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1.
Int J Obes (Lond) ; 46(1): 68-76, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34493775

RESUMO

BACKGROUND/OBJECTIVES: Platelet-activating factor receptor (PAFR) activation controls adipose tissue (AT) expansion in animal models. Our objective was twofold: (i) to check whether PAFR signaling is involved in human obesity and (ii) investigate the PAF pathway role in hematopoietic or non-hematopoietic cells to control adipocyte size. MATERIALS/SUBJECTS AND METHODS: Clinical parameters and adipose tissue gene expression were evaluated in subjects with obesity. Bone marrow (BM) transplantation from wild-type (WT) or PAFR-/- mice was performed to obtain chimeric PAFR-deficient mice predominantly in hematopoietic or non-hematopoietic-derived cells. A high carbohydrate diet (HC) was used to induce AT remodeling and evaluate in which cell compartment PAFR signaling modulates it. Also, 3T3-L1 cells were treated with PAF to evaluate fat accumulation and the expression of genes related to it. RESULTS: PAFR expression in omental AT from humans with obesity was negatively correlated to different corpulence parameters and more expressed in the stromal vascular fraction than adipocytes. Total PAFR-/- increased adiposity compared with WT independent of diet-induced obesity. Differently, WT mice receiving PAFR-/--BM exhibited similar adiposity gain as WT chimeras. PAFR-/- mice receiving WT-BM showed comparable augmentation in adiposity as total PAFR-/- mice, demonstrating that PAFR signaling modulates adipose tissue expansion through non-hematopoietic cells. Indeed, the PAF treatment in 3T3-L1 adipocytes reduced fat accumulation and expression of adipogenic genes. CONCLUSIONS: Therefore, decreased PAFR signaling may favor an AT accumulation in humans and animal models. Importantly, PAFR signaling, mainly in non-hematopoietic cells, especially in adipocytes, appears to play a significant role in regulating diet-induced AT expansion.


Assuntos
Tecido Adiposo/fisiopatologia , Obesidade/complicações , Glicoproteínas da Membrana de Plaquetas/farmacologia , Tecido Adiposo/metabolismo , Adulto , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Paris , Receptores Acoplados a Proteínas G , Transdução de Sinais/fisiologia
2.
Eur J Immunol ; 49(7): 1038-1051, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30939218

RESUMO

Sphingosine-1-phosphate (S1P) is an important sphingolipid derived from plasma membrane and has a known role in productive phase of inflammation, but its role in neutrophil survival and resolution phase of inflammation is unknown. Here, we investigated the effects of inhibition of S1P receptors and the blockade of S1P synthesis in BALB/c mice and human neutrophils. S1P and S1PR1-3 receptors expression were increased in cells from the pleural cavity stimulated with LPS. Using different antagonists of S1PRs and inhibitors of different steps of the metabolic pathway of S1P production, we show that S1P and its receptors are involved in regulating neutrophil survival and resolution of inflammation in the pleural cavity. Given the role of the S1P-S1PR axis in resolution of inflammation, we sought to identify whether blockade at different levels of the sphingosine-1-phosphate synthesis pathway could affect neutrophil survival in vitro. Inhibitors of the S1P pathway were also able to induce human neutrophil apoptosis. In addition, blockade of S1P synthesis or its receptor facilitated the efferocytosis of apoptotic neutrophil. Taken together, our data demonstrate a fundamental role for S1P in regulating the outcome of inflammatory responses, and position S1P-S1PR axis as a potential target for treatment of neutrophilic inflammation.


Assuntos
Inflamação/imunologia , Lisofosfolipídeos/metabolismo , Neutrófilos/imunologia , Cavidade Pleural/imunologia , Receptores de Esfingosina-1-Fosfato/metabolismo , Esfingosina/análogos & derivados , Animais , Apoptose , Sobrevivência Celular , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ativação de Neutrófilo , Transdução de Sinais , Esfingosina/metabolismo , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores
3.
Mar Drugs ; 11(7): 2595-615, 2013 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-23873335

RESUMO

Lithothamnion muelleri (Hapalidiaceae) is a marine red alga, which is a member of a group of algae with anti-inflammatory, antitumor, and immunomodulatory properties. The present study evaluated the effects of treatment with Lithothamnion muelleri extract (LM) in a model of acute graft-versus-host disease (GVHD), using a model of adoptive splenocyte transfer from C57BL/6 donors into B6D2F1 recipient mice. Mice treated with LM showed reduced clinical signs of disease and mortality when compared with untreated mice. LM-treated mice had reduced tissue injury, less bacterial translocation, and decreased levels of proinflammatory cytokines and chemokines (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 3 (CCL3) and chemokine (C-C motif) ligand 5 (CCL5)). The polysaccharide-rich fraction derived from LM could inhibit leukocyte rolling and adhesion in intestinal venules, as assessed by intravital microscopy. LM treatment did not impair the beneficial effects of graft-versus-leukaemia (GVL). Altogether, our studies suggest that treatment with Lithothamnion muelleri has a potential therapeutic application in GVHD treatment.


Assuntos
Anti-Inflamatórios/imunologia , Doença Enxerto-Hospedeiro/imunologia , Inflamação/imunologia , Rodófitas/imunologia , Animais , Adesão Celular/imunologia , Linhagem Celular , Citocinas/imunologia , Modelos Animais de Doenças , Células Endoteliais/imunologia , Intestinos/imunologia , Leucócitos/imunologia , Hepatopatias/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL
4.
Eur J Pharmacol ; 901: 174089, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33826922

RESUMO

The participation of the peripheral opioid and cannabinoid endogenous systems in modulating muscle pain and inflammation has not been fully explored. Thus, the aim of this study was to investigate the involvement of these endogenous systems during muscular-tissue hyperalgesia induced by inflammation. Hyperalgesia was induced by carrageenan injection into the tibialis anterior muscles of male Wistar rats. We padronized an available Randal-Sellito test adaptation to evaluate nociceptive behavior elicited by mechanical insult in muscles. Western blot analysis was performed to evaluate the expression levels of opioid and cannabinoid receptors in the dorsal root ganglia. The non-selective opioid peptide receptor antagonist (naloxone) and the selective mu opioid receptor MOP (clocinnamox) and kappa opioid receptor KOP (nor-binaltorphimine) antagonists were able to intensify carrageenan-induced muscular hyperalgesia. On the other hand, the selective delta opioid receptor (DOP) antagonist (naltrindole) did not present any effect on nociceptive behavior. Moreover, the selective inhibitor of aminopeptidases (Bestatin) provoked considerable dose-dependent analgesia when intramuscularly injected into the hyperalgesic muscle. The CB1 receptor antagonist (AM251), but not the CB2 receptor antagonist (AM630), intensified muscle hyperalgesia. All irreversible inhibitors of anandamide hydrolase (MAFP), the inhibitor for monoacylglycerol lipase (JZL184) and the anandamide reuptake inhibitor (VDM11) decreased carrageenan-induced hyperalgesia in muscular tissue. Lastly, MOP, KOP and CB1 expression levels in DRG were baseline even after muscular injection with carrageenan. The endogenous opioid and cannabinoid systems participate in peripheral muscle pain control through the activation of MOP, KOP and CB1 receptors.


Assuntos
Mialgia/tratamento farmacológico , Receptores de Canabinoides/fisiologia , Receptores Opioides/fisiologia , Animais , Ácidos Araquidônicos/antagonistas & inibidores , Carragenina , Cinamatos/farmacologia , Endocanabinoides/antagonistas & inibidores , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/psicologia , Masculino , Monoacilglicerol Lipases/antagonistas & inibidores , Derivados da Morfina/farmacologia , Mialgia/induzido quimicamente , Mialgia/psicologia , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Medição da Dor/efeitos dos fármacos , Alcamidas Poli-Insaturadas/antagonistas & inibidores , Ratos , Ratos Wistar , Receptores de Canabinoides/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos , Receptores Opioides delta/efeitos dos fármacos , Receptores Opioides kappa/efeitos dos fármacos , Receptores Opioides mu/efeitos dos fármacos
5.
Cells ; 8(9)2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31450835

RESUMO

Uncontrolled inflammation leads to tissue damage and it is central for the development of chronic inflammatory diseases and autoimmunity. An acute inflammatory response is finely regulated by the action of anti-inflammatory and pro-resolutive mediators, culminating in the resolution of inflammation and restoration of homeostasis. There are few studies investigating intracellular signaling pathways associated with the resolution of inflammation. Here, we investigate the role of Rho-associated kinase (ROCK), a serine/threonine kinase, in a model of self-resolving neutrophilic inflammatory. We show that ROCK activity, evaluated by P-MYPT-1 kinetics, was higher during the peak of lipopolysaccharide-induced neutrophil influx in the pleural cavity of mice. ROCK inhibition by treatment with Y-27632 decreased the accumulation of neutrophils in the pleural cavity and was associated with an increase in apoptotic events and efferocytosis, as evaluated by an in vivo assay. In a model of gout, treatment with Y-27632 reduced neutrophil accumulation, IL-1ß levels and hypernociception in the joint. These were associated with reduced MYPT and IκBα phosphorylation levels and increased apoptosis. Finally, inhibition of ROCK activity also induced apoptosis in human neutrophils and destabilized cytoskeleton, extending the observed effects to human cells. Taken together, these data show that inhibition of the ROCK pathway might represent a potential therapeutic target for neutrophilic inflammatory diseases.


Assuntos
Amidas/administração & dosagem , Inflamação/tratamento farmacológico , Lipopolissacarídeos/efeitos adversos , Neutrófilos/citologia , Piridinas/administração & dosagem , Quinases Associadas a rho/metabolismo , Amidas/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas I-kappa B/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Camundongos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Piridinas/farmacologia
6.
PLoS One ; 10(4): e0123004, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25875016

RESUMO

Graft versus host disease (GVHD) is an immunological disorder triggered by bone marrow transplantation that affects several organs, including the gastrointestinal tract and liver. Fullerenes and their soluble forms, fullerols, are nanocomposites with a closed symmetrical structure with anti-inflammatory and anti-oxidant properties. The present study evaluated the effects of treatment with the fullerol (C60(OH)18-20) in the development and pathogenesis of GVHD in a murine model. Mice with experimental GVHD that were treated with the fullerol showed reduced clinical signs of disease and mortality compared with untreated mice. Treatment with the fullerol decreased the hepatic damage associated with reduced hepatic levels of reactive oxygen species, pro-inflammatory cytokines and chemokines (IFN-γ TNF-α, CCL2, CCL3 and CCL5) and reduced leukocyte accumulation. The amelioration of GVHD after treatment with the fullerol was also associated with reduced intestinal lesions and consequent bacterial translocation to the blood, liver and peritoneal cavity. Moreover, the fullerol treatment alleviated the GVHD while preserving effects of the graft against a leukemia cell line (GFP+P815). In summary, the fullerol was effective in reducing the GVHD inflammatory response in mice and may suggest novel ways to treat this disease.


Assuntos
Antineoplásicos/química , Fulerenos/química , Doença Enxerto-Hospedeiro/terapia , Nanocompostos/química , Animais , Transplante de Medula Óssea/efeitos adversos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Inflamação , Fígado/patologia , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Neutrófilos/citologia , Espécies Reativas de Oxigênio/metabolismo
7.
PLoS One ; 9(5): e96464, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24798414

RESUMO

Intense exercise is a physiological stress capable of inducing the interaction of neutrophils with muscle endothelial cells and their transmigration into tissue. Mechanisms driving this physiological inflammatory response are not known. Here, we investigate whether production of reactive oxygen species is relevant for neutrophil interaction with endothelial cells and recruitment into the quadriceps muscle in mice subjected to the treadmill fatiguing exercise protocol. Mice exercised until fatigue by running for 56.3±6.8 min on an electric treadmill. Skeletal muscle was evaluated by intravital microscopy at different time points after exercise, and then removed to assess local oxidative stress and histopathological analysis. We observed an increase in plasma lactate and creatine kinase (CK) concentrations after exercise. The numbers of monocytes, neutrophils, and lymphocytes in blood increased 12 and 24 hours after the exercise. Numbers of rolling and adherent leukocytes increased 3, 6, 12, and 24 hours post-exercise, as assessed by intravital microscopy. Using LysM-eGFP mice and confocal intravital microscopy technology, we show that the number of transmigrating neutrophils increased 12 hours post-exercise. Mutant gp91phox-/- (non-functional NADPH oxidase) mice and mice treated with apocynin showed diminished neutrophil recruitment. SOD treatment promoted further adhesion and transmigration of leukocytes 12 hours after the exercise. These findings confirm our hypothesis that treadmill exercise increases the recruitment of leukocytes to the postcapillary venules, and NADPH oxidase-induced ROS plays an important role in this process.


Assuntos
Músculo Esquelético/citologia , Neutrófilos/metabolismo , Esforço Físico/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Acetofenonas/farmacologia , Animais , Creatina Quinase/sangue , Ácido Láctico/sangue , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Neutrófilos/citologia , Neutrófilos/fisiologia
8.
J Leukoc Biol ; 91(4): 629-39, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22301794

RESUMO

PAF is a potent lipid mediator involved in several manifestations of acute inflammation, including leukocyte influx, leukocyte interaction with endothelium, and production of inflammatory cytokines. The present study evaluated the relevance of PAFR for the pathogenesis of acute GVHD using a model of adoptive transfer of splenocytes from WT or PAFR(-/-) C57BL/6J to B6D2F1 mice. Mice, which received PAFR(-/-) splenocytes or treatment with the PAFR antagonist, showed reduced clinical signs of disease and no mortality. In GVHD mice receiving PAFR(-/-) splenocytes, there was deceased bacterial translocation and tissue injury. Furthermore, production of proinflammatory cytokines and chemokines (TNF-α, IFN-γ, CCL2, CCL3, and CCL5) and accumulation of CD8(+) cells in intestine and liver were reduced in mice transplanted with the PAFR(-/-) splenocyte. Mechanistically, an absence or pharmacological blockade of PAFR was associated with decreased rolling and adhesion of leukocytes to the mesenteric microcirculation, as assessed by intravital microscopy. Despite decreased GVHD, there was maintained GVL activity when PAFR(-/-) leukocytes were transferred into WT mice. In conclusion, PAFR on donor leukocytes plays a critical role in GVHD by mediating leukocyte influx and cytokine production in target tissues. PAFR antagonist may potentially be useful in the treatment of GVHD in bone marrow-transplanted patients.


Assuntos
Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/metabolismo , Leucócitos/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transferência Adotiva , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Leucócitos/patologia , Masculino , Camundongos , Camundongos Knockout , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Glicoproteínas da Membrana de Plaquetas/genética , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/genética , Baço/metabolismo , Baço/patologia , Transplante Homólogo
9.
J Leukoc Biol ; 89(6): 955-64, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21402770

RESUMO

PI(3)Kγ is thought to mediate leukocyte migration to injured tissues and may be important in the pathogenesis of various T-lymphocyte-dependent pathologies, including autoimmune and inflammatory diseases. The present study evaluated the relevance of PI(3)Kγ in donor cells for the pathogenesis of acute GVHD using a model of adoptive transfer of splenocytes from WT or PI(3)Kγ(-/-) C57BL/6J mice to B6D2F1 mice, and mice that received PI(3)Kγ(-/-) cells showed reduced clinical signs of disease, bacterial translocation, tissue injury, and lethality rates. This was associated with reduced production of proinflammatory cytokines and chemokines (TNF-α, IFN-γ, CCL2, CCL3, and CCL5) and reduced infiltration of CD8(+), CD4(+), and CD11c(+) cells in the small intestine. Mechanistically, in addition to decreasing production of proinflammatory mediators, absence or pharmacological blockade of PI(3)Kγ was associated with decreased rolling and adhesion of leukocytes to the mesenteric microcirculation, as assessed by intravital microscopy. Despite decreased GVHD, there was maintained GVL activity when PI(3)Kγ(-/-) leukocytes were transferred into WT mice. In conclusion, PI(3)Kγ plays a critical role in GVHD by mediating leukocyte influx and activation in tissues. PI(3)Kγ inhibitors may be useful in the treatment of GVHD in patients undergoing BMT.


Assuntos
Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/mortalidade , Efeito Enxerto vs Leucemia/imunologia , Intestino Delgado/imunologia , Leucócitos/metabolismo , Fígado/imunologia , Fosfatidilinositol 3-Quinases/fisiologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Técnicas Imunoenzimáticas , Intestino Delgado/lesões , Intestino Delgado/metabolismo , Leucócitos/efeitos dos fármacos , Fígado/lesões , Fígado/metabolismo , Masculino , Mastocitoma/imunologia , Mastocitoma/metabolismo , Mastocitoma/patologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Baço/citologia , Baço/transplante , Taxa de Sobrevida
10.
J Leukoc Biol ; 87(5): 895-904, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20103769

RESUMO

PDE4 inhibitors are effective anti-inflammatory drugs whose effects and putative mechanisms on resolution of inflammation and neutrophil apoptosis in vivo are still unclear. Here, we examined the effects of specific PDE4 inhibition on the resolution of neutrophilic inflammation in the pleural cavity of LPS-challenged mice. LPS induced neutrophil recruitment that was increased at 4 h, peaked at 8-24 h, and declined thereafter. Such an event in the pleural cavity was preceded by increased levels of KC and MIP-2 at 1 and 2 h. Treatment with the PDE4 inhibitor rolipram, at 4 h after LPS administration, decreased the number of neutrophils and increased the percentage of apoptotic cells in the pleural cavity in a PKA-dependent manner. Conversely, delayed treatment with a CXCR2 antagonist failed to prevent neutrophil recruitment. Forskolin and db-cAMP also decreased the number of neutrophils and increased apoptosis in the pleural cavity. The proapoptotic effect of rolipram was associated with decreased levels of the prosurvival protein Mcl-1 and increased caspase-3 cleavage. The pan-caspase inhibitor zVAD-fmk prevented rolipram-induced resolution of inflammation. LPS resulted in a time-dependent activation of Akt, which was blocked by treatment with rolipram or PI3K and Akt inhibitors, and PI3K and Akt inhibitors also enhanced apoptosis and promoted neutrophil clearance. Although LPS induced NF-kappaB activation, which was blocked by rolipram, NF-kappaB inhibitors did not promote resolution of neutrophil accumulation in this model. In conclusion, our data show that PDE4 inhibition resolves neutrophilic inflammation by promoting caspase-dependent apoptosis of inflammatory cells by targeting a PKA/PI3K/Akt-dependent survival pathway.


Assuntos
Apoptose/imunologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inflamação/imunologia , Neutrófilos/imunologia , Transdução de Sinais/imunologia , Animais , Western Blotting , Quimiotaxia de Leucócito , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/imunologia , Fragmentação do DNA , Ensaio de Desvio de Mobilidade Eletroforética , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática , Inflamação/induzido quimicamente , Inflamação/enzimologia , Lipopolissacarídeos/imunologia , Camundongos , NF-kappa B/metabolismo , Neutrófilos/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Cavidade Pleural/imunologia , Cavidade Pleural/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
11.
Biochem Pharmacol ; 78(4): 396-405, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19422809

RESUMO

Selective and timely induction of apoptosis is an effective means of resolving inflammation. The effects and putative mechanisms by which cyclic AMP (cAMP) modulates leukocyte apoptosis in vivo are still unclear. The present study aims at identifying intracellular pathways underlying the ability of cAMP elevating agents to resolve eosinophilic inflammation in a model of allergic pleurisy in mice. Ovalbumin (OVA) challenge of immunized mice induced eosinophil recruitment that peaked at 24h and persisted till 48h. Treatment with the PDE4 inhibitor rolipram, cAMP mimetic db-cAMP or adenylate cyclase activator forskolin, at 24h after antigen-challenge resulted in profound resolution of eosinophilic inflammation, without a decrease of mononuclear cell numbers. There was a concomitant increase in number of apoptotic cells in the pleural cavity. The effects of rolipram and db-cAMP were inhibited by the PKA inhibitor H89. Inhibition of PI3K/Akt or NF-kappaB induced resolution of inflammation that was associated with increased apoptosis. OVA-challenge resulted in a time-dependent activation of Akt and NF-kappaB, which was blocked by treatment with rolipram or PI3K/Akt pathway inhibitors. Thus, cAMP elevating agents resolve established eosinophilic inflammation by inducing leukocyte apoptosis. Mechanistically, the actions of cAMP are dependent on PKA and target a PI3K/Akt-dependent NF-kappaB survival pathway.


Assuntos
Apoptose/efeitos dos fármacos , AMP Cíclico/efeitos adversos , Eosinófilos/fisiologia , Hipersensibilidade/patologia , NF-kappa B/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Pleurisia/induzido quimicamente , Animais , Células Cultivadas , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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