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1.
Biochim Biophys Acta ; 1845(1): 53-65, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24316024

RESUMO

The Wnt (wingless-type) signaling pathway plays an important role in embryonic development, tissue homeostasis, and tumor progression becaluse of its effect on cell proliferation, migration, and differentiation. Secreted frizzled-related proteins (SFRPs) are extracellular inhibitors of Wnt signaling that act by binding directly to Wnt ligands or to Frizzled receptors. In recent years, aberrant expression of SFRPs has been reported to be associated with numerous cancers. As gene expression of SFRP members is often lost through promoter hypermethylation, inhibition of methylation through the use of epigenetic modifying agents could renew the expression of SFRP members and further antagonize deleterious Wnt signaling. Several reports have described epigenetic silencing of these Wnt signaling antagonists in various human cancers, suggesting their possible role as tumor suppressors. SFRP family members thus come across as potential tools in combating Wnt-driven tumorigenesis. However, little is known about SFRP family members and their role in different cancers. This review comprehensively covers all the available information on the role of SFRP molecules in various human cancers.


Assuntos
Glicoproteínas/fisiologia , Neoplasias/etiologia , Proteínas Wnt/antagonistas & inibidores , Animais , Glicoproteínas/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/fisiologia , Via de Sinalização Wnt
2.
J Cell Biochem ; 112(8): 2179-88, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21480361

RESUMO

The treatment of inflammatory diseases today is largely based on interrupting the synthesis or action of the mediators that drive the host's response to injury. It is on the basis of this concept that most of the anti-inflammatory drugs have been developed. In our continuous search for novel anti-inflammatory agents from traditional medicinal plants, Saposhnikovia divaricata has been a focus of our investigations. Anomalin, a pyranocoumarin constituent of S. divaricata, exhibits potent anti-inflammatory activity. To clarify the cellular signaling mechanisms underlying the anti-inflammatory action of anomalin, we investigated the effect of anomalin on the production of inflammatory molecules in LPS-stimulated murine macrophages. The anomalin dose-dependently inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA and protein expression in LPS-stimulated RAW 264.7 macrophage. Molecular analysis using quantitative real time polymerase chain reaction (qRT-PCR) revealed that several pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were reduced by anomalin, and this reduction correlated with the down-regulation of the NF-κB signaling pathway. In addition, anomalin suppressed the LPS-induced phosphorylation and degradation of IκBα. To further study the mechanisms underlying its anti-inflammatory activity, an electrophoretic mobility shift assay (EMSA) using a (32) P-labeled NF-κB probe was conducted. LPS-induced NF-κB DNA binding was drastically abolished by anomalin. The present data suggest that anomalin is a major anti-inflammatory agent and may be a potential therapeutic candidate for the treatment of inflammatory disorders.


Assuntos
Anti-Inflamatórios/farmacologia , Cumarínicos/farmacologia , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Animais , Anti-Inflamatórios/química , Apiaceae/química , Linhagem Celular , Cumarínicos/química , Ciclo-Oxigenase 2/biossíntese , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo II/biossíntese
3.
Planta Med ; 77(3): 242-7, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20717871

RESUMO

Glycyrrhiza uralensis (Leguminosae) has long been used to treat inflammatory ailments, such as gastric ulcers, arthritis, and rheumatism. From this traditional herbal plant, glycyrol, a coumestan with anti-bacterial and anti-inflammatory activities, was first isolated and synthesized to test its apoptosis-inducing properties in human Jurkat cells. Flow cytometry analysis indicated that glycyrol can arrest the cell cycle in S phase and subsequently induce apoptosis in both time- and dose-dependent manners. Consequently, it was shown that caspase-8 and -9 were involved in the activation of apoptosis after glycyrol treatment. Despite its known NF- κB inhibitory activity, glycyrol did not influence the prosurvival Bcl-2 and the proapoptotic Bax. Interestingly, glycyrol was revealed to enhance the Fas level independently from p53, which even slightly decreased. Thus, glycyrol acts in a similar manner as known cytostatic drugs and may have a potential as lead for the development of drugs for cancer treatment.


Assuntos
Apoptose/efeitos dos fármacos , Caspase 8/metabolismo , Flavonoides/farmacologia , Glycyrrhiza/química , Células Jurkat/efeitos dos fármacos , Extratos Vegetais/farmacologia , Receptor fas/metabolismo , Caspase 9/metabolismo , Ciclo Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteína Ligante Fas/metabolismo , Humanos
4.
Sci Adv ; 7(12)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33731348

RESUMO

What covalent modifications control the temporal ubiquitination of ERα and hence the duration of its transcriptional activity remain poorly understood. We show that GREB1, an ERα-inducible enzyme, catalyzes O-GlcNAcylation of ERα at residues T553/S554, which stabilizes ERα protein by inhibiting association with the ubiquitin ligase ZNF598. Loss of GREB1-mediated glycosylation of ERα results in reduced cellular ERα levels and insensitivity to estrogen. Higher GREB1 expression in ERα+ve breast cancer is associated with greater survival in response to tamoxifen, an ERα agonist. Mice lacking Greb1 exhibit growth and fertility defects reminiscent of phenotypes in ERα-null mice. In summary, this study identifies GREB1, a protein with an evolutionarily conserved domain related to DNA-modifying glycosyltransferases of bacteriophages and kinetoplastids, as the first inducible and the only other (apart from OGT) O-GlcNAc glycosyltransferase in mammalian cytoplasm and ERα as its first substrate.


Assuntos
Neoplasias da Mama , Receptor alfa de Estrogênio , Proteínas de Membrana/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proteínas de Transporte/genética , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Glicosilação , Glicosiltransferases/genética , Humanos , Mamíferos/metabolismo , Camundongos , Proteínas de Neoplasias/metabolismo
5.
Cancers (Basel) ; 12(8)2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32781681

RESUMO

Multiple myeloma (MM) is the second most common hematologic malignancy in the world. Even though survival rates have significantly risen over the past years, MM remains incurable, and is also far from reaching the point of being managed as a chronic disease. This paper reviews the evolution of MM therapies, focusing on anti-MM drugs that target the molecular mechanisms of nuclear factor kappa B (NF-κB) signaling. We also provide our perspectives on contemporary research findings and insights for future drug development.

6.
Arch Pharm Res ; 32(10): 1385-92, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19898801

RESUMO

Cimiside E was isolated from the Cimicifuga heracleifolia Komarov extract, which has been previously demonstrated to possess apoptotic action on gastric cancer cells. The IC(50) value of cimiside E on gastric cancer cells for 24 h was 14.58 microM. The mechanism of apoptosis was further elucidated through western blot, RT-PCR, morphology, Annexin V-FITC/PI staining and cell cycle analysis. Cell cycle arrest was induced by cimiside E in S phase at a lower concentration (30 microM) and G2/M phase at higher concentrations (60 and 90 microM). Cimiside E mediated apoptosis through the induction of the caspase cascade for both the extrinsic and intrinsic pathways. These findings suggest that cimiside E may be an effective chemopreventive agent against cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Cimicifuga/química , Fragmentação do DNA/efeitos dos fármacos , Saponinas/farmacologia , Neoplasias Gástricas/patologia , Triterpenos/farmacologia , Anexina A5/metabolismo , Antineoplásicos Fitogênicos/isolamento & purificação , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteína Ligante Fas/metabolismo , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Saponinas/isolamento & purificação , Triterpenos/isolamento & purificação , Receptor fas/metabolismo
7.
Arch Pharm Res ; 32(3): 399-405, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19387584

RESUMO

Schisandrin is the main active ingredient isolated from Schisandra chinensis Baill. Recent studies have demonstrated that schisandrin exhibits anti-inflammatory effects in vivo and in vitro. In this study, we examined whether the order of lipopolysaccharide (LPS) treatment affects the mechanism of schisandrin anti-inflammatory activity. We found that the antiinflammatory mechanisms are not the same depending on whether macrophages were treated with schisandrin before or after LPS. The main difference is that inhibitor kappaBalpha (IkappaBalpha) degradation was not inhibited when macrophages were pretreated by LPS before schisandrin and was weakly inhibited when macrophages were pretreated by schisandrin before LPS.


Assuntos
Anti-Inflamatórios/farmacologia , Ciclo-Octanos/farmacologia , Lignanas/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Compostos Policíclicos/farmacologia , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Proteínas I-kappa B/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Macrófagos/enzimologia , Macrófagos/metabolismo , Camundongos , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , Fatores de Tempo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Oncogene ; 38(12): 2206-2222, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30470823

RESUMO

Obesity increases the risk of hepatocellular carcinoma (HCC), but precise identification and characterization of druggable oncogenic pathways that contribute to the progression of NAFLD to HCC, and hence to the increased incidence and aggressiveness of HCC in obese individuals is lacking. In this regard, we demonstrate that the Indian Hedgehog (Ihh) signaling pathway is upregulated in the fatty livers of mice consuming a high fat diet, and furthermore sustained in HCC tumors specifically within the context of a NAFLD microenvironment. Using a diet-induced mouse model of HCC wherein only obese mice develop HCC, targeted ablation of hepatocyte-secreted Ihh results in a decreased tumor burden and lower grade tumors. Ihh activation regulates the transdifferentiation of ciliated stellate cells and proliferation of Epcam+ ductal cells to promote fibrosis. Mechanistically, increased expression of hitherto uncharacterized effectors of Hh pathway, namely Myc and Tgf-ß2 is critical to the observed physiology. This pro-tumorigenic response is driven by increased expression of Wnt5a to effect a poorly-differentiated and invasive tumor phenotype. Wnt5a secreted from activated stellate cells act on Ror2-expressing hepatocytes. We further demonstrate that Wnt5a expression is also elevated in poorly-differentiated HCC cells, suggesting that these ligands are also able to function in an autocrine positive feedback manner to sustain poorly-differentiated tumors. Taken together, our study provides a mechanistic understanding for how Ihh signaling promotes HCC tumorigenesis specifically in obese mice. We propose that therapeutic targeting of the Hh pathway offers benefit for patients with dietary / NAFLD-driven steatotic HCC.


Assuntos
Carcinogênese , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas Hedgehog/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Obesidade/complicações , Animais , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/genética , Proliferação de Células , Células Estreladas do Fígado/patologia , Hepatócitos/patologia , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/genética , Camundongos , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta2/genética , Fator de Crescimento Transformador beta2/metabolismo , Regulação para Cima
9.
Eur J Pharmacol ; 586(1-3): 340-9, 2008 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-18378223

RESUMO

The extracts or constituents from the bark of Magnolia (M.) obovata are known to have many pharmacological activities. 4-Methoxyhonokiol, a neolignan compound isolated from the stem bark of M. obovata, was found to exhibit a potent anti-inflammatory effect in different experimental models. Pretreatment with 4-methoxyhonokiol (i.p.) dose-dependently inhibited the dye leakage and paw swelling in an acetic-acid-induced vascular permeability assay and a carrageenan-induced paw edema assay in mice, respectively. In the lipopolysaccharide (LPS)-induced systemic inflammation model, 4-methoxyhonokiol significantly inhibited plasma nitric oxide (NO) release in mice. To identify the mechanisms underlying this anti-inflammatory action, we investigated the effect of 4-methoxyhonokiol on LPS-induced responses in a murine macrophage cell line, RAW 264.7. The results demonstrated that 4-methoxyhonokiol significantly inhibited LPS-induced NO production as well as the protein and mRNA expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, 4-methoxyhonokiol inhibited LPS-mediated nuclear factor-kappaB (NF-kappaB) activation via the prevention of inhibitor kappaB (IkappaB) phosphorylation and degradation. 4-Methoxyhonokiol had no effect on the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK), whereas it attenuated the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun NH2-terminal kinase (JNK) in a concentration-dependent manner. Taken together, our data suggest that 4-methoxyhonokiol is an active anti-inflammatory constituent of the bark of M. obovata, and that its anti-inflammatory property might be a function of the inhibition of iNOS and COX-2 expression via down-regulation of the JNK and p38 MAP kinase signal pathways and inhibition of NF-kappaB activation in RAW 264.7 macrophages.


Assuntos
Compostos Alílicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Compostos de Bifenilo/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/biossíntese , Inibidores Enzimáticos/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Macrófagos/metabolismo , NF-kappa B/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Ácido Acético/farmacologia , Animais , Permeabilidade Capilar/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Edema/induzido quimicamente , Edema/prevenção & controle , Genes Reporter/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Espectroscopia de Ressonância Magnética , Magnolia/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Nitratos/sangue , Óxido Nítrico Sintase Tipo II/biossíntese , Nitritos/sangue , Espectrofotometria Ultravioleta
10.
Eur J Pharmacol ; 591(1-3): 293-9, 2008 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-18625216

RESUMO

Schisandrin is the main active ingredient isolated from the fruit of Schisandra chinensis Baill. Recent studies have demonstrated that schisandrin exhibits anti-oxidative effects in vivo. In the present study, the effect of schisandrin on plasma nitrite concentration in lipopolysaccharide (LPS)-treated mice was evaluated. It also significantly inhibited carrageenan-induced paw edema and acetic acid-induced vascular permeability in mice. Furthermore, schisandrin had a protective effect on lipopolysaccharide (LPS)-induced sepsis. In vitro, our results are the first that show that the anti-inflammatory properties of schisandrin result from the inhibition of nitric oxide (NO) production, prostaglandin E(2) (PGE(2)) release, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, which in turn results from the inhibition of nuclear factor-kappaB (NF-kappaB), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activities in a RAW 264.7 macrophage cell line.


Assuntos
Anti-Inflamatórios/farmacologia , Ciclo-Octanos/farmacologia , Inflamação/tratamento farmacológico , Lignanas/farmacologia , Compostos Policíclicos/farmacologia , Schisandra/química , Animais , Anti-Inflamatórios/isolamento & purificação , Permeabilidade Capilar/efeitos dos fármacos , Linhagem Celular , Ciclo-Octanos/isolamento & purificação , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/antagonistas & inibidores , Dinoprostona/metabolismo , Frutas , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/etiologia , Inflamação/fisiopatologia , Lignanas/isolamento & purificação , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Nitritos/sangue , Compostos Policíclicos/isolamento & purificação , Sepse/prevenção & controle
11.
Int Immunopharmacol ; 8(11): 1524-32, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18621150

RESUMO

The anti-inflammatory effects of glycyrol, a benzofuran coumarin isolated from Glycyrrhizae Radix, were studied. Glycyrol of 5, 25 and 50 microM dose-dependently inhibited nitric oxide (NO) production by down-regulating inducible nitric oxide synthase (iNOS), and alleviated cyclooxygenase-2 (COX-2) expression in LPS-stimulated RAW264.7 macrophages, in both the mRNA and the protein. Furthermore, glycyrol dose-dependently decreased the mRNA of the pro-inflammatory cytokines IL-1beta and IL-6. LPS-induced NF-kappaB activation was prevented in RAW264.7 macrophages by inhibition of I-kappaBalpha phosphorylation. In addition, administration of glycyrol (30 and 100 mg/kg, i.p) reduced the thickness of carrageenan-induced mouse-paw edema swelling. Taken together, our results indicate that glycyrol is an important anti-inflammatory constituent of Glycyrrhizae Radix, and that its anti-inflammatory effect is attributed to the inhibition I-kappaBalpha phosphorylation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Flavonoides/farmacologia , Glycyrrhiza uralensis/química , Inflamação/imunologia , Macrófagos/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/isolamento & purificação , Carragenina/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/imunologia , Ciclo-Oxigenase 2/metabolismo , Edema/induzido quimicamente , Edema/imunologia , Edema/metabolismo , Flavonoides/isolamento & purificação , Quinase I-kappa B/efeitos dos fármacos , Quinase I-kappa B/imunologia , Quinase I-kappa B/metabolismo , Inflamação/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Masculino , Camundongos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/imunologia , Quinase Induzida por NF-kappaB
12.
Arch Pharm Res ; 31(4): 490-6, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18449507

RESUMO

Demethoxycurcumin and bisdemethoxycurcumin are the main active ingredients isolated from Curcumae Longae Radix. Recent studies demonstrated that both compounds exhibit antioxidative and anti-inflammatory effects as well as effects on cancer cell lines. In this study, we compared the activities of demethoxycurcumin and bisdemethoxycurcumin, and both compounds were evaluated on lipopolysaccharide (LPS)-induced nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), cycloxygenase-2 (COX-2) and nuclear factor-kappaB (NF-kappaB) activity in a RAW 264.7 macrophage cell line. The evaluation:results suggested that the anti-inflammatory properties of demethoxycurcumin and bisdemethoxycurcumin were attributed to the inhibition of iNOS and COX-2 expression, as initiated by the inhibition of NF-kappaB activity. Additionally, both of them significantly inhibited carrageenan-induced paw edema in mice. Taken together, all of the results showed that the suppressive effect of demethoxycurcumin was stronger than that of bisdemethoxycurcumin, indicating that the methoxy group had enhanced demethoxycurcumin's anti-inflammation effects.


Assuntos
Anti-Inflamatórios/farmacologia , Curcumina/análogos & derivados , Edema/prevenção & controle , Mediadores da Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Animais , Anti-Inflamatórios/uso terapêutico , Carragenina , Linhagem Celular , Curcumina/farmacologia , Curcumina/uso terapêutico , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Diarileptanoides , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Proteínas I-kappa B/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/enzimologia , Macrófagos/metabolismo , Camundongos , Inibidor de NF-kappaB alfa , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , Transfecção
13.
Sci Rep ; 7(1): 8094, 2017 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-28808254

RESUMO

NFκB signaling has a pivotal role in regulation of development, innate immunity, and inflammation. Ikk2 is one of the two critical kinases that regulate the NFκB signaling pathway. While the role of Ikk2 in immunity, inflammation and oncogenesis has received attention, an understanding of the role of Ikk2 in vertebrate development has been compounded by the embryonic lethality seen in mice lacking Ikk2. We find that despite abnormal angiogenesis in IKK2 zygotic mutants of zebrafish, the maternal activity of Ikk2 supports embryogenesis and maturation of fertile animals and allows to study the role of IKK2 in development. Maternal-zygotic ikk2 mutants represent the first vertebrates globally devoid of maternal and zygotic Ikk2 activity. They are defective in cell proliferation as evidenced by abnormal cytokinesis, nuclear enlargement and syncytialisation of a significant portion of blastoderm. We further document that reduced phosphorylation of Aurora A by Ikk2 could underlie the basis of these defects in cell division.


Assuntos
Citocinese/fisiologia , Desenvolvimento Embrionário/fisiologia , Quinase I-kappa B/metabolismo , Vertebrados/metabolismo , Vertebrados/fisiologia , Animais , Animais Geneticamente Modificados/metabolismo , Animais Geneticamente Modificados/fisiologia , Divisão Celular/fisiologia , Proliferação de Células/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , NF-kappa B/metabolismo , Fosforilação/fisiologia , Transdução de Sinais/fisiologia , Peixe-Zebra
14.
Nat Genet ; 49(9): 1354-1363, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28740264

RESUMO

The transcriptional network acting downstream of LIF, WNT and MAPK-ERK to stabilize mouse embryonic stem cells (ESCs) in their naive state has been extensively characterized. However, the upstream factors regulating these three signaling pathways remain largely uncharted. PR-domain-containing proteins (PRDMs) are zinc-finger sequence-specific chromatin factors that have essential roles in embryonic development and cell fate decisions. Here we characterize the transcriptional regulator PRDM15, which acts independently of PRDM14 to regulate the naive state of mouse ESCs. Mechanistically, PRDM15 modulates WNT and MAPK-ERK signaling by directly promoting the expression of Rspo1 (R-spondin1) and Spry1 (Sprouty1). Consistent with these findings, CRISPR-Cas9-mediated disruption of PRDM15-binding sites in the Rspo1 and Spry1 promoters recapitulates PRDM15 depletion, both in terms of local chromatin organization and the transcriptional modulation of these genes. Collectively, our findings uncover an essential role for PRDM15 as a chromatin factor that modulates the transcription of upstream regulators of WNT and MAPK-ERK signaling to safeguard naive pluripotency.


Assuntos
Proteínas de Ligação a DNA/genética , Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica , Sistema de Sinalização das MAP Quinases/genética , Fatores de Transcrição/genética , Via de Sinalização Wnt/genética , Animais , Western Blotting , Linhagem Celular , Autorrenovação Celular/genética , Células Cultivadas , Reprogramação Celular/genética , Proteínas de Ligação a DNA/metabolismo , Imunofluorescência , Perfilação da Expressão Gênica/métodos , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos Knockout , Camundongos Nus , Camundongos Transgênicos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/metabolismo
15.
Life Sci ; 79(7): 695-701, 2006 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-16554073

RESUMO

Dehydroevodiamine is a major bioactive quinazoline alkaloid isolated from Evodiae Fructus. We investigated the anti-inflammatory properties of dehydroevodiamine in RAW 264.7 murine macrophages. The results indicated that dehydroevodiamine inhibited the expression of LPS-induced iNOS and COX-2 proteins and suppressed also their mRNAs from RT-PCR experiment on RAW 264.7 cells. Furthermore, this compound inhibited the level of LPS-stimulated prostaglandin E2 (PGE2) and LPS-induced nuclear factor-kappa B (NF-kappaB). Therefore, we suggested that the effect of dehydroevodiamine-mediated inhibition of the expression LPS-induced iNOS and COX-2 genes is due to under the suppression of NF-kappaB activation in the transcriptional level.


Assuntos
Alcaloides/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2 , Ciclo-Oxigenase 2/biossíntese , Lipopolissacarídeos/antagonistas & inibidores , Macrófagos/enzimologia , NF-kappa B/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/biossíntese , Animais , Western Blotting , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/enzimologia , Dinoprostona/biossíntese , Ensaio de Desvio de Mobilidade Eletroforética , Indução Enzimática/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , RNA/biossíntese , RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
Arch Pharm Res ; 29(4): 293-7, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16681034

RESUMO

The fruits of Evodia rutaecarpa Benth (Rutaceae) has long been used for inflammatory disorders and some anti-inflammatory actions of its constituents such as dehydroevodiamine, evodiamine and rutaecarpine were previously reported. Since the pharmacological data is not sufficient to clearly establish the scientific rationale of anti-inflammatory medicinal use of this plant material and the search for its active principles is limited so far, three major constituents (evodiamine, rutaecarpine, goshuyuamide II) were evaluated for their anti-inflammatory cellular action mechanisms in the present study. From the results, evodiamine and rutaecarpine were found to strongly inhibit prostaglandin E2 synthesis from lipopolysaccharide-treated RAW 264.7 cells at 1-10 microM. Evodiamine inhibited cyclooxygenase-2 induction and NF-kappaB activation, while rutaecarpine did not. On the other hand, goshuyuamide II inhibited 5-lipoxygenase from RBL-1 cells (IC50 = 6.6 microM), resulting in the reduced synthesis of leukotrienes. However, these three compounds were not inhibitory against inducible nitric oxide synthase-mediated nitric oxide production from RAW cells up to 50 micorM. These pharmacological properties may provide the additional scientific rationale for anti-inflammatory use of the fruits of E. rutaecarpa.


Assuntos
Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Evodia , Macrófagos/efeitos dos fármacos , Alcaloides/isolamento & purificação , Animais , Anti-Inflamatórios/isolamento & purificação , Araquidonato 5-Lipoxigenase/metabolismo , Calcimicina , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Evodia/química , Frutas/química , Alcaloides Indólicos , Leucotrieno C4/metabolismo , Lipopolissacarídeos , Inibidores de Lipoxigenase/isolamento & purificação , Inibidores de Lipoxigenase/farmacologia , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Quinazolinas/isolamento & purificação , Quinazolinas/farmacologia
17.
J Clin Invest ; 124(9): 3807-24, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25083991

RESUMO

Despite advancement in breast cancer treatment, 30% of patients with early breast cancers experience relapse with distant metastasis. It is a challenge to identify patients at risk for relapse; therefore, the identification of markers and therapeutic targets for metastatic breast cancers is imperative. Here, we identified DP103 as a biomarker and metastasis-driving oncogene in human breast cancers and determined that DP103 elevates matrix metallopeptidase 9 (MMP9) levels, which are associated with metastasis and invasion through activation of NF-κB. In turn, NF-κB signaling positively activated DP103 expression. Furthermore, DP103 enhanced TGF-ß-activated kinase-1 (TAK1) phosphorylation of NF-κB-activating IκB kinase 2 (IKK2), leading to increased NF-κB activity. Reduction of DP103 expression in invasive breast cancer cells reduced phosphorylation of IKK2, abrogated NF-κB-mediated MMP9 expression, and impeded metastasis in a murine xenograft model. In breast cancer patient tissues, elevated levels of DP103 correlated with enhanced MMP9, reduced overall survival, and reduced survival after relapse. Together, these data indicate that a positive DP103/NF-κB feedback loop promotes constitutive NF-κB activation in invasive breast cancers and activation of this pathway is linked to cancer progression and the acquisition of chemotherapy resistance. Furthermore, our results suggest that DP103 has potential as a therapeutic target for breast cancer treatment.


Assuntos
Neoplasias da Mama/patologia , Proteína DEAD-box 20/fisiologia , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Movimento Celular , Proteína DEAD-box 20/análise , Proteína DEAD-box 20/genética , Feminino , Humanos , Quinase I-kappa B/metabolismo , MAP Quinase Quinase Quinases/fisiologia , Metaloproteinase 9 da Matriz/análise , Metaloproteinase 9 da Matriz/genética , NF-kappa B/fisiologia , Invasividade Neoplásica , Metástase Neoplásica
18.
Arch Pharm Res ; 35(4): 723-32, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22553066

RESUMO

The roots of Angelica tenuissima have been commonly used for the treatment of cardiovascular diseases and menstrual discomfort in Asian countries, such as China and Korea. The primary volatile flavor components are essential oil ingredients, phthalide lactones. In this study, (Z)-ligustilide was tested for its anti-inflammatory activities in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. We found that (Z)-ligustilide strongly inhibitis the induction of LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at both the mRNA and protein levels in a dose-dependent manner. The transcriptional activity of nuclear factor kappa B (NF-B) was also down-regulated in a concentration-dependent manner. Further study revealed that (Z)-ligustilide inhibited the phosphorylation and subsequent degradation of IBα, an inhibitor protein of NF-B. In addition, (Z)-ligustilide inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK) in a dose-dependent manner. Taken together, these data suggest that (Z)-ligustilide can exert its antiinflammatory effects by regulating the NF-B and MAPK signal pathways.


Assuntos
4-Butirolactona/análogos & derivados , Anti-Inflamatórios não Esteroides/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , 4-Butirolactona/farmacologia , 4-Butirolactona/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Western Blotting , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Regulação para Baixo , Edema/tratamento farmacológico , Edema/enzimologia , Edema/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Fosforilação , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
Phytomedicine ; 18(8-9): 677-82, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21211951

RESUMO

This study investigates the anti-inflammatory effects of a diterpenoid, kaurenoic acid, isolated from the root of Aralia continentalis (Araliaceae). To determine its anti-inflammatory effects, LPS-induced RAW264.7 macrophages were treated with different concentrations of kaurenoic acid and carrageenan-induced paw edema mice model was used in vivo. Kaurenoic acid (ent-kaur-16-en-19-oic acid) dose-dependently inhibited nitric oxide (NO) production, prostaglandin E(2) (PGE(2)) release, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression at micromolar concentrations in LPS-induced RAW264.7 macrophages with IC(50) (the half maximal inhibitory concentration) values of 51.73 (±2.42) µM and 106.09 (±0.27) µM in NO production and PGE(2) release, respectively. Kaurenoic acid also dose-dependently inhibited LPS-induced activation of NF-κB as assayed by electrophorectic mobility shift assay (EMSA) and it almost abolished NF-κB DNA binding affinity at 100µM. Furthermore, the in vivo anti-inflammatory effect of kaurenoic acid was examined in a carrageenan-induced paw edema model. Eight ICR mice in each group were injected with carrageenan and observed hourly, compared with the control group. Kaurenoic acid dose-dependently reduced paw swelling up to 34.4% at 5h after induction, demonstrating inhibition in an acute inflammation model. Taken together, our data suggest that kaurenoic acid, a major diterpenoid from the root of A. continentalis shows anti-inflammatory activity and the inhibition of iNOS and COX-2 expression might be one of the mechanisms responsible for its anti-inflammatory properties.


Assuntos
Anti-Inflamatórios/farmacologia , Aralia/química , Diterpenos/farmacologia , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Ciclo-Oxigenase 2/biossíntese , Dinoprostona/antagonistas & inibidores , Dinoprostona/biossíntese , Diterpenos/isolamento & purificação , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/biossíntese , Fitoterapia , Extratos Vegetais/isolamento & purificação , Raízes de Plantas/química
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