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1.
Clin Cancer Res ; 26(15): 3936-3946, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32357963

RESUMO

PURPOSE: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. PATIENTS AND METHODS: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design). RESULTS: Thirty-eight participants have been treated across six dose levels (28-160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment-related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD. CONCLUSIONS: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.


Assuntos
Antineoplásicos/administração & dosagem , Proteínas Estimuladoras de Ligação a CCAAT/agonistas , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Oligorribonucleotídeos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Proteínas Estimuladoras de Ligação a CCAAT/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Infusões Intravenosas , Lipossomos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Nanopartículas/administração & dosagem , Estadiamento de Neoplasias , Oligorribonucleotídeos/efeitos adversos , Oligorribonucleotídeos/farmacocinética , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
2.
Endocr J ; 65(1): 43-52, 2018 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-28954935

RESUMO

Neuropeptide Y (NPY) is an important neurotransmitter in the control of energy metabolism. Several studies have shown that obesity is associated with increased levels of NPY in the hypothalamus. We hypothesized that the release of NPY has coordinated and integrated effects on energy metabolism in different tissues, such as adipocyte tissue, resulting in increased energy storage and decreased energy expenditure. Whether NPY has role in the molecular mechanism of human adipocyte tissue remains unclear. We established the model of human adipose derived stem cells (hADSCs) from human adipose tissue and differentiated it into adipocytes in the presence of NPY at different concentrations (10-15-10-6 mmol/L). We then assessed hADSCs proliferation and differentiation by quantifying lipid accumulation and examining the expression levels of related adipocyte markers after differentiation. Furthermore, the specific markers of white adipocyte tissue (WAT) in hADSCs were also analyzed. The results showed that low doses of NPY stimulated hADSCs proliferation (p < 0.05), while high doses of NPY inhibited hADSCs proliferation (p < 0.05). NPY significantly promoted lipid accumulation and increased the size of lipid droplets during human adipogenic differentiation; the levels of adipocyte markers PPAR-γ and C/EBPα were also increased. At the same time, NPY also increased the levels of WAT markers Cidec and RIP140 after adipocyte differentiation. The results suggested high dose NPY inhibits the proliferation of hADSCs while promotes adipocyte differentiation and increases the expression of WAT markers. This may be the reason why increased levels of NPY can lead to a rise in body weight.


Assuntos
Gordura Abdominal/metabolismo , Adipogenia , Células-Tronco Adultas/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/agonistas , Regulação da Expressão Gênica no Desenvolvimento , Neuropeptídeo Y/metabolismo , PPAR gama/agonistas , Gordura Abdominal/patologia , Gordura Abdominal/cirurgia , Proteínas Adaptadoras de Transdução de Sinal/agonistas , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Células-Tronco Adultas/patologia , Proteínas Reguladoras de Apoptose , Biomarcadores/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Proliferação de Células , Células Cultivadas , Procedimentos Cirúrgicos Eletivos , Feminino , Humanos , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos , Proteínas Nucleares/agonistas , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteína 1 de Interação com Receptor Nuclear , Concentração Osmolar , Sobrepeso/metabolismo , Sobrepeso/patologia , PPAR gama/genética , PPAR gama/metabolismo , Proteínas/agonistas , Proteínas/metabolismo , Receptores de Neuropeptídeo Y/agonistas , Receptores de Neuropeptídeo Y/genética , Receptores de Neuropeptídeo Y/metabolismo
3.
Diabetes ; 64(12): 4184-97, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26324181

RESUMO

Recruitment of innate immune cells from the bone marrow (BM) to an injury site is required for effective repair. In diabetes, this process is altered, leading to excessive recruitment and retention of dysfunctional myeloid cells that fail to promote angiogenesis, prolong inflammation, and block healing. The aberrant myeloid phenotype is partially mediated by stable intrinsic changes to developing cells in the BM that are induced by the diabetic (db) environment, but the exact mechanisms remain largely unknown. Here, we show that the db-derived Gr-1(+)CD11b(+) immature myeloid population has widespread misexpression of chromatin-remodeling enzymes and myeloid differentiation factors. Crucially, diabetes represses transcription of the key myeloid transcription factor CEBPA via diminished H3 Lys 27 promoter acetylation, leading to a failure in monocyte and granulocyte maturation. Restoring Cebpa expression by granulocyte colony-stimulating factor reverses the db phenotype and rescues myeloid maturation. Importantly, our data demonstrate a possible link between myeloid cell maturation and chronic inflammation.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Regulação para Baixo , Hematopoese , Imunidade Inata , Células Mieloides/metabolismo , Adulto , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/agonistas , Proteínas Estimuladoras de Ligação a CCAAT/sangue , Proteínas Estimuladoras de Ligação a CCAAT/genética , Células Cultivadas , Cruzamentos Genéticos , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Granulócitos/imunologia , Granulócitos/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Células Mieloides/imunologia , Células Mieloides/patologia , Receptores de Quimiocinas/sangue , Receptores de Quimiocinas/metabolismo , Proteínas Recombinantes/metabolismo
4.
Biosci Biotechnol Biochem ; 79(4): 636-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25516096

RESUMO

We examined the effect of perfluorooctanoic acid (PFOA) on adipose cells using 3T3-L1 adipocytes and found that PFOA increased adipocyte differentiation, triglyceride accumulation, and the mRNA level of factors related to adipocyte differentiation. In addition, PFOA bound to peroxisome proliferator-activated receptor γ (PPAR γ). These results suggest that PFOA promotes adipocyte differentiation as a PPAR γ ligand.


Assuntos
Adipócitos/efeitos dos fármacos , Caprilatos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Fluorocarbonos/farmacologia , PPAR gama/metabolismo , RNA Mensageiro/metabolismo , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Animais , Proteínas Estimuladoras de Ligação a CCAAT/agonistas , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Transportador de Glucose Tipo 4/agonistas , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Ligantes , Camundongos , PPAR gama/agonistas , PPAR gama/genética , Ligação Proteica , RNA Mensageiro/agonistas , RNA Mensageiro/genética , Triglicerídeos/metabolismo
5.
Biofactors ; 40(6): 646-57, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25529897

RESUMO

The thiazolidinedione (TZDs) class of drugs are very effective for the treatment of type 2 diabetes mellitus (T2DM). But due to the adverse effects of synthetic TZDs, their use is strictly regulated. The therapeutic actions of TZDs are mediated via modulation of peroxisome proliferator-activated receptor gamma (PPARγ). Naturally occurring PPARγ modulators are more desirable as they lack the serious adverse effects caused by TZDs. This has prompted the exploitation of medicinal plants used in traditional medicine, for their potential PPARγ activity. In the present work, we studied chebulagic acid (CHA) isolated from fruits of Terminalia chebula with respect to its effect on adipogenesis, glucose transport, and endocrine function of adipocyte. The mRNA expression profile of PPARγ target gene CCAAT/enhancer-binding protein alpha (C/EBP-α) was analyzed by qRT-PCR. The putative binding mode and the potential ligand-target interactions of CHA, with PPARγ was analyzed using docking software (Autodock and iGEMDOCKv2). The results showed that CHA enhances PPARγ signaling and adipogenesis dose dependently but in a moderate way, less than rosiglitazone. GLUT4 expression and adiponectin secretion was increased by CHA treatment. The mRNA expression of PPARγ target gene C/EBP-α was increased in CHA -treated adipocytes. The comparison of results of various parameters of adipogenesis, insulin sensitivity, endocrine function and molecular docking experiments of roziglitazone and chebulagic acid indicate that the latter behaves like partial PPARγ agonist which could be exploited for phytoceutical development against T2DM.


Assuntos
Adipócitos/efeitos dos fármacos , Benzopiranos/farmacologia , Glucose/metabolismo , Glucosídeos/farmacologia , Hipoglicemiantes/farmacologia , Insulina/metabolismo , PPAR gama/agonistas , Terminalia/química , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Adiponectina/agonistas , Adiponectina/genética , Adiponectina/metabolismo , Animais , Benzopiranos/isolamento & purificação , Transporte Biológico/efeitos dos fármacos , Proteínas Estimuladoras de Ligação a CCAAT/agonistas , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Diferenciação Celular , Frutas/química , Regulação da Expressão Gênica , Transportador de Glucose Tipo 4/agonistas , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Glucosídeos/isolamento & purificação , Hipoglicemiantes/isolamento & purificação , Insulina/farmacologia , Resistência à Insulina , Metanol , Camundongos , Simulação de Acoplamento Molecular , PPAR gama/genética , PPAR gama/metabolismo , Extratos Vegetais/química , Transdução de Sinais , Solventes
6.
Mol Cell Endocrinol ; 355(1): 25-40, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22273805

RESUMO

This study shows the effect of pterostilbene on intracellular neutral lipid accumulation in MCF-7 breast cancer cells leading to growth arrest and autophagy. On exposing the breast cancer cells with 30 µM pterostilbene for 72 h there was almost 2-folds increase in neutral lipids and triglycerides. Also the phytochemical caused a 4-folds increase in the expression of adipogenic differentiation marker c/EBPα. Further, pterostilbene inhibited 3ß-hydroxylsterol-Δ(7)-reductase, the enzyme which catalyzes the last step conversion of 7-dehydrocholesterol to cholesterol, and thereby causes the intracellular accumulation of the former sterol. These results were associated with over-expression of oxysterol binding protein homologue and liver X receptor (LXR) by ~7-folds. Pterostilbene also caused a simultaneous increase in the expression autophagic marker proteins Beclin 1 and LC3 II (microtubule-associated protein 1 light chain 3) by approximately 6-folds, which leads to an alternative pathway of autophagy. These effects were observed in association with the loss of mitotic and metastatic potential of MCF-7 cells which was abolished in the presence of catalase (ROS scavenger) or 3MA (autophagic inhibitor). Thus the present data shows that the long term exposure to pterostilbene causes growth arrest in MCF-7 cells which may be due to differentiation of the mammary carcinoma cells into normal epithelial cell like morphology and activation of autophagy.


Assuntos
Autofagia/efeitos dos fármacos , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Estilbenos/farmacologia , Proteínas Reguladoras de Apoptose/agonistas , Proteínas Reguladoras de Apoptose/genética , Proteína Beclina-1 , Biomarcadores/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/agonistas , Proteínas Estimuladoras de Ligação a CCAAT/genética , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Desidrocolesteróis/antagonistas & inibidores , Desidrocolesteróis/metabolismo , Feminino , Humanos , Receptores X do Fígado , Proteínas de Membrana/agonistas , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/agonistas , Proteínas Associadas aos Microtúbulos/genética , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Espécies Reativas de Oxigênio/metabolismo , Receptores de Esteroides/agonistas , Receptores de Esteroides/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Triglicerídeos/biossíntese
7.
J Biol Chem ; 284(10): 6116-25, 2009 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-19126543

RESUMO

Resistin antagonizes insulin action in mouse, making it a potential therapeutic target for treating metabolic diseases such as diabetes. To better understand how mouse resistin gene (Retn) expression is restricted to fat tissue, we identified an adipocyte-specific enhancer located approximately 8.8-kb upstream of the transcription start site. This region contains a binding site for the master adipogenic regulator peroxisome proliferator-activated receptor gamma (PPARgamma), and binds endogenous PPARgamma together with its partner retinoid-X receptor alpha (RXRalpha). It also contains three binding sites for CCAAT/enhancer-binding protein (C/EBP), and is bound by endogenous C/EBPalpha and C/EBPbeta in adipocytes. Exogenous expression of PPARgamma/RXRalpha and C/EBPalpha in non-adipocyte cells synergistically drives robust expression from the enhancer. Although PPARgamma ligands repress Retn transcription in adipocytes, rosiglitazone paradoxically stimulates the enhancer activity, suggesting that the enhancer is not directly involved in negative regulation. Unlike expression of Retn in mouse, human resistin (RETN) is expressed primarily in macrophages. Interestingly, the region homologous to the mouse Retn enhancer in the human gene contains all three C/EBP elements, but is not conserved for the sequence bound by PPARgamma. Furthermore, it displays little or no binding by PPARgamma in vitro. Taken together, the data suggest that a composite enhancer binding both PPARgamma and C/EBP factors confers adipocyte-specific expression to Retn in mouse, and its absence from the human gene may explain the lack of adipocyte expression in humans.


Assuntos
Adipócitos/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , PPAR gama/metabolismo , Resistina/biossíntese , Elementos de Resposta/fisiologia , Receptor X Retinoide alfa/metabolismo , Células 3T3-L1 , Animais , Proteína beta Intensificadora de Ligação a CCAAT/agonistas , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/agonistas , Proteínas Estimuladoras de Ligação a CCAAT/genética , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/terapia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Macrófagos/metabolismo , Camundongos , PPAR gama/agonistas , PPAR gama/genética , Resistina/genética , Receptor X Retinoide alfa/agonistas , Receptor X Retinoide alfa/genética , Rosiglitazona , Especificidade da Espécie , Tiazolidinedionas/farmacologia
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