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1.
Zhongguo Zhong Yao Za Zhi ; 44(9): 1869-1875, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31342715

RESUMO

To study the effects of ellagic acid(EA)on inflammation and oxidative stress in mice with fatty liver disease induced by AKT gene transfection,the 20 female FVB mice were randomly divided into normal control group,model group and ellagic acid administration group(150,300 mg·kg~(-1)·d~(-1))(n=5).EA experimental groups and model group were using a high pressure into the tail vein transfection plasmid AKT.The next day,EA was started to administered continuously for 5 weeks after the AKT gene transfection,while the model group and the normal control group were given the same amount of saline.After the administration,the liver tissue and serum of mice were taken.HE and oil red O staining were using to observe the histopathological changes in liver;liver function to detect the serum and liver tissue as well as MDA and SOD levels;real-time quantitative PCR(RT-qPCR)was used to measure the mR-NA expression of NF-κB and TNF-α;Western blot and immunohistochemistry were used to measure the expression of NF-κB,TNF-αand COX-2 in liver tissue.RESULTS:: show that after AKT gene transfection,the model group had significant increase in the serum levels of AST,ALT,elevated the levels of MDA and decreased the levels of SOD in serum and liver tissue,aggravated histopathology degeneration and Liver inflammation,and significantly higher expression of NF-κB,TNF-α,IL-6,COX-2 and other inflammatory-related factors in liver tissue.EA administration group significant reductions in the serum levels of AST,ALT,and improved in hepatocyte fatty degeneration and liver inflammation,lower the levels of MDA and increased the levels of SOD in serum and liver tissue,and significant reductions in the expression of NF-κB,TNF-α,IL-6 and COX-2 in liver tissue.These results suggest that EA has obvious anti-inflammatory effect and inhibits oxidative stress and EA has a significant therapeutic effecton AKT gene inducing fatty liver,and the mechanism possibly by inhibiting inflammatory factors of NF-κB,TNF-α,IL-6,COX-2 and anti-oxidative stress-related.


Assuntos
Ácido Elágico/farmacologia , Fígado Gorduroso/tratamento farmacológico , Inflamação/tratamento farmacológico , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/genética , Animais , Fígado Gorduroso/genética , Feminino , Camundongos , Distribuição Aleatória , Transfecção
2.
Food Funct ; 10(6): 3410-3420, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31123744

RESUMO

Previous studies in humans have indicated that de novo lipogenesis contributes considerably to redundant lipid storage and steatosis in the liver of patients with nonalcoholic fatty liver disease (NAFLD), and then more severe complications occur. Recently, ellagic acid (EA) has drawn attention mainly due to its biological functionalities and a series of molecular targets. However, the molecular mechanism by which EA attenuates hepatic steatosis in individuals with undesirable hepatic genetic alterations remains rarely studied. Here, we evaluate the therapeutic efficacy of EA in a hepatic steatosis mouse model featuring elevated expression of sterol regulatory element-binding protein-1 (SREBP-1) and its downstream modulators of lipogenesis by hydrodynamic injection of v-akt murine thymoma viral oncogene homolog (AKT). Hematoxylin and eosin staining, oil red O staining, immunohistochemistry, immunoblotting, and quantitative polymerase chain reaction (qPCR) were performed for mechanistic investigations. Human hepatoma cell lines were used for mechanical validation in vitro. The results suggest that EA lightens the accumulation of lipids in hepatocytes of AKT-injected mice and an oleic acid-induced in vitro hepatic steatosis model. Mechanistically, EA administration decreases the expression of phospho-AKT (Thr308) and suppresses two effectors lying downstream of the AKT/mTORC1 pathway, ribosomal protein S6 (RPS6) and SREBP-1, in the AKT-injected mice. The consequence of the EA-mediated decrease of SREBP-1 is found to be a transcriptional and translational inhibition of fatty acid synthase (FASN), accompanied by the downregulation of acetyl-CoA carboxylase (ACC). Consistent with in vivo findings, EA efficiently represses the SREBP-1/FASN axis in vitro. Collectively, our study provides a novel mechanism whereby EA alleviates AKT-triggered hepatic de novo lipogenesis, indicating that EA might serve as a potential agent in the therapy of hepatic steatosis in patients with NAFLD and/or steatosis-associated complications, especially in that characterized by activation of AKT/mTORC1 signaling in the liver.

3.
Drug Dev Ind Pharm ; 45(7): 1052-1060, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30939950

RESUMO

Objective: The objective of this study was to enhance the solubility and bioavailability of Lupeol. Methods: Utilizing a thin-film dispersion method, we prepared Lupeol-loaded PEGylated liposomes and Lupeol-loaded liposomes, which was characterized using SEM, mean diameter, PDI, zeta potential, and entrapment efficiency (EE). The EE, in vitro release, and stability of Lupeol-loaded PEGylated liposomes were detected using HPLC. In addition to the safety evaluation, the evaluation was carried out on HepG2 cells in vitro; the pharmacokinetics were carried out after i.v. in the rats. Results: The size, PDI, zeta potential, and EE of Lupeol-loaded PEGylated liposomes and Lupeol-loaded liposomes were 126.9 nm, 0.246, -1.97 mV, 87%; 97.23 nm, 0.25, 1.6 mV, 86.2%, respectively. Lupeol-loaded PEGylated liposomes showed the slow-release effect in vitro release experiments. Lupeol-loaded PEGylated liposomes offered significant advantages over other experimental groups in vitro studies, such as the highest inhibition rate and the highest apoptosis rate. We also found that Lupeol-loaded PEGylated liposomes blocked cells in the G2M phase. The pharmacokinetics result showed that the AUC of Lupeol-loaded PEGylated liposomes group was 3.2 times higher than free Lupeol group after i.v., the MRT and t1/2 values of Lupeol-loaded PEGylated liposomes (MRT = 6.09 h, t1/2 =12.94 h) showed improvements of 2.5 and 4.1 times compared to free Lupeol (MRT = 2.43 h, t1/2 = 3.16 h). Conclusion: The Lupeol-loaded PEGylated liposomes have successfully solved its poor hydrophilicity, low bioavailability.

4.
Toxicol Appl Pharmacol ; 365: 51-60, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30625338

RESUMO

Hepatocellular carcinoma (HCC) is a lethal malignancy with few effective options for therapeutic treatment in its advanced stages. Metformin, a first-line oral agent used in the treatment of type 2 diabetes, exhibits efficacy in metabolic reprogramming fueling changes in cell growth and proliferation for multiple cancer types, including HCC. However, the molecular mechanism by which metformin delays hepatocarcinogenesis in individuals with hepatic steatosis remains rare. Here, we investigate the preventive efficacy of metformin in a rapid AKT/c-Met-triggered HCC mouse model featuring excessive levels of steatosis. Hematoxylin and eosin staining, Oil Red O staining and immunoblotting were applied for mechanistic investigations. Pharmacological and biochemical strategies were employed to illuminate molecular evidence for HCC cell lines. The results show that metformin obstructs the malignant transformation of hepatocytes in AKT/c-Met mice. Mechanistically, metformin reduces the expression of phospho-ERK (Thr202/Tyr204) and two forms of proto-oncogenes, Cyclin D1 and c-Myc, in AKT/c-Met mice. Moreover, metformin ameliorates FASN-mediated aberrant lipogenesis and HK2/PKM2-driven ATP generation in vivo. Furthermore, metformin represses the expression of FASN and HK-2 by targeting c-Myc in an AMPK-dependent manner in vitro. In addition, metformin is effective at inhibiting PKM2 expression in the presence of an AMPK inhibitor compound C, suggesting that its functioning in PKM2 is AMPK-independent. Our study experimentally validates a novel molecular mechanism by which metformin alleviates enhanced lipogenesis and high energy metabolism during hepatocarcinogenesis, indicating that metformin may serve as an agent for the prevention of HCC in patients with nonalcoholic fatty liver diseases.


Assuntos
Trifosfato de Adenosina/metabolismo , Anticarcinógenos/farmacologia , Carcinoma Hepatocelular/prevenção & controle , Transformação Celular Neoplásica/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Lipogênese/efeitos dos fármacos , Neoplasias Hepáticas/prevenção & controle , Fígado/efeitos dos fármacos , Metformina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Ácido Graxo Sintase Tipo I/metabolismo , Fígado Gorduroso/enzimologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Hexoquinase/metabolismo , Humanos , Fígado/enzimologia , Fígado/patologia , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-met/genética , Piruvato Quinase/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
Mol Carcinog ; 58(1): 31-41, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30182439

RESUMO

Previous studies have demonstrated that the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib shows efficacy against multiple cancers, including hepatocellular carcinoma. However, whether celecoxib is effective in alleviating steatosis during hepatocarcinogenesis is unknown. In a rapid hepatocellular carcinoma (HCC) mouse model established via hydrodynamic transfection of activated forms of AKT and c-Met proto-oncogenes, we investigated the antisteatotic and anticarcinogenic efficacy of celecoxib in vivo. Multiple HCC cell lines were employed for in vitro evaluation. Additionally, immunoblotting, immunohistochemistry, hematoxylin and eosin staining and Oil Red O staining were applied for mechanistic investigation. The results revealed that if celecoxib was administered in the early stage of AKT/c-Met-induced HCC, it resulted in disease stabilization. Moreover, celecoxib could alleviate lipid accumulation in the HCC mice and in an oleic acid-induced in vitro hepatic steatosis model. Further evidence at the molecular level indicated that celecoxib down-regulated the expression of phospho-ERK (Thr202/Tyr204) and proliferating cell nuclear antigen (PCNA) in the HCC mice. In addition, celecoxib efficiently repressed the phosphor-Akt (Thr308)/fatty acid synthase (FASN) axis both in vivo and in vitro. Altogether, this study suggests that celecoxib exerts its antilipogenic efficacy by targeting a COX-2/AKT/FASN cascade, which contributes to its ability to delay hepatocarcinogenesis.


Assuntos
Carcinoma Hepatocelular/prevenção & controle , Celecoxib/farmacologia , Ciclo-Oxigenase 2/química , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Apoptose , Carcinogênese , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células , Inibidores de Ciclo-Oxigenase 2/farmacologia , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/prevenção & controle , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/prevenção & controle , Camundongos , Ácido Oleico/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Braz J Med Biol Res ; 51(7): e7220, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29742265

RESUMO

An abnormality in the Lin28/let-7a axis is relevant to the progression of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC), which could be a novel therapeutic target for this malignant tumor. The present study aimed to investigate the antiproliferative and anti-invasive effects of urolithin A in a stable full-length HBV gene integrated cell line HepG2.2.15 using CCK-8 and transwell assays. The RNA and protein expressions of targets were assessed by quantitative PCR and western blot, respectively. Results revealed that urolithin A induced cytotoxicity in HepG2.2.15 cells, which was accompanied by the cleavage of caspase-3 protein and down-regulation of Bcl-2/Bax ratio. Moreover, urolithin A suppressed the protein expressions of Sp-1, Lin28a, and Zcchc11, and elevated the expression of microRNA let-7a. Importantly, urolithin A also regulated the Lin28a/let-7a axis in transient HBx-transfected HCC HepG2 cells. Furthermore, urolithin A decelerated the HepG2.2.15 cell invasion, which was involved in suppressing the let-7a downstream factors HMGA2 and K-ras. These findings indicated that urolithin A exerted the antiproliferative effect by regulating the Lin28a/let-7a axis and may be a potential supplement for HBV-infected HCC therapy.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Cumarínicos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/efeitos dos fármacos , Proteínas de Ligação a RNA/efeitos dos fármacos , Análise de Variância , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , MicroRNAs/análise , Proteínas de Ligação a RNA/análise , Reação em Cadeia da Polimerase em Tempo Real , Valores de Referência , Reprodutibilidade dos Testes , Sincalida/análise , Fatores de Tempo , Replicação Viral/efeitos dos fármacos
7.
Artigo em Inglês | MEDLINE | ID: mdl-29692859

RESUMO

Ellagitannins in Phyllanthus emblica L. (emblic leafflower fruits) have been thought of as the beneficial constituents for ameliorating endocrinal and metabolic diseases including diabetes. However, the effect of emblic leafflower fruits on diabetic vascular complications involved in ellagitannin-derived urolithin metabolites is still rare. In this study, acetylcholine-induced endothelium-independent relaxation in aortas was facilitated upon emblic leafflower fruit consumption in the single dose streptozotocin-induced hyperglycemic rats. Emblic leafflower fruit consumption also suppressed the phosphorylation of Akt (Thr308) in the hyperglycemic aortas. More importantly, urolithin A (UroA) and its derived phase II metabolites were identified as the metabolites upon emblic leafflower fruit consumption by HPLC-ESI-Q-TOF-MS. Moreover, UroA reduced the protein expressions of phosphor-Akt (Thr308) and ß-catenin in a high glucose-induced A7r5 vascular smooth muscle cell proliferation model. Furthermore, accumulation of ß-catenin protein and activation of Wnt signaling in LiCl-triggered A7r5 cells were also ameliorated by UroA treatment. In conclusion, our data demonstrate that emblic leafflower fruit consumption facilitates the vascular function in hyperglycemic rats by regulating Akt/ß-catenin signaling, and the effects are potentially mediated by the ellagitannin metabolite urolithin A.

8.
Braz. j. med. biol. res ; 51(7): e7220, 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-889115

RESUMO

An abnormality in the Lin28/let-7a axis is relevant to the progression of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC), which could be a novel therapeutic target for this malignant tumor. The present study aimed to investigate the antiproliferative and anti-invasive effects of urolithin A in a stable full-length HBV gene integrated cell line HepG2.2.15 using CCK-8 and transwell assays. The RNA and protein expressions of targets were assessed by quantitative PCR and western blot, respectively. Results revealed that urolithin A induced cytotoxicity in HepG2.2.15 cells, which was accompanied by the cleavage of caspase-3 protein and down-regulation of Bcl-2/Bax ratio. Moreover, urolithin A suppressed the protein expressions of Sp-1, Lin28a, and Zcchc11, and elevated the expression of microRNA let-7a. Importantly, urolithin A also regulated the Lin28a/let-7a axis in transient HBx-transfected HCC HepG2 cells. Furthermore, urolithin A decelerated the HepG2.2.15 cell invasion, which was involved in suppressing the let-7a downstream factors HMGA2 and K-ras. These findings indicated that urolithin A exerted the antiproliferative effect by regulating the Lin28a/let-7a axis and may be a potential supplement for HBV-infected HCC therapy.


Assuntos
Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Cumarínicos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/efeitos dos fármacos , Proteínas de Ligação a RNA/efeitos dos fármacos , Análise de Variância , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , MicroRNAs/análise , Reação em Cadeia da Polimerase em Tempo Real , Valores de Referência , Reprodutibilidade dos Testes , Proteínas de Ligação a RNA/análise , Sincalida/análise , Fatores de Tempo , Replicação Viral/efeitos dos fármacos
9.
Braz. J. Pharm. Sci. (Online) ; 53(3): e00215, 2017. tab, graf
Artigo em Inglês | LILACS | ID: biblio-889399

RESUMO

ABSTRACT Various benefits of flavonoids for ameliorating cardiovascular diseases have been demonstrated. However, the lowering effects on blood pressure caused by antiproliferative potentials of flavonoids in vascular smooth muscle cells are rare. In this study, the antihypertensive effects of total flavonoids from Ampelopsis megalophylla were investigated. The dynamic pressure values and the rate of media thickness versus lumen diameter were measured by the tail-cuff system and H&E staining in vivo, respectively. The mRNA expressions of ACE, Ang II, eNOS, c-Myc, cyclin D1 and p27Kip1 in thoracic aorta or A7r5 cells were measured by qPCR, respectively. The protein expressions of c-Myc, Cyclin D1, p27Kip1 and ß-catenin in tissues or A7r5 cells were measured by Western blot assay. Total flavonoids of A. megalophylla (TFAM) reduced the expressions of ACE and Ang II, and elevated the content of eNOS in thoracic aorta cells of SHRs. Furthermore, TFAM decreased the mRNA and protein expressions of c-Myc and cyclin D1 by repressing the Wnt/ß-catenin-mediated TCF/LEF transcriptional activation both in vivo and in vitro, which is synergetic with the up-regulation of p27Kip1 expression. Our study provided evidence for developing flavonoids from A. megalophylla as herbal supplements to prevent against cardiovascular diseases by suppressing vascular remodeling


Assuntos
Animais , Ratos , Flavonoides/efeitos adversos , Ampelopsis/classificação , Plantas Medicinais/classificação , Ratos Endogâmicos SHR , Anti-Hipertensivos/análise
10.
Food Chem Toxicol ; 97: 375-384, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27725205

RESUMO

Urolithins are bioactive ellagic acid-derived metabolites produced by human colonic microflora. Although previous studies have demonstrated the cytotoxicity of urolithins, the effect of urolithins on miRNAs is still unclear. In this study, the suppressing effects of methylated urolithin A (mUA) on cell viability in human prostate cancer DU145 cells was investigated. mUA induced caspase-dependent cell apoptosis, mitochondrial depolarization and down-regulation of Bcl-2/Bax ratio. The results showed that upon exposure to mUA, miR-21 expression was decreased and the expression of PTEN and Pdcd4 protein was elevated. mUA could further suppress Akt phosphorylation and increase protein expression of FOXO3a, and the effects of mUA on Akt phosphorylation and protein expression of FOXO3a were blocked by PTEN silence. Moreover, mUA suppressed the Wnt/ß-catenin-mediated transcriptional activation of MMP-7 and c-Myc, and this function of mUA on MMP-7 and c-Myc was attenuated by over-expression of miR-21. In conclusion, our data suggest that mUA can suppress cell viability in DU145 cells through modulating miR-21 and its downstream series-wound targets, including PTEN, Akt and Wnt/ß-catenin signaling.


Assuntos
Apoptose/efeitos dos fármacos , Cumarínicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Neoplasias da Próstata/patologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Western Blotting , Proliferação de Células , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/genética , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Masculino , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genética , beta Catenina/metabolismo
11.
Zhongguo Zhong Yao Za Zhi ; 41(16): 2968-2974, 2016 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-28920333

RESUMO

Ellagitannins is a kind of phenolic compounds with many biological activities. Recent studies have found that the effective ingredients of these compounds have close relationship with their colon-derived bacteria metabolites, that is urolithins. The objective of this study was to review the structure characteristics, types and distribution of urolithins, improvement in diseases related to prostate, breast and colon, as well as anti-cancer, anti-oxidation, anti-inflammation and other biological activities. The present review will lay the foundation for development and utilization of urolithins.


Assuntos
Cumarínicos/química , Taninos Hidrolisáveis/química , Neoplasias da Mama , Neoplasias do Colo , Feminino , Humanos , Inflamação , Intestinos/microbiologia , Masculino , Neoplasias da Próstata
12.
Eur J Pharmacol ; 762: 55-62, 2015 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-26004524

RESUMO

Lupeol is a naturally available triterpenoid with selective anticancerous potential on various human cancer cells. The present study shows that lupeol can inhibit cell proliferation of hepatocellular carcinoma (HCC) HCCLM3 cells in a time- and dose-dependent manner, through caspase-3 dependent activation and Poly ADP-Ribose Polymerase (PARP) cleavage. Lupeol-induced cell death is associated with a marked decrease in the protein expression of Brain-Derived Neurotrophic Factor (BDNF) and ser-9-phosphoryltion of Glycogen Synthase Kinase 3 Beta (GSK-3ß), with concomitant suppression of Akt1, phosphatidyl inositol 3-kinase (PI3K), ß-catenin, c-Myc and Cyclin D1 mRNA expression. Suppressing overexpression of BDNF by lupeol results in decreased protein expression of p-Akt and PI3K (p110α), as well as reactivation of GSK-3ß function in HepG2 cells. Lupeol treatment also inhibits LiCl-induced activation of Wnt signaling pathway and exerts the in vitro anti-invasive activity in Huh-7 cells. LiCl-triggered high expression of ß-catenin, c-Myc and Cyclin D1 protein is reduced followed by lupeol exposure. The findings suggest a mechanistic link between caspase dependent pathway, BDNF secretion and Akt/PI3K/GSK-3ß in HCC cells. These results indicate that lupeol can suppress HCC cell proliferation by inhibiting BDNF secretion and phosphorylation of GSK-3ß(Ser-9), cooperated with blockade of Akt/PI3K and Wnt signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Carcinoma Hepatocelular/patologia , Quinase 3 da Glicogênio Sintase/metabolismo , Neoplasias Hepáticas/patologia , Triterpenos Pentacíclicos/farmacologia , Antineoplásicos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reativadores Enzimáticos/farmacologia , Glicogênio Sintase Quinase 3 beta , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
13.
Toxicol In Vitro ; 29(5): 1107-15, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25910917

RESUMO

The intestinal metabolites of ellagic acid (EA), urolithins are known to effectively inhibit cancer cell proliferation. This study investigates antiproliferative and antioxidant effects of urolithin A (UA) on cell survival of the HepG2 hepatic carcinomas cell line. The antiproliferative effects of UA (0-500 µM) on HepG2 cells were determined using a CCK assay following 12-36 h exposure. Effects on ß-catenin and other factors of expression were assessed by using real-time PCR and Western blot. We found that UA showed potent antiproliferative activity on HepG2 cells. When cell death was induced by UA, it was found that the expression of ß-catenin, c-Myc and Cyclin D1 were decreased and TCF/LEF transcriptional activation was notably down-regulated. UA also increased protein expression of p53, p38-MAPK and caspase-3, but suppressed expression of NF-κB p65 and other inflammatory mediators. Furthermore, the antioxidant assay afforded by UA and EA treatments was associated with decreases in intracellular ROS levels, and increases in intracellular SOD and GSH-Px activity. These results suggested that UA could inhibit cell proliferation and reduce oxidative stress status in liver cancer, thus acting as a viably effective constituent for HCC prevention and treatment.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Cumarínicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Colo/metabolismo , Ácido Elágico/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , beta Catenina/genética , beta Catenina/metabolismo
14.
Phytother Res ; 29(3): 415-22, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25572695

RESUMO

miRNAs and their validated miRNA targets appear as novel effectors in biological activities of plant polyphenols; however, limited information is available on miR-34a mediated cytotoxicity of pomegranate rind polyphenols in cancer cell lines. For this purpose, cell viability assay, Realtime quantitative PCR for mRNA quantification, western blot for essential protein expression, p53 silencing by shRNA and miR-34a knockdown were performed in the present study. EJ cell treatment with 100 µg (GAE)/mL PRE for 48 h evoked poor cell viability and caspase-dependent pro-apoptosis appearance. PRE also elevated p53 protein and triggered miR-34a expression. The c-Myc and CD44 were confirmed as direct targets of miR-34a in EJ cell apoptosis induced by PRE. Our results provide sufficient evidence that polyphenols in PRE can be potential molecular clusters to suppress bladder cancer cell EJ proliferation via p53/miR-34a axis.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , MicroRNAs/metabolismo , Polifenóis/farmacologia , Punicaceae/química , Proteína Supressora de Tumor p53/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Células Epiteliais/efeitos dos fármacos , Frutas/química , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Receptores de Hialuronatos/metabolismo , Masculino , Camundongos Nus , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Interferente Pequeno , Ratos , Proteína Supressora de Tumor p53/genética , Neoplasias da Bexiga Urinária/patologia
15.
Food Chem Toxicol ; 59: 428-37, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23811531

RESUMO

Urolithins were the metabolites of ellagic acid by intestinal flora in gastrointestinal tract. In previous research, it was found that urolithins could mainly inhibit prostate cancer and colon cancer cell growth. However, there is no report about bladder cancer therapy of urolithins. In this paper, three urolithin-type compounds (urolithin A, urolithin B, 8-OMe-urolithin A) and ellagic acid were evaluated for antiproliferative activity in vitro against human bladder cancer cell lines T24. The IC50 values for T24 cell inhibition were 43.9, 35.2, 46.3 and 33.7 µM for urolithin A, urolithin B, 8-OMe-urolithin A and ellagic acid, respectively. After the administration of urolithins and ellagic acid, we found these compounds could increase mRNA and protein expression of Phospho-p38 MAPK, and decrease mRNA and protein expression of MEKK1 and Phospho-c-Jun in T24 cells. Caspase-3 was also activated and PPAR-γ protein expression increased in drug-induced apoptosis. And what's more, the antioxidant assay afforded by three urolithins and EA treatments were associated with decreases in the intracellular ROS and MDA levels, and increased SOD activity in H2O2-treated T24 cells. The results suggested that these compounds could inhibit cell proliferation by p38-MAPK and/or c-Jun medicated caspase-3 activation and reduce the oxidative stress status in bladder cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cumarínicos/farmacologia , Ácido Elágico/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antineoplásicos Fitogênicos/metabolismo , Antioxidantes/metabolismo , Caspase 3/química , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colo/microbiologia , Cumarínicos/metabolismo , Ácido Elágico/metabolismo , Enterobacteriaceae/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Peroxidação de Lipídeos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metilação , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/agonistas , PPAR gama/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Bexiga Urinária/enzimologia , Neoplasias da Bexiga Urinária/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Hepatology ; 56(5): 1760-9, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22576474

RESUMO

UNLABELLED: KIAA0101 overexpression was detected in numerous malignant solid tumors and involved in tumor progression; however, the correlation between KIAA0101 expression level and human hepatocellular carcinoma (HCC) was controversial. Our data revealed abnormal expression of the KIAA0101 transcript variant 1 (KIAA0101 tv1) at both messenger RNA and protein levels in HCC tissues and cell lines assessed by semiquantitative reverse-transcription polymerase chain reaction (RT-PCR), virtual northern blot, western blot, and immunohistochemical analysis, especially in stage 3-4 HCCs. NIH3T3 cells transfected with KIAA0101 tv1 induced colony formation in vitro and tumor xenorafts in vivo, implying the oncogenic potential of KIAA0101 tv1. Semiquantitative RT-PCR, real-time quantitative RT-PCR, and western blot analysis demonstrated that doxorubicin (Adriamycin, ADR) treatment down-regulated expression of the KIAA0101 tv1, whereas it increased the acetylation of the p53 protein. Additionally, KIAA0101 tv1 prevented cells from apoptosis caused by ADR through suppressing the acetylation of p53 at Lys382. Immunoprecipitation analysis and mammalian two-hybrid assay indicated that KIAA0101 tv1 bound to the transactivation region (1-42 amino acids) of p53 and strongly inhibits its transcriptional activity. Taken together, our data suggest that KIAA0101 tv1 played an important role in the late stage of metastatic HCC and prevented apoptosis after chemotherapeutic drug treatment through inhibiting the transcriptional activity of the p53 gene. CONCLUSION: KIAA0101 tv1 may function as a regulator, promoting cell survival in HCC through regulating the function of p53. Suppression of the KIAA0101 tv1 function is likely to be a promising strategy to develop novel cancer therapeutic drugs.


Assuntos
Carcinoma Hepatocelular/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes p53/genética , Neoplasias Hepáticas/genética , Acetilação/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Transporte/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Células NIH 3T3 , Transplante de Neoplasias , RNA Mensageiro/metabolismo , Ativação Transcricional , Transfecção , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima
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