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1.
Nat Commun ; 11(1): 5769, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188182

RESUMO

Transcription factor phosphorylation at specific sites often activates gene expression, but how environmental cues quantitatively control transcription is not well-understood. Activating protein 1 transcription factors are phosphorylated by mitogen-activated protein kinases (MAPK) in their transactivation domains (TAD) at so-called phosphoswitches, which are a hallmark in response to growth factors, cytokines or stress. We show that the ATF2 TAD is controlled by functionally distinct signaling pathways (JNK and p38) through structurally different MAPK binding sites. Moreover, JNK mediated phosphorylation at an evolutionarily more recent site diminishes p38 binding and made the phosphoswitch differently sensitive to JNK and p38 in vertebrates. Structures of MAPK-TAD complexes and mechanistic modeling of ATF2 TAD phosphorylation in cells suggest that kinase binding motifs and phosphorylation sites line up to maximize MAPK based co-regulation. This study shows how the activity of an ancient transcription controlling phosphoswitch became dependent on the relative flux of upstream signals.


Assuntos
Fator 2 Ativador da Transcrição/metabolismo , Regulação da Expressão Gênica , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Transcrição Genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Fator 2 Ativador da Transcrição/química , Motivos de Aminoácidos , Sequência de Aminoácidos , Células HEK293 , Humanos , Luciferases/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Fosforilação , Ligação Proteica , Dedos de Zinco
2.
Chem Biol Interact ; 331: 109276, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33002459

RESUMO

Ulcerative colitis (UC) is a chronic disease driven primarily by uncontrolled pervasive inflammatory responses affecting the colon and rectum. Currently available medications carry multiple detrimental adverse effects, which have emphasized the mandatory need for safer and more efficient novel therapeutic alternatives. Melittin is the main constituent of bee venom and exhibits potent anti-inflammatory properties. The antiulcerogenic effect of oral melittin (40 µg/kg) was explored in the current study using the acetic acid-induced colitis model. Increase in body weight and decrease in colon mass index were observed in the melittin group. Microscopically, melittin ameliorated acetic acid-induced histological damage. Melittin administration has efficiently amended the elevated levels of the cytokines, tumor necrosis factor (TNF-α) and interleukin 6 (IL-6) seen in the colitis group. This was accompanied by inhibition of the upstream signaling molecules, Toll-like receptor 4 (TLR4), tumor necrosis factor receptor (TNF-R)-associated factor (TRAF6), mitogen-activated protein kinase 38 (p38 MAPK), and nuclear factor kappaB (NF-κB) in the melittin group. Moreover, treatment with melittin resulted in marked decrease in colonic level of prostaglandin E2 (PGE2) together with the enzymes involved in its synthesis, secretory phospholipase A2 (sPLA2) and cyclooxygenase 2 (COX-2). Additionally, melittin has attenuated acetic acid-induced oxidative stress as manifested by the significant diminishment in malondialdehyde (MDA) as well as the increase in superoxide dismutase (SOD) and reduced glutathione (GSH) levels. Therefore, melittin mitigated UC pathogenesis and could be considered as a potent and promising therapeutic alternative for UC treatment.


Assuntos
Antiulcerosos/farmacologia , Meliteno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor 4 Toll-Like/metabolismo , Ácido Acético/toxicidade , Administração Oral , Animais , Antiulcerosos/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo/metabolismo , Colo/patologia , Ciclo-Oxigenase 2/metabolismo , Interleucina-6/metabolismo , Malondialdeído/metabolismo , Meliteno/uso terapêutico , Camundongos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Nat Commun ; 11(1): 4865, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978396

RESUMO

The metabolic state of an organism instructs gene expression modalities, leading to changes in complex life history traits, such as longevity. Dietary restriction (DR), which positively affects health and life span across species, leads to metabolic reprogramming that enhances utilisation of fatty acids for energy generation. One direct consequence of this metabolic shift is the upregulation of cytoprotective (CyTP) genes categorized in the Gene Ontology (GO) term of "Xenobiotic Detoxification Program" (XDP). How an organism senses metabolic changes during nutritional stress to alter gene expression programs is less known. Here, using a genetic model of DR, we show that the levels of polyunsaturated fatty acids (PUFAs), especially linoleic acid (LA) and eicosapentaenoic acid (EPA), are increased following DR and these PUFAs are able to activate the CyTP genes. This activation of CyTP genes is mediated by the conserved p38 mitogen-activated protein kinase (p38-MAPK) pathway. Consequently, genes of the PUFA biosynthesis and p38-MAPK pathway are required for multiple paradigms of DR-mediated longevity, suggesting conservation of mechanism. Thus, our study shows that PUFAs and p38-MAPK pathway function downstream of DR to help communicate the metabolic state of an organism to regulate expression of CyTP genes, ensuring extended life span.


Assuntos
Ácidos Graxos Insaturados/genética , Ácidos Graxos Insaturados/metabolismo , Regulação da Expressão Gênica , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Fenômenos Bioquímicos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Regulação da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Ácido Linoleico/metabolismo , Longevidade , Redes e Vias Metabólicas/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo
4.
PLoS One ; 15(9): e0238528, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881908

RESUMO

Quercetin is a yellow pigment that is found in many common dietary plants, and that protects against oxidative stress, inflammation, and arteriosclerosis. It has also been suggested to prolong the lifespan of, and enhance heat-stress tolerance in nematodes; thus, the present study investigated its effects on both the nematode life- and health span by assessing its capacity to promote nematode motility after aging and/or heat stress, as well as the mechanisms underlying these effects. The results of the conducted analyses showed that quercetin feeding prolonged lifespan, suppressed age-related motility retardation, improved motility recovery after heat stress, and decreased the production of both intercellular and mitochondrial reactive oxygen species in the analysed Caenorhabditis elegans strains, likely by modulating the insulin-like signalling (ILS) pathway and p38-mitogen-activated protein kinase (MAPK) pathway. In particular, the transcription factors DAF-16 and SKN-1 were found to mediate the observed quercetin-induced effects, consistent with their previously demonstrated roles as regulators of aging. Furthermore, we demonstrated, for the first time, that quercetin induced heat-stress tolerance in C. elegans by modulating HSF-1 expression and/or activity. Thus, the present study provides valuable insights into the mechanisms by which quercetin inhibit aging and enhance heat-stress tolerance via ILS and MAPK pathway in C. elegans.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Resposta ao Choque Térmico/efeitos dos fármacos , Quercetina/farmacologia , Animais , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
PLoS One ; 15(8): e0237929, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822403

RESUMO

BACKGROUND: Neuroinflammation causes neurodegenerative conditions like Alzheimer's disease (AD). Ipriflavone (IP), therapeutic compound to postmenopausal osteoporosis, has limited estrogenic activity and is accounted as AChE inhibitor. The developing of drug delivery systems to enable drug targeting to specific sites increases the drug therapeutic effect. OBJECTIVE: The aim of the present study was to formulate and evaluate ipriflavone loaded albumin nanoparticles (IP-Np) along with free ipriflavone against lipopolysaccharide (LPS) induced neuroinflammation in rats. METHODS: Neuroinflammation was induced by intra-peritoneal (i.p) injection of LPS (250 µg/kg rat body weight) then treatments were conducted with (1) ipriflavone at two doses 50 mg/kg and 5 mg/kg, (2) IP-Np (5 mg ipriflavone/kg) or (3) IP-Np coated with polysorbate 80 (IP-Np-T80) (5 mg ipriflavone/kg). The alteration of the inflammatory response in male adult Wistar rats' brain hippocampus was investigated by examining associated indices using biochemical and molecular analyses. RESULTS: A significant upsurge in inflammatory mediators and decline in antioxidant status were observed in LPS-induced rats. In one hand, ipriflavone (50 mg/kg), IP-Np and IP-Np-T80 ameliorated LPS induced brain hippocampal inflammation where they depreciated the level of pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß) and enhanced antioxidant status. In another hand, ipriflavone at dose (5 mg/kg) didn't show the same therapeutic effect. CONCLUSION: The current study provides evidence for the potential neuroprotective effect of ipriflavone (50 mg/kg) against LPS-induced neuroinflammation in rats through its anti-inflammatory and antioxidant activities. Moreover, nanoparticles significantly attenuated neuroinflammation in concentration lower than the effective therapeutic dose of free drug ten times.


Assuntos
Hipocampo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Isoflavonas/uso terapêutico , Nanopartículas , Fármacos Neuroprotetores/uso terapêutico , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Inibidores da Colinesterase/farmacologia , Citocinas/metabolismo , Sistemas de Liberação de Medicamentos , Hipocampo/enzimologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Isoflavonas/administração & dosagem , Isoflavonas/farmacologia , Lipopolissacarídeos/toxicidade , Masculino , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Nanopartículas/ultraestrutura , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Soroalbumina Bovina/química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Life Sci ; 261: 118348, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32860803

RESUMO

AIMS: 3,3'-Diindolylmethane (DIM) has limited anti-cancer effects in gastric cancer. Hydrogen sulfide (H2S) plays an important role in the tumor development and therapy, cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE), two key endogenous H2S biosynthesis enzymes, can affect endogenous H2S levels and alter cancer treatment. Our main objective was to investigate whether the aminooxyacetic acid (AOAA) and DL-Propargylglycine (PAG), two specific inhibitors of CBS and CSE, could assist DIM to exert a stronger anti-cancer effects in gastric cancer BGC-823 and SGC-7901 cells. MATERIALS AND METHODS: Cell proliferation was assayed by MTT and cell colony-forming assay. Apoptosis and migration were detected by Hoechst staining and scratch test respectively. Western blot was used to evaluate the expression of proteins related to proliferation, apoptosis and migration. KEY FINDINGS: Combination of AOAA or PAG with DIM synergistically inhibited proliferation and migration, increased apoptosis in gastric cancer cells. The p38-p53 axis was also further activated by the combination of AOAA or PAG with DIM. Exogenous H2S from sodium hydrosulfide, attenuated the efficacy of DIM in cancer cells by reducing the activation level of p38-p53 axis. Taken together, AOAA or PAG inhibited the expression of endogenous H2S biosynthesis enzymes and effectively enhanced susceptibility of gastric cancer to DIM through activating p38-p53 axis. SIGNIFICANCE: The current study highlight more precise requirements for the clinical application of sulfur-containing anti-cancer drugs, and open a new way to enhance the sensitivity of DIM in chemotherapy of gastric cancer.


Assuntos
Anticarcinógenos/farmacologia , Sulfeto de Hidrogênio/antagonistas & inibidores , Indóis/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Alquinos/administração & dosagem , Alquinos/farmacologia , Ácido Amino-Oxiacético/administração & dosagem , Ácido Amino-Oxiacético/farmacologia , Anticarcinógenos/administração & dosagem , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Sinergismo Farmacológico , Glicina/administração & dosagem , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Sulfeto de Hidrogênio/metabolismo , Indóis/administração & dosagem , Neoplasias Gástricas/patologia , Proteína Supressora de Tumor p53/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
PLoS One ; 15(8): e0237442, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790767

RESUMO

BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths among adult males globally. The poor prognosis of PCa is largely due to late diagnosis of the disease when it has already progressed to an advanced stage marked by androgen-independence, thus necessitating new strategies for early detection and treatment. We construe that these direly needed advances are limited by our poor understanding of early events in the progression of PCa and that would thus represent ideal targets for early intervention. To begin to fill this void, we interrogated molecular "oncophenotypes" that embody the transition of PCa from an androgen-dependent (AD) to-independent (AI) state. METHODS: To accomplish this aim, we used our previously established AD and AI murine PCa cell lines, PLum-AD and PLum-AI, respectively, which recapitulate primary and progressive PCa morphologically and molecularly. We statistically surveyed global gene expressions in these cell lines by microarray analysis. Differential profiles were functionally interrogated by pathways, gene set enrichment and topological gene network analyses. RESULTS: Gene expression analysis of PLum-AD and PLum-AI transcriptomes (n = 3 each), revealed 723 differentially expressed genes (392 upregulated and 331 downregulated) in PLum-AI compared to PLum-AD cells. Gene set analysis demonstrated enrichment of biological functions and pathways in PLum-AI cells that are central to tumor aggressiveness including cell migration and invasion facilitated by epithelial-to-mesenchymal transition (EMT). Further analysis demonstrated that the p38 mitogen-activated protein kinase (MAPK) was predicted to be significantly activated in the PLum-AI cells, whereas gene sets previously associated with favorable response to the p38 inhibitor SB203580 were attenuated (i.e., inversely enriched) in the PLum-AI cells, suggesting that these aggressive cells may be therapeutically vulnerable to p38 inhibition. Gene set and gene-network analysis also alluded to activation of other signaling networks particularly those associated with enhanced EMT, inflammation and immune function/response including, but not limited to Tnf, IL-6, Mmp 2, Ctgf, and Ptges. Accordingly, we chose SB203580 and IL-6 to validate their effect on PLum-AD and PLum-AI. Some of the common genes identified in the gene-network analysis were validated at the molecular and functional level. Additionally, the vulnerability to SB203580 and the effect of IL-6 were also validated on the stem/progenitor cell population using the sphere formation assay. CONCLUSIONS: In summary, our study highlights pathways associated with an augmented malignant phenotype in AI cells and presents new high-potential targets to constrain the aggressive malignancy seen in the castration-resistant PCa.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imidazóis/farmacologia , Interleucina-6/farmacologia , Neoplasias da Próstata/patologia , Piridinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Androgênios/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Imidazóis/uso terapêutico , Interleucina-6/uso terapêutico , Masculino , Camundongos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Piridinas/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
PLoS One ; 15(8): e0237577, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790741

RESUMO

Abnormal skin melanin homeostasis results in refractory pigmentary diseases. Melanogenesis is influenced by gene regulation, ultraviolet radiation, and host epigenetic responses. Steroid receptor RNA activator (SRA), a long noncoding RNA, is known to regulate steroidogenesis and tumorigenesis. However, how SRA contributes to melanogenesis remains unknown. Using RNA interference against SRA in B16 and A375 melanoma cells, we observed increased pigmentation and increased expression of TRP1 and TRP2 at transcriptional and translational levels only in B16 cells. The constitutive phosphorylation of p38 in B16-shCtrl cells was inhibited in cells with knocked down SRAi. Moreover, the melanin content of control B16 cells was increased by SB202190, a p38 inhibitor. Furthermore, reduced p38 phosphorylation, enhanced TRP1 expression, and hypermelanosis were observed in A375 cells with RNA interference. These results indicate that SRA-p38-TRP1 axis has a regulatory role in melanin homeostasis and that SRA might be a potential therapeutic target for treating pigmentary diseases.


Assuntos
Oxirredutases Intramoleculares/metabolismo , Melaninas/metabolismo , Melanoma Experimental/patologia , Glicoproteínas de Membrana/metabolismo , Oxirredutases/metabolismo , RNA Longo não Codificante/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Regulação Neoplásica da Expressão Gênica , Oxirredutases Intramoleculares/genética , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Glicoproteínas de Membrana/genética , Camundongos , Oxirredutases/genética , Fosforilação , RNA Longo não Codificante/genética , RNA Interferente Pequeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
9.
Gene ; 763: 145030, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32755658

RESUMO

OBJECTIVE: To investigate the impact and the mechanism of Gadd45α mediating p38MAPK pathway on the retinal ganglion cells (RGCs) injury in chronic ocular hypertension (COH) rats. METHODS: COH model in rats were established and intraocular pressure (IOP) was tested. Retrograde labeling was used for counting RGCs and TUNEL staining was performed for RGCs apoptosis. Western Blotting was conducted to examine the expression of Gadd45α and p38MAPK pathway. Besides, RGC-5 cells cultured in vitro were treated with H2O2. Cell viability was detected by CCK-8, ROS level tested by DCFH-DA assay, and cell apoptosis examined by flow cytometry. RESULTS: COH rats had increased expression of Gadd45α and p-p38/p38 protein 1-4 weeks after surgery. Rats in COH group enhanced obviously in IOP, RGC apoptosis rate and the protein expression of Gadd45α, p-p38/p38, Bax/Bcl-2 and cleaved caspase-3, but declined appreciably in RGC counting. However, the above indicators of COH rats were effectively improved by Gadd45α shRNA treatment. Additionally, RGC-5 cells in H2O2 group reduced in cell viability and went up in ROS level and apoptosis rate. The H2O2-induced RGC-5 cells treated with Gadd45α shRNA were improved apparently in those indicators, and cells treated with pcDNA Gadd45α showed an opposite trend. Moreover, p38 MAPK inhibitor SB203580 can effectively reverse the damage of pcDNA Gadd45α from H2O2-induced RGC-5 cells. CONCLUSION: Silencing Gadd45α can reduce the RGC damage in COH rats by inhibiting p38MAPK pathway and such a protective role may be associated with the suppression of RGC apoptosis and the mitigation of oxidative stress.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Sistema de Sinalização das MAP Quinases , Hipertensão Ocular/metabolismo , Células Ganglionares da Retina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose , Proteínas de Ciclo Celular/genética , Células Cultivadas , Humanos , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
10.
J Pharmacol Sci ; 144(1): 23-29, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32653342

RESUMO

Microglia maintain brain homeostasis as the main immune cells in the central nervous system. Activation of sigma-1 receptor (Sig1R) plays neuroprotective and anti-inflammatory roles in microglia. Recent studies showed that Sig1R expression level has been reduced in the brain of the patients with neurodegenerative diseases including Alzheimer's disease. However, the mechanisms underlying the down regulation of the Sig1R has not been clear. Treatment of rat primary cultured microglia with the inflammogen lipopolysaccharide (LPS) significantly decreased the expression of Sig1R mRNA in a concentration and time-dependent manner. The effects of LPS were blocked by pretreatment with TAK-242, a toll-like receptor 4 (TLR4) antagonist. Furthermore, inhibitors of transforming growth factor beta-activated kinase 1 (TAK1), p38 mitogen-activated protein kinase (MAPK) and histone deacetylase 6 (HDAC6) restored the LPS-induced downregulation of Sig1R. Thus, the current findings demonstrate that TLR4 activation leads to the downregulation of the Sig1R expression via TLR4-TAK1-p38 MAPK pathway and the inhibition of HDAC6 can increase Sig1R expression in microglia. The current findings suggest that downregulation of Sig1R may contribute to neuroinflammation-induced microglial dysfunction, regulation of microglial Sig1R may be novel therapeutic drug candidates for neurodegenerative and neuroinflammatory diseases.


Assuntos
Regulação da Expressão Gênica/genética , Expressão Gênica/genética , Desacetilase 6 de Histona/fisiologia , MAP Quinase Quinase Quinases/fisiologia , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Microglia/metabolismo , Doenças Neurodegenerativas/genética , Receptores sigma/genética , Receptores sigma/metabolismo , Receptor 4 Toll-Like/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia , Animais , Células Cultivadas , Regulação para Baixo/genética , MAP Quinase Quinase Quinases/metabolismo , Terapia de Alvo Molecular , Doenças Neurodegenerativas/tratamento farmacológico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptores sigma/fisiologia , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(7): 583-589, 2020 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-32727641

RESUMO

Objective To investigate the protective effects of kaempferol (KAE) on PC12 cells against neurotoxin 6-hydroxydopamine (6-OHDA)-induced inflammatory damage and explore whether it is related to the inhibition of the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway. Methods After being cultured for 24 hours, PC12 cells were divided into 4 groups: control, 6-OHDA (100 µmol/L), 6-OHDA combined with (20, 40, 60, 80, 100) µmol/L KAE and KAE groups. The morphological features of PC12 cells were observed under an inverted microscope, and the cell viability was detected by CCK-8 assay. In the case of the optimal effective dose of KAE, the expression of cyclooxygenase-2 (COX2), inducible nitric oxide synthase (iNOS), nuclear factors (NF)-κB were evaluated by immunocytochemical staining and Western blot analysis. To explore the mechanism underlying the protective role of KAE, KAE and SB203580 (p38 MAPK pathway inhibitor) (10 µmol/L) were separately added into 6-OHDA culture medium of PC12 cells. The protein levels of iNOS, COX2, NF-κB, p38 MAPK and p-p38 MAPK were tested by Western blotting. Results Compared with the control group, the number of cells in the 6-OHDA group was significantly reduced, with most cell bodies shrunk and aggregated into clumps. Compared with the 6-OHDA group, the number of cells increased and the morphology was effectively improved in the 6-OHDA combined with KAE (20, 40, 60, 80, and 100 µmol/L) group. KAE at 80 µmol/L was demonstrated the best protective effects in the present work. In the 6-OHDA group, the expression of COX2, iNOS, NF-κB significantly increased. Compared with the 6-OHDA group, the expression of the above molecules decreased markedly in the 6-OHDA combined with 80 µmol/L KAE group. The protein expression levels of COX2, iNOS, NF-κB, p38 MAPK and p-p38 MAPK went up significantly in the 6-OHDA group as compared with the control group, while they were down-regulated obviously by both KAE and SB203580. Conclusion KAE exerts neuroprotective effects on PC12 cells against the damage induced by 6-OHDA probably through the p38 MAPK signaling pathway.


Assuntos
Sistema de Sinalização das MAP Quinases , Animais , Quempferóis , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Oxidopamina/toxicidade , Células PC12 , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Environ Toxicol ; 35(12): 1318-1325, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32656944

RESUMO

In this study, we report the potential of cannabidiol, one of the major cannabis constituents, for enhancing osteoblastic differentiation in U2OS and MG-63 cells. Cannabidiol increased the expression of Angiopoietin1 and the enzyme activity of alkaline phosphatase in U2OS and MG-63. Invasion and migration assay results indicated that the cell mobility was activated by cannabidiol in U2OS and MG-63. Western blotting analysis showed that the expression of tight junction related proteins such as Claudin1, Claudin4, Occuludin1, and ZO1 was increased by cannabidiol in U2OS and MG-63. Alizarin Red S staining analysis showed that calcium deposition and mineralization was enhanced by cannabidiol in U2OS and MG-63. Western blotting analysis indicated that the expression of osteoblast differentiation related proteins such as distal-less homeobox 5, bone sialoprotein, osteocalcin, type I collagen, Runt-related transcription factor 2 (RUNX2), osterix (OSX), and alkaline phosphatase was time dependently upregulated by cannabidiol in U2OS and MG-63. Mechanistically, cannabidiol-regulated osteoblastic differentiation in U2OS and MG-63 by strengthen the protein-protein interaction among RUNX2, OSX, or the phosphorylated p38 mitogen-activated protein kinase (MAPK). In conclusion, cannabidiol increased Angiopoietin1 expression and p38 MAPK activation for osteoblastic differentiation in U2OS and MG-63 suggesting that cannabidiol might provide a novel therapeutic option for the bone regeneration.


Assuntos
Angiopoietina-1/metabolismo , Canabidiol/farmacologia , Diferenciação Celular/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Fosfatase Alcalina/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Humanos , Osteoblastos/citologia , Osteoblastos/metabolismo , Fosforilação
13.
Am J Chin Med ; 48(5): 1159-1178, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32668973

RESUMO

Hepatic ischemia-reperfusion (IR) injury remains the major cause of liver damage post-liver surgery or transplantation. Diminishing oxidative stress and inflammatory responses is a powerful channel to reduce the rate of morbidity and mortality. Gastrodin (GSTD), a bioactive compound extracted from the traditional Chinese herbal agent with a long history of clinical application in nervous system diseases, is suggested to possess anti-oxidative effects on liver diseases, such as nonalcoholic fatty liver disease. However, the therapeutic potential of GSTD in liver IR injury remains unclear. In this paper, we performed surgery to set up the 70% hepatic IR injury models in mice after a three-day pretreatment of GSTD. We found the administration of GSTD reduced liver damage, which correlated with lower histological Suzuki's score, lower serum alanine transaminase (AST) and alanine transaminase (ALT) levels, less oxidative stress, and cell apoptosis in a dose-responsive manner, as compared to the parallel control. Meanwhile, we observed a great induction of heme oxygenase-1 (HO-1) and an activation of the p38 mitogen-activated protein kinases/nuclear factor erythroid 2-related factor 2 (p38MAPK/Nrf2) pathway in response to the GSTD pretreatment, while the protective effects upon GSTD diminished in mice with HO-1 heterozygous mutation. In addition, GSTD inhibited IR induced toll-like receptor (TLR) 4, but not TLR2 in a HO-1 dependent manner, leading to a down-regulation of cytokines, such as interleukin (IL)-6 and TNF-[Formula: see text]. Collectively, our findings revealed GSTD attenuated liver IR injury via activation of the HO-1 pathway, providing a novel therapeutic strategy to minimize the IR induced oxidative stress in the process of liver transplantation.


Assuntos
Antioxidantes , Álcoois Benzílicos/administração & dosagem , Álcoois Benzílicos/farmacologia , Glucosídeos/administração & dosagem , Glucosídeos/farmacologia , Fígado , Fator 2 Relacionado a NF-E2/metabolismo , Fitoterapia , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas , Heme Oxigenase-1/metabolismo , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Cuidados Pré-Operatórios , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
Am J Physiol Renal Physiol ; 319(3): F414-F422, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32715760

RESUMO

We used patch-clamp and Western blot analysis to test whether PGF2α stimulates the basolateral 10-pS Cl- channel and thiazide-sensitive Na+-Cl- cotransporter (NCC) in the distal convoluted tubule (DCT) via a prostaglandin F receptor (FP-R). Single channel and whole cell recordings demonstrated that PGF2α stimulated the 10-pS Cl- channel in the DCT. The stimulatory effect of PGF2α on the Cl- channel was mimicked by a FP-R agonist, latanoprost, but was abrogated by blocking FP-R with AL8810. Also, the effect of PGF2α on the Cl- channel in the DCT was recapitulated by stimulating PKC but was blocked by inhibiting PKC. Furthermore, inhibition of p38 MAPK but not ERK blocked the effect of PGF2α on the 10-pS Cl- channel. Inhibition of NADPH oxidase also abrogated the stimulatory effect of PGF2α on the 10-pS Cl- channel, while the addition of 10 µM H2O2 mimicked the stimulatory effect of PGF2α on the 10-pS Cl- channel. Moreover, superoxide-related species may mediate the stimulatory effect of PGF2α on the 10-pS Cl- channel because the stimulatory effect of PGF2α and H2O2 was not additive. Western blot analysis showed that infusion of PGF2α in vivo not only increased the expression of FP-R but also increased the expression of total NCC and phosphorylated NCC. We conclude that PGF2α stimulates the basolateral 10-pS Cl- channel in the DCT by activating FP-R through PKC/p38 MAPK and NADPH oxidase-dependent pathways. The stimulatory effects of PGF2α on the Cl- channel and NCC may contribute to PGF2α-induced increases in NaCl reabsorption in the DCT.


Assuntos
Proteínas de Transporte de Ânions/metabolismo , Canais de Cloreto/metabolismo , Dinoprosta/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Túbulos Renais Distais/metabolismo , Receptores de Droga/metabolismo , Simportadores de Cloreto de Sódio/metabolismo , Animais , Proteínas de Transporte de Ânions/genética , Canais de Cloreto/genética , Feminino , Túbulos Renais Distais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ocitócicos/farmacologia , Técnicas de Patch-Clamp , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Receptores de Droga/genética , Simportadores de Cloreto de Sódio/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Int J Nanomedicine ; 15: 4659-4676, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32636624

RESUMO

Background: Titanium implants are widely used in dental and orthopedic medicine. Nevertheless, there is limited osteoinductive capability of titanium leading to a poor or delayed osseointegration, which might cause the failure of the implant therapy. Therefore, appropriate modification on the titanium surface for promoting osseointegration of existing implants is still pursued. Purpose: Graphene oxide (GO) is a promising candidate to perform implant surface biofunctionalization for modulating the interactions between implant surface and cells. So the objective of this study was to fabricate a bioactive GO-modified titanium implant surface with excellent osteoinductive potential and further investigate the underlying biological mechanisms. Materials and Methods: The large particle sandblasting and acid etching (SLA, commonly used in clinical practice) surface as a control group was first developed and then the nano-GO was deposited on the SLA surface via an ultrasonic atomization spraying technique to create the SLA/GO group. Their effects on rat bone marrow mesenchymal stem cells (BMSCs) responsive behaviors were assessed in vitro, and the underlying biological mechanisms were further systematically investigated. Moreover, the osteogenesis performance in vivo was also evaluated. Results: The results showed that GO coating was fabricated on the titanium substrates successfully, which endowed SLA surface with the improved hydrophilicity and protein adsorption capacity. Compared with the SLA surface, the GO-modified surface favored cell adhesion and spreading, and significantly improved cell proliferation and osteogenic differentiation of BMSCs in vitro. Furthermore, the FAK/P38 signaling pathways were proven to be involved in the enhanced osteogenic differentiation of BMSCs, accompanied by the upregulated expression of focal adhesion (vinculin) on the GO coated surface. The enhanced bone regeneration ability of GO-modified implants when inserted into rat femurs was also observed and confirmed that the GO coating induced accelerated osseointegration and osteogenesis in vivo. Conclusion: GO modification on titanium implant surface has potential applications for achieving rapid bone-implant integration through the mediation of FAK/P38 signaling pathways.


Assuntos
Quinase 1 de Adesão Focal/metabolismo , Grafite/farmacologia , Osteogênese/efeitos dos fármacos , Próteses e Implantes , Titânio , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Grafite/química , Interações Hidrofóbicas e Hidrofílicas , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Osseointegração/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Propriedades de Superfície
16.
Cell ; 182(3): 685-712.e19, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32645325

RESUMO

The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Pneumonia Viral/metabolismo , Proteômica/métodos , Células A549 , Animais , Antivirais/farmacologia , Células CACO-2 , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/metabolismo , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Fosforilação , Pneumonia Viral/virologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Toxicol Lett ; 332: 140-145, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32659472

RESUMO

Fumonisin B1 (FB1) is a congener of fumonisins produced by Fusarium species that may be found as corn contaminants threatening health of humans and animals. FB1 causes a variety of toxicity effects, including hepatotoxic, nephrotoxic and cytotoxic effects. However, detailed mechanisms associated with FB1 immunotoxicity in neutrophils are still unclear. To accomplish this, we utilized neutrophils to study the mechanisms of FB1 immunotoxicity. In the current study, we found that FB1 induced the formation of neutrophil extracellular traps (NETs), increased reactive oxygen species (ROS) levels, and decreased SOD and CAT activities. Concurrently, FB1 treatment led to the concentration-dependent phosphorylation of ERK-1/2 and p38 in neutrophils. Moreover, we demonstrated that FB1-induced NET formation was dependent of NADPH oxidase activity. Pretreatment of neutrophils with DPI, U0126 and SB202190 significantly reduced ROS generation, and prevented NET formation, further suggesting that ROS dependent activation of ERK 1/2 and p38 pathways, which possibly mediate FB1-induced NET release in neutrophils. Thus, NET formation and ROS production could be attributed to FB1 immunotoxicity, which might enrich the toxicological mechanisms of FB1.


Assuntos
Armadilhas Extracelulares/efeitos dos fármacos , Fumonisinas/toxicidade , Imunotoxinas/toxicidade , Micotoxinas/toxicidade , Neutrófilos/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Catalase/sangue , Bovinos , Armadilhas Extracelulares/imunologia , Técnicas In Vitro , L-Lactato Desidrogenase/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NADPH Oxidases/metabolismo , Neutrófilos/imunologia , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/sangue , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
PLoS Pathog ; 16(6): e1008610, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32603377

RESUMO

Newcastle disease virus (NDV), a member of the Paramyxoviridae family, can activate PKR/eIF2α signaling cascade to shutoff host and facilitate viral mRNA translation during infection, however, the mechanism remains unclear. In this study, we revealed that NDV infection up-regulated host cap-dependent translation machinery by activating PI3K/Akt/mTOR and p38 MAPK/Mnk1 pathways. In addition, NDV infection induced p38 MAPK/Mnk1 signaling participated 4E-BP1 hyperphosphorylation for efficient viral protein synthesis when mTOR signaling is inhibited. Furthermore, NDV NP protein was found to be important for selective cap-dependent translation of viral mRNAs through binding to eIF4E during NDV infection. Taken together, NDV infection activated multiple signaling pathways for selective viral protein synthesis in infected cells, via interaction between viral NP protein and host translation machinery. Our results may help to design novel targets for therapeutic intervention against NDV infection and to understand the NDV anti-oncolytic mechanism.


Assuntos
Proteínas Aviárias , Fator de Iniciação 4E em Eucariotos , Sistema de Sinalização das MAP Quinases , Vírus da Doença de Newcastle , Nucleoproteínas , RNA Mensageiro , RNA Viral , Proteínas Virais , Animais , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Embrião de Galinha , Galinhas , Fator de Iniciação 4E em Eucariotos/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Células HEK293 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Vírus da Doença de Newcastle/genética , Vírus da Doença de Newcastle/metabolismo , Nucleoproteínas/biossíntese , Nucleoproteínas/genética , Nucleoproteínas/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Biossíntese de Proteínas , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteínas Virais/biossíntese , Proteínas Virais/genética , Proteínas Virais/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Life Sci ; 257: 118086, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679147

RESUMO

AIMS: To investigate the role of PP2A in calcified aortic valve disease (CAVD). MATERIALS AND METHODS: The expressions of PP2A subunits were detected by real-time polymerase chain reaction (RT-PCR) and western blot in aortic valves from patients with CAVD and normal controls, the activities of PP2A were analyzed by commercial assay kit at the same time. Aortic valve calcification of mice was evaluated through histological and echocardiographic analysis. ApoE-/- mice and ApoE-/- mice injected intraperitoneally with PP2A inhibitor LB100 were fed a high-cholesterol diet for 24 weeks. Immunofluorescent staining was used to locate the cell-type in which PP2A activity was decreased, the PP2A activity of valvular interstitial cells (VICs) treated with osteogenic induction medium was assessed by western blot and commercial assay kit. After changing the activity of VICs through pharmacologic and genetic intervention, the osteoblast differentiation and mineralization were assessed by western blot and Alizarin Red staining. Finally, the mechanism was clarified by using several specific inhibitors. KEY FINDINGS: PP2A activity was decreased both in calcified aortic valves and human VICs under osteogenic induction. The PP2A inhibitor LB100 aggravated the aortic valve calcification of mice. Furthermore, PPP2CA overexpression inhibited osteogenic differentiation of VICs, whereas PPP2CA knockdown promoted the process. Further study revealed that the ERK/p38 MAPKs signaling pathways mediated the osteogenic differentiation of VICs induced by PP2A inactivation. SIGNIFICANCE: This study demonstrated that PP2A plays an important role in CAVD pathophysiology, PP2A activation may provide a novel strategy for the pharmacological treatment of CAVD.


Assuntos
Estenose da Valva Aórtica/fisiopatologia , Valva Aórtica/patologia , Apolipoproteínas E/genética , Calcinose/fisiopatologia , Osteogênese/genética , Proteína Fosfatase 2/genética , Animais , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/genética , Calcinose/genética , Diferenciação Celular/genética , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Piperazinas/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
J Pharmacol Exp Ther ; 374(3): 512-520, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32571958

RESUMO

The chemoresistance of hepatocellular carcinoma (HCC) is a serious problem that directly hinders the effect of chemotherapeutic agents. We previously reported that Aminopeptidase N (CD13) inhibition can enhance the cytotoxic efficacy of chemotherapy agents. In the present study, we use liver cancer cells to explore the molecular mechanism accounting for the relationship between CD13 and chemoresistance. We demonstrate that CD13 overexpression activates the P38/heat shock protein 27/cAMP response element-binding protein (CREB) signaling pathway to limit the efficacy of cytotoxic agents. Moreover, blockade of P38 or CREB sensitizes HCC cells to 5-fluorouracil. Then we reveal that CREB binds to the autophagy related 7 (ATG7) promoter to induce autophagy and promote HCC cell chemoresistance. CD13 inhibition also downregulates the expression of ATG7, autophagy, and tumor cell growth in vivo. Overall, the combination a CD13 inhibitor and chemotherapeutic agents may be a potential strategy for overcoming drug resistance in HCC. SIGNIFICANCE STATEMENT: Our study demonstrates that Aminopeptidase N (CD13) promotes hepatocellular carcinoma (HCC) cell chemoresistance via the P38/heat shock protein 27/cAMP response element-binding protein (CREB) pathway. CREB regulates autophagy related 7 transcription and expression to induce autophagy. Our results collectively suggest that CD13 may serve as a potential target for overcoming HCC resistance.


Assuntos
Autofagia/fisiologia , Antígenos CD13/metabolismo , Carcinoma Hepatocelular/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias Hepáticas/metabolismo , Transdução de Sinais/fisiologia , Animais , Antineoplásicos/farmacologia , Proteína 7 Relacionada à Autofagia/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Proteínas de Choque Térmico/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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