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1.
Phytomedicine ; 66: 153135, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31790895

RESUMO

BACKGROUND: Gut microbiota is increasingly recognized as the key participant in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) by translocation of its products, such as lipopolysaccharide (LPS), via the dysfunctional intestinal barrier. Qushi Huayu decoction (QHD), a traditional Chinese medicine, is developed specially for NAFLD and used in clinic in China for more than a decade and previously found to ameliorate non-alcoholic steatohepatitis (NASH) induced by high-fat diet (HFD) in mice accompanied with inhibited metabolic endotoxemia and hepatic LPS signalling. PURPOSE: To investigate the mechanism of LPS gut-leakage inhibition by QHD in NASH. METHODS: Effects of QHD on gut microbioa and intestinal barrier were evaluated in NASH induced by HFD in mice. 16S rRNA sequencing is employed to analyse the gut microbiota composition. To identify the potential signalling pathway responsible for tight junction regulation, the colonic phosphoprotein profile is screened via the Phospho Explorer Antibody Array and verified in NASH, intestinal barrier dysfunctional mouse and Caco-2 cells. RESULTS: QHD ameliorates NASH accompanied with regulating the gut microbiota composition, protecting intestinal tight junctions and inhibiting LPS gut-leakage without decreasing the abundance of identified Gram-negative bacteria. The validated data of phosphorylated proteins suggested that mitogen-activated protein kinase (MAPK) pathway is predominantly responsible for the colonic tight junction regulation by QHD. CONCLUSION: QHD inhibits LPS gut-leakage in NASH, which is associated with downregulation of intestinal MAPK pathway.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Células CACO-2 , China , Colo/metabolismo , Humanos , Intestinos/enzimologia , Lipopolissacarídeos/administração & dosagem , Masculino , Medicina Tradicional Chinesa , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Junções Íntimas/metabolismo
2.
J Enzyme Inhib Med Chem ; 34(1): 1678-1689, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31530032

RESUMO

A series of novel 4-ferrocenylchroman-2-one derivatives were designed and synthesised to discover potent anti-inflammatory agents for treatment of arthritis. All the target compounds had been screened for their anti-inflammatory activity by evaluating the inhibition effect of LPS-induced NO production in RAW 264.7 macrophages. Among them, 4-ferrocenyl-3,4-dihydro-2H-benzo[g]chromen-2-one (3h) was found to be the most potent compound in inhibiting the productions of NO with low toxicity. This compound also exhibited significant inhibition of the productions of IL-6 and TNF-α in RAW 264.7 macrophages. Preliminary mechanism studies indicated that compound 3h could inhibit the activation of LPS-induced NF-κB and MAPKs signalling pathways. The in vivo anti-inflammatory effect of this compound was determined in the rat adjuvant-induced arthritis model.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite/tratamento farmacológico , Cromonas/farmacologia , Interleucina-6/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Artrite/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Adjuvante de Freund , Interleucina-6/biossíntese , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estrutura Molecular , NF-kappa B/metabolismo , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese
3.
Int J Mol Med ; 44(3): 982-994, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31524235

RESUMO

Therapeutic agents used to treat sepsis­induced cardiac dysfunction are designed to suppress tumor necrosis factor (TNF)­α release and inhibit cell apoptosis. Exogenous administration of growth arrest­specific 6 (Gas6) exerts several biological and pharmacological effects; however, the role of Gas6 in sepsis­induced myocardial dysfunction remains unclear. In this study, H9C2 cardiomyocytes were stimulated with LPS (10 µg/ml) to mimic septic cardiac dysfunction and Gas6 (100 ng/ml) was applied exogenously. Subsequently, mitogen­activated protein kinase (MAPK) and nuclear factor (NF)­κB activation, TNF­α expression, and apoptosis in the presence or absence of TP­0903 (15 nM) and Wortmannin (3 nM) were evaluated. The morphological alterations of H9C2 cells were visualized by phase­contrast microscopy. Cell viability was determined using the Cell Counting kit 8 assay and lactate dehydrogenase release, and TNF­α release was analyzed by ELISA analysis. Cell apoptosis was analyzed by flow cytometry and TUNEL assay. Nuclear morphological alterations were detected by Hoechst staining and caspase­3 activity was measured using biochemical methods. The expression levels of Bax and Bcl­2, and the phosphorylation and expression levels of Axl, Akt, IκB­α, p65, c­Jun N­terminal protein kinase (JNK), extracellular signal­regulated kinase (ERK) and p38 were determined by western blotting. Furthermore, immunofluorescence analysis was performed to visualize translocation of NF­κB p65. The results demonstrated that Gas6 suppressed TNF­α release and inhibited cell apoptosis, and attenuated nuclear factor (NF)­κB and mitogen­activated protein kinase (MAPK) activation via the Axl/PI3K/Akt pathway. Furthermore, the cardioprotective properties of Gas6 on the suppression of LPS­induced TNF­α release and apoptosis were abolished by treatment with TP­0903 (an Axl inhibitor) and Wortmannin (a PI3K inhibitor). Pretreatment with TP­0903 and Wortmannin abrogated the effects of Gas6 on phosphorylated­IκB­α, IκB­α, NF­κB, ERK1/2, JNK and p38 MAPK. These findings suggested that activation of Axl/PI3K/Akt signaling by Gas6 may inhibit LPS­induced TNF­α expression and apoptosis, as well as MAPK and NF­κB activation.


Assuntos
Apoptose/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Lipopolissacarídeos/farmacologia , Modelos Biológicos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética
4.
Arch Dermatol Res ; 311(9): 711-719, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31385019

RESUMO

We conducted this experimental study to analyze the relationship between sphingosine-1-phosphate (S1P)-induced mitogen-activated protein (MAP) kinase pathways and keloid formation. We collected samples of the normal tissue and the keloid tissue from 10 normal healthy individuals and 12 patients with keloid scars, respectively. Then, we compared the level of sphingosine-1-phosphate receptor (S1PR1/S1PR2) mRNA/protein expression between the normal tissue and the keloid tissue. Moreover, we also compared the level of S1PR protein expression, that of S1P-induced COL1A1 (collagen Type I, α-1 chain) expression, that of S1P-induced JNK/ERK phosphorylation, that of S1P-induced COL1A1 expression following the treatment with 30 µM PD98059 (ERK inhibitor) or 30 µM SP600125 (JNK inhibitor) and that of S1P-induced COL1A1 expression following the treatment with W146 (S1PR1 inhibitor) or JTE013 (S1PR2 inhibitor) between the normal fibroblasts and the keloid fibroblasts. We found that the level of S1PR1/S1PR2 mRNA/protein expression was significantly higher in the keloid tissue as compared with the normal tissue. Our results also showed that the level of S1P-induced COL1A1 expression and that of S1P-induced JNK/ERK phosphorylation were significantly higher in the keloid fibroblasts as compared with the normal ones (P < 0.05). Furthermore, there were significant decreases in the level of S1P-induced COL1A1 expression when the keloid fibroblasts were treated with 30 µM SP600125 or 30 µM PD98059 and that of S1P-induced COL1A1 expression when the treated with 100 nM W146 or 100 nM JTE013 (P < 0.05). Our results indicate that S1P-induced signal transduction is associated with increased collagen synthesis via S1PR-mediated signaling pathways in the keloid tissue.


Assuntos
Colágeno Tipo I/metabolismo , Queloide/patologia , Lisofosfolipídeos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Esfingosina/análogos & derivados , Adulto , Anilidas/farmacologia , Antracenos/farmacologia , Linhagem Celular , Feminino , Fibroblastos , Flavonoides/farmacologia , Humanos , Queloide/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Organofosfonatos/farmacologia , Fosforilação/efeitos dos fármacos , Pirazóis/farmacologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Esfingosina/metabolismo , /metabolismo , Adulto Jovem
5.
Ecotoxicol Environ Saf ; 183: 109508, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31408819

RESUMO

As a new type of antibacterial agent, nanosilver has attracted great attention in biomedical applications. However, the safety of nanosilver to humans and the environment has not been well elucidated. The objective of this study was to investigate the influence of nanosilver on novel effector mechanism of neutrophil extracellular traps (NETs), and its possible molecular mechanisms. In this study, nanosilver (10, 20 and 40 µg/mL) was incubated with neutrophils for 90 min. Then, nanosilver-induced the release of NETs was observed by laser confocal microscopy. Nanosilver-induced NETs release was also quantitatively detected by pico Green®. In addition, the role of NADPH oxidase, extracellular signal-regulated kinase (ERK) and p38 signaling pathways in nanosilver-induced NETs release were detected by the inhibitors and pico Green®. The results indicated that nanosilver significantly activated polymorphonuclear neutrophils (PMN) to release NETs, which was a DNA-based network structure modified with histones (H3) and neutrophil elastase (NE). The inhibitors of NADPH oxidase, ERK and p38 signaling pathways significantly inhibited the formation of nanosilver-induced NETs. Furthermore, nanosilver did not alter the extracellular lactate dehydrogenase (LDH) level of PMN cells. All these results showed that nanosilver significantly induced NETs release, and the potential molecular mechanisms were correlated with reactive oxygen species (ROS) production-dependent on NADPH oxidase, ERK and p38 signaling pathways, which might provide a new perspective on nanosilver-induced excess NETs release related to the host immune damage.


Assuntos
Antibacterianos/toxicidade , Armadilhas Extracelulares/metabolismo , Nanopartículas Metálicas/toxicidade , Neutrófilos/efeitos dos fármacos , Prata/toxicidade , Animais , Antibacterianos/química , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Nanopartículas Metálicas/química , Camundongos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Neutrófilos/enzimologia , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Prata/química
6.
Arch Pharm Res ; 42(8): 695-703, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31327152

RESUMO

Neuroinflammation is a specific or nonspecific immunological reaction in the central nervous system that is induced by microglia activation. Appropriate regulation of activated microglial cells is therefore important for inhibiting neuroinflammation. Hesperetin is a natural flavanone and an aglycone of hesperidin that is found in citrus fruits. Hesperetin reportedly possesses anti-inflammatory, anti-cancer, and antioxidant effects. However, the anti-neuroinflammatory effects of hesperetin on microglia are still unknown. Here, we investigated the anti-neuroinflammatory effects of hesperetin on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. We found that hesperetin strongly inhibited nitric oxide production and expression of inducible nitric oxide synthase in LPS-stimulated BV-2 microglial cells. Hesperetin also significantly reduced secretion of inflammatory cytokines including interleukin (IL)-1ß and IL-6. Furthermore, hesperetin down-regulated the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase, exerting anti-inflammatory effects. Hesperetin suppressed astrocyte and microglia activation in the LPS-challenged mouse brain. Collectively, our findings indicate that hesperetin inhibits microglia-mediated neuroinflammation and could be a prophylactic treatment for neurodegenerative diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Citocinas/antagonistas & inibidores , Hesperidina/farmacologia , Inflamação/tratamento farmacológico , Microglia/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/química , Linhagem Celular , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Hesperidina/química , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/metabolismo , Microglia/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Relação Estrutura-Atividade
7.
Int Immunopharmacol ; 75: 105749, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31306981

RESUMO

Acute lung injury (ALI) is a pulmonary diffuse dysfunction disease caused by immoderate inflammatory response breaking the coordination of physiological structures and functions, and there are very few effective treatments to reduce high morbidity of ALI in critical patients. Glycitin is a natural ingredient derived from the seeds of leguminous plants and may have potent anti-inflammation features. The purpose of this study was to investigate the anti-inflammation effect of glycitin on LPS-induced ALI in mice and elucidate its possible anti-inflammatory mechanisms. The results of histopathological changes, the wet/dry weight ratio as well as the myeloperoxidase (MPO) activity indicated that glycitin obviously alleviated the lung injury induced by LPS. In addition, qPCR and ELISA results found that glycitin could dose-dependently decrease the expressions of pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α. Western blotting was performed to revealed that glycitin inhibited the activation of NF-κB and MAPKs signaling pathways by suppressing the expression of TLR4 protein and the phosphorylation of IKKß, IκBα, p65, p38, ERK, and JNK. All data indicated that glycitin could protect lung tissues from LPS-induced inflammation via inhibiting TLR4-mediated NF-κB and MAPKs signaling pathways.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Isoflavonas/uso terapêutico , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/genética , Citocinas/imunologia , Células HEK293 , Humanos , Isoflavonas/farmacologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/imunologia , NF-kappa B/imunologia , Neutrófilos/imunologia , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética
8.
Eur J Pharmacol ; 859: 172517, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31265843

RESUMO

Tissue factor (TF) is the primary cause of atherothrombosis, the rupture of atherosclerotic plaques with subsequent thrombosis, leading to acute cardiovascular events, such as myocardial infarction and stroke. Wogonin (Wog) is an active component of Scutellaria baicalensis, used for inflammatory diseases, atherosclerosis, and hyperlipidemia. The anticoagulant effect of Wog on TF expression remains unexplored. In this study, we have investigated the effects of Wog on TF gene expression and its underlying molecular mechanism in human vascular endothelial cells (ECs). We found that Wog dose-dependently inhibited PMA-enhanced TF mRNA, protein, and activity in ECs. This inhibition was attributed to its decreasing nuclear accumulations of transcription factors, phospho-c-Jun and early growth response-1(Egr-1), not nuclear factor-κB (NF-κB), through blocking extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways. Reduction by Wog of Egr-1 nuclear level and Egr-1/DNA binding activity was associated with its inhibition of Egr-1 de novo synthesis. Wog as well as inhibitors to ERK and JNK suppressed TF promoter activity and protein expression in reporter gene and Western blot analyses. Furthermore, it also exhibited anticoagulant function by inhibiting TF expression and activity in tumor necrosis factor-alpha (TNF-α)- and lipopolysaccharide (LPS)-treated ECs and THP-1 cells. These results suggest that Wog inhibits ERK/Egr-1- and JNK/AP-1-mediated transactivation of TF promoter activity, leading to downregulation of TF expression and activity induced by inflammatory mediators. Wog targeting pathological TF expression without affecting its basal level may be a safer templet in the development of anticoagulant agent for cardiovascular thrombotic diseases related to atherothrombosis.


Assuntos
Anticoagulantes/farmacologia , Flavanonas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Tromboplastina/genética , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Tromboplastina/metabolismo , Ativação Transcricional/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia
9.
Int J Med Sci ; 16(5): 636-643, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31217730

RESUMO

Chemotherapy is now in common use for the treatment of tumors; however, with tumor growth retardation comes the severe side effects that occur after a chemotherapy cycle. Eicosapentaenoic acids (EPA) used in combination with chemotherapy has an additive effects and provides a rationale for using EPA in tandem with chemotherapy. To improve the efficacy and safety of this combination therapy, a further understanding that EPA modulates with the tumor microenvironment is necessary. Connexin 43 (Cx43) is involved in enhancing chemosensitivity that was suppressed in a tumor microenvironment. We aim to investigate the role of EPA in chemosensitivity in murine melanoma by inducing Cx43 expression. The dose-dependent upregulation of Cx43 expression and gap junction intercellular communication were observed in B16F10 cells after EPA treatment. Furthermore, EPA significantly increased the expression levels of mitogen-activated protein kinases (MAPK) signaling pathways. The EPA-induced Cx43 expression was reduced after MAPK inhibitors. Knockdown Cx43 in B16F10 cells reduced the therapeutic effects of combination therapy (EPA plus 5-Fluorouracil). Our results demonstrate that the treatment of EPA is a tumor induced Cx43 gap junction communication and enhances the combination of EPA and chemotherapeutic effects.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Conexina 43/metabolismo , Ácido Eicosapentaenoico/farmacologia , Melanoma Experimental/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Conexina 43/genética , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Ácido Eicosapentaenoico/uso terapêutico , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Neoplasias Cutâneas/patologia , Microambiente Tumoral/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
10.
Invest Ophthalmol Vis Sci ; 60(7): 2764-2772, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31247083

RESUMO

Purpose: To analyze the activity of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinases/mechanistic target of rapamycin (PI3K/mTOR) pathways in benign and malignant conjunctival melanocytic proliferations and explore whether specific inhibitors can suppress growth of conjunctival melanoma (CJM) cells. Methods: The presence of a BRAF V600E mutation and activation of ERK, MEK, S6, and AKT were assessed with immunohistochemistry in 35 conjunctival nevi and 31 melanomas. Three CJM cell lines were used: CRMM1, carrying the BRAF V600E mutation; CRMM2, harboring the NRAS Q61L mutation; and T1527A, with a BRAF G466E mutation. WST-1 assays were performed with a BRAF inhibitor (vemurafenib), two MEK inhibitors (trametinib, selumetinib), a PI3K inhibitor (pictilisib), and a dual PI3K/mTOR inhibitor (dactolisib). The phosphorylation of ERK, MEK, and S6 were tested with western blots and apoptosis with cleaved caspase-3 immunostaining. Results: A BRAF V600E mutation was detected in 42.6% of nevi and in 35.5% of CJM. MEK and ERK activation were higher in CJM, occurring in 62.9% and 45.7% of the nevi and 90.3% and 96.8% of the CJM, respectively. There was also a significant increase in S6 activation in CJM (90.3%) compared with the nevi (20%). CRMM1 was sensitive to trametinib and the PI3K inhibitors but only marginally to vemurafenib. CRMM2 was moderately sensitive to pictilisib, whereas T1527A was resistant to all drugs tested. Conclusions: The MAPK pathway activity in CJM is increased, not only as a consequence of the BRAF V600E mutation. Targeted therapy may be useful for patients with CJM, especially those with activating BRAF mutations, whereas NRAS-mutated melanomas are relatively resistant.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Túnica Conjuntiva/tratamento farmacológico , Melanoma/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Terapia de Alvo Molecular , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/uso terapêutico , Western Blotting , Neoplasias da Túnica Conjuntiva/enzimologia , Neoplasias da Túnica Conjuntiva/patologia , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Masculino , Melanoma/enzimologia , Melanoma/patologia , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Quinolinas/uso terapêutico , Sulfonamidas/uso terapêutico , Células Tumorais Cultivadas
11.
Food Chem Toxicol ; 131: 110544, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31201898

RESUMO

Aging is a multifactorial universal process characterized by a gradual decrease in physiological and biochemical functions. Given that life expectancy is on the rise, a better understanding of molecular mechanisms of the aging process is necessary in order to develop anti-aging interventions. Uncontrolled cellular senescence promotes persistent inflammation and accelerates the aging process by decreasing tissue renewal, repair and regeneration. Senescence of immune cells, immunesenescence, is another hallmark of aging. Targeting pro-senescent enzymes increases survival and therefore the lifespan. Although the upregulation of Mitogen Activated Protein Kinases (MAPK) enzymes in aging is still controversial, increasing evidence shows that dysregulation of those enzymes are associated with biological processes that contribute to aging such as irreversible senescence. In this manuscript components of the MAPK pathway will be summarized, including extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38, as well as natural flavonoids, phenolic and diterpenoids with anti-senescence activity that shows positive effects on longevity and MAPK inhibition. Although more studies using additional aging models are needed, we suggest that these selected natural bioactive compounds that regulate MAPK enzymes and reduce senescent cells can be potentially used to improve longevity and prevent/treat age-related diseases.


Assuntos
Produtos Biológicos/farmacologia , Senescência Celular/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Transdução de Sinais/efeitos dos fármacos
12.
Drug Des Devel Ther ; 13: 1163-1170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31043769

RESUMO

Purpose: Umbelliferone (Umb), a member of coumarin family, is found in many plants and is a promising molecule with potential anti-inflammatory, anti-oxidative, and anti-tumor activities. However, the effect of Umb on arthritis remains unclear. Methods: A rat model with Freund's complete adjuvant (FCA)-induced arthritis was developed and used to test the efficacy of Umb on arthritis rats. Rats were given an intragastric injection of Umb (20 and 40 mg/kg) once daily from days 21 to 28 after the administration of FCA. Hind paw volume was assessed using a volume meter. The pro-inflammatory cytokine levels and prostaglandin E2 (PEG2) level in serum and synovial fluid were detected by ELISA. HE staining was used to determine representative histological changes in joint tissues, and Western blot analysis was employed to study the effects of Umb on MAPK/NF-κB signaling pathway. Results: Our results showed that Umb suppressed the release of IL-6, IL-1ß, tumor necrosis factor-alpha, and PEG2. In addition, Umb could also dramatically ameliorate the pathological changes observed in rat joints. Based on the results of Western blot, we also observed that Umb could strikingly suppress the expression of MAPK/NF-κB pathway molecules. Conclusion: These results proved that treatment with Umb is very effective for arthritis and inhibiting the MAPK/NF-κB signaling pathway may be a potential therapeutic target for treatment of arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Umbeliferonas/farmacologia , Animais , Artrite Experimental/metabolismo , Citocinas/biossíntese , Citocinas/sangue , Injeções Intraventriculares , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Umbeliferonas/administração & dosagem , Umbeliferonas/química
13.
Inflammation ; 42(4): 1336-1349, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30937840

RESUMO

Tizoxanide is the main active metabolite of nitazoxanide. Nitazoxanide and tizoxanide have a broad-spectrum anti-infective effect, including parasites, bacteria, and virus. In the present study, we investigated the anti-inflammatory effect of tizoxanide on lipopolysaccharide (LPS)-stimulated RAW264.7 cells and revealed underlying molecular mechanisms. The results showed that tizoxanide significantly suppressed production of NO as well as pro-inflammatory cytokines, such as IL-1ß, IL-6, and TNF-α in dose-dependent manner. Meanwhile, the levels of gene expression of these cytokines were inhibited significantly by tizoxanide that was discovered using RT-PCR. The increased protein levels of inducible nitric oxide synthase, heme oxygenase-1, and cyclooxygenase-2 by LPS in the cells were also reduced by tizoxanide. Moreover, we found that tizoxanide inhibited the phosphorylation of IKK-α and degradation of IκB by LPS in macrophage cells. The increased protein levels of p65 induced by LPS in the cytoplasm and nucleus were both decreased by tizoxanide, and the nuclear translocation of p65 was also restrained in cell imaging. In addition, tizoxanide considerably also inhibited LPS-activated JNK, p38, and ERK phosphorylation in RAW264.7 cells. Taken together, our results suggested that tizoxanide exerts anti-inflammatory effects, by inhibiting the production of pro-inflammatory cytokines and suppressing of the activation of the NF-κB and the MAPK signaling pathways in LPS-treated macrophage cells.


Assuntos
Inflamação/prevenção & controle , Macrófagos/patologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Tiazóis/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Camundongos , Óxidos de Nitrogênio/metabolismo , Células RAW 264.7 , Tiazóis/uso terapêutico
14.
Inflammation ; 42(4): 1463-1473, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31011928

RESUMO

Twelve polyketones were isolated from the fermentation broth of Penicillium sp., including six new compounds (supplementary material). Penicillium sp. is widely used in clinic as a highly effective and low toxic antibiotic. Among these compounds, (3R, 7R)-7-acetoxyl-9-oxo-de-O-methyllasiodiplodin named PS-2 showed significant anti-inflammatory activity. So, the anti-inflammatory mechanism of PS-2 was investigated by using lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. The results showed that PS-2 can significantly inhibit the overproduction of nitric oxide (NO), prostaglandin E2 (PGE2), and interleukin-6 (IL-6), whereas it showed no inhibition on the release of pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α). Cell-free colorimetric method demonstrated that PS-2 could obviously inhibit the enzymatic activity of cyclooxygenase-2 (COX-2). Western blot results indicated that PS-2 could significantly inhibit high expression of iNOS and COX-2 proteins. Further investigations on the anti-inflammatory mechanism showed that PS-2 could suppress the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), but did not exhibit obvious inhibition on the phosphorylation of c-JunN-terminal kinase (JNK) and phosphorylated 38 (p38). In addition, PS-2 inhibited the degradation of inhibitor of kappa-B alpha (IκB-α) and translocation to nucleus of nuclear factor kappa-B (NF-κB) p65 in RAW 264.7 macrophages. These results suggested that PS-2 might be an effective intervention against inflammatory diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/prevenção & controle , Macrolídeos/farmacologia , Macrófagos/patologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Penicillium/metabolismo , Animais , Mediadores da Inflamação , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , Células RAW 264.7
15.
Drug Des Devel Ther ; 13: 739-745, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863013

RESUMO

Background: Inflammation and oxidative stress play a crucial role in the pathogenesis of renal ischemia/reperfusion injury (IRI). Maresin 1 (MaR1), which has shown strong anti-inflammatory and antioxidant effects, was recently reported to have protective properties in several different animal models. Aim: The objectives of our study were to determine whether MaR1 alleviates renal IRI and to identify the underlying mechanisms. Materials and methods: The mouse model in this study was induced by ischemia of the left kidney for 45 minutes and by nephrectomy of the right kidney. All mice were intravenously injected with a vehicle or MaR1. Renal histopathologic changes, function, proinflammatory cytokines, and oxidative stress were assessed. The expression of proteins was measured by Western blot. Results: The results indicated that MaR1 markedly protected against renal IRI. The protective effects were accompanied by the reduction of histologic changes and reduction of renal dysfunction. Meanwhile, MaR1 remarkably mitigated renal IRI-induced inflammation and oxidative stress. In addition, our results showed that MaR1 significantly inhibited the expression of TLR4 and the expression of phosphorylated Erk, JNK, and P38. Furthermore, MaR1 decreased the nuclear translocation of NF-κB and increased the nuclear translocation of Nrf2. Conclusion: MaR1 protects against renal IRI by inhibiting the TLR4/MAPK/NF-κB pathways, which mediate anti-inflammation, and by activating the Nrf2 pathway, which mediates antioxidation.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Nefropatias/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Receptor 4 Toll-Like/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Receptor 4 Toll-Like/antagonistas & inibidores
16.
Biol Pharm Bull ; 42(4): 617-622, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30700647

RESUMO

Activation of mitogen-activated protein kinases (MAPKs) in neurons may underlie the pathogenesis of Alzheimer's disease (AD). Acrolein, a ubiquitous pollutant, has been reported to implicate in the etiology of AD. Our previous data showed that acrolein changed the levels of key AD-associated proteins, including advanced glycation end products (RAGE), A-disintegrin and metalloprotease (ADAM-10), and beta-site amyloid-beta peptide cleaving enzyme 1 (BACE-1). In this study, we investigated whether acrolein-induced alterations of AD-associated proteins are relevant to MAPKs activation, and strategies to inhibit MAPKs activation yield benefits to acrolein-induced neurotoxicity in HT22 mouse hippocampal cells. We found that acrolein activated MAPKs signaling pathways to mediate cells apoptosis, and then altered the levels of AD-associated proteins ADAM-10, BACE-1 and RAGE. Inhibitors of MAPKs signaling pathways attenuated the cells death and restored the proteins levels of ADAM-10, BACE-1 and RAGE in varying degrees induced by acrolein. Taken together, activated MAPKs signaling pathways should be underlying the pathology of acrolein-induced neuronal disorders. Inhibitors of MAPKs pathways might be promising agents for acrolein-related diseases, such as AD.


Assuntos
Acroleína/toxicidade , Hipocampo/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Proteína ADAM10/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Apoptose/efeitos dos fármacos , Ácido Aspártico Endopeptidases/metabolismo , Técnicas de Cultura de Células , Linhagem Celular , Inibidores Enzimáticos/farmacologia , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Receptor para Produtos Finais de Glicação Avançada/metabolismo
17.
Org Lett ; 21(2): 373-377, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30596417

RESUMO

An efficient method for the synthesis of [1,2,4]triazolo[4,3- a]piperazine derivatives was established based on a gold(I)-catalyzed domino cyclization of an amidrazone substrate with a terminal alkyne. The amidoxime congeners were converted into [1,2,4]oxadiazolo[4,5- a]piperazine derivatives in the presence of a gold catalyst. The oxadiazolopiperazine is a promising scaffold for the design of novel inhibitors against p38 mitogen activated protein kinase (MAP kinase).


Assuntos
Compostos Aza/síntese química , Inibidores Enzimáticos/síntese química , Ouro/química , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Triazóis/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Catálise , Ciclização , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Triazóis/química , Triazóis/farmacologia
18.
Pigment Cell Melanoma Res ; 32(4): 528-539, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30614626

RESUMO

The role of Notch signaling in melanoma drug resistance is not well understood. In this study, we show that although NOTCH proteins are upregulated in metastatic melanoma cell lines, Notch signaling inhibition had no effect on cell survival, growth, migration or the sensitivity of BRAFV600E-melanoma cells to MAPK inhibition (MAPKi). We found that NOTCH1 is downregulated in melanoma cell lines with intrinsic and acquired resistance to MAPKi. Forced expression of NICD1, the active form of Notch1, caused apoptosis of the NOTCHlo , MAPKi-resistant cells, but not the NOTCHhi , MAPKi-sensitive melanoma cell lines. Whole transcriptome-sequencing analyses of NICD1-transduced MAPKi-sensitive and MAPKi-resistant cells revealed differential regulation of endothelin 1 (EDN1) by NICD1, that is, downregulation in MAPKi-resistant cells and upregulation in MAPKi-sensitive cells. Knockdown of EDN1 partially mimicked the effect of NICD1 on the survival of MAPKi-resistant cells. We show that the opposite regulation of EDN1 by Notch signaling is mediated by the differential regulation of c-JUN by NICD1. Our data show that MAPKi-resistant melanoma cells acquire vulnerability to Notch signaling activation and suggest that Notch-c-JUN-EDN1 axis is a potential therapeutic target in MAPKi-resistant melanoma.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Melanoma/enzimologia , Melanoma/patologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Receptores Notch/metabolismo , Transdução de Sinais , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Endotelina-1/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ligantes , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição HES-1/metabolismo , Transcriptoma/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
19.
Bioorg Med Chem ; 27(3): 516-524, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30617018

RESUMO

Magnesium Isoglycyrrhizinate (MgIG), a novel molecular compound extracted from licorice root, has exhibited greater anti-inflammatory activity and hepatic protection than glycyrrhizin and ß-glycyrrhizic acid. In this study, we investigated the anti-inflammatory effect and the potential mechanism of MgIG on Lipopolysaccharide (LPS)-treated RAW264.7 cells. MgIG down-regulated LPS-induced pro-inflammatory mediators and enzymes in LPS-treated RAW264.7 cells, including TNF-α, IL-6, IL-1ß, IL-8, NO and iNOS. The generation of reactive oxygen species (ROS) in LPS-treated RAW264.7 cells was also reduced. MgIG attenuated NF-κB translocation by inhibiting IKK phosphorylation and IκB-α degradation. Simultaneously, MgIG also inhibited LPS-induced activation of MAPKs, including p38, JNK and ERK1/2. Taken together, these results suggest that MgIG suppresses inflammation by blocking NF-κB and MAPK signaling pathways, and down-regulates ROS generation and inflammatory mediators.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estrutura Molecular , NF-kappa B/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
20.
Toxicol Appl Pharmacol ; 366: 83-95, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30690042

RESUMO

Thulium laser resection of the prostate (TmLRP), a major treatment for benign prostatic hyperplasia (BPH), has several postoperative complications that affect the patients' quality of life. The aim of this study was to investigate the effect of the M1 macrophage-secreted reactive oxygen species (ROS) on prostatic wound healing, and the role of MAPK signaling in this process. A co-culture model in vitro was established using macrophages and prostate epithelial or stromal cells. Cell proliferation, migration, apoptosis, MAPK pathway-related gene expression levels were evaluated by standard assays. In addition, an in vivo model of prostatectomy was established in beagles by subjecting them to TmLRP, and were either treated with N-acetyl-L-cysteine (NAC) and or placebo. Wound healing and re-epithelialization were analyzed histopathologically in both groups, in addition to macrophage polarization, oxidative stress levels and MAPK pathway-related proteins expressions. Intracellular ROS levels were significantly increased in the prostate epithelial and stromal cells following co-culture with M1-like macrophages and H2O2 exposure via MAPK activation, which affected their proliferation, migration and apoptosis, and delayed the wound healing process. The cellular functions and wound healing capacity of the prostate cells were restored by blocking or clearing the macrophage-secreted ROS. In the beagle model, increased ROS levels impaired cellular functions, and appropriate removing ROS accelerated the wound healing process.


Assuntos
Terapia a Laser , Macrófagos/enzimologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estresse Oxidativo , Próstata/cirurgia , Espécies Reativas de Oxigênio/metabolismo , Cicatrização , Animais , Antioxidantes/farmacologia , Apoptose , Movimento Celular , Proliferação de Células , Técnicas de Cocultura , Cães , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal , Humanos , Terapia a Laser/instrumentação , Lasers , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Próstata/enzimologia , Próstata/patologia , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Células Estromais/enzimologia , Células Estromais/patologia , Células THP-1 , Túlio , Fatores de Tempo , Cicatrização/efeitos dos fármacos
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