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1.
Mar Drugs ; 19(10)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34677428

RESUMO

To discover the new medical entity from edible marine algae, our continuously natural product investigation focused on endophytes from marine macroalgae Grateloupia sp. Two new azaphilones, 8a-epi-hypocrellone A (1), 8a-epi-eupenicilazaphilone C (2), together with five known azaphilones, hypocrellone A (3), eupenicilazaphilone C (4), ((1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2,4-dihydroxy-3-methylbenzaldehyde (5), sclerotiorin (6), and isochromophilone IV (7) were isolated from the alga-derived fungus Penicillium sclerotiorum. The structures of isolated azaphilones (1-7) were elucidated by spectrometric identification, especially HRESIMS, CD, and NMR data analyses. Concerning bioactivity, cytotoxic, anti-inflammatory, and anti-fibrosis activities of those isolates were evaluated. As a result, compound 1 showed selective toxicity toward neuroblastoma cell line SH-SY5Y among seven cancer and one fibroblast cell lines. 20 µM of compounds 1, 3, and 7 inhibited the TNF-α-induced NFκB phosphorylation but did not change the NFκB activity. Compounds 2 and 6 respectively promoted and inhibited SMAD-mediated transcriptional activities stimulated by TGF-ß.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Microalgas , Penicillium , Pigmentos Biológicos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Organismos Aquáticos , Benzopiranos/química , Benzopiranos/uso terapêutico , Linhagem Celular Tumoral/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Alimento Funcional , Neuroblastoma/tratamento farmacológico , Pigmentos Biológicos/química , Pigmentos Biológicos/uso terapêutico , Relação Estrutura-Atividade
2.
Int J Mol Sci ; 20(5)2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30862120

RESUMO

Internal tandem duplication of FLT3 juxtamembrane domain (FLT3-ITD)-positive acute myeloid leukemia (AML) leads to poor clinical outcomes after chemotherapy. We aimed to establish a cytarabine-resistant line from FLT3-ITD-positive MV4-11 (MV4-11-P) cells and examine the development of resistance. The FLT3-ITD mutation was retained in MV4-11-R; however, the protein was underglycosylated and less phosphorylated in these cells. Moreover, the phosphorylation of ERK1/2, Akt, MEK1/2 and p53 increased in MV4-11-R. The levels of Mcl-1 and p53 proteins were also elevated in MV4-11-R. A p53 D281G mutant emerged in MV4-11-R, in addition to the pre-existing R248W mutation. MV4-11-P and MV4-11-R showed similar sensitivity to cabozantinib, sorafenib, and MK2206, whereas MV4-11-R showed resistance to CI-1040 and idarubicin. MV4-11-R resistance may be associated with inhibition of Akt phosphorylation, but not ERK phosphorylation, after exposure to these drugs. The multi-kinase inhibitor cabozantinib inhibited FLT3-ITD signaling in MV4-11-R cells and MV4-11-R-derived tumors in mice. Cabozantinib effectively inhibited tumor growth and prolonged survival time in mice bearing MV4-11-R-derived tumors. Together, our findings suggest that Mcl-1 and Akt phosphorylation are potential therapeutic targets for p53 mutants and that cabozantinib is an effective treatment in cytarabine-resistant FLT3-ITD-positive AML.


Assuntos
Citarabina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Deleção de Genes , Mutação , Sequências de Repetição em Tandem , Proteína Supressora de Tumor p53/genética , Tirosina Quinase 3 Semelhante a fms/genética , Anilidas/farmacologia , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Biomarcadores , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Análise Mutacional de DNA , Relação Dose-Resposta a Droga , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Redes e Vias Metabólicas , Piridinas/farmacologia
3.
J Anat ; 214(1): 183-95, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19166481

RESUMO

CD200 is a highly glycosylated cell surface protein containing two immunoglobulin superfamily domains in the extracellular region and performs immunosuppressive activities. It is widely distributed in various tissues including the vascular endothelium. We report here the distribution of CD200 in rat endothelia from different vascular beds. Endothelial CD200 immunoreactivity was weakly expressed in most arteries but was intensely expressed in the arterioles, most veins and venules, as well as continuous and fenestrated capillaries. The distribution of CD200 in the sinusoidal and lymphatic endothelia was variable. Immunoelectron microscopic studies revealed that endothelial CD200 varied considerably not only in different microvasculatures but also in the membrane domains at the subcellular level. Endothelial CD200 expression was differentially regulated by lipopolysaccharide in cell types both in vivo and in vitro. Functional assessments of endothelial CD200 suggested that the physical binding between CD200 and CD200 receptor (CD200R) was involved in T-cell adhesion to the endothelium but not in macrophage-endothelium interaction. In the latter, however, CD200 agonist, a synthetic peptide from complementarity-determining region 3 of mouse CD200, may trigger CD200R signaling in macrophages to suppress their adhesion to the endothelium. Our findings demonstrate that the distribution, subcellular localization, and lipopolysaccharide-regulation of endothelial CD200 are heterogeneous, and provide evidence elucidating the functional roles of endothelial CD200 during tissue inflammation.


Assuntos
Antígenos CD/análise , Células Endoteliais/química , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Vasos Sanguíneos , Adesão Celular , Linhagem Celular , Células Cultivadas , Células Endoteliais/imunologia , Endotoxinas/farmacologia , Citometria de Fluxo , Imuno-Histoquímica , Lipopolissacarídeos/farmacologia , Linfa , Vasos Linfáticos , Microscopia Imunoeletrônica , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Linfócitos T/imunologia
4.
Arterioscler Thromb Vasc Biol ; 24(1): 73-9, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14615388

RESUMO

OBJECTIVE: Vascular endothelial cells (ECs) are subjected to shear stress and cytokine stimulation. We studied the interplay between shear stress and cytokine in modulating the expression of adhesion molecule genes in ECs. METHODS AND RESULTS: Shear stress (20 dynes/cm2) was applied to ECs prior to and/or following the addition of tumor necrosis factor (TNF)-alpha. Shear stress increased the TNF-alpha-induced expression of intercellular adhesion molecule-1 (ICAM-1) at both mRNA and surface protein levels, but decreased the TNF-alpha-induced expression of vascular adhesion molecule-1 (VCAM-1) and E-selectin. Transfection studies using promoter reporter gene constructs of ICAM-1, VCAM-1, and E-selectin demonstrated that these shear stress modulations of gene expression occur at the transcriptional levels. After 24-hour preshearing followed by 1 hour of static incubation, the effect of preshearing on TNF-alpha-induced ICAM-1 mRNA expression vanished. The recovery of the TNF-alpha-induced VCAM-1 and E-selectin mRNA expressions following preshearing, however, required a static incubation time of >6 hours (complete recovery at 24 hours). Pre- and postshearing caused a reduction in the nuclear factor-kappaB-DNA binding activity induced by TNF-alpha in the EC nucleus. CONCLUSIONS: Our findings suggest that shear stress plays differential roles in modulating the TNF-alpha-induced expressions of ICAM-1 versus VCAM-1 and E-selectin genes in ECs.


Assuntos
Selectina E/biossíntese , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Regulação da Expressão Gênica , Molécula 1 de Adesão Intercelular/biossíntese , Estresse Mecânico , Fator de Necrose Tumoral alfa/farmacologia , Molécula 1 de Adesão de Célula Vascular/biossíntese , Núcleo Celular/metabolismo , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , DNA/genética , DNA/metabolismo , Selectina E/genética , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Molécula 1 de Adesão Intercelular/genética , NF-kappa B/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética
5.
Chin J Physiol ; 45(4): 169-76, 2002 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-12817708

RESUMO

The interplay between shear stress and cytokines in regulating vascular endothelial function remains largely unexplored. In the present study, the potential role of shear stress in regulating tumor necrosis factor-alpha (TNF-alpha)-induced gene expression in endothelial cells (ECs) was investigated. The TNF-alpha-induced monocyte chemotactic protein-1 (MCP-1) mRNA expressions were significantly attenuated in ECs subjected to a high level of shear stress (20 dynes/cm2) for 4 or 24 h prior to the addition of TNF-alpha in the presence of flow. Less inhibition of TNF-alpha-induced MCP-1 mRNA expression was found in ECs pre-exposed to a low level of shear stress (1.2 dynes/cm2) for 24 h as compared with the cells presheared (pre-exposed to shear stress) for 4 h. Simultaneous exposure of ECs to TNF-alpha and a high or low level of shear stress down-regulated TNF-alpha-induced MCP-1 gene expressions, suggesting that the post-flow condition modulates endothelial responses to cytokine stimulation. Individually or combined, an endothelial nitric oxide synthase (eNOS) inhibitor and a glutathione (GSH) biosynthesis inhibitor had no effect on this shear stress-mediated inhibition. Moreover, in ECs either presheared or remained in a static condition prior to stimulation by TNF-alpha while under shear flow, the ability of TNF-alpha to induce AP-1-DNA binding activity in the nucleus was reduced. Our findings suggest that shear stress plays a protective role in vascular homeostasis by inhibiting endothelial responses to cytokine stimulation.


Assuntos
Antineoplásicos/farmacologia , Quimiocina CCL2/genética , Endotélio Vascular/fisiologia , Fator de Necrose Tumoral alfa/farmacologia , Núcleo Celular/metabolismo , Endotélio Vascular/citologia , Inibidores Enzimáticos/farmacologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Glutationa/metabolismo , Humanos , Monócitos/fisiologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo III , Oxirredução , Estresse Mecânico , Fator de Transcrição AP-1/metabolismo , Cordão Umbilical/citologia , ômega-N-Metilarginina/farmacologia
6.
Leuk Res ; 38(5): 625-31, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24703161

RESUMO

Let-7a-3 transcribes the miRNA let-7a, of which the expression is dysregulated in cancer. We evaluated the significance of let-7a-3 gene methylation in patients with de novo acute myeloid leukemia (AML). Let-7a-3 was methylated in 81.1% (73/90), partially methylated in 12.2% (11/90), or unmethylated in 6.7% (6/90) of patients. Let-7a-3 methylation correlated with AML karyotyping and CCAAT/enhancer binding protein α (CEBPA) methylation. Kaplan-Meier survival analysis predicted that let-7a-3 hypermethylation correlated with better survival in AML with hypomethylated CEBPA or with hypomethylated CEBPA without the favorable karyotype. We conclude that let-7a-3 methylation is a positive prognosticator for AML patients with hypomethylated CEBPA.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Metilação de DNA , Leucemia Mieloide Aguda/genética , MicroRNAs/genética , Regiões Promotoras Genéticas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Humanos , Cariotipagem , Leucemia Mieloide Aguda/mortalidade , Pessoa de Meia-Idade
7.
Cancer Lett ; 309(1): 46-53, 2011 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-21683516

RESUMO

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a phytoalexin found in grapes and other plants, plays a protective role in human atherosclerosis and carcinogenesis. We examined the effects of resveratrol on the anaplastic large-cell lymphoma (ALCL) cell line SR-786. Resveratrol inhibited growth and induced cellular differentiation, as demonstrated by morphological changes and elevated expression of T cell differentiation markers CD2, CD3, and CD8. Resveratrol also triggered cellular apoptosis, as demonstrated by morphological observations, DNA fragmentation, and cell cycle analyses. Further, the surface expression of the death receptor Fas/CD95 was increased by resveratrol treatment. Our data suggest that resveratrol may have potential therapeutic value for ALCL.


Assuntos
Anticarcinógenos/farmacologia , Linfoma Anaplásico de Células Grandes , Estilbenos/farmacologia , Receptor fas/metabolismo , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Humanos , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patologia , Resveratrol
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