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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.
Int J Hyperthermia ; 36(1): 403-407, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30829551

RESUMO

BACKGROUND: The peritoneum is the most frequent site of disease recurrence in gastric cancer, and the prognosis remains poor. This study assessed the role of adjuvant intraperitoneal (IP) chemotherapy with whole abdominal hyperthermia using external radiofrequency in gastric cancer patients after D2 dissection. METHODS: Patients with gastric cancer who underwent gastrectomy with D2 regional lymph node dissection were enrolled in the study. Patients received IP chemotherapy with whole abdominal hyperthermia. Preheated normal saline containing 75 mg/m2 of cisplatin was delivered into the abdominal cavity through a Tenckhoff catheter at McBurney's point. Regional hyperthermia was performed using two sets of orthogonal radiofrequency waves immediately after all saline was irrigated into the abdominal cavity. For each patient, recurrent or metastatic sites and adverse events were evaluated. RESULTS: A total of 22 patients were finally included. All patients tolerated hyperthermia well. Only two patients experienced grade 1 superficial thermal injury. The most frequent grade 3/4 adverse events were myelosuppression, nausea/vomiting, trichomadesis and liver dysfunction. We also found IP chemotherapy with whole abdominal hyperthermia could reduce the total recurrent/metastatic rate, especially peritoneal metastasis (4.5%). CONCLUSIONS: This hypothesis-generating study indicated that IP chemotherapy with whole abdominal hyperthermia might be feasible for gastric cancer patients after D2 resection.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/métodos , Hipertermia Induzida/métodos , Neoplasias Gástricas/radioterapia , Neoplasias Gástricas/cirurgia , Estômago/irrigação sanguínea , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Gástricas/patologia
3.
Pharmazie ; 73(1): 42-48, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29441950

RESUMO

AIMS: Long non-coding RNAs (lncRNAs) play key roles in cancers, yet their potential molecular mechanisms are not well understood. The objective of this study is to examine the expression, biological functions and mechanism of lncRNA CCAL in gastric cancer (GC). METHODS: MTT and Colony formation assay were used to detect cell proliferation and the colony formation ability of gastric cancer cells. Wound healing, Migration, and invasion assay were respectively used to explore the migration, and invasion in gastric cancer cell lines. Real-time polymerase chain reaction (RT-PCR) was performed to determine the expression level of CCAL. Western Blot was used to determine the expression of related proteins. RESULTS: In the present study, we found that CCAL was upregulated in gastric cancer cell lines. Patients whose tumors had high CCAL expression had a shorter overall survival than patients whose tumors had low CCAL expression. Overexpression CCAL promoted the proliferation, migration and invasion of GC by regulating the expression of myc. CONCLUSION: The present study reveals that CCAL is an oncogenic lncRNA that promotes the tumorigenesis and progression of GC.


Assuntos
Proliferação de Células/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Humanos , Invasividade Neoplásica/genética , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias Gástricas/genética , Regulação para Cima , Cicatrização/genética
4.
Oncol Res ; 25(9): 1589-1599, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-28337962

RESUMO

Gastric cancer (GC) is one of the most common malignant tumors of the digestive system. The etiology of GC is complex, and much more attention should be paid to genetic factors. In this study, we explored the role and function of LINC00052 in GC. We applied qRT-PCR and Northern blot to detect the expression of LINC00052 and found it was highly expressed during GC. We also investigated the effects of LINC00052 on tumor prognosis and progression and found that LINC00052 indicated poor prognosis and tumor progression. By performing MTT, colony formation, and Transwell assays, we found that LINC00052 promoted MGC-803 cell proliferation and metastasis. Pull-down and RIP assays showed that LINC00052 could interact with ß-catenin and methyltransferase SMYD2, and immunoprecipitation detection showed that LINC00052 promoted ß-catenin methylation to maintain its stability, so as to activate the Wnt/ß-catenin pathway. Furthermore, XAV939 (inhibitor of ß-catenin) was used to treat MGC-803 cells, and we found that LINC00052 promoted proliferation and metastasis, possibly by activation of the Wnt/ß-catenin pathway. In conclusion, our research demonstrated a carcinogenic role for LINC000052 in GC, which may represent a new approach for the prevention and therapy of this cancer.


Assuntos
RNA Longo não Codificante/biossíntese , Neoplasias Gástricas/metabolismo , Via de Sinalização Wnt , Adulto , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , RNA Longo não Codificante/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Transfecção , beta Catenina/antagonistas & inibidores
6.
Nan Fang Yi Ke Da Xue Xue Bao ; 27(4): 468-70, 2007 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-17545033

RESUMO

OBJECTIVE: To investigate the differentiation of bone marrow stem cells in transplanted livers and its impact on the long-term survival of rats with orthotopic liver transplantation. METHODS: Twenty-four female recipient rats with orthotopic liver transplantation were randomized into blank-control group, D-hanks solution group, bone marrow stem cells group with postoperative infusion of stem cells, and the pathological changes of the liver grafts and survival time of the rats were observed. The differentiation of the bone marrow stem cells were assessed 60 days after transplantation using in situ hybridization histochemistry for Sry gene and alpha-fetoprotein (AFP) immunohistochemistry. RESULTS: In rats with postoperative infusion of bone marrow stem cells through the portal vein, the median long-term graft survival time exceeded 180 days, significantly longer than that in the other two groups (P<0.05), and no obvious evidence of acute rejection was observed with positive Sry expression and AFP expression. CONCLUSION: Infusion of bone marrow stem cells through the portal vein following liver transplantation may alleviate acute graft rejection and promote long-term liver graft survival and AFP expression.


Assuntos
Diferenciação Celular , Sobrevivência de Enxerto , Células-Tronco Hematopoéticas/citologia , Transplante de Fígado , Animais , Feminino , Rejeição de Enxerto/prevenção & controle , Fígado/patologia , Veia Porta , Ratos , Ratos Wistar
7.
Zhonghua Gan Zang Bing Za Zhi ; 13(9): 652-5, 2005 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-16174451

RESUMO

OBJECTIVE: To investigate the possibility of the human bone marrow multipotent adult progenitor cells (hMAPCs) to differentiate into hepatocytes with hepatocyte growth factor (HGF)/ fibroblast growth factor-4 (FGF-4) in vitro. METHODS: (1) Obtaining the hMAPCs. Bone marrow was obtained from volunteers and then centrifuged through density gradient centrifugation methods. The collected mononuclear cells were cultured through adheret culture to get mesenchymal stem cells (MSCs). The hMAPCs were obtained through collecting and isolating the MSCs by magnetic activated cell sorting (MACS) through depletion selection by use of CD45 and GlyA microbeads. (2) Differentiation of the hMAPCs with HGF+FGF-4. Group A: HGF (20 ng/ml) + FGF-4 (10 ng/ml) induced hMAPCs; group B (positive control group): L-02 human hepatocytes(cell lines); and group C (negative control group): the undifferentiated hMAPCs. (3) The expressions of albumin (Alb), alpha fetoprotein (AFP), cytokeratin-18 (CK-18), and cytokeratin-19 (CK-19) were detected with immunocytochemistry to identify the characteristics of the differentiated cells at different times and the ratio of the positive cells was determined. (4) ALB, AFP, CK-18, and CK-19 expressions of the differentiated cells were detected by RT-PCR assay to investigate the mRNA transcriptions of characteristic hepatic proteins. (5) Alb expressions of the differentiated cells at different times were detected by Western blot on the 21st and 35th days. RESULTS: (1) The results of immunocytochemistry. The staining of Alb, CK18 were essentially positive in group A. As an early marker of immature hepatocytes, AFP staining was positive on the 7th day but negative in later differentiating periods in group A. (2) The results of RT-PCR. On the 7th day, the differentiated hMAPCs expressed AFP mRNA but were negative in later differentiating periods. On the contrary, the mRNA of Alb and CK-18 were positive at all times. (3) The results of Western blot assay. Alb protein was positive on the 21st day and 35th day. CONCLUSIONS: Under some definite inducing conditions hMAPCs can differentiate into hepatocyte-like cells. They may serve as a potential cell source for liver engineering.


Assuntos
Diferenciação Celular , Fator 4 de Crescimento de Fibroblastos/farmacologia , Fator de Crescimento de Hepatócito/farmacologia , Hepatócitos/citologia , Células-Tronco Mesenquimais/citologia , Células da Medula Óssea/citologia , Células Cultivadas , Humanos
8.
World J Gastroenterol ; 10(7): 1019-27, 2004 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-15052686

RESUMO

AIM: To investigate the significance of protein kinase C(PKC), P44/42 mitogen-activated protein kinase (MAPKs) and heat shock protein (HSP)70 signal transduction during hepatocyte ischemic preconditioning. METHODS: In this study we used an in vitro ischemic preconditioning (IP) model for hepatocytes and an in vivo model for rat liver to investigate the significance of protein kinase C (PKC), P44/42 mitogen-activated protein kinase (P44/42 MAPKs) and heat shock protein 70 (HSP70) signal transduction in IP. Through a normal liver cell hypoxic preconditioning (HP) model in which cultured normal liver cells were subjected to 3 cycles of 5 min of incubation under hypoxic conditions followed by 5 min of reoxygenation and subsequently exposed to hypoxia and reoxygenation for 6 h and 9 h respectively. PKC inhibitor, activator and MEK inhibitor were utilized to analyze the phosphorylation of PKC, the expression of P44/42 MAPKs and HSP70. Viability and cellular ultrastructure were also observed. By using rat liver as an in vivo model of liver preconditioning (3 cycles of 10-min occlusion and 10-min reperfusion), in vivo phosphorylation of PKC and P44/42MAPKs, HSP70 expression were further analyzed. AST/ALT concentration, cellular structure and ultrastructure were also observed. All the data were statistically analyzed. RESULTS: Similar results were obtained in both in vivo and in vitro IP models. Compared with the control without IP (or HP), the phosphorylation of PKC and P44/42 MAPKs and the expression of HSP70 were obviously increased in IP (or HP) treated model in which cytoprotection could be found. The effects of preconditioning were mimicked by stimulating PKC with 4beta phorobol-12-myristate13-acetate (PMA). Conversely, inhibiting PKC with chelerythrine abolished the protection given by preconditioning. PD98059, inhibitor of MEK (the upstream kinase of P44/42MAPKs), also reverted the cytoprotection exerted by preconditioning. CONCLUSION: The results demonstrate that preconditioning induces a rapid activation of P44/42MAPKs and PKC activation plays a pivotal role in the activation of P44/42 MAPKs pathway that participates in the preservation of liver cells. HSP expression is regulated by signals in PKC dependent P44/42 MAPKs pathway.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Precondicionamento Isquêmico , Circulação Hepática , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteína Quinase C/metabolismo , Transdução de Sinais , Animais , Ativação Enzimática , Hepatócitos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Ratos , Ratos Sprague-Dawley
9.
Zhonghua Yi Xue Za Zhi ; 83(3): 242-6, 2003 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-12812671

RESUMO

OBJECTIVE: To investigate the significance of PKC, P44/42 MAPKs and HSP70 signal transduction in IP. METHODS: Through an in vivo rat liver IP model, PKC inhibitor, activator and MEK inhibitor were utilized to analyze the phosphorylation of PKC and P44/42 MAPKs. HSP expression, AST/ALT concentration, cellular structure and ultrastructure were also observed. All the data were statistically analyzed. RESULTS: Compared with the control without IP, the phosphorylation of PKC was significantly increased in IP treated models and PKC activated group (P < 0.01) and P44/42 MAPKs and the expression of HSP were also obviously increased. In contrast, opposite changes were found in PKC or MEK inhibited groups, the phosphorylation PKC was decreased in PKC inhibited group (P < 0.01). CONCLUSION: The model has shown that PKC activation plays a pivotal role in the activation of P44/42 MAPKs pathway that participates in the preservation of liver cells. At the same time, HSP expression is regulated by signals in P44/42 MAPKs pathway.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Precondicionamento Isquêmico , Fígado/irrigação sanguínea , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteína Quinase C/metabolismo , Animais , Ativação Enzimática , Hepatócitos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Ratos , Ratos Sprague-Dawley
10.
Zhonghua Gan Zang Bing Za Zhi ; 11(3): 166-9, 2003 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-12681066

RESUMO

OBJECTIVE: To investigate the significance of PKC and p44/42 mitogen-activated protein kinase (MAPK) signal transduction in ischemic preconditioning (IP). METHODS: Through liver cell IP models, PKC inhibitor and MEK inhibitor were utilized to analyze the phosphorylation level of p44/42 MAPK and cell viability was also observed. Rat liver IP models were established which were treated with various drugs. Then the phosphorylation level of p44/42 MAPK in vivo and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) concentrations were detected. And cellular structures were observed under light microscopy. RESULTS: Similar results were obtained in vivo and in vitro IP models. Compared with the ischemia reperfusion (IR) group in vivo, the phosphorylation level of p44/42 MAPK was obviously increased in IP treated rats (q = 27.217, P < 0.01), and the cellular structure injured slightly. The concentrations of serum ALT and AST in IP group were significantly lower than those in IR group (281.0 U/L +/-35.6 U/L vs 762.8 U/L +/-130.5 U/L and 407.7 U/L +/-73.7 U/L vs 820.9 U/L +/-111.3 U/L, P < 0.01). However, opposite changes were found in PKC and MEK inhibited groups, when compared to IP group. The phosphorylation level of p44/42 MAPK was obviously decreased, the liver tissues injured evidently, and the concentrations of serum ALT and AST (645.61 U/L +/-90.4 U/L, 678.6 U/L +/-136.5U/L and 466.2 U/L +/-82.8 U/L, 732.9 U/L +/-91.1 U/L, respectively) were significantly greater than those in IP group. CONCLUSION: These results suggest that p44/42 MAPK pathway plays a vital role in the protection of hepatocytes in ischemic preconditioning.


Assuntos
Precondicionamento Isquêmico , Fígado/irrigação sanguínea , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Transdução de Sinais , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Hepatócitos/citologia , Hepatócitos/fisiologia , Humanos , Fígado/citologia , Masculino , Fosforilação , Proteína Quinase C/metabolismo , Ratos , Ratos Sprague-Dawley
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