for 1 month, followed by acute ethanol administration (4.0 g/kg). The alcohol elimination rate (AER), area under the blood alcohol concentration curve (AUC), and the maximum blood alcohol concentration (Cmax ) were calculated. The liver content, activity, and mRNA levels of ADH were evaluated. RESULTS: Chronic alcohol consumption increased the AER and reduced the AUC in all ADH genotypes. The increased ADH1 content was correlated with AER in WT mice but not in the Adh3-/- mice. Similarly, the increased ADH3 content was also correlated with AER in both WT and Adh1-/- mice. The Cmax was significantly higher in Adh3-/- control mice than in WT control mice. It decreased in the Adh1-/- mice by CAC along with an increase in the ADH3 content. CONCLUSIONS: Alcohol dehydrogenases 1 and 3 would accomplish the pharmacokinetic adaptation to CAC in the early period. ADH1 contributes to the metabolic pharmacokinetics of CAC with a decrease in AUC in conjunction with an increase of AER by increasing the enzyme content in the presence of ADH3. ADH3 also contributes to a decrease in AUC in conjunction with not only an increase in AER but also a decrease in Cmax by increasing the enzyme content.


Assuntos
Álcool Desidrogenase/metabolismo , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/metabolismo , Etanol/metabolismo , Fígado/enzimologia , Álcool Desidrogenase/genética , Animais , Etanol/sangue , Genótipo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Tempo
7.
Mol Neurobiol ; 61(9): 7168-7180, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38374315

RESUMO

Oxaliplatin, a platinum-based chemotherapeutic agent, frequently causes acute and chronic peripheral sensory neuropathy, for which no effective treatment has been established. In particular, chronic neuropathy can persist for years even after treatment completion, thus worsening patients' quality of life. To avoid the development of intractable adverse effects, a predictive biomarker early in treatment is awaited. In this study, we explored extracellular long non-coding RNAs (lncRNAs) released from primary sensory neurons as biomarker candidates for oxaliplatin-induced peripheral neuropathy. Because many human-specific lncRNA genes exist, we induced peripheral sensory neurons from human induced pluripotent stem cells. Oxaliplatin treatment changed the levels of many lncRNAs in extracellular vesicles (EVs) released from cultured primary sensory neurons. Among them, the levels of release of lncRNAs that were considered to be selectively expressed in dorsal root ganglia were correlated with those of lncRNAs in plasma EV obtained from healthy individuals. Several lncRNAs in plasma EVs early after the initiation of treatment showed greater changes in patients who did not develop chronic neuropathy that persisted for more than 1 year than in those who did. Therefore, these extracellular lncRNAs in plasma EVs may represent predictive biomarkers for the development of chronic peripheral neuropathy induced by oxaliplatin.


Assuntos
Biomarcadores , Células-Tronco Pluripotentes Induzidas , Oxaliplatina , Doenças do Sistema Nervoso Periférico , RNA Longo não Codificante , Células Receptoras Sensoriais , Oxaliplatina/efeitos adversos , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/sangue , Células-Tronco Pluripotentes Induzidas/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia , Masculino , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/efeitos dos fármacos , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Doença Crônica , Pessoa de Meia-Idade , Células Cultivadas
8.
Front Immunol ; 14: 1185322, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37614230

RESUMO

Primary sensory neurons regulate inflammatory processes in innervated regions through neuro-immune communication. However, how their immune-modulating functions are regulated in concert remains largely unknown. Here, we show that Neat1 long non-coding RNA (lncRNA) organizes the proinflammatory gene expressions in the dorsal root ganglion (DRG) in chronic intractable neuropathic pain in rats. Neat1 was abundantly expressed in the DRG and was upregulated after peripheral nerve injury. Neat1 overexpression in primary sensory neurons caused mechanical and thermal hypersensitivity, whereas its knockdown alleviated neuropathic pain. Bioinformatics analysis of comprehensive transcriptome changes indicated the inflammatory response was the most relevant function of genes upregulated through Neat1. Consistent with this, upregulation of proinflammatory genes in the DRG following nerve injury was suppressed by Neat1 knockdown. Expression changes of these proinflammatory genes were regulated through Neat1-mRNA interaction-dependent and -independent mechanisms. Notably, Neat1 increased proinflammatory genes by stabilizing its interacting mRNAs in neuropathic pain. Finally, Neat1 in primary sensory neurons contributed to spinal inflammatory processes that mediated peripheral neuropathic pain. These findings demonstrate that Neat1 lncRNA is a key regulator of neuro-immune communication in neuropathic pain.


Assuntos
Neuralgia , RNA Longo não Codificante , Traumatismos do Sistema Nervoso , Animais , Ratos , RNA Longo não Codificante/genética , Gânglios Espinais , Neuralgia/genética , RNA Mensageiro , Transcriptoma
9.
J Nippon Med Sch ; 86(4): 215-221, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31061251

RESUMO

BACKGROUND: Neuropathic pain is an intractable chronic pain condition caused by damage to the somatosensory system. Although non-coding RNAs such as microRNAs are important regulators of neuropathic pain, the role of long non-coding RNAs (lncRNAs) is poorly understood. METHODS: This study used a rat model of neuropathic pain induced by lumbar fifth spinal nerve ligation (SNL). Microarray analysis of lncRNAs in the lumbar fifth dorsal root ganglion was performed at day 14 after SNL. Expression levels of H19 were examined by using quantitative PCR. In situ hybridization was used to determine the distribution of H19 at day 14 after SNL. Schwann cells were isolated from peripheral nerves at day 14 after SNL. RESULTS: H19 lncRNA was greatly increased in the L5 dorsal root ganglion at day 14 after SNL and was significantly higher at and after day 4. In the dorsal root ganglion, H19 was detected mainly in non-neuronal cells but not in primary sensory neurons. Consistent with this, H19 expression was upregulated in Schwann cells isolated from peripheral nerves after SNL. CONCLUSION: Increased H19 lncRNA in Schwann cells might be involved in neuropathic pain.


Assuntos
Gânglios Espinais , Expressão Gênica , Neuralgia/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Células de Schwann/metabolismo , Animais , Doença Crônica , Modelos Animais de Doenças , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Masculino , Neuralgia/metabolismo , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real
10.
J Nippon Med Sch ; 85(6): 322-329, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30568058

RESUMO

BACKGROUND: Alcohol dehydrogenase 3 (ADH3) plays major roles not only in alcohol metabolism but also in nitric oxide metabolism as S-nitrosoglutathione reductase (GSNOR). ADH3/GSNOR regulates both adipogenesis and osteogenesis through the denitrosylation of peroxisome proliferator-activated receptor γ. The current study investigated the contribution of ADH3 to the development of alcoholic osteoporosis in chronic alcohol consumption (CAC). METHODS: Nine-week-old male mice of different ADH genotypes [wild-type (WT) and Adh3-/-] were administered a 10% ethanol solution for 12 months. The femurs were evaluated by histochemical staining and computed tomography-based bone densitometry. The mRNA levels of ADH3 were evaluated in the WT mice by reverse transcription-quantitative polymerase chain reaction. RESULTS: The Adh3-/- control mice exhibited increased activities of both osteoblasts and osteoclasts and lower bone masses than the WT control mice. CAC exhibited no remarkable change in osteoblastic and osteoclastic activities, but decreased bone masses were observed in WT mice despite an increase in the mRNA levels of ADH3. Conversely, bone masses in the Adh3-/- control mice were not reduced after CAC. CONCLUSIONS: The Adh3-/- control mice exhibited a high turnover of osteoporosis since osteoclastogenesis dominated osteoblastogenesis; however, bone resorption was not enhanced after CAC. In comparison, CAC lead to alcoholic osteoporosis in WT mice, accompanied by increased mRNA levels of ADH3. Hence, ADH3 can prevent osteoporosis development in normal ADH genotypes with no alcohol ingestion. However, ADH3 contributes to the development of alcoholic osteoporosis under CAC by participating in alcohol metabolism, increasing metabolic toxicity, and lowering GSNO reducing activity.


Assuntos
Álcool Desidrogenase/genética , Etanol/toxicidade , Fêmur/efeitos dos fármacos , Osteoporose/genética , Álcool Desidrogenase/metabolismo , Animais , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/metabolismo , Depressores do Sistema Nervoso Central/toxicidade , Etanol/administração & dosagem , Etanol/metabolismo , Fêmur/diagnóstico por imagem , Fêmur/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Genótipo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoporose/induzido quimicamente , Osteoporose/enzimologia , Tomografia Computadorizada por Raios X
11.
Nat Commun ; 8: 16079, 2017 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-28677679

RESUMO

miR-17-92 is a microRNA cluster with six distinct members. Here, we show that the miR-17-92 cluster and its individual members modulate chronic neuropathic pain. All cluster members are persistently upregulated in primary sensory neurons after nerve injury. Overexpression of miR-18a, miR-19a, miR-19b and miR-92a cluster members elicits mechanical allodynia in rats, while their blockade alleviates mechanical allodynia in a rat model of neuropathic pain. Plausible targets for the miR-17-92 cluster include genes encoding numerous voltage-gated potassium channels and their modulatory subunits. Single-cell analysis reveals extensive co-expression of miR-17-92 cluster and its predicted targets in primary sensory neurons. miR-17-92 downregulates the expression of potassium channels, and reduced outward potassium currents, in particular A-type currents. Combined application of potassium channel modulators synergistically alleviates mechanical allodynia induced by nerve injury or miR-17-92 overexpression. miR-17-92 cluster appears to cooperatively regulate the function of multiple voltage-gated potassium channel subunits, perpetuating mechanical allodynia.


Assuntos
Dor Crônica/metabolismo , Hiperalgesia/metabolismo , MicroRNAs/metabolismo , Neuralgia/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Aminopiridinas , Animais , Dor Crônica/etiologia , Regulação para Baixo , Gânglios Espinais/metabolismo , Hiperalgesia/etiologia , Masculino , Neuralgia/etiologia , Neurônios/metabolismo , Compostos de Fenilureia , Ratos Sprague-Dawley , Tetrazóis
12.
Br J Pharmacol ; 174(5): 386-395, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28012171

RESUMO

BACKGROUND AND PURPOSE: Although oxaliplatin is an effective anti-cancer platinum compound, it can cause painful chronic neuropathy, and its molecular mechanisms are poorly understood. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression in a sequence-specific manner. Although miRNAs have been increasingly recognized as important modulators in a variety of pain conditions, their involvement in chemotherapy-induced neuropathic pain is unknown. EXPERIMENTAL APPROACH: Oxaliplatin-induced chronic neuropathic pain was induced in rats by i.p. injections of oxaliplatin (2 mg·kg-1 ) for five consecutive days. The expression levels of miR-15b and ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1 also known as ß-secretase 1) were examined in the dorsal root ganglion (DRG). To examine the function of miR-15b, an adeno-associated viral vector encoding miR-15b was injected into the DRG in vivo. KEY RESULTS: Among the miRNAs examined in the DRG in the late phase of oxaliplatin-induced neuropathic pain, miR-15b was most robustly increased. Our in vitro assay results determined that BACE1 was a target of miR-15b. BACE1 and miR-15b were co-expressed in putative myelinated and unmyelinated DRG neurons. Overexpression of miR-15b in DRG neurons caused mechanical allodynia in association with reduced expression of BACE1. Consistent with these results, a BACE1 inhibitor dose-dependently induced significant mechanical allodynia. CONCLUSIONS AND IMPLICATIONS: These findings suggest that miR-15b contributes to oxaliplatin-induced chronic neuropathic pain at least in part through the down-regulation of BACE1.


Assuntos
Secretases da Proteína Precursora do Amiloide/genética , Ácido Aspártico Endopeptidases/genética , MicroRNAs/genética , Neuralgia/induzido quimicamente , Compostos Organoplatínicos/toxicidade , Animais , Antineoplásicos/toxicidade , Regulação para Baixo/genética , Gânglios Espinais/metabolismo , Injeções Intraperitoneais , Masculino , Neuralgia/genética , Neurônios/metabolismo , Oxaliplatina , Ratos , Ratos Sprague-Dawley
13.
Exp Anim ; 65(4): 447-454, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27356855

RESUMO

Several drug-metabolizing cytochrome P450 (CYP) enzymes exhibit sexual dimorphism depending on the pituitary growth hormone (GH) secretory patterns. However, the mechanism underlying CYP sexual dimorphism remains unclear. We previously established a transgenic (Alb-DsRed2 Tg) rat that expressed red fluorescent DsRed2 protein, particularly in hepatocytes, to visualize cell differentiation and multiplication and found that hepatic DsRed2 expression exhibited sexual dimorphism that was limited to adult males. In this study, we compared the expression patterns between sexual dimorphic Cyps and DsRed2 in Tg rats after experimentally reversing the GH secretory patterns in males and females. Postnatal day 1 male and female Tg rats were gonadectomized and then testosterone propionate (0.25 mg/rat) was subcutaneously administered to ovariectomized females immediately after surgery. Cyp mRNA and DsRed2 expression levels were quantified using RT-PCR and an in vivo imaging system, respectively. GH-dependent Cyps and hepatic DsRed2 expression patterns were reversed in males and females at 9 weeks after birth and were significantly correlated (P<0.05). This suggested that DsRed2 expression in these Tg rats depended on GH secretory patterns. Based on DsRed2 fluorescence, this Tg rat model could become a tool to readily and effectively evaluate changes in GH-dependent Cyp expression.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Família 2 do Citocromo P450/genética , Expressão Gênica , Hormônio do Crescimento/metabolismo , Esteroide 16-alfa-Hidroxilase/genética , Esteroide Hidroxilases/genética , Animais , Hidrocarboneto de Aril Hidroxilases/metabolismo , Família 2 do Citocromo P450/metabolismo , Feminino , Fígado/metabolismo , Proteínas Luminescentes/química , Masculino , Modelos Animais , RNA Mensageiro/metabolismo , Ratos , Ratos Transgênicos , Ratos Wistar , Caracteres Sexuais , Esteroide 16-alfa-Hidroxilase/metabolismo , Esteroide Hidroxilases/metabolismo , Proteína Vermelha Fluorescente
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