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1.
Hum Gene Ther ; 31(1-2): 103-109, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31802713

RESUMO

Liver fibrosis is a chronic liver disease that could further develop to cirrhosis and liver carcinoma. Hepatic stellate cells (HSCs) are primary effector cells to initiate liver fibrosis. We aimed to explore the function and underlying mechanisms of mitochondrial fusion protein Mitofusin-2 (MFN2) in liver fibrosis. First, we utilized an alpha-smooth muscle actin promoter to overexpress MFN2 specifically in HSCs using adeno-associated virus (AAV) vector (AAV-MFN2). Overexpression of MFN2 was specifically achieved in HSC-T6 cells, but not in murine bone marrow-derived macrophages or hepatocyte AML-12 cells. We found that high expression of MFN2 induced apoptosis of HSC-T6 cells. Mechanistically, we demonstrated that high level of MFN2 inhibited TGF-ß1/Smad signaling pathway, triggered downregulation of type I, type III, and type IV collagen, and antagonized the formation of factors associated with liver fibrosis. Furthermore, we found that overexpression of MFN2 using AAV-MFN2 ameliorated CCl4-induced liver fibrosis in vivo with significantly decreased immune cell infiltration. Taken together, our findings indicate that MFN2 is critical in regulating apoptosis and liver fibrosis in HSCs, which might be a useful therapeutic target to treat liver fibrosis.

2.
Gut Liver ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31694365

RESUMO

Background/Aims: The pathogenesis of nonalcoholic fatty liver disease (NAFLD) has not be fully elucidated, and the lack of therapeutic strategies for NAFLD is an urgent health problem. Guanine nucleotide binding protein, alpha inhibiting activity polypeptide 3 (GNAI3) participates in several biological processes, but its relationship with lipid metabolism and NAFLD has not yet been reported. We aimed to determine the function of GNAI3 in the development of NAFLD. Methods: Mice were fed a methionine and choline-deficient diet to induce NAFLD. An NAFLD model in HepG2 cells was induced by free fatty acid treatment. GNAI3 levels in HepG2 cells were downregulated by shRNA. Protein levels of related proteins were evaluated by Western blotting, and mRNA levels were determined by quantitative reverse transcription polymerase chain reaction. Hematoxylin and eosin and Oil Red O staining were used to observe histological changes in liver tissue. Results: The dysregulated hepatic lipid metabolism in the NAFLD mouse model was enhanced by GNAI3 knockout, which also provoked worse liver damage. In the NAFLD model in HepG2 cells, the downregulation of GNAI3 promoted cellular lipid accumulation and enhanced the changes in lipid metabolic enzyme levels. Conclusions: This study demonstrates that GNAI3 participates in the development of NAFLD in both cellular and mouse models. The data indicate that GNAI3 is a potential new target for the treatment of NAFLD in humans.

3.
Naunyn Schmiedebergs Arch Pharmacol ; 392(12): 1551-1560, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31359090

RESUMO

Hepatocellular carcinoma (HCC) patients have low 5-year survival due to the delayed diagnosis, so it is necessary to develop an alternative treatment. Preferentially expressed antigen of melanoma (PRAME) has a high expression in HCC patients, and the effects of evodiamine on HCC are less characterized, although evodiamine has anti-tumor activities in several tumor types. To investigate the effects of evodiamine on PRAME expression, the in vitro PRAME expression in HepG2 cells after incubated with evodiamine was determined by RT-PCR and western blot. Cell viability, migration, invasion, and apoptosis of evodiamine-incubated HepG2 cells were evaluated by Cell Counting Kit-8, wound healing, transwell assay, and Annexin V-FITC/PI double-staining assay, respectively. To evaluate the mechanism of the regulation of evodiamine on the PRAME expression, chromatin immunoprecipitation coupled with quantitative PCR was employed. Xenograft model was used to evaluate the effects of evodiamine on tumor growth, survival rate, and the PRAME expression. The PRAME expression was inhibited in evodiamine-treated HepG2 cells in vitro and in vivo. The tumor metastasis and growth were inhibited resulting from evodiamine incubation. The evodiamine inhibited the PRAME expression through trimethylation of H3K27. In this study, evodiamine contributes to in vitro and in vivo tumor cell growth inhibition. To achieve this inhibition, the PRAME expression may be repressed through trimethylation resulting from epigenetic regulation of evodiamine.

4.
Cell Physiol Biochem ; 45(3): 1121-1135, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29439259

RESUMO

BACKGROUND/AIMS: The expression of PRAME and its role in hepatocellular carcinoma (HCC) remain unknown. The aim of this study was to examine the functional role of PRAME in HCC development and exploring the molecular mechanism. METHODS: We first detected PRAME expression in 96 human HCC tissue samples and correlated with clinicopathological characteristics and prognosis of the patients. We then established stable HCC cell lines with PRAME overexpression and knockdown followed by functional analysis in vitro. Further, we examined the relationship between PRAME and p53 pathway in vitro by using Western blotting. Finally, PRAME expression was detected to evaluate its correlation with p-p53 and p53 pathway related apoptotic proteins in xenograft tumor mouse model using immunohistochemistry. RESULTS: PRAME expression was significantly higher in HCC tissues than in adjacent non-tumor tissues and their expression was positively correlated with alpha fetoprotein levels and tumor size. In addition, PRAME expression was associated with AJCC stage and is a potential biomarker of poor prognosis regarding 5-year overall survival in HCC. In vitro studies, we found that PRAME expression was higher in HCC cell lines than in normal hepatic cell line. Inhibited cell proliferation and increased cell apoptosis was observed in PRAME knockdown HCC cells. Futher, increased cell apoptosis was correlated with the proportion of cells in G0/G1 stage, activated p53 mediated apoptosis, and increased cyclin p21 expression. Xenograft analysis in nude mice also found that PRAME knockdown inhibited tumorigenesis while PRAME overexpression had opposite effect. CONCLUSIONS: In HCC, PRAME serves as a potential biomarker for poor prognosis and novel therapeutic target in treating this cancer. PRAME is a potential biomarker of poor prognosis in HCC. PRAME surpresses HCC cell death in vitro and in vivo by regulating p53 apoptotic signaling and may serve as a potential therapeutic target in HCC.


Assuntos
Antígenos de Neoplasias/genética , Apoptose/genética , Carcinoma Hepatocelular/patologia , Regulação para Baixo , Neoplasias Hepáticas/patologia , Proteína Supressora de Tumor p53/metabolismo , Adulto , Animais , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Antígeno Ki-67/metabolismo , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais
5.
Cell Physiol Biochem ; 41(6): 2289-2306, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28456796

RESUMO

BACKGROUND & AIMS: To investigate the expression and prognostic value of α1-ACT (Alpha1-antichymotrypsin) in patients with HCC (hepatocellular carcinoma) and identify the mechanism by which α1-ACT inhibits proliferation and promotes apoptosis of HCC. METHODS: We first measured α1-ACT expression levels and determined their relationship with the clinicopathological characteristics and prognosis of patients with HCC.We then established stable HCC cell lines with both α1-ACT overexpression and knockdown and performed a functional analysis in vitro.We first examined the relationship between α1-ACT and the PTEN/PI3K/AKT/mTOR pathway using Western blotting. Then, we determined whether α1-ACT can directly bind to PTEN using co-immunoprecipitation. Finally, we measured α1-ACT expression to evaluate its correlation with the PI3K/AKT/mTOR pathway-related apoptosis proteins in a xenograft tumour mouse model using immunohistochemistry. RESULTS: The α1-ACT expression level was significantly lower in the HCC tissues than in the paratumour tissues and was negatively positively correlated with the level of Ki67, AFP, the AJCC stage, tumour size and tumour invasion. The overexpression of α1-ACT can inhibit cell proliferation and increase cell apoptosis by activating PI3K/AKT/mTOR-mediated apoptosis via binding to PTEN and activating it in vitro. Additionally, the overexpression of α1-ACT can also increase the proportion of cells in the G0/G1 stage by increasing cyclin p21 expression and inhibiting the migration and invasion abilities of HCC cells by regulating MMP2 and MMP9. The xenotransplantation studies with nude mice also showed that overexpression of α1-ACT inhibited tumourigenesis and knockdown of α1-ACT had the opposite effect. CONCLUSIONS: Our study demonstrates that α1-ACT suppresses liver cancer development and metastasis via targeting the PTEN/PI3K/AKT/mTOR signalling pathway, which may be a potential target for therapeutic intervention in HCC.


Assuntos
Carcinoma Hepatocelular/fisiopatologia , Neoplasias Hepáticas/fisiopatologia , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serpinas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adulto , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Interferência de RNA , Serpinas/química , Serpinas/genética , Transdução de Sinais/fisiologia
6.
Clin Exp Pharmacol Physiol ; 35(5-6): 546-51, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-17973931

RESUMO

1. High-density lipoprotein (HDL) is widely accepted as a lipoprotein that protects against coronary artery and other atherosclerotic diseases. Recently, a new apolipoprotein encoded by the APOM gene, which plays an important role in affecting the intrinsic properties of HDL, has been reported. Genetic variations exist in the APOM gene, but their significance is presently unclear. The aim of the present study was to elucidate whether the APOM T-855C mutant allele is implicated in coronary artery disease (CAD). 2. In the present study, 418 patients with CAD and 372 controls were studied, all of whom were Han Chinese from Jiangsu Province, China. Plasma levels of triglycerides (TG), total cholesterol (TC), HDL-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) were evaluated. Genomic DNA from the whole blood from these subjects was subjected to polymerase chain reaction amplification and restriction enzyme digestion to determine genotype with respect to the APOM T-855C polymorphism. 3. The allelic frequencies were in Hardy-Weinberg equilibrium. Plasma HDL levels were significantly lower in subjects with CAD than in control subjects (1.08 +/- 0.31 vs 1.25 +/- 0.32, respectively; P < 0.001) and the distribution of genotypes and allelic frequencies was significantly different in the two groups (P = 0.013 and 0.005, respectively). Multiple logistic regression analysis after adjustment for age, gender, smoking, body mass index, hypertension and serum glucose showed that, compared with the wild-type TT genotype, carriers of the C allele had an increased risk of CAD (odds ratio = 1.819, 95% confidence interval 1.142-2.898; P = 0.012). 4. In conclusion, the results of the present study suggest that the APOM T-855C polymorphism carries an increased risk for CAD in this Chinese population.


Assuntos
Apolipoproteínas/genética , Grupo com Ancestrais do Continente Asiático/genética , Doença das Coronárias/genética , Predisposição Genética para Doença/genética , Variação Genética , Idoso , Alelos , Apolipoproteínas M , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Lipocalinas , Masculino , Pessoa de Meia-Idade , Fatores de Risco
7.
Zhen Ci Yan Jiu ; 32(5): 323-6, 2007 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-18050624

RESUMO

OBJECTIVE: To observe the effect of small needle-knife lysis on plasma calcitonin gene-related peptide (CGRP), endothelin (ET), 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), thromboxane A2 (TXA2) contents in rats with experimental third lumbar vertebra transverse process syndrome (TLVTPS) so as to explore its underlying mechanism in clinical treatment. METHODS: Forty SD rats were randomly divided into normal control, model, lysis and EA groups. TLVTPS model was established by embedding a piece of gelatin sponge (0.5 cm x 0.5 cm) to the transverse process of the 3rd lumbar vertebra under anesthesia. EA (2/100 Hz, 1-2 mA) was applied to left "Shenshu" (BL23) -"Yaoyangguan" (GV3) for 20 min, once every other day, 6 times altogether. For animals of lysis group, the lysis was performed by using a small needle-knife in the induration spot or cord-like region near the incision, once a week and twice altogether. Four weeks later after modeling, plasma CGRP, ET, 6-keto-PGF1alpha and TXA2 contents were detected by using radioimmunoassay and enzyme linked immunosorbent assay (ELISA). RESULTS: Compared with normal control group, plasma CGRP, ET, TXA2 and 6-keto-PGF1alpha increased significantly in model group (P<0.01); in comparison with model group, plasma CGRP, TXA2 and 6-keto-PGF1alpha in both EA and lysis groups decreased considerably (P<0.05, 0.01). No significant differences were found between EA and lysis groups in plasma CGRP, ET and 6-keto-PGF1alpha levels (P>0.05). CONCLUSION: Both EA and lysis of acupotomology have an adjusting effect on vasoactive substances (CGRP, TXA2 and 6-keto-PGF1alpha) levels in TLVTPS rats, which may contribute to their effects in improving local blood circulation and relieving soft tissue injury in the treatment of third lumbar vertebra transverse process syndrome.


Assuntos
6-Cetoprostaglandina F1 alfa/sangue , Peptídeo Relacionado com Gene de Calcitonina/sangue , Eletroacupuntura , Endotelinas/sangue , Vértebras Lombares , Medicina Tradicional Chinesa , Doenças da Coluna Vertebral/terapia , Tromboxano A2/sangue , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Síndrome
8.
Zhongguo Zhen Jiu ; 26(5): 316-8, 2006 May.
Artigo em Chinês | MEDLINE | ID: mdl-16739840

RESUMO

OBJECTIVE: To compare therapeutic effects of needle-knife therapy and acupuncture on cervical spondylosis. METHODS: Multi-central clinical randomized controlled trial was adopted. The patients were divided into a needle-knife treatment group treated with needle-knife therapy at the upper and lower interspinal ligaments of the affected vertebral body and bilateral posterior joint capsules; and the acupuncture control group were treated with acupuncture at Laozhen, Ashi points and cervical Jiaji points, etc. The short-term and the long-term therapeutic effects were observed at the end of the therapeutic course and 6 months after the end of the therapeutic course. RESULTS: The short-term therapeutic effect and the long-term therapeutic effect were 91.3% and 94.7% in the needle-knife treatment group and 59.4% and 56.6% in the acupuncture control group, respectively, with a very significant difference between the two groups (P < 0.01). CONCLUSION: The needle-knife treatment in the therapeutic effect on cervical spondylosis is superior to acupuncture treatment.


Assuntos
Terapia por Acupuntura , Vértebras Cervicais , Osteofitose Vertebral/cirurgia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteofitose Vertebral/etiologia , Osteofitose Vertebral/terapia
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