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1.
Drug Discov Ther ; 14(1): 35-41, 2020 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-32023558

RESUMO

Lysosomes are involved in many cellular functions, and in turn lysosomal dysfunction underlies a variety of diseases, including cancer and neurodegenerative diseases. Lysosomes are distributed broadly in the cytoplasm and can move throughout the cell in kinesin- and dynein-dependent manners. Although many mechanisms of lysosomal transport have been reported, how lysosomal transport is regulated has yet to be fully elucidated. In this study we analyzed c-Jun NH2-terminal kinase-associated leucine zipper protein (JLP), an adaptor of kinesin and dynein motor proteins, and found that lysosomes were localized toward the cell periphery in JLP knockdown cells, leading to the impairment of autophagosome-lysosome fusion. Furthermore, we performed rescue experiments using wild-type JLP and its various deletion mutants. The results indicated that JLP may regulate lysosome localization and autophagy through interaction of JLP with kinesin-1 heavy chain, but not with dynactin p150Glued or lysosomal transmembrane protein 55b. Our findings provide new insights into the mechanisms of lysosomal trafficking regulation. This study contributes to the understanding of how lysosomes exert their multiple functions, potentially leading to the identification of molecular targets for diseases caused by lysosomal dysfunction.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Autofagia , Lisossomos/metabolismo , Complexo Dinactina/metabolismo , Humanos , Cinesina/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo
2.
Artif Cells Nanomed Biotechnol ; 47(1): 2545-2552, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31213095

RESUMO

Tetramethylpyrazine (TMP) is a traditional Chinese medicine with anti-inflammation and immunomodulatory effects. In this context, our purpose was to investigate the associated regulatory mechanisms of TMP against lipopolysaccharide (LPS)-caused pancreatic ß cell Min6 injury. The injury of Min6 cells was induced by 10 µg/mL of LPS. Viability of Min6 cells was detected through CCK-8 assay, apoptosis process through flow cytometry, and the proteins involved in apoptosis through western blot. Insulin secretion was valued through the glucose-stimulated insulin secretion (GSIS) assay. microRNA-101 (miR-101) was measured through qRT-PCR. Mitogen-activated protein kinase phosphatase 1 (MKP-1) and signaling regulators was measured through western blot. We found that, TMP treatment effectively attenuated LPS-induced injury in Min6 cells by suppressing cell apoptosis and promoting insulin secretion. Further investigation revealed that TMP exerted protective effect through down-regulating miR-101, and MKP-1 was demonstrated as a target of miR-101. Moreover, TMP attenuated LPS-triggered inflammation by inactivating the JNK1/2 and NF-κB through the down-regulation of miR-101. In conclusion, our present study revealed that TMP alleviated LPS-induced injury in pancreatic ß-cell Min6 injury via regulation of miR-101/MKP-1 with the bluntness of JNK1/2 and NF-κB pathways.


Assuntos
Fosfatase 1 de Especificidade Dupla/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Lipopolissacarídeos/efeitos adversos , MicroRNAs/genética , Pirazinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Citoproteção/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/citologia , Camundongos , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Biochemistry (Mosc) ; 84(5): 553-561, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31234769

RESUMO

Obesity is accompanied by dyslipidemia, hypoxia, endoplasmic reticulum (ER) stress, and inflammation, representing the major risk factor for the development of insulin resistance (IR) and type 2 diabetes. We modeled these conditions in cultured 3T3-L1 adipocytes and studied their effect on insulin signaling, glucose uptake, and inflammatory response via activation of stress-dependent JNK1/2 kinases. Decreased insulin-induced phosphorylation of the insulin cascade components IRS, Akt, and AS160 was observed under all tested conditions (lipid overloading of cells by palmitate, acute inflammation induced by bacterial lipopolysaccharide, hypoxia induced by Co2+, and ER stress induced by brefeldin A). In all the cases, except the acute inflammation, glucose uptake by adipocytes was reduced, and the kinetics of JNK1/2 activation was bi-phasic exhibiting sustained activation for 24 h. By contrast, in acute inflammation, JNK1/2 phosphorylation increased transiently and returned to the basal level within 2-3 h of stimulation. These results suggest a critical role of sustained (latent) vs. transient (acute) inflammation in the induction of IR and impairment of glucose utilization by adipose tissue. The components of the inflammatory signaling can be promising targets in the development of new therapeutic approaches for preventing IR and type 2 diabetes.


Assuntos
Inflamação , Resistência à Insulina , Obesidade/patologia , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácidos Graxos não Esterificados/farmacologia , Inflamação/etiologia , Insulina/farmacologia , Lipopolissacarídeos/farmacologia , Camundongos , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Obesidade/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Nat Commun ; 10(1): 2148, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089135

RESUMO

Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1, but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/patologia , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Proteínas Serina-Treonina Quinases/deficiência , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , MAP Quinase Quinase 7/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína Quinase 9 Ativada por Mitógeno/genética , Proteínas Serina-Treonina Quinases/genética , Taxa de Sobrevida , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo
5.
ACS Chem Biol ; 14(7): 1426-1435, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31063355

RESUMO

Overexpression and activation of c-Jun N-terminal kinases (JNKs) have been observed in multiple cancer cell lines and tumor samples. Various JNK isoforms have been reported to promote lung and liver cancer, as well as keratinocyte transformation, suggesting an important role of JNK signaling in promoting tumor development. However, there are three JNK isoforms, and it is unclear how each individual isoform, especially the ubiquitously expressed JNK1 and JNK2, functions in melanoma. Our previous study found that C116S mutations in both JNK1 and JNK2 rendered them insensitive to the covalent pan-JNK inhibitor JNK-IN-8 while retaining kinase activity. To delineate the specific roles of JNK1 and JNK2 in melanoma cell proliferation and invasiveness, we expressed the wild type (WT) and C116S mutants in melanoma cell lines and used JNK-IN-8 to enable chemical-genetic dissection of JNK1 and JNK2 activity. We found that the JNK2C116S allele consistently enhanced colony proliferation and cell invasiveness in the presence of JNK-IN-8. When cells individually expressing WT or C116S JNK1/2 were subcutaneously implanted into immunodeficient mice, we again found that bypass of JNK-IN-8-mediated inhibition of JNK signaling by expression of JNK2C116S specifically resulted in enhanced tumor growth in vivo. In addition, we observed a high level of JNK pathway activation in some human BRAF inhibitor (BRAFi) resistant melanoma cell lines relative to their BRAFi sensitive isogenic counterparts. JNK-IN-8 significantly enhanced the response to dabrafenib in resistant cells overexpressing JNK1WT, JNK2WT, and JNK1C116S but had no effect on cells expressing JNK2C116S, suggesting that JNK2 signaling is also crucial for BRAFi resistance in a subset of melanomas. Collectively, our data show that JNK2 activity is specifically required for melanoma cell proliferation, invasiveness, and BRAFi resistance and that this activity is most important in the context of JNK1 suppression, thus providing a compelling rationale for the development of JNK2 selective inhibitors as a potential therapy for the treatment of melanoma.


Assuntos
Carcinogênese/metabolismo , Melanoma/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Neoplasias Cutâneas/metabolismo , Animais , Carcinogênese/genética , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/genética , Camundongos , Camundongos Nus , Proteína Quinase 9 Ativada por Mitógeno/genética , Invasividade Neoplásica/genética , Neoplasias Cutâneas/genética
6.
Plant Mol Biol ; 100(4-5): 411-431, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30953279

RESUMO

KEY MESSAGE: Physical interaction and phosphorylation by CaMPK9 protects the degradation of CaWRKY40 that induces resistance response in chickpea to Fusarium wilt disease by modulating the transcription of defense responsive genes. WRKY transcription factors (TFs) are the global regulators of plant defense signaling that modulate immune responses in host plants by regulating transcription of downstream target genes upon challenged by pathogens. However, very little is known about immune responsive role of Cicer arietinum L. (Ca) WRKY TFs particularly. Using two contrasting chickpea genotypes with respect to resistance against Fusarium oxysporum f. sp. ciceri Race1 (Foc1), we demonstrate transcript accumulation of different CaWRKYs under multiple stresses and establish that CaWRKY40 triggers defense. CaWRKY40 overexpressing chickpea mounts resistance to Foc1 by positively modulating the defense related gene expression. EMSA, ChIP assay and real-time PCR analyses suggest CaWRKY40 binds at the promoters and positively regulates transcription of CaDefensin and CaWRKY33. Further studies revealed that mitogen Activated Protein Kinase9 (CaMPK9) phosphorylates CaWRKY40 by directly interacting with its two canonical serine residues. Interestingly, CaMPK9 is unable to interact with CaWRKY40 when the relevant two serine residues were replaced by alanine. Overexpression of serine mutated WRKY40 isoform in chickpea fails to provide resistance against Foc1. Mutated WRKY40Ser.224/225 to AA overexpressing chickpea resumes its ability to confer resistance against Foc1 after application of 26S proteasomal inhibitor MG132, suggests that phosphorylation is essential to protect CaWRKY40 from proteasomal degradation. CaMPK9 silencing also led to susceptibility in chickpea to Foc1. Altogether, our results elucidate positive regulatory roles of CaMPK9 and CaWRKY40 in modulating defense response in chickpea upon Foc1 infection.


Assuntos
Cicer/imunologia , Fusarium/fisiologia , Proteínas de Plantas/fisiologia , Cicer/metabolismo , Cicer/microbiologia , Proteína Quinase 9 Ativada por Mitógeno/genética , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/fisiologia , Fosforilação , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , RNA Mensageiro/metabolismo , Estresse Fisiológico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia
7.
J Pathol ; 247(1): 110-122, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30264435

RESUMO

Ibuprofen is a worldwide used non-steroidal anti-inflammatory drug which may cause acute liver injury (ALI) requiring liver transplantation. We aimed to unveil the molecular pathways involved in triggering ibuprofen-induced ALI, which, at present, remain elusive. First, we investigated activation of essential pathways in human liver sections of ibuprofen-induced ALI. Next, we assessed the cytotoxicity of ibuprofen in vitro and developed a novel murine model of ibuprofen intoxication. To assess the role of JNK, we used animals carrying constitutive deletion of c-Jun N-terminal kinase 1 (Jnk1-/- ) or Jnk2 (Jnk2-/- ) expression and included investigations using animals with hepatocyte-specific Jnk deletion either genetically (Jnk1Δhepa ) or by siRNA (siJnk2Δhepa ). We found in human and murine samples of ibuprofen-induced acute liver failure that JNK phosphorylation was increased in the cytoplasm of hepatocytes and other non-liver parenchymal cells (non-LPCs) compared with healthy tissue. In mice, ibuprofen intoxication resulted in a significantly stronger degree of liver injury compared with vehicle-treated controls as evidenced by serum transaminases, and hepatic histopathology. Next, we investigated molecular pathways. PKCα, AKT, JNK and RIPK1 were significantly increased 8 h after ibuprofen intoxication. Constitutive Jnk1-/- and Jnk2-/- deficient mice exhibited increased liver dysfunction compared to wild-type (WT) animals. Furthermore, siJnk2Δhepa animals showed a dramatic increase in biochemical markers of liver function, which correlated with significantly higher serum liver enzymes and worsened liver histology, and MAPK activation compared to Jnk1Δhepa or WT animals. In our study, cytoplasmic JNK activation in hepatocytes and other non-LPCs is a hallmark of human and murine ibuprofen-induced ALI. Functional in vivo analysis demonstrated a protective role of hepatocyte-specific Jnk2 during ibuprofen ALI. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Hepatócitos/enzimologia , Ibuprofeno , Falência Hepática Aguda/prevenção & controle , Fígado/enzimologia , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Animais , Morte Celular , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Ativação Enzimática , Hepatócitos/patologia , Humanos , Fígado/patologia , Falência Hepática Aguda/enzimologia , Falência Hepática Aguda/genética , Falência Hepática Aguda/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/deficiência , Proteína Quinase 9 Ativada por Mitógeno/genética , Fosforilação , Transdução de Sinais
8.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 34(11): 1000-1007, 2018 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-30591109

RESUMO

Objective To investigate the effect of c-Jun N-terminal kinase 1 (JNK1) or JNK2 overexpression on the proliferation and apoptosis of SCL-1 human cutaneous squamous cell carcinoma cell lines. Methods JNK1 and JNK2 were separately combined with pHBAD-EF1-MCS-3FLAG-CMV-GFP vector to construct the recombinant adenovirus expression vectors of JNK1 and JNK2. The recombinant vectors were used to infect SCL-1 cells. After the optimization of the infection conditions, the fold changes of over-expression were identified by real-time quantitative PCR (qRT-PCR) and Western blot analysis. CCK-8 assay was performed to determine the proliferative activity of SCL-1 cells. Cell colony forming ability was evaluated by cell colony formation assay. Wound healing assay was used to detect the scratch healing rate of SCL-1 cells. Cell apoptosis was determined by flow cytometry. The qRT-PCR was used to detect the mRNA levels of JNK1, JNK2 and c-Jun. The protein level of phosphorylated c-Jun was tested by Western blot analysis. Results The optimal infection condition of JNK1- and JNK2-overexpressing adenoviral vectors was multiplicity of infection (MOI) of 100. The expression levels of JNK1 and JNK2 in SCL-1 cells significantly increased 48 hours after the infection. Compared with the control group, the over-expression of JNK1 had no significant effect on the proliferation and anti-apoptosis ability of SCL-1 cells. The proliferation and anti-apoptosis ability of Ad-JNK2 was significantly enhanced compared with Ad-JNK1, and the phosphorylated c-Jun protein level was up-regulated. Conclusion JNK2 has the function of enhancing the proliferation and anti-apoptotic ability of SCL-1 human cutaneous squamous cell carcinoma cells.


Assuntos
Apoptose , Carcinoma de Células Escamosas/patologia , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Cutâneas/metabolismo
9.
Redox Biol ; 19: 375-387, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30237126

RESUMO

It is generally recognized that hepatic fibrogenesis is an end result of increased extracellular matrix (ECM) production from the activation and proliferation of hepatic stellate cells (HSCs). An in-depth understanding of the mechanisms of HSC necroptosis might provide a new therapeutic strategy for prevention and treatment of hepatic fibrosis. In this study, we attempted to investigate the effect of curcumol on necroptosis in HSCs, and further to explore the molecular mechanisms. We found that curcumol ameliorated the carbon tetrachloride (CCl4)-induced mice liver fibrosis and suppressed HSC proliferation and activation, which was associated with regulating HSC necroptosis through increasing the phosphorylation of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3). Moreover, curcumol promoted the migration of RIPK1 and RIPK3 into necrosome in HSCs. RIPK3 depletion impaired the anti-fibrotic effect of curcumol. Importantly, we showed that curcumol-induced RIPK3 up-regulation significantly increased mitochondrial reactive oxygen species (ROS) production and mitochondrial depolarization. ROS scavenger, N-acetyl-L-cysteine (NAC) impaired RIPK3-mediated necroptosis. In addition, our study also identified that the activation of c-Jun N-terminal kinase1/2 (JNK1/2) was regulated by RIPK3, which mediated curcumol-induced ROS production. Down-regulation of RIPK3 expression, using siRIPK3, markedly abrogated JNK1/2 expression. The use of specific JNK1/2 inhibitor (SP600125) resulted in the suppression of curcumol-induced ROS production and mitochondrial depolarization, which in turn, contributed to the inhibition of curcumol-triggered necroptosis. In summary, our study results reveal the molecular mechanism of curcumol-induced HSC necroptosis, and suggest a potential clinical use of curcumol-targeted RIPK1/RIPK3 complex-dependent necroptosis via JNK1/2-ROS signaling for the treatment of hepatic fibrosis.


Assuntos
Células Estreladas do Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Necrose/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Sesquiterpenos/farmacologia , Acetilcisteína/farmacologia , Animais , Tetracloreto de Carbono/toxicidade , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/genética , Distribuição Aleatória , Espécies Reativas de Oxigênio/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética
10.
Int J Nanomedicine ; 13: 5187-5205, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30233180

RESUMO

Background: A direct and independent role of inflammation in atherothrombosis was recently highlighted by the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial, showing the benefit of inhibiting signaling molecules, eg, interleukins. Accordingly, we sought to devise a flexible platform for preventing the inflammatory drivers at their source to preserve plaque endothelium and mitigate procoagulant risk. Methods: p5RHH-siRNA nanoparticles were formulated through self-assembly processes. The therapeutic efficacy of p5RHH-JNK2 siRNA nanoparticles was evaluated both in vitro and in vivo. Results: Because JNK2 is critical to macrophage uptake of oxidized lipids through scavenger receptors that engender expression of myriad inflammatory molecules, we designed an RNA-silencing approach based on peptide-siRNA nanoparticles (p5RHH-siRNA) that localize to atherosclerotic plaques exhibiting disrupted endothelial barriers to achieve control of JNK2 expression by macrophages. After seven doses of p5RHH-JNK2 siRNA nanoparticles over 3.5 weeks in ApoE-/- mice on a Western diet, both JNK2 mRNA and protein levels were significantly decreased by 26% (P=0.044) and 42% (P=0.042), respectively. Plaque-macrophage populations were markedly depleted and NFκB and STAT3-signaling pathways inhibited by 47% (P<0.001) and 46% (P=0.004), respectively. Endothelial barrier integrity was restored (2.6-fold reduced permeability to circulating 200 nm nanoparticles in vivo, P=0.003) and thrombotic risk attenuated (200% increased clotting times to carotid artery injury, P=0.02), despite blood-cholesterol levels persistently exceeding 1,000 mg/dL. No adaptive or innate immunoresponses toward the nanoparticles were observed, and blood tests after the completion of treatment confirmed the largely nontoxic nature of this approach. Conclusion: The ability to formulate these nanostructures rapidly and easily interchange or multiplex their oligonucleotide content represents a promising approach for controlling deleterious signaling events locally in advanced atherosclerosis.


Assuntos
Aterosclerose/complicações , Endotélio/patologia , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Nanoestruturas/química , Peptídeos/metabolismo , Placa Aterosclerótica/complicações , RNA Interferente Pequeno/metabolismo , Trombose/complicações , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Aterosclerose/patologia , Aterosclerose/terapia , Modelos Animais de Doenças , Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Nanopartículas/química , Placa Aterosclerótica/patologia , Placa Aterosclerótica/terapia , Células RAW 264.7 , Interferência de RNA , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Trombose/patologia , Trombose/terapia
11.
J Biol Chem ; 293(42): 16376-16389, 2018 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-30190325

RESUMO

Reactive oxygen species (ROS), in particular H2O2, regulate intracellular signaling through reversible oxidation of reactive protein thiols present in a number of kinases and phosphatases. H2O2 has been shown to regulate mitogen-activated protein kinase (MAPK) signaling depending on the cellular context. We report here that in human articular chondrocytes, the MAPK family member c-Jun N-terminal kinase 2 (JNK2) is activated by fibronectin fragments and low physiological levels of H2O2 and inhibited by oxidation due to elevated levels of H2O2 The kinase activity of affinity-purified, phosphorylated JNK2 from cultured chondrocytes was reversibly inhibited by 5-20 µm H2O2 Using dimedone-based chemical probes that react specifically with sulfenylated cysteines (RSOH), we identified Cys-222 in JNK2, a residue not conserved in JNK1 or JNK3, as a redox-reactive site. MS analysis of human recombinant JNK2 also detected further oxidation at Cys-222 and other cysteines to sulfinic (RSO2H) or sulfonic (RSO3H) acid. H2O2 treatment of JNK2 resulted in detectable levels of peptides containing intramolecular disulfides between Cys-222 and either Cys-213 or Cys-177, without evidence of dimer formation. Substitution of Cys-222 to alanine rendered JNK2 insensitive to H2O2 inhibition, unlike C177A and C213A variants. Two other JNK2 variants, C116A and C163A, were also resistant to oxidative inhibition. Cumulatively, these findings indicate differential regulation of JNK2 signaling dependent on H2O2 levels and point to key cysteine residues regulating JNK2 activity. As levels of intracellular H2O2 rise, a switch occurs from activation to inhibition of JNK2 activity, linking JNK2 regulation to the redox status of the cell.


Assuntos
Condrócitos/metabolismo , Cisteína/metabolismo , Peróxido de Hidrogênio/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Células Cultivadas , Fibronectinas , Humanos , Peróxido de Hidrogênio/farmacologia , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
12.
Biomed Pharmacother ; 106: 1063-1071, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30119172

RESUMO

JNK1/2 and NF-κB signal are essential signaling pathways that mediate a variety of cellular processes, including cell survival, apoptosis, inflammation and angiogenesis. JNK1/2 activation and NF-κBp65 nuclear translocation have been found in ischemia/reperfusion (I/R)-induced injury. However, the regulation of JNK1/2-NF-κBp65 signaling pathway remains unclear. To examine the function and possible mechanism of HMGB2 in I/R-induced cell injury, human AC16 cardiomyocytes transfected with pLVX-Puro-HMGB2 were treated with SP600125 (JNK1/2 inhibitor) or PDTC (NF-κB inhibitor) and that following I/R injury were transfected with HMGB2-shRNA. The cell proliferation and apoptosis were measured by CCK-8, flow cytometry and TUNEL, respectively. The expression of HMGB2, Cleaved PARP and Caspase-3, Bax and Bcl-2 and activity of MAPKs and NF-κBp65 were measured by Western blot. Here, we found that I/R time-dependently induced the increase in the expression of HMGB2 in AC16 cardiomyocytes. HMGB2 silencing significantly inhibited I/R-induced the cell proliferation reduction, cell apoptosis, activation of ERK1/2, JNK1/2 and NF-κBp65, increased Bax, Cleaved PARP and Caspase-3 and decreased Bcl-2 expression. HMBG2 overexpression mimicked the effect of I/R-induced injury in AC16 cardiomyocytes, which was reversed by treatment with SP600125 or PDTC. Moreover, PDTC treatment in rats following I/R injury also showed decreases in the cell apoptosis, HMGB2, Cleaved PARP and Caspase-3 and Bax expression, and JNK1/2 activation. Taken together, our findings suggest that HMBG2 overexpression promotes I/R-induced cell apoptosis through activating the JNK1/2-NF-κBp65 signaling in AC16 cardiomyocytes.


Assuntos
Apoptose , Proteína HMGB2/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Traumatismo por Reperfusão Miocárdica/enzimologia , Miócitos Cardíacos/enzimologia , Fator de Transcrição RelA/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antracenos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Proliferação de Células , Modelos Animais de Doenças , Feminino , Proteína HMGB2/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/antagonistas & inibidores , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Inibidores de Proteínas Quinases/farmacologia , Pirrolidinas , Ratos Sprague-Dawley , Transdução de Sinais , Tiocarbamatos , Fatores de Tempo , Fator de Transcrição RelA/antagonistas & inibidores , Adulto Jovem
13.
Int J Mol Sci ; 19(7)2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30011811

RESUMO

Farrerol, a type of 2, 3-dihydro-flavonoid, is obtained from Rhododendron. Previous studies have shown that Farrerol performs multiple biological activities, such as anti-inflammatory, antibacterial, and antioxidant activity. In this study, we aim to investigate the effect of Farrerol on colonic inflammation and explore its potential mechanisms. We found that the effect of Farrerol was evaluated via the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model in mice and found that Farrerol has a protective effect on TNBS-induced colitis. Farrerol administration significantly improved the weight change, clinical scores, colon length, and intestinal epithelium barrier damage and markedly decreased the inflammatory cytokines production in TNBS-induced mice. The protective effect of Farrerol was also observed in LPS-induced RAW264.7 cells. We found that Farrerol observably reduced the production of inflammatory mediators including IL-1ß, IL-6, TNF-α, COX-2, and iNOS in LPS-induced RAW264.7 cells via suppressing AKT, ERK1/2, JNK1/2, and NF-κB p65 phosphorylation. In conclusion, the study found that Farrerol has a beneficial effect on TNBS-induced colitis and might be a natural therapeutic agent for IBD treatment.


Assuntos
Cromonas/farmacologia , Colite/prevenção & controle , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Colite/induzido quimicamente , Citocinas/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Fitoterapia/métodos , Células RAW 264.7 , Rhododendron/química , Ácido Trinitrobenzenossulfônico
14.
Cell Death Dis ; 9(6): 705, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29899326

RESUMO

The cJun N-terminal kinases (JNKs; JNK1, JNK2, and JNK3) promote degenerative processes after neuronal injury and in disease. JNK2 and JNK3 have been shown to promote retinal ganglion cell (RGC) death after optic nerve injury. In their absence, long-term survival of RGC somas is significantly increased after mechanical optic nerve injury. In glaucoma, because optic nerve damage is thought to be a major cause of RGC death, JNKs are an important potential target for therapeutic intervention. To assess the role of JNK2 and JNK3 in an ocular hypertensive model of glaucoma, null alleles of Jnk2 and Jnk3 were backcrossed into the DBA/2J (D2) mouse. JNK activation occurred in RGCs following increased intraocular pressure in D2 mice. However, deficiency of both Jnk2 and Jnk3 together did not lessen optic nerve damage or RGC death. These results differentiate the molecular pathways controlling cell death in ocular hypertensive glaucoma compared with mechanical optic nerve injury. It is further shown that JUN, a pro-death component of the JNK pathway in RGCs, can be activated in glaucoma in the absence of JNK2 and JNK3. This implicates JNK1 in glaucomatous RGC death. Unexpectedly, at younger ages, Jnk2-deficient mice were more likely to develop features of glaucomatous neurodegeneration than D2 mice expressing Jnk2. This appears to be due to a neuroprotective effect of JNK2 and not due to a change in intraocular pressure. The Jnk2-deficient context also unmasked a lesser role for Jnk3 in glaucoma. Jnk2 and Jnk3 double knockout mice had a modestly increased risk of neurodegeneration compared with mice only deficient in Jnk2. Overall, these findings are consistent with pleiotropic effects of JNK isoforms in glaucoma and suggest caution is warranted when using JNK inhibitors to treat chronic neurodegenerative conditions.


Assuntos
Glaucoma/enzimologia , Glaucoma/patologia , Proteína Quinase 9 Ativada por Mitógeno/deficiência , Degeneração Neural/enzimologia , Degeneração Neural/patologia , Hipertensão Ocular/enzimologia , Hipertensão Ocular/patologia , Animais , Axônios/metabolismo , Morte Celular , Ativação Enzimática , Regulação da Expressão Gênica , Glaucoma/fisiopatologia , Pressão Intraocular , Camundongos Endogâmicos DBA , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Degeneração Neural/fisiopatologia , Hipertensão Ocular/fisiopatologia , Nervo Óptico/enzimologia , Nervo Óptico/patologia , Nervo Óptico/fisiopatologia , Retina/enzimologia , Retina/patologia , Retina/fisiopatologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia
15.
Autophagy ; 14(9): 1586-1595, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29950132

RESUMO

Autophagy is required for cellular homeostasis and can determine cell viability in response to stress. It is established that MTOR is a master regulator of starvation-induced macroautophagy/autophagy, but recent studies have also implicated an essential role for the MAPK8/cJun NH2-terminal kinase 1 signal transduction pathway. We found that MAPK8/JNK1 and MAPK9/JNK2 were not required for autophagy caused by starvation or MTOR inhibition in murine fibroblasts and epithelial cells. These data demonstrate that MAPK8/9 has no required role in starvation-induced autophagy. We conclude that the role of MAPK8/9 in autophagy may be context-dependent and more complex than previously considered. ABBREVIATIONS: AKT: thymoma viral proto-oncogene;ALB: albumin; ATG4: autophagy related 4; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1, autophagy related; BNIP3: BCL2/adenovirus E1B interacting protein 3; CQ: chloroquine diphosphate; DMEM: Dulbecco's modified Eagle's medium; EDTA: ethylenediaminetetraacetic acid; EBSS: Earle's balanced salt solution; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HRAS: Harvey rat sarcoma virus oncogene; IgG: Immunoglobulin G; MAPK3/ERK1: mitogen-activated protein kinase 3; MAPK8/JNK1: mitogen-activated protein kinase 8; MAPK9/JNK2: mitogen-activated protein kinase 9; MAPK10/JNK3: mitogen-activated protein kinase 10; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MEFs: mouse embryonic fibroblasts; MTOR: mechanistic target of rapamycin kinase; RPS6KB1/p70: ribosomal protein S6 kinase, polypeptide 1; PPARA: peroxisome proliferator activated receptor alpha; SEM: standard error of the mean; SQSTM1/p62: sequestosome 1; TORC1: target of rapamycin complex 1; TORC2: target of rapamycin complex 2; TRP53: transforming related protein 53; TUBA: tubulin alpha; UV: ultraviolet; WT: wild-type.


Assuntos
Aminoácidos/deficiência , Autofagia , Sistema de Sinalização das MAP Quinases , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Animais , Autofagia/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Naftiridinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Proteínas ras/metabolismo
16.
Exp Eye Res ; 175: 181-191, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29935949

RESUMO

Matrix metalloproteinase (MMP)-8 is the most potent MMP for degrading collagen type-1 and plays an important role in inflammatory reactions and tissue remolding processes. MMP-8 is expressed mainly by polymorphonuclear leukocytes and is not expressed constitutively by most non-leukocytes. We studied the constitutive and TNF-α-induced expression of MMP-8 in cultured human uveal melanocytes (UM) and the relevant signal pathways involved. Conditioned media and cells were collected from UM and other cell types. MMP-8 proteins and mRNA were measured using ELISA kit, western blot and real time RT-PCR, respectively. Phosphorylated p38 MAPK, ERK1/2, and JNK1/2 were measured by ELISA kit and western blot. Very high levels of MMP-8 proteins and mRNA were detected in the conditioned media and cell lysates in 11 UM cell lines and three uveal melanoma cell lines cultured without serum, but not in media and cell lysates from other ocular resident cells or 12 malignant cell lines from other tissues, with exception of cutaneous melanoma cells. TNF-α moderately increased MMP-8 mRNA and protein levels in a dose- and time-dependent manner, accompanied by a significant increase of phosphorylated JNK1/2 and ERK1/2 in cell lysates. ERK1/2 (U0126) and JNK1/2 (SP600125) inhibitors significantly blocked TNF-α-induced and constitutive expression of MMP-8 in UM. This is the first report on the expression and secretion of MMP-8 by UM and uveal melanoma cells. The data suggest that UM may play a role in the remolding process and pathogenesis of inflammatory-related diseases in the eye via secretion of MMP-8.


Assuntos
Regulação da Expressão Gênica/fisiologia , Metaloproteinase 8 da Matriz/genética , Metaloproteinase 8 da Matriz/metabolismo , Melanócitos/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Úvea/citologia , Adulto , Idoso , Western Blotting , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Melanócitos/metabolismo , Pessoa de Meia-Idade , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Future Oncol ; 14(24): 2471-2481, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29714074

RESUMO

AIM: To explore JNK1/2 and ERK1/2 activation in hepatocellular carcinoma (HCC) patients. PATIENTS & METHODS: Phosphorylated-JNK1/2 and -ERK1/2 (p-JNK1/2 and p-ERK1/2) expressions were determined and analyzed in 104 unique HCC tissue specimens. RESULTS: Expression of p-JNK1/2 and p-ERK1/2 was not correlated with clinicopathological characteristics. High p-JNK1/2 and low p-ERK1/2 expressions predicated significantly lower tumor recurrence for HCC patients. However, HCC patients with low p-JNK1/2 and high p-ERK1/2 had higher tumor recurrence. Moreover, p-JNK1/2 positively, but p-ERK1/2 negatively, associated with overall survival (OS) and recurrence-free survival (RFS) in HCC patients. In addition, HCC patients with simultaneous low p-JNK1/2 and high p-ERK1/2 had poorer OS and RFS. On the contrary, patients with high p-JNK1/2 and low p-ERK1/2 presented better OS and RFS. CONCLUSION: HCC patients with low p-JNK1/2 and high p-ERK1/2 either independently or simultaneously, had significantly higher tumor recurrence and worse OS.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/enzimologia
18.
J Pineal Res ; 65(3): e12507, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29766567

RESUMO

Osteosarcoma, with its high metastatic potential, is the most prevalent malignant bone tumor in children and adolescents. Melatonin possesses multiple tumor-suppressing properties for a myriad of tumors, but little is known about the effects of melatonin on osteosarcoma metastasis. In this study, we demonstrated that melatonin elicited very low cytotoxicity and significantly inhibited cellular motility, migration, and invasion in human osteosarcoma U2OS and HOS cells. Moreover, using RNA sequencing technology, we revealed that melatonin repressed C-C motif chemokine ligand 24 (CCL24) gene expression in U2OS cells. Manipulation of CCL24 levels influenced the motility of osteosarcoma cells as cell migration and invasion were enhanced by the addition of recombinant human CCL24 and attenuated by the silencing of CCL24. Moreover, melatonin increased and decreased the activation of extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2, respectively, in a dose-dependent manner in U2OS and HOS cells while exerting no evident influence on the level and activation of p38, Akt, FAK, steroid receptor coactivator, or Raf. In further functional experiments, the use of JNK inhibitors (SP600125 and DN-JNK) confirmed that the pharmaceutic inhibition of JNK augmented the melatonin-mediated CCL24 suppression and migration of U2OS cells. Overall, our results revealed that melatonin attenuated chemokine CCL24 levels through inhibition of the JNK pathway to hinder human osteosarcoma cell invasion, thereby highlighting the therapeutic potential of melatonin for osteosarcoma metastasis.


Assuntos
Neoplasias Ósseas/metabolismo , Quimiocina CCL24/metabolismo , Melatonina/farmacologia , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Proteínas de Neoplasias/metabolismo , Osteossarcoma/metabolismo , Adolescente , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Invasividade Neoplásica , Osteossarcoma/patologia
19.
J Immunol ; 201(1): 145-156, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29777028

RESUMO

Enterovirus 71 (EV71) induces significantly elevated levels of cytokines and chemokines, leading to local or systemic inflammation and severe complications. As shown in our previous study, microRNA (miR) 302c regulates influenza A virus-induced IFN expression by targeting NF-κB-inducing kinase. However, little is known about the role of the miR-302 cluster in EV71-mediated proinflammatory responses. In this study, we found that the miR-302 cluster controls EV71-induced cytokine expression. Further studies demonstrated that karyopherin α2 (KPNA2) is a direct target of the miR-302 cluster. Interestingly, we also found that EV71 infection upregulates KPNA2 expression by downregulating miR-302 cluster expression. Upon investigating the mechanisms behind this event, we found that KPNA2 intracellularly associates with JNK1/JNK2 and p38, leading to translocation of those transcription factors from the cytosol into the nucleus. In EV71-infected patients, miR-302 cluster expression was downregulated and KPNA2 expression was upregulated compared with controls, and their expression levels were closely correlated. Taken together, our work establishes a link between the miR-302/ KPNA2 axis and EV71-induced cytokine expression and represents a promising target for future antiviral therapy.


Assuntos
Citocinas/metabolismo , Enterovirus Humano A/imunologia , Imunidade Inata/imunologia , MicroRNAs/metabolismo , alfa Carioferinas/metabolismo , Transporte Ativo do Núcleo Celular/fisiologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Células THP-1 , Fator de Transcrição RelA/metabolismo , alfa Carioferinas/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Environ Toxicol ; 33(6): 679-685, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29663662

RESUMO

Glabridin, a flavonoid extracted from licorice (Glycyrrhiza glabra), possesses various biological properties, including anticancer activities. However, the effect of glabridin on oral cancer cell apoptosis and the underlying molecular mechanisms has not been elucidated. In this study, we demonstrated that glabridin treatment significantly inhibits cell proliferation in human oral cancer SCC-9 and SAS cell lines. Flow cytometric assays demonstrated that glabridin induced several features of apoptosis, such as sub-G1 phase cell increase and phosphatidylserine externalization. Furthermore, glabridin induced apoptosis dose-dependently in SCC-9 cells through caspase-3, -8, and -9 activation and poly (ADP-ribose) polymerase cleavage. Moreover, glabridin increased the phosphorylation of the extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase (JNK) pathways in a dose-dependent manner. Moreover, the inhibition of the JNK1/2 inhibitor significantly reversed the glabridin-induced activation of the caspase pathway. In conclusion, our findings suggest that glabridin induces oral cancer cell apoptosis through the JNK1/2 pathway and is a potential therapeutic agent for oral cancer.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Isoflavonas/farmacologia , Neoplasias Bucais/patologia , Fenóis/farmacologia , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Neoplasias Bucais/metabolismo , Fosforilação/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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