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1.
Molecules ; 26(4)2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669666

RESUMO

Preliminary bioassay-guided fractionation was performed to identify cytotoxic compounds from Hechtia glomerata, a plant that is used in Mexican ethnomedicine. Organic and aqueous extracts were prepared from H. glomerata's leaves and evaluated against two cancer cell lines. The CHCl3/MeOH (1:1) active extract was fractionated, and the resulting fractions were assayed against prostate adenocarcinoma PC3 and breast adenocarcinoma MCF7 cell lines. Active fraction 4 was further analyzed by high-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry analysis to identify its active constituents. Among the compounds that were responsible for the cytotoxic effects of this fraction were flavonoids, phenolic acids, and aromatic compounds, of which p-coumaric acid (p-CA) and its derivatives were abundant. To understand the mechanisms that underlie p-CA cytotoxicity, a microarray assay was performed on PC3 cells that were treated or not with this compound. The results showed that mitogen-activated protein kinases (MAPKs) that regulate many cancer-related pathways were targeted by p-CA, which could be related to the reported effects of reactive oxygen species (ROS). A molecular docking study of p-CA showed that this phenolic acid targeted these protein active sites (MAPK8 and Serine/Threonine protein kinase 3) at the same binding site as their inhibitors. Thus, we hypothesize that p-CA produces ROS, directly affects the MAPK signaling pathway, and consequently causes apoptosis, among other effects. Additionally, p-CA could be used as a platform for the design of new MAPK inhibitors and re-sensitizing agents for resistant cancers.


Assuntos
Bromeliaceae/química , Ácidos Cumáricos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Extratos Vegetais/química , Inibidores de Proteínas Quinases/farmacologia , Bioensaio , Morte Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Ácidos Cumáricos/química , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Humanos , Células MCF-7 , Proteínas Quinases Ativadas por Mitógeno/química , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Células PC-3 , Fenóis/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
2.
J Cancer Res Clin Oncol ; 147(1): 3-22, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33389079

RESUMO

PURPOSE: This paper reviews marine compounds that target the mitogen-activated protein kinase (MAPK) signaling pathway and their main sources, chemical structures, major targeted cancers and possible mechanisms to provide comprehensive and basic information for the development of marine compound-based antitumor drugs in clinical cancer therapy research. METHODS: This paper searched the PubMed database using the keywords "cancer", "marine*" and "MAPK signaling pathway"; this search was supplemented by the literature-tracing method. The marine compounds screened for review in this paper are pure compounds with a chemical structure and have antitumor effects on more than one tumor cell line by targeting the MAPK signaling pathway. The PubChem database was used to search for the PubMed CID and draw the chemical structures of the marine compounds. RESULTS: A total of 128 studies were searched, and 32 marine compounds with unique structures from extensive sources were collected for this review. These compounds are cytotoxic to cancer cell lines, although their targets are still unclear. This paper describes their anticancer effect mechanisms and the protein expression changes in the MAPK pathway induced by these marine compound treatments. This review is the first to highlight MAPK signaling pathway-targeted marine compounds and their use in cancer therapy. CONCLUSION: The MAPK signaling pathway is a promising potential target for cancer therapy. Searching for marine compounds that exert anticancer effects by targeting the MAPK signaling pathway and developing them into new marine anticancer drugs will be beneficial for cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Organismos Aquáticos/química , Descoberta de Drogas , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Animais , Humanos , Neoplasias/enzimologia , Neoplasias/patologia
3.
J Ethnopharmacol ; 269: 113669, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33338591

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Tiao Geng (TG) decoction is a Chinese herbal medicine extract that has been utilized for the treatment of menopausal symptoms for a history of over 30 years. In our previous study, we suggest that TG decoction possibly exerts an anti-apoptotic effect on hypothalamic neurons of ovariectomized rats via the ASK1/MKK7/JNK pathway. Tributyltin chloride (TBTC) causes oxidative damage and induces apoptosis of primary hypothalamic neurons in rats. AIM OF THE STUDY: The present work aimed to explore the inhibition of TG decoction on TBTC-induced GT1-7 cell apoptosis and its possible molecular mechanism. MATERIALS AND METHODS: The GT1-7 cell line was exposed to TG decoction at diverse doses (31.25, 62.5, 125 µg/mL) for 24 h and later with TBTC (1 mg/L) for 1 h, with 17ß-E2 (100 nM) treatment being the positive control. Then, CCK8 assay was conducted to evaluate cell viability, while flow cytometric analysis was conducted to examine the apoptosis level. Related pathways and differentially expressed proteins were identified by tandem mass tag (TMT)-based quantitative phosphoproteomics. qRT-PCR was carried out to examine mRNA levels of Bax and B-cell lymphoma-2 (Bcl-2). Western blotting was performed to detect the levels of Bax, Bcl-2, c-Jun, c-Jun N-terminal kinase (JNK), Caspase-3 (Casp3), Mitogen-activated protein kinase kinase 7 (MKK7), and apoptosis signal-regulating kinase 1 (ASK1) . Finally, cells were pretreated with SP600125, an inhibitor of JNK, later the expression of JNK and Casp3 was measured. RESULTS: Application of TG decoction mitigated the GT1-7 cell apoptosis and injury caused by TBTC; besides, it inhibited the activation of the ASK1/MKK7/JNK pathway. Moreover, Bcl-2/Bax ratio became higher, and the MKK7, ASK1, Casp3 and c-Jun levels were inhibited. Besides, TG decoction combined with SP600125 (the JNK inhibitor) more significantly inhibited GT1-7 cell apoptosis caused by TBTC. CONCLUSION: As discovered from the experiment in this study, TG decoction has a neuroprotective effect, which is achieved through inhibiting the ASK1/MKK7/JNK signal transduction pathway to reduce GT1-7 cell apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , MAP Quinase Quinase Quinase 5/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Compostos de Trialquitina/toxicidade , Animais , Apoptose/fisiologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , MAP Quinase Quinase Quinase 5/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Compostos de Trialquitina/antagonistas & inibidores
4.
Signal Transduct Target Ther ; 5(1): 218, 2020 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-33011739

Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Glicosídeos Cardíacos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Animais , Antivirais/química , Betacoronavirus/patogenicidade , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Bufanolídeos/química , Bufanolídeos/farmacologia , Glicosídeos Cardíacos/química , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cloroquina/química , Cloroquina/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Digoxina/química , Digoxina/farmacologia , Ensaios de Triagem em Larga Escala , Interações Hospedeiro-Patógeno/genética , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Janus Quinases/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Pandemias , Fenantrenos/química , Fenantrenos/farmacologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Transdução de Sinais , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos
5.
Inflamm Res ; 69(12): 1257-1270, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33037469

RESUMO

OBJECTIVE AND DESIGN: Methyl gallate (MG) is a prevalent polyphenol in the plant kingdom, which may be related to the effects of several medicinal plants. Although it is widely reported that polyphenols have therapeutic effects, there are few studies demonstrating that MG has anti-inflammatory action. This study aimed to investigate the molecular mechanism behind the anti-inflammatory activity of MG and its effect on hyperalgesia. METHODS: Swiss mice were pretreated orally with different doses of MG and subjected to i.pl. injection of zymosan to induce paw edema. RAW264.7 macrophages and BMDMs stimulated with different TLR agonists such as zymosan, LPS, or Pam3CSK4 were used to investigate the molecular mechanisms of MG RESULTS: MG inhibits zymosan-induced paw edema and hyperalgesia and modulates molecular pathways crucial for inflammation development. Pretreatment with MG inhibited cytokines production and NF-κB activity by RAW 264.7 cells stimulated with zymosan, Pam3CSK4 or LPS, but not with PMA. Moreover, pretreatment with MG decreased IκB degradation, nuclear translocation of NF-κBp65, c-jun and c-fos and ERK1/2, p38 and JNK phosphorylation. CONCLUSION: Thus, the results of this study demonstrate that MG has a promising anti-inflammatory effect and suggests an explanation of its mechanism of action through the inhibition of NF-κB signaling and the MAPK pathway.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ácido Gálico/análogos & derivados , Inflamação/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Citocinas/metabolismo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Ácido Gálico/farmacologia , Ácido Gálico/uso terapêutico , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Células RAW 264.7 , Zimosan
6.
Mol Cell ; 80(1): 164-174.e4, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32877642

RESUMO

SARS-CoV-2 infections are rapidly spreading around the globe. The rapid development of therapies is of major importance. However, our lack of understanding of the molecular processes and host cell signaling events underlying SARS-CoV-2 infection hinders therapy development. We use a SARS-CoV-2 infection system in permissible human cells to study signaling changes by phosphoproteomics. We identify viral protein phosphorylation and define phosphorylation-driven host cell signaling changes upon infection. Growth factor receptor (GFR) signaling and downstream pathways are activated. Drug-protein network analyses revealed GFR signaling as key pathways targetable by approved drugs. The inhibition of GFR downstream signaling by five compounds prevents SARS-CoV-2 replication in cells, assessed by cytopathic effect, viral dsRNA production, and viral RNA release into the supernatant. This study describes host cell signaling events upon SARS-CoV-2 infection and reveals GFR signaling as a central pathway essential for SARS-CoV-2 replication. It provides novel strategies for COVID-19 treatment.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/genética , Fosfatidilinositol 3-Quinase/genética , Receptores de Fatores de Crescimento/genética , Proteínas Virais/genética , Corticosteroides/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Células CACO-2 , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilação , Receptores de Fatores de Crescimento/antagonistas & inibidores , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacos
8.
Biochem Pharmacol ; 177: 113992, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32335141

RESUMO

IL-17A combined with TNF-α plays a vital role in inflammatory response and interference of the synergistic effect is an effective strategy for treating inflammatory diseases. Ellipticine, a natural alkaloid, has biological activities on anti-tumor and anti-HIV. However, it is still unknown whether ellipticine can inhibit IL-17A and TNF-α-mediated signaling and has treatment effect on PALI. Here, we reported that ellipticine significantly inhibited the production of pro-inflammatory cytokines and chemokines in pulmonary epithelial cell BEAS-2B treated with IL-17A and TNF-α, but not IL-17A or TNF-α alone. Meanwhile, ellipticine attenuated NF-κB and MAPKs activation in response to IL-17A and TNF-α treatment, inhibited Act1 and TRAF6-mediated NF-κB activation, and blocked the interaction of Act1 with TRAF6. Furthermore, we found that ellipticine significantly alleviated CAE and LPS-induced SAP/PALI. Ellipticine treatment dramatically reduced inflammatory cells infiltration, MPO activity, serum amylase and lipase activity and the protein concentration of BALF. Collectively, our findings indicate that ellipticine inhibits the synergistic effect of IL-17A and TNF-α by targeting on Act1 and TRAF6 interaction and is a potential therapeutic agent for the treatment of SAP/PALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Elipticinas/farmacologia , Interleucina-17/antagonistas & inibidores , Pancreatite/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Amilases/antagonistas & inibidores , Amilases/genética , Amilases/metabolismo , Animais , Linhagem Celular Transformada , Ceruletídeo/administração & dosagem , Modelos Animais de Doenças , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Interleucina-17/farmacologia , Lipase/antagonistas & inibidores , Lipase/genética , Lipase/metabolismo , Lipopolissacarídeos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Pancreatite/induzido quimicamente , Pancreatite/complicações , Pancreatite/genética , Peroxidase/antagonistas & inibidores , Peroxidase/genética , Peroxidase/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/antagonistas & inibidores , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
9.
Cancer Cell ; 37(4): 543-550, 2020 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-32289276

RESUMO

KRAS mutations occur in a quarter of all of human cancers, yet no selective drug has been approved to treat these tumors. Despite the recent development of drugs that block KRASG12C, the majority of KRAS oncoproteins remain undruggable. Here, we review recent efforts to validate individual components of the mitogen-activated protein kinase (MAPK) pathway as targets to treat KRAS-mutant cancers by comparing genetic information derived from experimental mouse models of KRAS-driven lung and pancreatic tumors with the outcome of selective MAPK inhibitors in clinical trials. We also review the potential of RAF1 as a key target to block KRAS-mutant cancers.


Assuntos
Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Terapia de Alvo Molecular , Mutação , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Humanos , Neoplasias/genética , Neoplasias/patologia
10.
Reprod Sci ; 27(1): 163-171, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32046373

RESUMO

The methionine adenosyltransferase 2ß gene (Mat2b) encodes for the regulatory subunit of methionine adenosyltransferase (MAT), which catalyzes the biosynthesis of S-adenosylmethionine. MAT2B interacts with G protein-coupled receptor kinase interacting ArfGAP1 to increase the activity of extracellular signal-regulated kinases (ERKs) for the regulation of cell growth, metabolism, and differentiation. ERK activity is also essential for oocyte meiosis in mice. However, the regulatory role of MAT2B in mouse oocyte meiosis remains unclear. Accordingly, this study investigated the effect of MAT2B on mouse oocyte maturation. Immunostaining showed that MAT2B localized predominantly in the nucleus of fully grown germinal vesicle (GV) oocytes. After germinal vesicle breakdown (GVBD), MAT2B homogeneously localized in the cytoplasm. A low oocyte maturation rate was observed in Mat2b siRNA-treated oocytes. Furthermore, Mat2b knockdown repressed the phosphorylation of ERK1/2 and consequently blocked MAPK. Denuded oocytes treated with 20 µM U0126 mainly blocked MAPK phosphorylation and affected oocyte maturation. The oocytes arrested at GVBD and metaphase I (MI) by Mat2b silencing or U0126 treatment had several types of abnormal microtubule assembly. Furthermore, Mat2b knockdown or U0126 treatment resulted in the aberrant expression of six maternal transcripts, namely, Fgf8, Cdc2, Gdf9, Padi6, Polr2d, and Tecb2. To the best of our knowledge, this study is the first to demonstrate that Mat2bs play an important role in mouse oocyte maturation though MAPK signaling.


Assuntos
Sistema de Sinalização das MAP Quinases/fisiologia , Metionina Adenosiltransferase/metabolismo , Oócitos/metabolismo , Oogênese/fisiologia , Animais , Butadienos/farmacologia , Inibidores Enzimáticos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Nitrilos/farmacologia , Oócitos/efeitos dos fármacos , Oócitos/crescimento & desenvolvimento , Oogênese/efeitos dos fármacos , Fosforilação/efeitos dos fármacos
11.
BMB Rep ; 53(2): 106-111, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31964467

RESUMO

Glutaredoxin 1 (GLRX1) has been recognized as an important regulator of redox signaling. Although GLRX1 plays an essential role in cell survival as an antioxidant protein, the function of GLRX1 protein in inflammatory response is still under investigation. Therefore, we wanted to know whether transduced PEP-1-GLRX1 protein inhibits lipopolysaccharide (LPS)- and 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced inflammation. In LPS-exposed Raw 264.7 cells, PEP-1-GLRX1 inhibited cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), activation of mitogen activated protein kinases (MAPKs) and nuclear factor-kappaB (NF-κB) expression levels. In a TPA-induced mouse-ear edema model, topically applied PEP-1-GLRX1 transduced into ear tissues and significantly ameliorated ear edema. Our data reveal that PEP-1-GLRX1 attenuates inflammation in vitro and in vivo, suggesting that PEP-1-GLRX1 may be a potential therapeutic protein for inflammatory diseases. [BMB Reports 2020; 53(2): 106-111].


Assuntos
Anti-Inflamatórios/farmacologia , Cisteamina/análogos & derivados , Glutarredoxinas/farmacologia , Inflamação/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/metabolismo , Peptídeos , Animais , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Edema/induzido quimicamente , Edema/metabolismo , Edema/terapia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologia
12.
Curr Opin Oncol ; 32(2): 91-97, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31833956

RESUMO

PURPOSE OF REVIEW: Thanks to mitogen-activated protein kinase inhibitors (MAPKi) and immune checkpoint inhibitors (ICI), major progress has been made in the field of melanoma treatment. However, long-term success is still scarce because of the development of resistance. Understanding these mechanisms of resistance and identifying predictive genomic biomarkers are now key points in the therapeutic management of melanoma patients. RECENT FINDINGS: Multiple and complex mechanisms of resistance to MAPKi or ICI have been uncovered in the past few years. The lack of response can be driven by mutations and nonmutational events in tumor cells, as well as by changes in the tumor microenvironment. Melanoma cells are also capable of rapidly switching their molecular and cellular phenotype, leading to an initial drug-tolerant favorizing melanoma resistance. Tumor molecular profiling and circulating tumor cell analyses are of high interest as predictive biomarkers as well as studying immunogenic changes and microbiome in ICI-treated patients. SUMMARY: Resistance to MAPKi and ICI is a key point in therapeutic management of metastatic melanoma patients. Validated biomarkers predicting response to therapy are urgently needed to move toward personalized medicine. Combinatory treatments guided by the understanding of resistance mechanisms will be of major importance in the future of melanoma therapy.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunoterapia/métodos , Melanoma/metabolismo , Melanoma/patologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Terapia de Alvo Molecular , Metástase Neoplásica , Valor Preditivo dos Testes
13.
Biochem Biophys Res Commun ; 523(1): 147-152, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-31836141

RESUMO

Hepatocellular carcinoma which is featured with the extensive vascularization is the third most frequent cause of cancer-related deaths with limited therapeutic options, particularly for advanced disease. Cobimetinib, a MEK inhibitor, has been approved for the treatment of melanomas with a BRAF mutation. In this work, we investigated the efficacy of cobimetinib in sensitive and resistant HCC cells. Using a panel of HCC cell lines and normal hepatocellular cells as control, we showed that cobimetinib is active against HCC cells and spare normal hepatocellular cells. Cobimetinib at nanomolar concentration inhibited proliferation and induced apoptosis in sorafenib-resistant HCC cells (Hep3B-r), suggesting its ability to overcome HCC resistance to standard of care. This was further demonstrated by our results that cobimetinib significantly augmented the inhibitory effects of sorafenib and doxorubicin in HCC cells. Notably, cobimetinib dose-dependently inhibited tumor angiogenesis by inhibiting HCC endothelial cell (HCCEC) growth, survival and capillary network work formation. Cobimetinib suppressed ERK/RSK without affecting JNK or p38 signaling pathways in Hep3B-r and HCCEC cells. In addition, cobimetinib negatively influenced the apoptosis pathways by increasing pro-apoptotic protein Bim and decreasing anti-apoptotic proteins Mcl-1 and Bcl-2. In addition, we validated the in vitro findings in HCC xenograft mouse model and demonstrated that cobimetinib inhibited ERK signaling, promoted apoptosis, and was active against resistant HCC growth and angiogenesis in vivo, without causing significant toxicity in mice. Our findings support the clinical trials of cobimetinib for HCC treatment and highlight the therapeutic value of inhibiting MEK/ERK/RSK to overcome HCC resistance.


Assuntos
Antineoplásicos/farmacologia , Azetidinas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Neovascularização Patológica/tratamento farmacológico , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Azetidinas/química , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Piperidinas/química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
14.
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
15.
J Microbiol Biotechnol ; 30(1): 31-37, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31752054

RESUMO

We previously identified a new heparinase inhibitor fungal metabolite, named CRM646-A, which showed inhibition of heparinase and telomerase activities in an in vitro enzyme assay and antimetastatic activity in a cell-based assay. In this study, we elucidated the mechanism by which CRM646-A rapidly induced nucleus condensation, plasma membrane disruption and morphological changes by increasing intracellular Ca2+ levels. Furthermore, PD98059, a mitogen-activated protein kinase (MEK) inhibitor, inhibited CRM646-A-induced nucleus condensation through ERK1/2 activation in rat 3Y1 fibroblast cells. We identified CRM646-A as a Ca2+ ionophore-like agent with a distinctly different chemical structure from that of previously reported Ca2+ ionophores. These results indicate that CRM646-A has the potential to be used as a new and effective antimetastatic drug.


Assuntos
Cálcio/metabolismo , Núcleo Celular/metabolismo , Fibroblastos/efeitos dos fármacos , Hidroxibenzoatos/farmacologia , Animais , Linhagem Celular , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Fibroblastos/metabolismo , Fungos/química , Heparina Liase/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Ratos , Transdução de Sinais
16.
Arch Physiol Biochem ; 126(1): 74-81, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30320514

RESUMO

This study evaluated the anti-inflammatory potential of a 40% prethanol extract of Trifolium pratense leaves (40% PeTP) using in vitro (RAW264.7 cells) and in vivo (carrageenan-induced inflammation model) experiments. Pretreatment with 40% PeTP significantly inhibited the LPS-induced expression of nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and inflammatory cytokines, including tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in RAW264.7 cells, without inducing cytotoxicity. The inhibitory effects of 40% PeTP are mediated through suppression of the nuclear translocation of nuclear factor (NF)-κB and the phosphorylation of mitogen-activated protein kinases (MAPKs). Oral administration of 40% PeTP at 50, 100, and 200 mg/kg of body weight suppressed carrageenan-induced oedema in a dose-dependent manner. Collectively, our results suggested that 40% PeTP exerts potential anti-inflammatory effects by suppressing the activation of the NF-κB and MAPK pathways in vitro, and by reducing carrageenan-induced paw oedema in vivo.


Assuntos
Anti-Inflamatórios/farmacologia , Edema/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/genética , NF-kappa B/genética , Extratos Vegetais/farmacologia , Trifolium/química , Administração Oral , Animais , Carragenina/administração & dosagem , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/antagonistas & inibidores , Dinoprostona/biossíntese , Modelos Animais de Doenças , Esquema de Medicação , Edema/induzido quimicamente , Edema/genética , Edema/patologia , Regulação da Expressão Gênica , Inflamação , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Folhas de Planta/química , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
17.
Dev Biol ; 459(2): 72-78, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31881199

RESUMO

In the sea urchin larva, most neurons lie within an ectodermal region called the ciliary band. Our understanding of the mechanisms of specification and patterning of these peripheral ciliary band neurons is incomplete. Here, we first examine the gene regulatory landscape from which this population of neural progenitors arise in the neuroectoderm. We show that ciliary band neural progenitors first appear in a bilaterally symmetric pattern on the lateral edges of chordin expression in the neuroectoderm. Later in development, these progenitors appear in a salt-and-pepper pattern in the ciliary band where they express soxC, and prox, which are markers of neural specification, and begin to express synaptotagminB, a marker of differentiated neurons. We show that the ciliary band expresses the acid sensing ion channel gene asicl, which suggests that ciliary band neurons control the larva's ability to discern touch sensitivity. Using a chemical inhibitor of MAPK signaling, we show that this signaling pathway is required for proper specification and patterning of ciliary band neurons. Using live imaging, we show that these neural progenitors undergo small distance migrations in the embryo. We then show that the normal swimming behavior of the larvae is compromised if the neurogenesis pathway is perturbed. The developmental sequence of ciliary band neurons is very similar to that of neural crest-derived sensory neurons in vertebrates and may provide insights into the evolution of sensory neurons in deuterostomes.


Assuntos
Padronização Corporal/genética , Ectoderma/crescimento & desenvolvimento , Neurogênese/genética , Neurônios/metabolismo , Ouriços-do-Mar/embriologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Butadienos/farmacologia , Regulação da Expressão Gênica no Desenvolvimento , Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Larva/crescimento & desenvolvimento , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Nitrilos/farmacologia , Proteína Nodal/metabolismo , Fatores de Transcrição SOXC/metabolismo , Transdução de Sinais/genética , Sinaptotagminas/metabolismo
18.
Nat Commun ; 10(1): 5157, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727958

RESUMO

Most targeted cancer therapies fail to achieve complete tumor regressions or attain durable remissions. To understand why these treatments fail to induce robust cytotoxic responses despite appropriately targeting oncogenic drivers, here we systematically interrogated the dependence of cancer cells on the BCL-2 family of apoptotic proteins after drug treatment. We observe that multiple targeted therapies, including BRAF or EGFR inhibitors, rapidly deplete the pro-apoptotic factor NOXA, thus creating a dependence on the anti-apoptotic protein MCL-1. This adaptation requires a pathway leading to destabilization of the NOXA mRNA transcript. We find that interruption of this mechanism of anti-apoptotic adaptive resistance dramatically increases cytotoxic responses in cell lines and a murine melanoma model. These results identify NOXA mRNA destabilization/MCL-1 adaptation as a non-genomic mechanism that limits apoptotic responses, suggesting that sequencing of MCL-1 inhibitors with targeted therapies could overcome such widespread and clinically important resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-bcl-2/genética , Estabilidade de RNA/genética , Animais , Apoptose , Sequência de Bases , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Tristetraprolina/metabolismo
19.
Trends Pharmacol Sci ; 40(11): 897-910, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31662208

RESUMO

Recent clinical and therapeutic success with RAF and MEK1/2 inhibitors has revolutionized the existing treatment schemes for previously incurable cancers like melanomas. However, the overall therapeutic efficacies are still largely compromised by the dose-limiting side effects and emerging drug resistance mechanisms. Accumulating evidence has revealed the intricate nature of the RAS-RAF-MEK1/2-ERK1/2 pathway, such as activation mechanisms, kinase-substrate relationships, crosstalk with parallel signaling pathways, feedback regulations, and intimate interplay with immune responses. Limited strategies are currently available to exploit the benefits of combining RAF-MEK1/2-ERK1/2 pathway inhibitors with other targeted therapies or immunotherapies. Here, we compiled the kinase-substrate relationships and analyzed the intricate signaling networks of the renowned pathway, providing an integrated and simplified visualization, to reveal the potentials of RAS-RAF-MEK1/2-ERK1/2-based combination therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Fatores Imunológicos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/administração & dosagem , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/imunologia , Neoplasias/enzimologia , Neoplasias/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinases raf/antagonistas & inibidores , Quinases raf/imunologia , Quinases raf/metabolismo , Proteínas ras/antagonistas & inibidores , Proteínas ras/imunologia , Proteínas ras/metabolismo
20.
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
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