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1.
Mol Autism ; 15(1): 14, 2024 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570876

RESUMO

BACKGROUND: SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) monogenic mutations or deficiency leads to excessive stereotypic behavior and impaired sociability, which frequently occur in autism cases. To date, the underlying mechanisms by which Shank3 mutation or deletion causes autism and the part of the brain in which Shank3 mutation leads to the autistic phenotypes are understudied. The hypothalamus is associated with stereotypic behavior and sociability. p38α, a mediator of inflammatory responses in the brain, has been postulated as a potential gene for certain cases of autism occurrence. However, it is unclear whether hypothalamus and p38α are involved in the development of autism caused by Shank3 mutations or deficiency. METHODS: Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and immunoblotting were used to assess alternated signaling pathways in the hypothalamus of Shank3 knockout (Shank3-/-) mice. Home-Cage real-time monitoring test was performed to record stereotypic behavior and three-chamber test was used to monitor the sociability of mice. Adeno-associated viruses 9 (AAV9) were used to express p38α in the arcuate nucleus (ARC) or agouti-related peptide (AgRP) neurons. D176A and F327S mutations expressed constitutively active p38α. T180A and Y182F mutations expressed inactive p38α. RESULTS: We found that Shank3 controls stereotypic behavior and sociability by regulating p38α activity in AgRP neurons. Phosphorylated p38 level in hypothalamus is significantly enhanced in Shank3-/- mice. Consistently, overexpression of p38α in ARC or AgRP neurons elicits excessive stereotypic behavior and impairs sociability in wild-type (WT) mice. Notably, activated p38α in AgRP neurons increases stereotypic behavior and impairs sociability. Conversely, inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3-/- mice. In contrast, activated p38α in pro-opiomelanocortin (POMC) neurons does not affect stereotypic behavior and sociability in mice. LIMITATIONS: We demonstrated that SHANK3 regulates the phosphorylated p38 level in the hypothalamus and inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3-/- mice. However, we did not clarify the biochemical mechanism of SHANK3 inhibiting p38α in AgRP neurons. CONCLUSIONS: These results demonstrate that the Shank3 deficiency caused autistic-like behaviors by activating p38α signaling in AgRP neurons, suggesting that p38α signaling in AgRP neurons is a potential therapeutic target for Shank3 mutant-related autism.


Assuntos
Transtorno Autístico , Animais , Camundongos , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Núcleo Arqueado do Hipotálamo/metabolismo , Transtorno Autístico/genética , Transtorno Autístico/metabolismo , Hipotálamo/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/metabolismo
2.
Chin J Integr Med ; 30(3): 230-242, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37815727

RESUMO

OBJECTIVE: To examine the therapeutic effect of Fangji Fuling Decoction (FFD) on sepsis through network pharmacological analysis combined with in vitro and in vivo experiments. METHODS: A sepsis mouse model was constructed through intraperitoneal injection of 20 mg/kg lipopolysaccharide (LPS). RAW264.7 cells were stimulated by 250 ng/mL LPS to establish an in vitro cell model. Network pharmacology analysis identified the key molecular pathway associated with FFD in sepsis. Through ectopic expression and depletion experiments, the effect of FFD on multiple organ damage in septic mice, as well as on cell proliferation and apoptosis in relation to the mitogen-activated protein kinase 14/Forkhead Box O 3A (MAPK14/FOXO3A) signaling pathway, was analyzed. RESULTS: FFD reduced organ damage and inflammation in LPS-induced septic mice and suppressed LPS-induced macrophage apoptosis and inflammation in vitro (P<0.05). Network pharmacology analysis showed that FFD could regulate the MAPK14/FOXO signaling pathway during sepsis. As confirmed by in vitro cell experiments, FFD inhibited the MAPK14 signaling pathway or FOXO3A expression to relieve LPS-induced macrophage apoptosis and inflammation (P<0.05). Furthermore, FFD inhibited the MAPK14/FOXO3A signaling pathway to inhibit LPS-induced macrophage apoptosis in the lung tissue of septic mice (P<0.05). CONCLUSION: FFD could ameliorate the LPS-induced inflammatory response in septic mice by inhibiting the MAPK14/FOXO3A signaling pathway.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno , Radioisótopos de Oxigênio , Sepse , Wolfiporia , Camundongos , Animais , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Lipopolissacarídeos/farmacologia , Sepse/complicações , Transdução de Sinais , Inflamação/tratamento farmacológico
3.
J Tradit Chin Med ; 43(6): 1103-1109, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37946472

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulating Zusanli (ST36), Sanyinjiao (SP6) on inhibition of osteoclastogenesis and the role of the adenosine A2A receptor (A2AR) and the p38α Mitogen-Activated Protein Kinase (MAPK) signaling pathway in mediating this effect. METHODS: Mice with collagen induced arthritis (CIA) received different treatments. Immunohistochemistry and western blotting were used to determine the levels of multiple signaling molecules in these joints [receptor activator of nuclear transcription factor-κB (NF-κB) ligand (RANKL), receptor activator of NF-κB (RANK), tumor necrosis factor receptor associated factor 6 (TRAF6), p38α, NF-κB, and nuclear factor of activated T cells C1 (NFATc1)]. Osteoclasts were identified using tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: The immunohistochemistry results indicated upregulation of p38α, NF-κB, and NFATc1 in the CIA-control and CIA-EA-SCH58261 groups, but reduced levels in the CIA-EA group. Western blotting indicated upregulation of RANKL, RANK, TRAF6, p38α, NF-κB, and NFATc1 in the CIA-control and CIA-EA-SCH58261 groups, but reduced expression in the CIA-EA group. Osteoclasts were more abundant in the CIA-control and CIA-EA-SCH58261 groups than in the CIA-EA group. CONCLUSIONS: EA treatment enhanced the A2AR activity and inhibited osteoclast formation by inhibition of RANKL, RANK, TRAF6, p38α, NF-κB, and NFATc1. SCH58261 reversed the effect of EA. These results suggest that EA regulated p38α-MAPK signaling by increasing A2AR activity, which inhibited osteoclastogenesis.


Assuntos
Artrite Experimental , Eletroacupuntura , Proteína Quinase 14 Ativada por Mitógeno , Animais , Camundongos , Osteogênese , NF-kappa B/genética , NF-kappa B/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Receptor A2A de Adenosina/metabolismo , Fator 6 Associado a Receptor de TNF/genética , Diferenciação Celular , Transdução de Sinais , Ligante RANK/genética , Ligante RANK/metabolismo
4.
Biomed Pharmacother ; 158: 114122, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36566522

RESUMO

Postmenopausal osteoporosis (PMOP) is a common bone disease characterized by decreased bone density and increased bone fragility due to decreased estrogen levels. Qiangguyin (QGY) is transformed from the famous traditional Chinese medicine BuShen Invigorating Blood Decoction. In this study, we used QGY to treat PMOP. We observed that QGY significantly reduced fat accumulation in the chondro-osseous junction. However, its specific mechanism of action remains unclear. To determine the specific molecular mechanism of QGY, we explored the pharmacological mechanism by which QGY reduces fat accumulation in the chondro-osseous junction through network pharmacological analysis. The active components and targets related to PMOP and QGY were screened from different databases, forming a composition-target-disease network. Next, a comprehensive analysis platform including protein-protein interaction (PPI) network, Gene Ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were established. The results revealed that QGY inhibits adipogenic differentiation by activating the mitogen-activated protein kinase (MAPK) signaling pathway, thus reducing the accumulation of fat in the chondro-osseous junction. For further verification. In vitro and in vivo experiments were carried out. Our data showed that QGY significantly reversed the high expression of fatty acid binding protein 4 (FABP4) and peroxisome proliferator-activated receptor γ (PPARγ). Further, QGY prevents fat accumulation by inhibiting the expression of p38. In summary, the results of this study suggested that QGY-induced phenotypic changes are related to the activation of the p38 MAPK signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas , Proteína Quinase 14 Ativada por Mitógeno , Camundongos , Animais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Transdução de Sinais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Medicina Tradicional Chinesa
5.
J Ethnopharmacol ; 296: 115496, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-35750104

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium wilfordii polyglycosides (TWP) are extracted from Tripterygium wilfordii Hook. f., which has the significant effects of anti-inflammation and immunosuppression and has been widely used to treat autoimmune diseases in traditional Chinese medicine. AIM OF STUDY: In Chinese clinical dermatology, TWP was generally used for the treatment of autoimmune skin diseases including psoriasis (PSO), systemic lupus erythematosus (SLE) and pemphigus (PEM). However, the potential hepatotoxicity (HPT) induced by TWP was also existing with the long-term use of TWP. This study aims to explore the potential shared therapeutic mechanism of TWP treating PSO, SLE, PEM and the possible hepatotoxic mechanism induced by TWP. MATERIALS AND METHODS: Network pharmacology was used to predict the potential targets and pathways in this study. The main bioactive compounds in TWP was screened according to TCMSP, PubChem, ChEMBL databases and Lipinski's Rule of Five. The potential targets of these chemical constituents were obtained from PharmMapper, SEA and SIB databases. The related targets of PSO, SLE, PEM and HPT were collected from GeneCards, DrugBank, DisGeNET and CTD databases. The target network construction was performed through STRING database and Cytoscape. GO enrichment, KEGG enrichment and molecular docking were then performed, respectively. In particular, imiquimod (IMQ)-induced PSO model was selected as the representative for the experimental verification of effects and shared therapeutic mechanisms of TWP. RESULTS: 41 targets were considered as the potential shared targets of TWP treating PSO, SLE and PEM. KEGG enrichment indicated that IL-17 signaling pathway and Th17 cell differentiation were significant in the potential shared therapeutic mechanism of TWP. The animal experimental verification demonstrated that TWP could notably ameliorate skin lesions (P˂0.001), decrease inflammatory response (P˂0.05, P˂0.01, P˂0.001) and inhibit the differentiation of Th1/Th17 cells (P˂0.05, P˂0.01) compared to PSO model group. The molecular docking and qPCR validation then showed that TWP could effectively act on MAPK14, IL-2, IL-6 and suppress Th17 cell differentiation and IL-17 signaling pathway. The possible hepatotoxic mechanism of TWP indicated that there were 145 hepatotoxic targets and it was also associated with IL-17 signaling pathway and Th17 cell differentiation, especially for the key role of ALB, CASP3 and HSP90AA1. Meanwhile, the potential correlations between efficacy and hepatotoxicity of TWP showed that 28 targets were shared by therapeutic and hepatotoxic mechanisms such as IL-6, IL-2, MAPK14, MMP9, ALB, CASP3 and HSP90AA1. These significant relevant targets were also involved in IL-17 signaling pathway and Th17 cell differentiation. CONCLUSIONS: There were shared disease targets in PSO, SLE and PEM, and TWP could treat them by potential shared therapeutic mechanisms of suppressing IL-17 signaling pathway and Th17 cell differentiation. The possible hepatotoxicity induced by TWP was also significantly associated with the regulation of IL-17 signaling pathway and Th17 cell differentiation. Meanwhile, the potential correlations between efficacy and hepatotoxicity of TWP also mainly focused on IL-17 signaling pathway and Th17 cell differentiation, which provided a potential direction for the study of the mechanism of "You Gu Wu Yun" theory of TWP treating autoimmune skin diseases in the future.


Assuntos
Doenças Autoimunes , Doença Hepática Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas , Lúpus Eritematoso Sistêmico , Proteína Quinase 14 Ativada por Mitógeno , Psoríase , Dermatopatias , Animais , Caspase 3/metabolismo , Diferenciação Celular , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/toxicidade , Interleucina-17/metabolismo , Interleucina-2 , Interleucina-6 , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Transdução de Sinais , Células Th17 , Tripterygium/química
6.
Biomed Pharmacother ; 143: 112215, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34649346

RESUMO

Orchids are basically ornamental, and biological functions are seldom evaluated. This research investigated the effects of Acampe ochracea methanol extract (AOME) in ameliorating the paracetamol (PCM) induced liver injury in Wistar albino rats, evaluating its phytochemical status through UPLC-qTOF-MS analysis. With molecular docking and network pharmacology, virtual screening verified the inevitable interactions between the UPLC-qTOF-MS-characterized compounds and hepatoprotective drug receptors. The AOME has explicit a dose-dependent decrease of liver enzymes acid phosphatase (ACP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), total bilirubin, as well as an increase of serum total protein and antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GSH) with a virtual normalization (p < 0.05-p < 0.001) and the values were almost equivalent to the reference drug silymarin. After pretreatment with AOME, PCM-induced malondialdehyde (MDA) levels were considerably decreased (p < 0.001). Histopathological examinations corroborated the functional and biochemical findings. The AOME upregulated the genes involved in antioxidative (CAT, SOD, ß-actin, PON1, and PFK1) and hepatoprotective mechanisms in PCM intoxicated rats. An array of 103 compounds has been identified from AOME through UPLC-qTOF-MS analysis. The detected compounds were substantially related to the targets of several liver proteins and antioxidative enzymes, according to an in silico study. Virtual prediction by SwissADME and admetSAR showed that AOME has drug-like, non-toxic, and potential pharmacological activities in hepatic damage. Furthermore, VEGFA, CYP19A1, MAPK14, ESR1, and PPARG genes interact with target compounds impacting the significant biological actions to recover PCM-induced liver damage.


Assuntos
Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fígado/efeitos dos fármacos , Orchidaceae , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Acetaminofen , Animais , Antioxidantes/isolamento & purificação , Antioxidantes/farmacocinética , Aromatase/genética , Aromatase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Regulação da Expressão Gênica , Fígado/metabolismo , Fígado/patologia , Masculino , Proteína Quinase 14 Ativada por Mitógeno/genética , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Farmacologia em Rede , Orchidaceae/química , Estresse Oxidativo/genética , PPAR gama/genética , PPAR gama/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacocinética , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacocinética , Mapas de Interação de Proteínas , Ratos Wistar , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Eur J Med Chem ; 187: 112004, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881458

RESUMO

Protein phosphorylation by kinases is of critical importance for the regulation of many cellular functions. When kinases are deregulated numerous biological processes are affected, which may cause a variety of diseases. Therefore, kinase inhibition plays an important role for therapeutic intervention. A number of kinase inhibitors have been approved as drugs, initially in oncology where promiscuous (multi-kinase) inhibitors were most efficacious. Exploring kinase inhibitor selectivity and promiscuity for therapy is among the most challenging aspects of kinase drug discovery. Herein, we thoroughly analyze a kinase profiling experiment in which 637 designated inhibitors of p38α MAP kinase (p38α) were tested against a panel of 60 kinases distributed across the human kinome. In this experiment, only 19% of the inhibitors were found to be promiscuous when the median p38α inhibition level was applied as an activity threshold. Promiscuous inhibitors had a median value of two targets per compound, and many of these inhibitors were only active against the p38α and closely related JNK3 enzymes. Promiscuity cliffs were identified and analyzed in a network representation revealing structural modifications that were implicated in triggering compound promiscuity. Taken together, the findings revealed a high degree of selectivity of designated p38α directed inhibitors although they target the ATP binding site that is largely conserved across the human kinome.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
8.
Eur J Med Chem ; 182: 111624, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31445234

RESUMO

This work describes the rational discovery of novel chemotypes of p38α MAPK inhibitors using a funnel approach consisting of several computer-aided drug discovery methods and biological experiments. Among the identified hits, four compounds belonging to different chemical families showed IC50 values lower than 10 µM. In particular, the 1,4-benzodioxane derivative 5 turned out to be a potent and efficient p38α MAPK inhibitor having IC50 = 0.07 µM, and LEexp and LipE values of 0.38 and 4.8, respectively; noteworthy, the compound had also a promising kinase selectivity profile and the capability to suppress p38α MAPK effects in human immune cells. Overall, the collected findings highlight that the applied strategy has been successful in generating chemical novelty in the inhibitor kinase field, providing suitable chemical candidates for further inhibitor optimization.


Assuntos
Descoberta de Drogas , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Voluntários Saudáveis , Humanos , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
9.
PLoS One ; 14(5): e0216948, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31141540

RESUMO

As an important part of the comprehensive treatment methods, the urate-lowering Chinese herbs could provide favorable clinical effects on hyperuricemia in its ability to invigorate spleen and remove dampness. Owing to the long-term duration, it brought up the potential adverse reactions (ADRs) and concerns about the drug-induced liver injury from these herbs. To address this problem, the bioinformatics approaches which combined the network pharmacology, computer simulation and molecular biology experiments were undertaken to elucidate the underlying drug-induced liver injury molecular mechanisms of urate-lowering Chinese herbs. Several electronic databases were searched to identify the potential liver injury compounds in published research. Then, the putative target profile of liver injury was predicted, and the interaction network was constructed based on the links between the compounds, corresponding targets and core pathways. Accordingly, the molecular docking simulation was performed to recognize the representative compounds with hepatotoxicity. Finally, the cell experiments were conducted to investigate the biochemical indicators and expression of the crucial protein that were closely associated with liver injury. In conclusion, the current research revealed that the compounds with potential liver injury including diosgenin, baicalin, saikosaponin D, tetrandrine, rutaecarpine and evodiamine from urate-lowering Chinese herbs, could lead to decline the survival rate of L-02 cell, increase the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) in cell-culture medium, enhance the expression of p-p38/p38, while the p38 inhibitor could achieve the trend of regulating and controlling liver injury. These research findings bring further support to the growing evidence that the mechanism of the liver injury induced by the compounds from urate-lowering Chinese herbs may be associated with the activation of p38α.


Assuntos
Antimetabólitos/efeitos adversos , Medicamentos de Ervas Chinesas/química , Regulação da Expressão Gênica/efeitos dos fármacos , Supressores da Gota/efeitos adversos , Proteína Quinase 14 Ativada por Mitógeno/química , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Antimetabólitos/química , Antimetabólitos/isolamento & purificação , Antimetabólitos/farmacologia , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Benzilisoquinolinas/efeitos adversos , Benzilisoquinolinas/química , Benzilisoquinolinas/isolamento & purificação , Benzilisoquinolinas/farmacologia , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Biologia Computacional/métodos , Flavonoides/efeitos adversos , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Supressores da Gota/química , Supressores da Gota/isolamento & purificação , Supressores da Gota/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Hiperuricemia/tratamento farmacológico , Hiperuricemia/fisiopatologia , Alcaloides Indólicos/efeitos adversos , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/genética , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Quinazolinas/efeitos adversos , Quinazolinas/química , Quinazolinas/isolamento & purificação , Quinazolinas/farmacologia , Saponinas/efeitos adversos , Saponinas/química
10.
Biochemistry ; 57(48): 6715-6725, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30418016

RESUMO

Evidence of physical interaction with the target protein is essential in the development of chemical probes and drugs. The cellular thermal shift assay (CETSA) allows evaluation of drug binding in live cells but lacks a framework to support quantitative interpretations and comparisons with functional data. We outline an experimental platform for such analysis using human kinase p38α. Systematic variations to the assay's characteristic heat challenge demonstrate an apparent loss of compound potency with an increase in duration or temperature, in line with expectations from the literature for thermal shift assays. Importantly, data for five structurally diverse inhibitors can be quantitatively explained using a simple model of linked equilibria and published binding parameters. The platform further distinguishes between ligand mechanisms and allows for quantitative comparisons of drug binding affinities and kinetics in live cells and lysates. We believe this work has broad implications in the appropriate use of the CETSA for target and compound validation.


Assuntos
Preparações Farmacêuticas/metabolismo , Ligação Proteica , Bioensaio , Avaliação Pré-Clínica de Medicamentos , Estabilidade Enzimática , Células HL-60 , Temperatura Alta , Humanos , Espaço Intracelular/metabolismo , Cinética , Ligantes , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Modelos Biológicos , Desnaturação Proteica , Inibidores de Proteínas Quinases/metabolismo , Estabilidade Proteica , Temperatura , Termodinâmica
11.
PLoS Biol ; 16(5): e2004225, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29750781

RESUMO

p38 has long been known as a central mediator of protein kinase A (PKA) signaling in brown adipocytes, which positively regulate the transcription of uncoupling protein 1 (UCP-1). However, the physiological role of p38 in adipose tissues, especially the white adipose tissue (WAT), is largely unknown. Here, we show that mice lacking p38α in adipose tissues display a lean phenotype, improved metabolism, and resistance to diet-induced obesity. Surprisingly, ablation of p38α causes minimal effects on brown adipose tissue (BAT) in adult mice, as evident from undetectable changes in UCP-1 expression, mitochondrial function, body temperature (BT), and energy expenditure. In contrast, genetic ablation of p38α in adipose tissues not only markedly facilitates the browning in WAT upon cold stress but also prevents diet-induced obesity. Consistently, pharmaceutical inhibition of p38α remarkably enhances the browning of WAT and has metabolic benefits. Furthermore, our data suggest that p38α deficiency promotes white-to-beige adipocyte reprogramming in a cell-autonomous manner. Mechanistically, inhibition of p38α stimulates the UCP-1 transcription through PKA and its downstream cAMP-response element binding protein (CREB), which form a positive feedback loop that functions to reinforce the white-to-beige phenotypic switch during cold exposure. Together, our study reveals that inhibition of p38α is able to promote WAT browning and confer metabolic benefits. Our study also indicates that p38α in WAT represents an exciting pharmacological target to combat obesity and metabolic diseases.


Assuntos
Tecido Adiposo/metabolismo , Imidazóis/uso terapêutico , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Obesidade/metabolismo , Piridinas/uso terapêutico , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Reprogramação Celular , Temperatura Baixa , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dieta Hiperlipídica , Avaliação Pré-Clínica de Medicamentos , Imidazóis/farmacologia , Camundongos , Camundongos Knockout , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/genética , Obesidade/prevenção & controle , Fenótipo , Piridinas/farmacologia , Termogênese
12.
Mol Med Rep ; 15(5): 2873-2880, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28447740

RESUMO

Anti-tumor therapies based on anti-inflammatory effects have been considered in cancer treatment. Survival, proliferation and, resultantly, invasion and metastasis of tumor cells are regulated by local inflammatory mediators. Primary inflammatory cytokines, such as tumor necrosis factor (TNF), are targets for anticancer therapy. Several anti­inflammatory agents isolated from natural products are becoming important chemopreventive and therapeutic agents for cancer. The present study aimed to investigate the expression of TNF­α, nuclear factor­κΒ (NF­κΒ) and p38α mitogen-activated protein kinase (p38α) genes, associated with proliferation and inflammation in the Caco­2 cell line treated with ethanolic and hexanic extracts of Calyptranthes grandifolia O.Berg (Myrtaceae). Caco­2 cells were cultured and treated with plant extract at different concentrations (25, 50, 100 and 200 µg/ml) and stimulated with lipopolysaccharide (LPS). For gene expression, analysis was performed by total RNA extraction followed by synthesis of complementary DNA and analysis by quantitative polymerase chain reaction. The release of TNF­α cytokine was evaluated by ELISA in RAW 264.7 murine macrophages activated by LPS. Among the evaluated genes, there was a decrease in TNF-α expression at 100 and 200 µg/ml concentrations only with the ethanolic extract (P<0.025). The p38α gene exhibited a tendency to increase expression only when treated with ethanolic extract and the NF­κΒ gene did not significantly differ compared with the positive control when treated with either analyzed extract. The inhibition of TNF-α cytokine in the RAW 264.7 cell line was significant (P<0.05) in ethanolic extract at 200 µg/ml compared with the positive control (LPS 1 µg/ml). In conclusion, the ethanolic extract may exhibit an anti­inflammatory activity by inhibiting TNF­α. However, further studies are required to confirm its potential anti-inflammatory effects.


Assuntos
Etanol/química , Regulação da Expressão Gênica/efeitos dos fármacos , Myrtaceae/química , Extratos Vegetais/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Animais , Células CACO-2 , Humanos , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Extratos Vegetais/química , Células RAW 264.7
13.
Inflamm Bowel Dis ; 22(6): 1306-15, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27104822

RESUMO

BACKGROUND: Kinases are key mediators of inflammation, highlighting the potential of kinase inhibitors as treatments for inflammatory disorders. Selective kinase inhibitors, however, have proved disappointing, particularly in the treatment of rheumatoid arthritis and inflammatory bowel disease. Consequently, to improve efficacy, attention has turned to multikinase inhibition. METHODS: The activity of a narrow spectrum kinase inhibitor, TOP1210, has been compared with selective kinase inhibitors (BIRB-796, dasatinib and BAY-61-3606) in a range of kinase assays, inflammatory cell assays, and in inflamed biopsies from patients with ulcerative colitis (UC). Effects on recombinant P38α, Src, and Syk kinase activities were assessed using Z-lyte assays (Invitrogen, Paisley, United Kingdom). Anti-inflammatory effects were assessed by measurement of proinflammatory cytokine release from peripheral blood mononuclear cells, primary macrophages, HT29 cells, inflamed colonic UC biopsies, and myofibroblasts isolated from inflamed colonic UC mucosa. RESULTS: TOP1210 potently inhibits P38α, Src, and Syk kinase activities. Similarly, TOP1210 demonstrates potent inhibitory activity against proinflammatory cytokine release in each of the cellular assays and the inflamed colonic UC biopsies and myofibroblasts isolated from inflamed colonic UC mucosa. Generally, the selective kinase inhibitors showed limited and weaker activity in the cellular assays compared with the broad inhibitory profile of TOP1210. However, combination of the selective inhibitors led to improved efficacy and potency in both cellular and UC biopsy assays. CONCLUSIONS: Targeted, multikinase inhibition with TOP1210 leads to a broad efficacy profile in both the innate and adaptive immune responses, with significant advantages over existing selective kinase approaches, and potentially offers a much improved therapeutic benefit in inflammatory bowel disease.


Assuntos
Benzamidas/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/enzimologia , Citocinas/metabolismo , Dasatinibe/uso terapêutico , Naftalenos/uso terapêutico , Niacinamida/análogos & derivados , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Benzamidas/farmacologia , Biópsia , Colite Ulcerativa/patologia , Citocinas/efeitos dos fármacos , Dasatinibe/farmacologia , Células HT29 , Humanos , Interleucina-8/metabolismo , Leucócitos Mononucleares/metabolismo , Macrófagos/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Miofibroblastos/metabolismo , Naftalenos/farmacologia , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Cultura Primária de Células , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Quinase Syk/antagonistas & inibidores , Quinase Syk/metabolismo , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/metabolismo
14.
ACS Chem Neurosci ; 6(4): 666-80, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25676389

RESUMO

The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38αMAPK as a potential neurotherapeutic target, but isoform selective p38αMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, pursuit of the neurotherapeutic hypothesis requires kinase isoform selective inhibitors with appropriate neuropharmacology features. Synaptic dysfunction disorders offer a potential for enhanced pharmacological efficacy due to stress-induced activation of p38αMAPK in both neurons and glia, the interacting cellular components of the synaptic pathophysiological axis, to be modulated. We report a novel isoform selective p38αMAPK inhibitor, MW01-18-150SRM (=MW150), that is efficacious in suppression of hippocampal-dependent associative and spatial memory deficits in two distinct synaptic dysfunction mouse models. A synthetic scheme for biocompatible product and positive outcomes from pharmacological screens are presented. The high-resolution crystallographic structure of the p38αMAPK/MW150 complex documents active site binding, reveals a potential low energy conformation of the bound inhibitor, and suggests a structural explanation for MW150's exquisite target selectivity. As far as we are aware, MW150 is without precedent as an isoform selective p38MAPK inhibitor or as a kinase inhibitor capable of modulating in vivo stress related behavior.


Assuntos
Encéfalo/efeitos dos fármacos , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Animais , Aprendizagem por Associação/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Progressão da Doença , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/fisiopatologia , Camundongos Transgênicos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/fisiologia , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Ratos Sprague-Dawley , Memória Espacial/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/fisiologia
15.
PLoS One ; 9(10): e110186, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25303320

RESUMO

Camelina oil-cakes results after the extraction of oil from Camelina sativa plant. In this study, camelina oil-cakes were fed to fattening pigs for 33 days and its effect on performance, plasma biochemical analytes, pro-/anti-inflammatory mediators and antioxidant detoxifying defence in spleen was investigated in comparison with sunflower meal. 24 crossbred TOPIG pigs were randomly assigned to one of two experimental dietary treatments containing either 12% sunflower meal (treatment 1-T1), or 12.0% camelina oil-cakes, rich in polyunsaturated fatty acids ω-3 (ω-3 PUFA) (treatment 2-T2). The results showed no effect of T2 diet (camelina cakes) on feed intake, average weight gain or feed efficiency. Consumption of camelina diet resulted in a significant decrease in plasma glucose concentration (18.47%) with a trend towards also a decrease of plasma cholesterol. In spleen, T2 diet modulated cellular immune response by decreasing the protein and gene expression of pro-inflammatory markers, interleukin 1-beta (IL-1ß), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interleukin (IL-8) and cyclooxigenase 2 (COX-2) in comparison with T1 diet. By contrast, T2 diet increased (P<0.05) in spleen the mRNA expression of antioxidant enzymes, catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase 1 (GPx1) by 3.43, 2.47 and 1.83 fold change respectively, inducible nitric oxide synthase (iNOS) (4.60 fold), endothelial nitric oxide synthase (eNOS) (3.23 fold) and the total antioxidant level (9.02%) in plasma. Camelina diet increased also peroxisome-proliferator activated receptor gamma (PPAR-γ) mRNA and decreased that of mitogen-activated protein kinase 14 (p38α MAPK) and nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB). At this level of inclusion (12%) camelina oil-cakes appears to be a potentially alternative feed source for pig which preserves a high content of ω-3 PUFA indicating antioxidant properties by the stimulation of detoxifying enzymes expression and the suppression of spleen pro-inflammatory markers.


Assuntos
Camellia/química , Ácidos Graxos Ômega-3/metabolismo , Óleos de Plantas/metabolismo , Baço/citologia , Baço/metabolismo , Ração Animal , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Análise Química do Sangue , Expressão Gênica , Perfilação da Expressão Gênica , Imunoglobulinas/sangue , Mediadores da Inflamação/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Transdução de Sinais , Suínos
16.
Bioinformatics ; 30(24): 3561-6, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25172926

RESUMO

MOTIVATION: Off-target interactions of a popular immunosuppressant Cyclosporine A (CSA) with several proteins besides its molecular target, cyclophilin A, are implicated in the activation of signaling pathways that lead to numerous side effects of this drug. RESULTS: Using structural human proteome and a novel algorithm for inverse ligand binding prediction, ILbind, we determined a comprehensive set of 100+ putative partners of CSA. We empirically show that predictive quality of ILbind is better compared with other available predictors for this compound. We linked the putative target proteins, which include many new partners of CSA, with cellular functions, canonical pathways and toxicities that are typical for patients who take this drug. We used complementary approaches (molecular docking, molecular dynamics, surface plasmon resonance binding analysis and enzymatic assays) to validate and characterize three novel CSA targets: calpain 2, caspase 3 and p38 MAP kinase 14. The three targets are involved in the apoptotic pathways, are interconnected and are implicated in nephrotoxicity.


Assuntos
Ciclosporina/química , Imunossupressores/química , Proteômica/métodos , Algoritmos , Calpaína/química , Calpaína/metabolismo , Caspase 3/química , Caspase 3/metabolismo , Ciclosporina/metabolismo , Humanos , Imunossupressores/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/química , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Proteoma/química , Transdução de Sinais , Ressonância de Plasmônio de Superfície
17.
J Med Chem ; 56(22): 9342-50, 2013 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-24171460

RESUMO

In this study, we developed an assignment-free approach for rapid identification of ligand-binding sites in target proteins by using NMR. With a sophisticated cell-free stable isotope-labeling procedure that introduces (15)N- or (13)C-labels to specific atoms of target proteins, this approach requires only a single series of ligand titrations with labeled targets. Using titration data, ligand-binding sites in the target protein can be identified without time-consuming assignment procedures. We demonstrated the feasibility of this approach by using structurally well-characterized interactions between mitogen-activated protein (MAP) kinase p38α and its inhibitor 2-amino-3-benzyloxypyridine. Furthermore, we confirmed the recently proposed fatty acid binding to p38α and confirmed the fatty acid-binding site in the MAP kinase insert region.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/química , Inibidores de Proteínas Quinases/farmacologia , Sítios de Ligação , Ácidos Graxos/metabolismo , Estudos de Viabilidade , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/química , Piridinas/química , Piridinas/farmacologia , Fatores de Tempo
18.
Am J Chin Med ; 41(3): 683-96, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23711149

RESUMO

Oral cancer is a common malignancy associated with high morbidity and mortality. While p38 MAPK is reported to be involved in different cellular activities such as proliferation and differentiation, reports rarely define the roles of the individual members of the p38 MAPK family in cancer. We used two unique cell lines developed by our lab representing chemically induced oral cancer cells (T28) and non-tumor cells (N28) obtained from tissues surrounding the induced cancer as a model to screen out whether p38 MAPK is involved in the malignant transformation processes. The results suggest an association between p38ß not p38α and oral cancer development. Additionally, the anti-cancer activity of thymoquinone (TQ) was screened out and we found evidences suggesting that the anti-tumor activity of TQ may be attributed to the downregulation of p38ß MAPK.


Assuntos
Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Proteína Quinase 11 Ativada por Mitógeno/antagonistas & inibidores , Neoplasias Bucais/tratamento farmacológico , Neoplasias de Células Escamosas/tratamento farmacológico , Nigella sativa/química , Extratos Vegetais/farmacologia , Animais , Anticarcinógenos/farmacologia , Anticarcinógenos/uso terapêutico , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Benzoquinonas/uso terapêutico , Linhagem Celular , Linhagem Celular Tumoral , Regulação para Baixo , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Mucosa Bucal/citologia , Mucosa Bucal/efeitos dos fármacos , Neoplasias Bucais/metabolismo , Neoplasias de Células Escamosas/metabolismo , Fitoterapia , Extratos Vegetais/uso terapêutico
19.
Life Sci ; 92(22): 1081-92, 2013 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-23624232

RESUMO

AIM: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. In this study, we explored the anti-cancer activity of WYC02-9, a synthetic protoapigenone, on human HCT116 CRC cells. MAIN METHODS: The anti-cancer activity of WYC02-9 and its underlying mechanisms were analyzed using XTT cell proliferation assays, colony formation assays, FACS analysis, annexin V staining, immunoblotting analysis, reactive oxygen species (ROS) generation assays, soft agar assays, a nude mice xenograft study and immunohistochemistry assays. KEY FINDINGS: Data showed that WYC02-9 suppressed CRC cell growth by arresting cells at G2/M and inducing cell death via apoptotic pathways. Further analysis demonstrated that WYC02-9-induced apoptosis was mediated by the activation of a ROS-mediated MAPK14 pathway. An in vivo xenograft study revealed that WYC02-9 enhanced MAP2K3/6 and MAPK14 phosphorylation, induced apoptosis, and suppressed CRC tumor growth. SIGNIFICANCE: WYC02-9 exerts its anti-tumor effect via ROS/MAPK14-induced apoptosis and has the potential to be developed as a chemotherapeutic agent for CRC.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/patologia , Cicloexanonas/farmacologia , Flavonas/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Extratos Vegetais/farmacologia , Transplante Heterólogo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Cell Signal ; 25(4): 939-54, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23333461

RESUMO

As an essential component of the diet, retinol supplementation is often considered harmless and its application is poorly controlled. However, recent works demonstrated that retinol may induce a wide array of deleterious effects, especially when doses used are elevated. Controlled clinical trials have demonstrated that retinol supplementation increased the incidence of lung cancer and mortality in smokers. Experimental works in cell cultures and animal models showed that retinol may induce free radical production, oxidative stress and extensive biomolecular damage. Here, we evaluated the effect of retinol on the regulation of the receptor for advanced glycation end-products (RAGE) in the human lung cancer cell line A549. RAGE is constitutively expressed in lungs and was observed to be down-regulated in lung cancer patients. A549 cells were treated with retinol doses reported as physiologic (2 µM) or therapeutic (5, 10 or 20 µM). Retinol at 10 and 20 µM increased free radical production, oxidative damage and antioxidant enzyme activity in A549 cells. These doses also downregulated RAGE expression. Antioxidant co-treatment with Trolox®, a hydrophilic analog of α-tocopherol, reversed the effects of retinol on oxidative parameters and RAGE downregulation. The effect of retinol on RAGE was mediated by p38 MAPK activation, as blockade of p38 with PD169316 (10 µM), SB203580 (10 µM) or siRNA to either p38α (MAPK14) or p38ß (MAPK11) reversed the effect of retinol on RAGE. Trolox also inhibited p38 phosphorylation, indicating that retinol induced a redox-dependent activation of this MAPK. Besides, we observed that NF-kB acted as a downstream effector of p38 in RAGE downregulation by retinol, as NF-kB inhibition by SN50 (100 µg/mL) and siRNA to p65 blocked the effect of retinol on RAGE, and p38 inhibitors reversed NF-kB activation. Taken together, our results indicate a pro-oxidant effect of retinol on A549 cells, and suggest that modulation of RAGE expression by retinol is mediated by the redox-dependent activation of p38/NF-kB signaling pathway.


Assuntos
Regulação para Baixo/efeitos dos fármacos , NF-kappa B/metabolismo , Receptores Imunológicos/metabolismo , Vitamina A/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Humanos , Imidazóis/farmacologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteína Quinase 11 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 11 Ativada por Mitógeno/genética , Proteína Quinase 11 Ativada por Mitógeno/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/genética , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , Oxirredução , Peptídeos/farmacologia , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptor para Produtos Finais de Glicação Avançada , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , alfa-Tocoferol/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética
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