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1.
Nat Commun ; 11(1): 258, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937753

RESUMO

BET bromodomain inhibitors (BETi), such as JQ1, have been demonstrated to effectively kill multiple types of cancer cells. However, the underlying mechanisms for BETi resistance remain largely unknown. Our evidences show that JQ1 treatment evicts BRD4 from the FOXD3-localized MIR548D1 gene promoter, leading to repression of miR-548d-3p. The loss of miRNA restores JunD expression and subsequent JunD-dependent transcription of RPS6KA2 gene. ERK1/2/5 kinases phosphorylate RSK3 (RPS6KA2), resulting in the enrichment of activated RSK3 and blockade of JQ1 killing effect. Dual inhibition of MEKs/ERKs or single EGFR inhibition are able to mimic the effect of JunD/RSK3-knockdown to reverse BETi resistance. Collectively, our study indicates that loss of BRD4/FOXD3/miR-548d-3p axis enhances JunD/RSK3 signalling and determines BET inhibition resistance, which can be reversed by targeting EGFR-MEK1/2/5-ERK1/2/5 signalling.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fatores de Transcrição Forkhead/metabolismo , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Antineoplásicos/farmacologia , Azepinas/farmacologia , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosforilação , Regiões Promotoras Genéticas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/genética , Triazóis/farmacologia
2.
Arch Virol ; 165(3): 671-681, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31942645

RESUMO

Dengue virus (DENV) is the most common mosquito-borne viral disease. The World Health Organization estimates that 400 million new cases of dengue fever occur every year. Approximately 500,000 individuals develop severe and life-threatening complications from dengue fever, such as dengue shock syndrome (DSS) and dengue hemorrhagic fever (DHF), which cause 22,000 deaths yearly. Currently, there are no specific licensed therapeutics to treat DENV illness. We have previously shown that the MEK/ERK inhibitor U0126 inhibits the replication of the flavivirus yellow fever virus. In this study, we demonstrate that the MEK/ERK inhibitor AZD6244 has potent antiviral efficacy in vitro against DENV-2, DENV-3, and Saint Louis encephalitis virus (SLEV). We also show that it is able to protect AG129 mice from a lethal challenge with DENV-2 (D2S20). The molecule is currently undergoing phase III clinical trials for the treatment of non-small-cell lung cancer. The effect of AZD6244 on the DENV life cycle was attributed to a blockade of morphogenesis. Treatment of AG129 mice twice daily with oral doses of AZD6244 (100 mg/kg/day) prevented the animals from contracting dengue hemorrhagic fever (DHF)-like lethal disease upon intravenous infection with 1 × 105 PFU of D2S20. The effectiveness of AZD6244 was observed even when the treatment of infected animals was initiated 1-2 days postinfection. This was also followed by a reduction in viral copy number in both the serum and the spleen. There was also an increase in IL-1ß and TNF-α levels in mice that were infected with D2S20 and treated with AZD6244 in comparison to infected mice that were treated with the vehicle only. These data demonstrate the potential of AZD6244 as a new therapeutic agent to treat DENV infection and possibly other flavivirus diseases.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Vírus da Dengue/crescimento & desenvolvimento , Dengue Grave/prevenção & controle , Animais , Linhagem Celular , Cricetinae , Vírus da Dengue/efeitos dos fármacos , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Interleucina-1beta/sangue , Camundongos , Dengue Grave/virologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangue
3.
Int J Mol Sci ; 20(17)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438541

RESUMO

Oxidative stress has been implicated in the pathogenesis of many diseases including chronic liver diseases. Nrf2 is a master transcriptional factor regulating the induction of cellular antioxidant defense systems. Here, the Nrf2-activating effect of the crude methanol extract of dried leaves of Pogostemon cablin Bentham was demonstrated by measuring the antioxidant response element (ARE)-driven luciferase activity and pachypodol, 4',5-dihydroxy-3,3',7-trimethoxyflavone, was isolated by bioactivity-guided fractionation and further separation using chromatographic techniques. To our knowledge, this is the first study to evaluate the antioxidant and cytoprotective effects of pachypodol in HepG2 cells as well as the underlying molecular mechanisms. Indeed, pachypodol protected HepG2 cells from cell death caused by tert-butylhydroperoxide-induced oxidative stress and also attenuated ROS production. The ability of pachypodol to activate Nrf2/ARE pathway was further confirmed by observing Nrf2 expression in nuclear fraction, mRNA levels of Nrf2 target antioxidants, and cellular glutathione content in HepG2 cells. Extracellular signal-regulated kinase (ERK) is one of the important kinases involved in Nrf2 activation. Pachypodol increased ERK phosphorylation and ERK inhibition by PD98059 totally abrogated the increase in ARE luciferase activity, nuclear Nrf2 accumulation and mRNA levels of antioxidant enzymes by pachypodol. In conclusion, pachypodol isolated from P. cablin can protect hepatocytes from oxidative injury, possibly mediated by enhancing endogenous antioxidant defense system through ERK-dependent Nrf2 activation.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Pogostemon/química , Quercetina/análogos & derivados , Antioxidantes/química , Antioxidantes/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Flavonoides/farmacologia , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Quercetina/química , Quercetina/farmacologia
4.
Appl Microbiol Biotechnol ; 103(17): 7017-7027, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31289905

RESUMO

Fibroblast growth factor (FGF) 13, a member of the FGF11 subfamily, is a kind of intracrine protein similar to other family members including FGF11, FGF12, and FGF14. Unlike classical FGF, FGF13 exerts its bioactivities independent of fibroblast growth factor receptors (FGFRs). However, the effect of exogenous administration of FGF13 still remains further investigated. In the present study, we established an Escherichia coli expression system for the large-scale production of FGF13 and then obtained two isoform proteins including recombinant human FGF13A (rhFGF13A) and rhFGF13B with a purity greater than 90% by column chromatography, respectively. Otherwise, soluble analysis indicated that both rhFGF13A and rhFGF13B expressed in E. coli BL21 (DE3) pLysS were soluble. Furthermore, cellular-based experiments demonstrated that rhFGF13A, rather than rhFGF13B, could promote the proliferation of NIH3T3 cells in the presence of heparin. Mechanistically, the mitogenic effect of FGF13 was mediated by activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), but not p38. Moreover, blockage of FGFRs also significantly attenuated the mitogenic effects of rhFGF13A, implying that FGFRs are still related to FGF13. Thus, our research shows that exogenous FGF13 can act as secreted FGF to participate in cell signal transmission and heparin is still required as an ancillary cofactor for the mitogenic effects of FGF13, which may help people to discover more potential functions of FGF13 in cell life activities.


Assuntos
Escherichia coli/metabolismo , Fatores de Crescimento de Fibroblastos/isolamento & purificação , Fatores de Crescimento de Fibroblastos/farmacologia , Mitógenos/isolamento & purificação , Mitógenos/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/isolamento & purificação , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Heparina/farmacologia , Humanos , Camundongos , Mitógenos/genética , Mitógenos/metabolismo , Células NIH 3T3 , Isoformas de Proteínas , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais
5.
Microbes Infect ; 21(10): 485-489, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31247328

RESUMO

Cell invasion by Trypanosoma cruzi extracellular amastigotes involves different signaling pathways to induce phagocytosis-like mechanisms. Previous works indicated that PI3K/Akt, Src and Erk might be involved in EA invasion; however, participation of these molecules in this process remains elusive. Here, we observed that EA activated Akt, Erk but not Src. Interference of EA invasion with specific inhibitors corroborated this observation. Our results show that EA is capable of selectively triggering complex signaling pathways. Activation of PI3K/Akt and Erk, kinases related to actin cytoskeleton rearrangement and phagocytosis, reinforces the idea that T. cruzi EA subverts the phagocytic machinery during invasion.


Assuntos
Doença de Chagas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Trypanosoma cruzi/fisiologia , Doença de Chagas/parasitologia , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Células HeLa , Humanos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
6.
Environ Toxicol ; 34(8): 968-978, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31077554

RESUMO

The aim of this study was to investigate the protective effects of Nano-Se against Ni-induced testosterone synthesis disorder in rats and determine the underlying protective mechanism. Sprague-Dawley rats were co-treated with Ni (5.0 mg/kg, i.p.) and Nano-Se (0.5, 1.0, and 2.0 mg/kg, oral gavage) for 14 days after which various endpoints were evaluated. The Ni-induced abnormal pathological changes and elevated 8-OHdG levels in the testes were attenuated by Nano-Se administration. Importantly, decreased serum testosterone levels in the Ni-treated rats were significantly restored by Nano-Se treatment, particularly at 1.0 and 2.0 mg/kg. Furthermore, the mRNA and protein levels of testosterone synthetase were increased by Nano-Se compared to the Ni group, whereas phosphorylated protein expression levels of mitogen-activated protein kinase (MAPK) pathways were suppressed by Nano-Se administration in the Ni-treated rats. Overall, the results suggest that Nano-Se may ameliorate the Ni-induced testosterone synthesis disturbance via the inhibition of ERK1/2, p38, and JNK MAPK pathways.


Assuntos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Níquel/toxicidade , Selênio/farmacologia , Testosterona/biossíntese , Animais , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Nanopartículas , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Testosterona/sangue , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1651-1665, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30954555

RESUMO

Loss of E-cadherin and epithelial to mesenchymal transition (EMT) are key steps in cancer progression. Reactive oxygen species (ROS) play significant roles in cellular physiology and homeostasis. Roles of E-cadherin (CDH1), EMT and ROS are intriguingly illustrated in many cancers without focusing their collective concert during cancer progression. We report that hydrogen peroxide (H2O2) treatment modulate CDH1 gene expression by epigenetic modification(s). Sublethal dosage of H2O2 treatment decrease E-cadherin, increase DNMT1, HDAC1, Snail, Slug and enrich H3K9me3 and H3K27me3 in the CDH1 promoter. The effect of H2O2 was attenuated by ROS scavengers; NAC, lupeol and beta-sitosterol. DNMT inhibitor, AZA prevented the H2O2 induced promoter-CpG-island methylation of CDH1. Treatment of cells with U0126 (inhibitor of ERK) reduced the expression of DNMT1, Snail and Slug, increased CDH1. This implicates that CDH1 is synergistically repressed by histone methylation, DNA methylation and histone deacetylation mediated chromatin remodelling and activation of Snail and Slug through ERK pathway. Increased ROS leads to activation of epigenetic machineries and EMT activators Snail/Slug which in their course of action inactivates CDH1 gene and lack of E-cadherin protein promotes EMT in breast cancer cells. ROS and ERK signaling facilitate epigenetic silencing and support the fact that subtle increase of ROS above basal level act as key cell signaling molecules. Free radical scavengers, lupeol and beta-sitosterol may be tested for therapeutic intervention of breast cancer. This work broadens the amplitude of epigenome and open avenues for investigations on conjoint effects of canonical and intrinsic metabolite signaling and epigenetic modulations in cancer.


Assuntos
Antígenos CD/genética , Neoplasias da Mama/genética , Caderinas/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Fatores de Transcrição da Família Snail/genética , Antioxidantes/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Butadienos/farmacologia , Caderinas/deficiência , Linhagem Celular , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Transição Epitelial-Mesenquimal/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Estimativa de Kaplan-Meier , Células MCF-7 , Nitrilos/farmacologia , Triterpenos Pentacíclicos/farmacologia , Transdução de Sinais , Sitosteroides/farmacologia , Fatores de Transcrição da Família Snail/metabolismo
8.
Neurochem Res ; 44(7): 1636-1652, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31006091

RESUMO

HIV-1 gp120, an important subunit of the envelope spikes that decorate the surface of virions, is known to play a vital role in neuronal injury during HIV-1-associated neurocognitive disorder (HAND), although the pathological mechanism is not fully understood. Our previous studies have suggested that the V3 loop of HIV-1 gp120 (HIV-1 gp120 V3 loop) can induce neuronal apoptosis in the hippocampus, resulting in impairment in spatial learning and memory in Sprague-Dawley (SD) rats. In this study, we demonstrated that autophagy was significantly increased in rat primary hippocampal neurons in response to treatment of HIV-1 gp120 V3 loop. Importantly, HIV-1 gp120 V3 loop-induced autophagy played a dual role in the cell survival and death. An increase in autophagy for a short period inhibited apoptosis of neurons, while persistent autophagy over an extended period of time played a detrimental role by augmenting the apoptotic cascade in rat primary hippocampal neurons. In addition, we found that the HIV-1 gp120 V3 loop induced autophagy via AMPK/mTOR-dependent and calpain/mTOR-independent pathways, and the ERK/mTOR pathway plays a partial role. These findings provide evidence that HIV-1-induced autophagy plays a dual role in the survival and apoptosis of the primary rat hippocampal neurons and persistent autophagy may contribute to the pathogenesis of HAND, and autophagy modulation may represent a potential therapeutic strategy for reducing neuronal damage in HAND.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína gp120 do Envelope de HIV/farmacologia , HIV-1/química , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/fisiologia , Adenina/análogos & derivados , Adenina/farmacologia , Sequência de Aminoácidos , Animais , Apoptose/fisiologia , Autofagia/fisiologia , Calpaína/antagonistas & inibidores , Calpaína/fisiologia , Inibidores de Cisteína Proteinase/farmacologia , Dipeptídeos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Flavonoides/farmacologia , Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/toxicidade , Hipocampo/patologia , Masculino , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/toxicidade , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley
9.
PLoS One ; 14(4): e0215255, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31017922

RESUMO

Intestinal epithelial cells (IECs) are regenerated continuously from intestinal stem cells (ISCs) near the base of intestinal crypts in order to maintain homeostasis and structural integrity of intestinal epithelium. Epidermal growth factor (EGF) is thought to be important to drive the proliferation and differentiation of IECs from ISCs, it remains unknown whether other growth factors or lipid mediators are also important for such regulation, however. Here we show that lysophosphatidic acid (LPA), instead of EGF, robustly promoted the development of intestinal organoids prepared from the mouse small intestine. Indeed, LPA exhibited the proliferative activity of IECs as well as induction of differentiation of IECs into goblet cells, Paneth cells, and enteroendocrine cells in intestinal organoids. Inhibitors for LPA receptor 1 markedly suppressed the LPA-promoted development of intestinal organoids. LPA also promoted the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in intestinal organoids, whereas inhibition of mitogen-activated protein kinase/ERK kinase (MEK) 1/2 significantly suppressed the development of, as well as the proliferative activity and differentiation of, intestinal organoids in response to LPA. Our results thus suggest that LPA is a key factor that drives the proliferation and differentiation of IECs.


Assuntos
Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Lisofosfolipídeos/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fator de Crescimento Epidérmico/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Mucosa Intestinal/metabolismo , Lisofosfolipídeos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Organoides/citologia , Organoides/efeitos dos fármacos , Organoides/metabolismo , Fosforilação , Receptores de Ácidos Lisofosfatídicos/metabolismo , Técnicas de Cultura de Tecidos
10.
Biomed Res Int ; 2019: 6360503, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30886861

RESUMO

Ebastine is a second-generation histamine H1 receptor antagonist that is used to attenuate allergic inflammation. Ebastine has also shown to affect hair loss; however, the immunoregulatory effect of ebastine cannot completely exclude the possibility of spontaneous hair regrowth in ebastine-treated mice. In this study, we examined the effects of ebastine on the growth of human follicle dermal papilla cells (HFDPC) using a WST-1 cell proliferation assay and a bromodeoxyuridine incorporation assay. Ebastine was shown to significantly increase the proliferation of HFDPC. The expression levels of cell-cycle regulatory proteins and an antiapoptotic protein were increased in ebastine-treated HFDPC. Furthermore, elevated expression levels of phospho-AKT and phospho-p44/42 extracellular signal-regulated kinase (ERK) were observed in ebastine-treated HFDPC. Ebastine-mediated HFDPC growth was completely reversed by blocking ERK kinase. The results from our present study suggest that the regulation of HFDPC proliferation by ebastine might be directly involved in hair regrowth through the ERK signaling pathway.


Assuntos
Alopecia/genética , Butirofenonas/farmacologia , Folículo Piloso/crescimento & desenvolvimento , Proteína Quinase 3 Ativada por Mitógeno/genética , Piperidinas/farmacologia , Alopecia/tratamento farmacológico , Alopecia/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Derme/efeitos dos fármacos , Derme/crescimento & desenvolvimento , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Cabelo/efeitos dos fármacos , Cabelo/crescimento & desenvolvimento , Folículo Piloso/efeitos dos fármacos , Humanos , Proteínas Proto-Oncogênicas c-akt/genética
11.
Mediators Inflamm ; 2019: 6085801, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30918469

RESUMO

IL-37 is an immunomodulatory cytokine that suppresses inflammation in various cell types and disease models. However, its role in keratinocytes has not been clearly understood, and there has been no report on the agents that can increase the expression of IL-37 in keratinocytes. In this study, we investigated the effects of silencing IL37 in HaCaT keratinocytes and the molecular mechanisms involved in the upregulation of IL-37 by PG102, a water-soluble extract from Actinidia arguta. It was found that knockdown of IL37 resulted in the augmented expression of antimicrobial peptides (AMPs) in response to cytokine stimulation. PG102 increased the expression of IL-37 at both mRNA and protein levels presumably by enhancing the phosphorylation of Smad3, ERK, and p38. Indeed, when cells were treated with specific inhibitors for these signaling molecules, the expression level of IL-37 was reduced. PG102 also promoted colocalization of phospho-Smad3 and IL-37. Our results suggest that IL-37 inhibits the expression of AMPs and that PG102 upregulates IL-37 through p38, ERK, and Smad3 pathways in HaCaT cells.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Interleucina-1/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Extratos Vegetais/farmacologia , Proteína Smad3/metabolismo , Butadienos/farmacologia , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Humanos , Imidazóis/farmacologia , Isoquinolinas/farmacologia , Nitrilos/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Regulação para Cima
12.
FEBS Open Bio ; 9(2): 335-347, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30761258

RESUMO

Sorafenib resistance is one of the major obstacles towards achieving a better outcome in patients with advanced hepatocellular carcinoma (HCC), in which aberrant activation of the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition pathway is frequently observed. Here, we report that HCC cells develop sorafenib resistance following HGF stimulation. Furthermore, HGF activates the downstream extracellular signal-related kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) pathway and induces epithelial-mesenchymal transition (EMT) by up-regulating Snail in HCC cells. Inhibition of ERK and STAT3 abolished the rescue effect of HGF by down-regulating Snail and EMT. Moreover, phosphoinositide 3-kinase/Akt was also activated in HGF-treated HCC cells, although it had no effect on Snail expression. Notably, we also found that regorafenib reversed HGF-induced sorafenib resistance by inhibiting ERK and STAT3, and subsequently down-regulating Snail and EMT. Taken together, our results indicate that HGF induces sorafenib resistance by activating phosporylated (P)-ERK/Snail/EMT and P-STAT3/Snail/EMT pathways. Inhibition of P-ERK and P-STAT3 by regorafenib can block HGF-induced EMT, thereby reversing HGF-induced sorafenib resistance.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fator de Crescimento de Hepatócito/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Sorafenibe/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Neoplasias Hepáticas/patologia , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Células Tumorais Cultivadas , Cicatrização/efeitos dos fármacos
13.
Cancer Immunol Immunother ; 68(5): 765-772, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30806748

RESUMO

BACKGROUND: Inhibition of the mitogen-activated protein kinase (MAPK) pathway as well as programmed death 1 receptor (PD-1) blockade was shown to prolong overall survival (OS) in patients with advanced B-Raf proto-oncogene (BRAF)-mutant melanoma. However, due to the lack of head-to-head trials, it remains unclear if one of these therapeutic approaches should be preferred in first-line therapy. Here, we present a retrospective analysis comparing anti-PD-1 monotherapy with BRAF/MAPK/ERK kinase (MEK) combined inhibition used as first-line agents in a real-world clinical setting. PATIENTS AND METHODS: Clinical data, routine blood counts and lactate dehydrogenase (LDH) levels of 301 patients with unresectable or metastatic melanoma harboring an activating mutation in BRAF (V600E/K) were included. Of these, 106 received anti-PD-1 antibodies, while 195 patients were treated with a selective BRAF inhibitor combined with an MEK inhibitor as palliative first-line therapy. Patients were sub-grouped according to previously described predictive and prognostic markers. RESULTS: OS was significantly longer in patients receiving anti-PD-1 monotherapy compared to patients receiving combined MAPK inhibitors. Subsequent therapies were comparable among these groups. The difference in OS was less pronounced in patients with high LDH levels and visceral metastatic spread. CONCLUSION: First-line treatment with a PD-1 blocking antibody might be associated with longer OS than first-line inhibition of the MAPK pathway in patients with advanced melanoma harboring mutant BRAF. These hypothesis-generating data need to be confirmed or rejected in prospective, randomized trials.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Nivolumabe/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Estudos de Coortes , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Humanos , Melanoma/mortalidade , Metástase Neoplásica , Receptor de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Estudos Retrospectivos , Transdução de Sinais , Neoplasias Cutâneas/mortalidade , Análise de Sobrevida
14.
Biochem Biophys Res Commun ; 510(3): 403-408, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30711254

RESUMO

Culture conditions determine embryo quality, which may be affected on many levels (timing of development, blastomere count, transcripts, metabolite content, apoptosis). Molecular interactions of signalling pathways like MEK/ERK and WNT/ß-catenin are critical for cell-to-cell communication and cellular differentiation. Both pathways are important regulators of apoptosis. We have aimed to verify the prolonged effect of MEK/ERK silencing and WNT activation by chemical inhibitors (2i or 3i systems) on bovine IVP embryos. Apoptotic index, total cell count and transcription of embryo quality markers were evaluated. A higher rate of apoptosis was observed in 2i blastocysts, but was not accompanied by changes in transcript content of genes controlling apoptosis (BAX, BCL2, BAK, BAX/BCL2 ratio). Therefore, alternative pathways of apoptotic activation cannot be ruled out. The expression of genes related to embryo quality (HSPA1A, SLC2A1) was not affected. GJA1 transcripts were significantly higher in 3i blastocysts, what indicates a stimulatory effect of the applied inhibitors on cell-to-cell interactions. The lowest mRNA level of the IFNT2 gene was found in 2i embryos. A variation in the SDHA gene transcript was observed (with the highest content in the 3i blastocysts), what may suggest their reduced quality. It may be concluded that the modifications of culture conditions (activation of the WNT and silencing of the MEK/ERK signalling) might alter pathways crucial for embryo development without causing embryonic death.


Assuntos
Apoptose/efeitos dos fármacos , Blastocisto/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Blastocisto/citologia , Blastocisto/enzimologia , Blastocisto/metabolismo , Bovinos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores
15.
BMC Cancer ; 19(1): 43, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626368

RESUMO

BACKGROUND: Currently, the major treatment modalities of advanced melanoma are immune check point and mitogen-activated protein kinase (MAPK) pathway inhibitors. As lacking head-to-head randomizedcontrolled trials (RCTs) comparing immune check point and MAPK pathway inhibitors, we evaluated the efficacy and toxicity with different treatment combinations of immune check point or MAPK pathway inhibitors for advanced melanoma by network meta-analysis. METHODS: We searched for RCTs in Pubmed, Embase, Ovid MEDLINE, Web of Science and Cochrane Central Register for Controlled Trials through March 2017. Two reviewers performed a network meta-analysis by assessing the hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), as well as by evaluating serious adverse events (SAEs). RESULTS: Twenty-four eligible RCTs involving 10,951 patients assigned to 11 treatment modalities were included. The combination of BRAF and MEK inhibitors demonstrated an improved OS benefit compared with all the other treatments except programmed death-1/ligand-1 (PD-1/L1) blockade because the difference in OS between the BRAF-MEK inhibitor combination and PD-1 blockade (HR: 0.85; 95% credible interval (CrI): 0.59, 1.21) was not significant. For PFS, the BRAF and MEK inhibitor combination showed a significant advantage compared with other treatments apart from the combination of PD-1/L1 and cytotoxic T lymphocyte-associated antigen-4(CTLA-4) blockade (HR:0.61; 95% CrI: 0.30, 1.25). The MEK inhibitor combined with chemotherapy was associated with the highest risk of SAEs (HR: 1.76 95% CrI: 1.21, 2.48). CONCLUSIONS: The combination of BRAF and MEK inhibitors exhibited a survival advantage in OS and PFS and comparable risk of toxicity compared with chemotherapy.


Assuntos
Tratamento Farmacológico , Imunoterapia , Melanoma/terapia , Idoso , Antígeno CTLA-4/antagonistas & inibidores , Terapia Combinada/efeitos adversos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Humanos , Imunoterapia/efeitos adversos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Melanoma/imunologia , Melanoma/metabolismo , Pessoa de Meia-Idade , Metanálise em Rede , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Resultado do Tratamento
16.
Phytomedicine ; 55: 1-8, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668419

RESUMO

BACKGROUND: Many bone-related diseases such as osteoporosis and rheumatoid arthritis are commonly associated with excessive activity of the osteoclast. Ganomycin I (GMI), a meroterpenoid isolated from Vietnamese mushroom Ganoderma lucidum, possesses a variety of beneficial effects on human health. However, its impact and underlying mechanism on osteoclastogenesis remain unclear. In the present study, we investigated the effect of GMI on RANKL-induced osteoclast formation in mouse BMMs and RAW264.7 cells. METHODS: BMMs or RAW264.7 cells were treated with GMI followed by an evaluation of cell viability, RANKL-induced osteoclast differentiation, actin-ring formation, and resorption pits activity. Effects of GMI on RANKL-induced phosphorylation of MAPKs as well as the expression levels of NFATc1 and c-Fos were evaluated by Western blot analysis. Expression levels of osteoclast marker genes were evaluated by Western blot analysis and reverse transcription-qPCR. RESULTS: GMI significantly inhibited RANKL-induced osteoclast differentiation by decreasing the number of osteoclasts, osteoclast actin-ring formation, and bone resorption in a dose-dependent manner without affecting cell viability. At molecular level, GMI inhibited the RANKL-induced phosphorylation of ERK, JNK, and p38 MAPKs, as well as the expression levels of c-Fos and NFATc1, which are known to be crucial transcription factors for osteoclast formation. In addition, GMI decreased expression levels of osteoclastogenesis specific marker genes including c-Src, CtsK, TRAP, MMP-9, OSCAR, and DC-STAMP in RANKL-stimulated BMMs. CONCLUSION: Our findings suggest that GMI can attenuate osteoclast formation by suppressing RANKL-mediated MAPKs and NFATc1 signaling pathways and the anti-osteoclastogenic activity of GMI may extend our understanding of molecular mechanisms underlying biological activities and pharmacological use of G. lucidum as a traditional anti-osteoporotic medicine.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Hidroquinonas/farmacologia , Fatores de Transcrição NFATC/antagonistas & inibidores , Osteogênese/efeitos dos fármacos , Ligante RANK/metabolismo , Animais , Reabsorção Óssea/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Hidroquinonas/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/fisiologia , Osteogênese/fisiologia , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Reishi/química
17.
EBioMedicine ; 40: 263-275, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30651219

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) remains difficult to be targeted. SET and cancerous inhibitor of protein phosphatase 2A (CIP2A) are intrinsic protein-interacting inhibitors of protein phosphatase 2A (PP2A) and frequently overexpressed in cancers, whereas reactivating PP2A activity has been postulated as an anti-cancer strategy. Here we explored this strategy in TNBC. METHODS: Data from The Cancer Genome Atlas (TCGA) database was analyzed. TNBC cell lines were used for in vitro studies. Cell viability was examined by MTT assay. The apoptotic cells were examined by flow cytometry and Western blot. A SET-PP2A protein-protein interaction antagonist TD19 was used to disrupt signal transduction. In vivo efficacy of TD19 was tested in MDA-MB-468-xenografted animal model. FINDINGS: TCGA data revealed upregulation of SET and CIP2A and positive correlation of these two gene expressions in TNBC tumors. Ectopic SET or CIP2A increased cell viability, migration, and invasion of TNBC cells. Notably ERK inhibition increased PP2A activity. ERK activation is known crucial for Elk-1 activity, a transcriptional factor regulating CIP2A expression, we hypothesized an oncogenic feedforward loop consisting of pERK/pElk-1/CIP2A/PP2A. This loop was validated by knockdown of PP2A and ectopic expression of Elk-1, showing reciprocal changes in loop members. In addition, ectopic expression of SET increased pAkt, pERK, pElk-1 and CIP2A expressions, suggesting a positive linkage between SET and CIP2A signaling. Moreover, TD19 disrupted this CIP2A-feedforward loop by restoring PP2A activity, demonstrating in vitro and in vivo anti-cancer activity. Mechanistically, TD19 downregulated CIP2A mRNA via inhibiting pERK-mediated Elk-1 nuclear translocation thereby decreased Elk-1 binding to the CIP2A promoter. INTERPRETATION: These findings suggested that a novel oncogenic CIP2A-feedforward loop contributes to TNBC progression and targeting SET to disrupt this oncogenic CIP2A loop showed therapeutic potential in TNBC.


Assuntos
Autoantígenos/metabolismo , Chaperonas de Histonas/metabolismo , Proteínas de Membrana/metabolismo , Proteína Fosfatase 2/metabolismo , Fatores de Transcrição/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autoantígenos/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Modelos Animais de Doenças , Cloridrato de Erlotinib/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/genética , Camundongos , Modelos Biológicos , Regiões Promotoras Genéticas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Int Immunopharmacol ; 66: 236-241, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30481683

RESUMO

Many studies confirmed that the over-activation of RAF-MEK-ERK signaling pathway plays a central role in human cancers. To avoid drug resistance during cancer treatment, many researchers focused on the study of the downstream therapeutic target of RAF-MEK-ERK signaling pathway. Therefore, ERK1/2 became a hot anticancer target. It has been shown that ERK phosphorylation could activate Th17 cells and therefore induce inflammatory diseases. Due to these results, inhibition of ERK, as a potential drug target, could provide a solution for autoimmune diseases, especially T cell mediated diseases. In this study, a small synthetic molecule JSI287 was found with the function of alleviating IMQ-induced mice skin lesions through ERK/IL-17 signaling pathway during the screening of small molecule databases targeting ERK. The results showed that JS1287 small molecule alleviated epidermal thickness, epidermis congestion, edema and inflammatory cell infiltration, decreased release of inflammatory cytokines of IL-6, IL-12 and IL-17A, and further regulated the mRNA expression of ATF1 and protein expression of ERK1/2 in IMQ-induced skin lesions. Our study suggested that ERK inhibitor JSI287 could be a promising candidate for psoriasis treatment.


Assuntos
Anti-Inflamatórios/uso terapêutico , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Interleucina-17/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Psoríase/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Células Th17/imunologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Imiquimode/toxicidade , Interleucina-12/metabolismo , Interleucina-6/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Psoríase/induzido quimicamente , Pele/patologia , Bibliotecas de Moléculas Pequenas , Quinases raf/metabolismo
19.
Cancer Lett ; 442: 483-490, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30423407

RESUMO

While the recently developed antiandrogen Enzalutamide (Enz) can extend survival for 4.8 months in castration-resistant prostate cancer (CRPC) patients, eventually most of these CRPC patients may develop resistance to the Enz without a clear mechanism. Here we found the expression of Beclin 1 was decreased in both Enz-resistant (EnzR) cell lines (EnzR1-C4-2 and EnzR2-C4-2B) as compared to their parental Enz-sensitive (EnzS) (EnzS1-C4-2 and EnzS2-C4-2B) cells, and targeting the Beclin 1 could lead to increase the Enz-sensitivity in these two CRPC cell lines. Mechanism dissection revealed that Enz might function via altering the interaction between Beclin 1 and the androgen receptor (AR) to decrease the activity of Beclin 1/Vps15/Vps34 complex thus increasing the ERK-mediated growth factor signaling to alter the Enz sensitivity. Interrupting the AR-Beclin 1/ERK signaling with ectopic BECN1 or ERK inhibitor led to alter the Enz sensitivity in both EnzR1-C4-2 and EnzR2-C4-2B cells compared to EnzS1-C4-2 and EnzS2-C4-2B cells, respectively. Together, these results suggest that targeting this newly identified AR-Beclin 1 complex-mediated ERK growth factor signaling with small molecule ERK inhibitor may help potentially develop new therapies to better suppress the EnzR CRPC.


Assuntos
Antagonistas de Androgênios/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteína Beclina-1/metabolismo , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores Androgênicos/metabolismo , Proteína Beclina-1/genética , Linhagem Celular Tumoral , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Masculino , Feniltioidantoína/farmacologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/genética , Transdução de Sinais/efeitos dos fármacos , Proteína VPS15 de Distribuição Vacuolar/metabolismo
20.
Korean J Anesthesiol ; 72(1): 60-67, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29969887

RESUMO

BACKGROUND: The pain-relief properties of tricyclic antidepressants can be attributed to several actions. Recent observations suggest that adenosine is involved in the antinociceptive effect of amitriptyline. The A3 adenosine receptor (A3AR) is the only adenosine subtype overexpressed in inflammatory and cancer cells. This study was performed to investigate the role of A3AR in the anti-nociceptive effect of amitriptyline. METHODS: Spinal nerve-ligated neuropathic pain was induced by ligating the L5 and L6 spinal nerves of male Sprague-Dawley rats. The neuropathic rats were randomly assigned to one of the following three groups (8 per group): a neuropathic pain with normal saline group, a neuropathic pain with amitriptyline group, and a neuropathic pain with amitriptyline and 3-ethyl-5-benzyl- 2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS) group. Amitriptyline or saline was administered intraperitoneally and 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191), an A3AR antagonist, was injected subcutaneously immediately before amitriptyline administration. The level of extracellular signal-regulated kinase P44/42 (ERK1/2), cyclic AMP response element-binding protein (CREB), and proinflammatory cytokines were assessed using immunoblotting or reverse-transciption polymerase chain reaction. RESULTS: Amitriptyline increased the mechanical withdrawal threshold of the neuropathic rats. The level of phospho-ERK1/2 and phospho-CREB proteins, and proinflammatory cytokines produced by spinal nerve ligation were significantly reduced by amitriptyline administration. However, the use of MRS-1191 before amitriptyline administration not only reduced the threshold of mechanical allodynia, but also increased the signaling protein and proinflammatory cytokine levels, which were reduced by amitriptyline. CONCLUSIONS: The results of this study suggest that the anti-nociceptive effect of amitriptyline involves the suppression of ERK1/2 and CREB signaling proteins, and A3AR activation also affects the alleviation of the inflammatory response.


Assuntos
Amitriptilina/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/antagonistas & inibidores , Citocinas/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Receptor A3 de Adenosina/fisiologia , Antagonistas do Receptor A3 de Adenosina/farmacologia , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley
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