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1.
Biochim Biophys Acta Mol Basis Dis ; 1870(7): 167336, 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38972433

RESUMO

Epiregulin (EREG) is a member of the epidermal growth factor (EGF) family. An increasing body of evidence has demonstrated the pivotal role of EREG in the pathogenesis and progression of various malignancies. However, the clinical significance and biological role of EREG in pancreatic ductal adenocarcinoma (PDAC) have yet to be fully elucidated. We found that EREG is highly expressed in PDAC tissues compared with paracancerous tissues through public databases and clinical samples. High EREG expression predicted worse overall survival (OS) and recurrence-free survival (RFS) in patients with PDAC. Multivariate analysis revealed that EREG can serve as an independent prognostic indicator. In addition, EREG silencing inhibited PDAC cell proliferation, migration, progression, altered cell cycle, facilitated apoptosis in vitro and suppressed tumor growth in vivo. Conversely, EREG overexpression facilitated the proliferation, migration, and invasion in PaTu-8988 t cell. Through transcriptome sequencing and experimental verification, we found EREG mediates PDAC tumorigenesis through ERK/p38 MAPK signaling pathway. Moreover, we found EREG expression is closely related to PD-L1 expression in PDAC tissues and cells. Therefore, EREG is expected to be a prospective prognostic and therapeutic marker for PDAC.

2.
Front Oncol ; 12: 924059, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35992798

RESUMO

Hepatocellular carcinoma (HCC) accounts for third most cancer death globally, and its prognosis continues to be poor even with many novel therapeutic approaches emerging. The advent of immunotherapy seems to offer new hope, but low response rates are an unresolved problem. To gain further knoeledge of the effect of immune-related genes in HCC, we examined the connection between immune-related genes and the immune microenvironment in HCC through the HCC transcriptome dataset. The study also aimed to construct and experimentally validate user-friendly molecular subtypes mediated by immune-related genes in HCC. The immune cell infiltration patterns differs in HCC adjacent non-disease tissues and cancerous tissues. Patients with HCC could be classified into 2 subtypes: subtype A and subtype B. Specifically, subtype A shows characteristics of a hot tumor, in which the infiltration of cells exhibiting antigens and the expression of other crucial factors associated with immune function are higher than in a cold tumor. In addition, we identified Hub genes for the different subtypes and constructed a prognostic prediction model based on six genes (KLRB1, KLF2, S100A9, MSC, ANXA5, and IMPDH1). Further experimental analysis of HCC samples exhibited that the expression levels of KLF2 and ANXA5 were associated with immune cell infiltration and expression of PD-L1 in cancer tissues. Our work suggests that the expression of immune-related genes has crucial effect on the tumor microenvironment and prognosis of HCC patients and may be associated with immunotherapeutic response, which provides new clues for the widespread and effective application of immunotherapy in HCC.

3.
Bioinorg Chem Appl ; 2022: 7803001, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35706846

RESUMO

Objective: In order to study the application of nanoparticles in the diagnosis and treatment of pancreatic cancer, we retrospectively analyzed pancreatic cancer patients after operation. Method: 60 cases of pancreatic cancer and surgical treatment were selected from our hospital. The time ranged from March 2018 to March 2019. The age ranged from 27 to 81 years. There were 36 males and 24 females, with an average age of 46.23 (7.63) years. Among them, the observation group consisted of nanotube artificial tubes, 16 males and 14 females, while the control group adopted nylon tube, male 18 and female 12. The patient was diagnosed by abdominal CT, and the patient's demographic data and basic clinical data were recorded at the same time. Result: In this study, 60 patients were divided into groups and compared. The patients underwent surgical resection of pancreaticoduodenum and reconstruction of pancreaticoduodenal papillary duct. Among them, the observation group used nanocomposite artificial tube, while the observation group used nanocomposite artificial tube and placed drainage tube to drain the peritoneal effusion to prevent the effusion from forming in abdominal hypertension and infection. The amount of postoperative bleeding, operation time, and postoperative concomitant symptoms were observed, and the differences between the two materials were analyzed. Conclusion: The reconstruction of pancreaticoduodenal papillary duct with nanomaterials has certain advantages for postoperative recovery, reduces postoperative complications, reduces the probability of infection, and improves the therapeutic effect.

4.
Front Med (Lausanne) ; 7: 148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32411713

RESUMO

Objective: To investigate the long-term effect of triple organ transplantation (liver, kidney, and pancreas) in a patient with end-stage liver disease, post chronic hepatitis B, cirrhosis, chronic renal failure, and insulin-dependent diabetes mellitus caused by chronic pancreatitis and to explore the optimal surgical procedure. Case: A 43-year-old man with progressive emaciation and hypourocrinia for 2 months. Results indicated exocrine pancreatic insufficiency and insulin-dependent diabetes related to chronic pancreatitis (CP) after developing end-stage hepatic and renal failure. Simultaneous piggyback orthotopic liver and heterotopic pancreas-duodenum and renal transplantation was performed in 2005. Pancreatic exocrine secretions were drained enterically to the jejunum, and the donor kidney was placed in the left iliac fossa. Patient was prescribed with prednisone, tacrolimus, mycophenolate mofetil, Rabbit Anti-human Thymocyte Immunoglobulin, and simulect for immunosuppression. Results: Satisfactory hepatic and pancreatic functional recovery was achieved within 7 days post-surgery. The kidney was not functional, and continuous renal replacement therapy was used. However, the donor kidney was removed at day 16 post-surgery due to acute rejection reaction. A new renal transplantation at the same position was performed, and satisfactory kidney function from the new graft was achieved 3 days later. In 14 years of follow-up, patient has not had any rejection reactions or other complications such as pancreatitis, thrombosis, and localized infections. The patient is insulin independent with normal liver and renal functions. FK506+Pred was used for immunosuppression, and the tac tough level maintained 3.0-4.5 ng/ml. Lamivudine was prescribed for long-term use to inhibit HBV virus duplication. Conclusion: Simultaneous piggyback orthotopic liver and heterotopic pancreas-duodenum and renal transplantation is a good therapeutic option for patients with exocrine pancreatic insufficiency and insulin-dependent diabetes combined with hepatic and renal failure.

5.
World J Surg Oncol ; 17(1): 163, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31526392

RESUMO

BACKGROUND: Pancreatic carcinoma (PC) is one of the most lethal malignancies, and its poor prognosis is strongly associated with invasion and metastasis. CA19.9 is considered to be the most sensitive serum marker for PC in clinical practice; however, the detection of CA19.9 in PC has a certain false positive and false negative rate. The expression of the calcium-binding protein S100A4 has been reported to be associated with poor prognosis in various cancers. This study aimed to investigate the relationship between S100A4 and CA19.9 and its prognostic significance in PC. METHODS: We performed immunohistochemical staining for S100A4 in formalin-fixed, paraffin-embedded blocks of 128 PC tissues. The levels of S100A4 expression and pre-operative serum CA19.9 were correlated with clinicopathological parameters. The possible correlation between S100A4 protein expression and pre-operative serum CA19.9 levels were evaluated using the chi-square test and Spearman correlation. Survival was assessed by Kaplan-Meier analysis together with a single variable or multivariate Cox analysis. RESULTS: A significant positive correlation between S100A4 expression and pre-operative serum CA19.9 level was observed in PC tissues (ρ = 0.202, P = 0.022). The co-expression of both proteins correlated significantly with tumor differentiation (ρ = - 0.280, P = 0.001), TNM stage (ρ = - 0.389, P = 0.000), and lymph node metastasis (ρ = 0.254, P = 0.008). Upregulation of S100A4 was identified as a significant, independent predictor of poor overall survival (P = 0.000). Moreover, higher serum CA19.9 levels (≥ 35 U/mL) were also recognized as an independent predictor of inferior overall survival (P = 0.001). Additionally, upregulation of S100A4 and higher pre-operative serum CA19.9 levels (≥ 35 U/mL) in patients with PC contributed to a significant decrease in overall survival (P = 0.000). CONCLUSIONS: The expression levels of S100A4 in PC tissues were positively correlated with pre-operative serum CA19.9 levels. S100A4 expression and pre-operative serum CA19.9 levels were significant, independent prognostic factors for the overall survival of patients with PC. S100A4 expression/pre-operative serum CA19.9 levels may prove useful as dual prognostic biomarkers for PC. Analysis of CA19.9 in combination with S100A4 can better predict the prognosis of PC.


Assuntos
Biomarcadores Tumorais/sangue , Antígeno CA-19-9/sangue , Pancreatectomia/mortalidade , Neoplasias Pancreáticas/patologia , Proteína A4 de Ligação a Cálcio da Família S100/sangue , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/cirurgia , Cuidados Pré-Operatórios , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias Pancreáticas
6.
Cancer Res ; 79(16): 4160-4172, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31266773

RESUMO

Tumor-associated macrophages (TAM) play pivotal roles in tumor progression and metastasis, but the contribution and regulation of different macrophage populations remain unclear. Here we show that Notch signaling plays distinct roles in regulating different TAM subsets in hepatocellular carcinoma (HCC). Myeloid-specific NOTCH blockade by conditional disruption of recombination signal binding protein Jκ (RBPj cKO) significantly delayed the growth of subcutaneously inoculated Lewis lung carcinoma (LLC), but accelerated orthotopically inoculated hepatic Hepa1-6 tumors in mice. In contrast to subcutaneous LLC, RBPj cKO significantly increased the number of TAMs in hepatic Hepa1-6 tumors despite impeded differentiation of monocyte-derived TAMs (moTAM). The dominating TAMs in orthotopic HCC manifested properties of Kupffer cells (KC) and hence are tentatively named KC-like TAMs (kclTAM). The increased proliferation of RBPj cKO kclTAMs was maintained even in Ccr2 -/- mice, in which moTAMs were genetically blocked. NOTCH signaling blockade accelerated proliferation of kclTAMs via enhanced ß-catenin-dependent WNT signaling, which also downregulated IL12 and upregulated IL10 expression by kclTAMs likely through c-MYC. In addition, myeloid-specific RBPj cKO facilitated hepatic metastasis of colorectal cancer but suppressed lung metastasis in mice, suggesting that the phenotype of RBPj cKO in promoting tumor growth was liver-specific. In patient-derived HCC biopsies, NOTCH signaling negatively correlated with WNT activation in CD68+ macrophages, which positively correlated with advanced HCC stages. Therefore, NOTCH blockade impedes the differentiation of moTAMs, but upregulates Wnt/ß-catenin signaling to promote the proliferation and protumor cytokine production of kclTAMs, facilitating HCC progression and hepatic metastasis of colorectal cancer. SIGNIFICANCE: These findings highlight the role of NOTCH and WNT signaling in regulating TAMs in hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patologia , Macrófagos/patologia , Receptores Notch/metabolismo , Via de Sinalização Wnt/fisiologia , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/secundário , Carcinoma Pulmonar de Lewis/metabolismo , Diferenciação Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Macrófagos/metabolismo , Masculino , Camundongos Knockout , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores Notch/genética
7.
Eur J Surg Oncol ; 2018 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-30470530

RESUMO

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

8.
J Gastroenterol Hepatol ; 33(8): 1538-1547, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29384233

RESUMO

BACKGROUND AND AIM: It has been well documented that Notch signaling is involved in liver regeneration. However, the exact molecular mechanism mediating this process is not fully elucidated. The current study aimed to investigate the role of Notch signaling regulating cell cycle in proliferating hepatocytes in liver regeneration after partial hepatectomy (PHx, 67% resection) and the related molecular mechanism. METHODS: Partial hepatectomy was performed in Sprague Dawley rats, and remnant livers were harvested 0, 1, 3, 5, and 7 days after operation, and primary hepatocytes were isolated to investigate the molecular mechanism. RESULTS: Notch signaling activation and hepatocyte proliferation were significantly increased after PHx, while treatment with FLI-06, the inhibitor of γ-secreting enzyme, blocked these trends. Besides, inhibition of Notch signaling led to dysregulation of cell cycle and cell-cycle components. Furthermore, Akti-1/2 (a selective Akt inhibitor) and PX-478 (a selective Hif-1α inhibitor) inhibited hepatocyte proliferation and liver regeneration after PHx, and the effect of downstream molecules activation by Jagged-1 (Notch-1 ligand) in hepatocytes was abolished by FLI-06, Akti-1/2, and PX-478. CONCLUSION: The current study demonstrated for the first time that Notch signaling regulated cell cycle in proliferating hepatocytes involved in liver regeneration through NICD/Akt Akt/Hif-1α pathway.


Assuntos
Ciclo Celular/genética , Ciclo Celular/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Hepatócitos/citologia , Hepatócitos/fisiologia , Regeneração Hepática/genética , Regeneração Hepática/fisiologia , Receptores Notch/fisiologia , Transdução de Sinais/fisiologia , Animais , Células HEK293 , Hepatectomia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Masculino , Proteínas Proto-Oncogênicas c-akt/fisiologia , Ratos Sprague-Dawley
9.
Xenotransplantation ; 24(5)2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28714241

RESUMO

BACKGROUND: Pig-to-nonhuman primate orthotopic liver xenotransplantation is often accompanied by thrombocytopenia and coagulation disorders. Furthermore, the release of cytokines can trigger cascade reactions of coagulation and immune attacks within transplant recipients. To better elucidate the process of inflammation in liver xenograft recipients, we utilized a modified heterotopic auxiliary liver xenotransplantation model for xeno-immunological research. We studied the cytokine profiles and the relationship between cytokine levels and xenograft function after liver xenotransplantation. METHODS: Appropriate donor and recipient matches were screened using complement-dependent cytotoxicity assays. Donor liver grafts from α1,3-galactosyltransferase gene-knockout (GTKO) pigs or GTKO pigs additionally transgenic for human CD47 (GTKO/CD47) were transplanted into Tibetan macaques via two different heterotrophic auxiliary liver xenotransplantation procedures. The cytokine profiles, hepatic function, and coagulation parameters were monitored during the clinical course of xenotransplantation. RESULTS: Xenograft blood flow was stable in recipients after heterotopic auxiliary transplantation. A Doppler examination indicated that the blood flow speed was faster in the hepatic artery (HA) and hepatic vein (HV) of xenografts subjected to the modified Sur II (HA-abdominal aorta+HV-inferior vena cava) procedure than in those subjected to our previously reported Sur I (HA-splenic artery+HV-left renal vein) procedure. Tibetan macaques receiving liver xenografts did not exhibit severe coagulation disorders or immune rejection. Although the recipients did suffer from a rapid loss of platelets, this loss was mild. In blood samples dynamically collected after xenotransplantation (post-Tx), dramatic increases in the levels of monocyte chemoattractant protein 1, interleukin (IL)-8, granulocyte-macrophage colony-stimulating factor, IL-6, and interferon gamma-induced protein 10 were observed at 1 hour post-Tx, even under immunosuppression. We further confirmed that the elevation in individual cytokine levels was correlated with the onset of graft damage. Finally, the release of cytokines might contribute to leukocyte infiltration in the xenografts. CONCLUSION: Here, we established a modified auxiliary liver xenotransplantation model resulting in near-normal hepatic function. Inflammatory cytokines might contribute to early damage in liver xenografts. Controlling the systemic inflammatory response of recipients might prevent early post-Tx graft dysfunction.


Assuntos
Citocinas/sangue , Galactosiltransferases/sangue , Transplante de Fígado , Transplante Heterólogo , Animais , Animais Geneticamente Modificados , Galactosiltransferases/genética , Galactosiltransferases/metabolismo , Técnicas de Inativação de Genes , Rejeição de Enxerto/imunologia , Xenoenxertos , Terapia de Imunossupressão , Fígado/imunologia , Macaca , Suínos , Tibet , Transplante Heterólogo/métodos , Transplantes/imunologia
10.
Cancer Med ; 6(8): 1941-1951, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28675698

RESUMO

Autophagy is a life phenomenon in which autophagosomes remove damaged or aging organelles and long-lived circulating proteins to maintain the cell's stability. However, disorders of excessive autophagy are a response of cancer cells to a variety of anticancer treatments which lead to cancer cell death. The Akt/mammalian target of rapamycin (mTOR) and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathways are both involved in nutrient-induced autophagic phenomenon and exhibit vital relevance to oncogenesis in various cancer cell types, including hepatocellular carcinoma (HCC). However, the influence of autophagy for cancer cell death remains controversial and few scientists have investigated the variation of these two signaling pathways in cancer cell autophagic phenomenon induced by anticancer treatment simultaneously. Here, we explored the anticancer efficacy and mechanisms of glycyrrhizin (GL), a bioactive compound of licorice with little toxicity in normal cells. It is interesting that inhibition of Akt/mTOR signaling in concurrence with enhanced ERK1/2 activity exists in GL-induced autophagy and cytotoxicity in HepG2 and MHCC97-H hepatocellular carcinoma cells. These results imply that the GL-related anticancer ability might correlate with the induction of autophagy. The influence of induced autophagic phenomenon on cell viability might depend on the severity of autophagy and be pathway specific. In the subsequent subcutaneous xenograft experiment in vivo with MHCC97-H cells, GL obviously exhibited its inhibitory efficacy in tumor growth via inducing excess autophagy in MHCC97-H cells (P < 0.05). Our data prompt that GL possesses a property of excess autophagic phenomenon induction in HCC and exerts high anticancer efficacy in vitro and in vivo. This warrants further investigation toward possible clinical applications in patients with HCC.


Assuntos
Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Ácido Glicirrízico/farmacologia , Neoplasias Hepáticas/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Ácido Glicirrízico/química , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Cancer Lett ; 397: 33-42, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28288874

RESUMO

Cancer-associated fibroblasts (CAFs) play a pivotal role in regulating tumour progression. Therefore, understanding how CAFs communicate with hepatocellular carcinoma (HCC) is crucial for HCC therapy. Recently, exosomes have been considered an important "messenger" between cells. In this study, we performed microRNA (miRNA) sequencing of exosomes derived from CAFs and corresponding para-cancer fibroblasts (PAFs) of HCC patients. We found a significant reduction in the miR-320a level in CAF-derived exosomes. Using exogenous miRNAs, we demonstrated that stromal cells could transfer miRNA to HCC cells. In vitro and in vivo studies further revealed that miR-320a could function as an antitumour miRNA by binding to its direct downstream target PBX3 to suppress HCC cell proliferation, migration and metastasis. The miR-320a-PBX3 pathway inhibited tumour progression by suppressing the activation of the MAPK pathway, which could induce the epithelial-mesenchymal transition and upregulate cyclin-dependent kinase 2 (CDK2) and MMP2 expression to promote cell proliferation and metastasis. In xenograft experiments involving CAFs mixed with MHCC97-H cells, miR-320a overexpression in CAFs could inhibit tumourigenesis. Therefore, these data suggest that CAF-mediated HCC tumour progression is partially related to the loss of antitumour miR-320a in the exosomes of CAFs and that promoting the transfer of stromal cell-derived miR-320a might be a potential treatment option to overcome HCC progression.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Carcinoma Hepatocelular/metabolismo , Movimento Celular , Proliferação de Células , Exossomos/metabolismo , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , Animais , Fibroblastos Associados a Câncer/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/secundário , Linhagem Celular Tumoral , Quinase 2 Dependente de Ciclina/metabolismo , Regulação para Baixo , Exossomos/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , Comunicação Parácrina , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Fatores de Tempo , Transfecção
12.
Oncotarget ; 8(1): 1714-1724, 2017 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-27974675

RESUMO

Overexpression of neural precursor cell expressed, developmentally downregulated 9 (NEDD9) is a prognostic marker of many cancers, including hepatocellular carcinoma (HCC). However, the functions and mechanisms of NEDD9 are unclear. We found that upregulation of NEDD9 promoted migration, invasion and cell-to-extracellular matrix adhesion of HCC cells. NEDD9 also induced the epithelial-mesenchymal transition (EMT) and expression of matrix metalloprotein 2 (MMP2). Increased aldehyde dehydrogenase (ALDH) activity and CD133-positive cells were observed in HCC cells with high expression of NEDD9, corresponding to greater sphere formation in cancer stem cells (CSCs). NEDD9 deregulated Smad7 expression to inhibit Smad signaling and binding to the FAK-Src-Crk complex. We propose that this is the mechanism by which NEDD9 induced CSC properties.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Hepatocelular/patologia , Transição Epitelial-Mesenquimal/fisiologia , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/patologia , Fosfoproteínas/metabolismo , Proteína Smad7/metabolismo , Antígeno AC133/metabolismo , Aldeído Desidrogenase/metabolismo , Animais , Adesão Celular/fisiologia , Movimento Celular , Matriz Extracelular/fisiologia , Quinase 1 de Adesão Focal/metabolismo , Humanos , Masculino , Metaloproteinase 2 da Matriz/biossíntese , Camundongos , Camundongos Nus , Invasividade Neoplásica/patologia , Proteínas Proto-Oncogênicas c-crk/metabolismo , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Transdução de Sinais/fisiologia , Esferoides Celulares/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Cell Physiol Biochem ; 36(1): 233-49, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25967963

RESUMO

BACKGROUND: The activation of tissue factor (TF) is one of the major reasons for coagulation dysregulation after pig-to-primate xenotransplantation. Tissue factor pathway inhibitor (TFPI) is the most important inhibitor of TF. Studies have demonstrated species incompatibility between pig TFPI and human TF. METHODS: A pig-to-macaque heterotopic auxiliary liver transplantation model was established to determine the origin of activated TF. Chimeric proteins of human and pig TFPI were constructed to assess the role of Kunitz domains in species incompatibility. Immortalised pig bone marrow mesenchymal stem cells transfected with human TFPI were tested for their ability to inhibit clotting in vitro. RESULTS: TF from recipient was activated early after liver xenotransplantation. Pig TFPI Kunitz domain 2 bound human FXa, but Kunitz domain 1 did not effectively inhibit human TF/FVIIa. Immortalised pig bone marrow mesenchymal cells (BMSCs) transfected with human TFPI showed a prolonged recalcification time in vitro and in a rodent model. CONCLUSION: Recipient TF is relevant to dysregulated coagulation after xenotransplantation. Kunitz domain 1 plays the most important role in species incompatibility between pig TFPI and human TF, and clotting can be inhibited by human TFPI-transfected pig BMSCs. Our study shows a possible way to resolve the incompatibility of pig TFPI.


Assuntos
Coagulação Sanguínea , Lipoproteínas/metabolismo , Fígado/metabolismo , Células-Tronco Mesenquimais/metabolismo , Tromboplastina/metabolismo , Animais , Células Cultivadas , Humanos , Técnicas In Vitro , Lipoproteínas/química , Lipoproteínas/genética , Transplante de Fígado , Macaca , Masculino , Transplante de Células-Tronco Mesenquimais , Modelos Animais , Estrutura Terciária de Proteína , Especificidade da Espécie , Suínos , Porco Miniatura , Tromboplastina/genética , Transplante Heterólogo , Transplante Heterotópico
14.
Oncol Rep ; 33(5): 2375-83, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25812772

RESUMO

Neural precursor cell expressed, developmentally downregulated 9 (NEDD9) plays an integral role in natural and pathological cell biology. Overexpression of NEDD9 protein has been correlated with poor prognosis in various types of cancer. However, few available data address the precise function of the NEDD9 gene in hepatocellular carcinoma (HCC). In the present study, we investigated NEDD9 expression in 40 primary human HCC tissues compared with matched adjacent non-tumor hepatic tissues using RT-qPCR and western blot analysis. Immunohistochemistry was performed to analyze the correlations between NEDD9 expression and clinicopathological factors. Statistical analyses were applied to derive prognostic values of NEDD9 in HCC. The results showed that the NEDD9 mRNA and protein expression levels in HCC tissues were significantly higher than those in matched adjacent non-tumor hepatic tissues. High NEDD9 expression was correlated with larger tumor size, advanced tumor grade, metastasis, intrahepatic venous invasion and high UICC TNM stages in HCC patients. Patients with high NEDD9 expression levels exhibited poorer recurrence-free and overall survival than those with a low NEDD9 expression. Additionally, NEDD9 expression status was an independent prognostic factor for survival. This correlation remained significant in patients with early-stage HCC or with normal serum AFP levels. The results of this study suggest that NEDD9 may be a valuable prognostic biomarker for HCC, including early-stage and AFP-normal patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Fosfoproteínas/genética , RNA Mensageiro/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Feminino , Veias Hepáticas/patologia , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase Via Transcriptase Reversa
15.
Pharm Biol ; 52(10): 1278-85, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25026357

RESUMO

CONTEXT: Salvia miltiorrhiza Bunge is a traditional Asian medicine used to treat cerebral and cardiac ischemia. However, the effects of the active compounds of S. miltiorrhiza on liver damage are unclear. OBJECTIVE: In this study, we tested the effects on acute liver injury of crude S. miltiorrhiza extracts from roots as well as neotanshinone B, dehydromiltirone, tanshinol A, tanshinone I, dihydrotanshinono I, neotanshinone A, cryptanshinono, tanshinone II A, and salvianolie acid B from purified S. miltiorrhiza extracts. MATERIALS AND METHODS: Various compounds or ethanol extract of S. miltiorrhiza (50, 100, and 200 mg/kg, p.o.) were administered to rats for five consecutive days. After acute carbon tetrachloride (CCl4)-induced liver injury by treatment of rats with a single dose of CCl4 (0.75 mL/kg, p.o), rat liver function was tested by measuring serum biochemical parameters. Serum cytokine concentrations were assessed by enzyme-linked immunosorbent assay (ELISA). Expression of p38 and NFκB was evaluated by western blot. RESULTS: All S. miltiorrhiza components showed their effects on liver function from the dose from 50 to 200 mg/kg. At the dose of 200 mg/kg, they reduced serum levels of alkaline phosphatase (ALP) by 34-77%, alanine aminotransferase (ALT) by 30-57%, aspartate aminotransferase (AST) by 43-72%, creatine total bilirubin (BIL-T) by 33-81%, albumin (ALB) by 37-67%, indicating that S. miltiorrhiza extracts protected liver from CCl4-induced damage. Moreover, S. miltiorrhiza extracts at 200 mg/kg reduced the increase in the proinflammatory cytokines tumor necrosis factor-α (TNF-α) by 25-82%, interleukin-1 (IL-1) by 42-74% and interleukin-6 (IL-6) by 67-83%, indicating an effect on alleviating liver inflammation. Furthermore, in vitro, S. miltiorrhiza extracts inhibited p38 and NFκB signaling in Kupffer cells. This effect could be a main mechanism by which S. miltiorrhiza protects against acute liver toxicity. DISCUSSION AND CONCLUSION: Active compounds of S. miltiorrhiza protected the liver from CCl4-induced injury. Protection might have been due to inhibition of p38 and NFκB signaling in Kupffer cells, which subsequently reduced inflammation in the liver.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Células de Kupffer/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Extratos Vegetais/uso terapêutico , Salvia miltiorrhiza , Animais , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Células de Kupffer/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , NF-kappa B/fisiologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Ratos
16.
Ann Hepatol ; 13(3): 399-403, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24756018

RESUMO

Liver transplantation is regarded as an effective treatment for Wilson's disease (WD), and recently has been shown to improve not only hepatic but also neurologic manifestations. Conventional auxiliary liver transplantation for WD is orthotopic liver transplantation and heterotopic liver transplantation. But the conventional procedure could not avoid the problem of space, functional competition, hemodynamic variation. Here we report a case of heterotopic auxiliary living-donor liver transplantation (HALDLT) to treat WD. We modified the operation to have a splenectomy, implant graft into the splenic fossa. The patient recovered well after the transplantation and has been symptom-free during a 5-year follow-up. This modified operation is more safe and simple. HALDLT might be an effective treatment for WD patients with splenomegaly.


Assuntos
Aloenxertos/diagnóstico por imagem , Degeneração Hepatolenticular/cirurgia , Transplante de Fígado/métodos , Doadores Vivos , Transplante Heterotópico/métodos , Aloenxertos/irrigação sanguínea , Criança , Feminino , Hepatectomia/métodos , Humanos , Radiografia , Cintilografia , Resultado do Tratamento
17.
Ann Hepatol ; 12(5): 815-21, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24018501

RESUMO

BACKGROUND: We have previously reported that Notch signaling pathway protects hepatocytes from ischemia/ reperfusion (I/R) injury by repressing reactive oxygen species (ROS) production. However, apart from hepatocytes, non-parenchymal cells including vascular endothelia cells, Kupffer cells and hepatic stellate cells are also reported to be involved in hepatic I/R injury. AIM: To clarify the role of Notch signaling in non-parenchymal cells subjected to I/R injury. MATERIALS AND METHODS: Human Umbilical Vein Endothelial Cells (HUVECs), mouse macrophage line RAW264.7 and rat hepatic stellate cell line HSC-T6 were cultured and subjected to I/R injury, respectively. Activation of Notch signaling was assessed by NICD western blot. Then, pharmacological inhibitor (γ-secretase inhibitor GSI) was used to block Notch signaling of related cell lines in vitro. Intracellular ROS was detected and analyzed by FACS and apoptosis was examined by TUNEL staining and Annexin V staining. RESULTS: Notch signaling responded to I/R injury and I/R injury induced activation of Notch signaling in nonparenchymal cells. Notch signal deficiency led to overproduction of ROS and aggravated cell death of non-parenchymal cells subjected to I/R injury. CONCLUSION: Notch signal protects non-parenchymal cells from I/R injury by repressing ROS.


Assuntos
Hepatopatias/prevenção & controle , Fígado/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Receptores Notch/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Apoptose , Linhagem Celular , Inibidores Enzimáticos/farmacologia , Células Estreladas do Fígado/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Macrófagos/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Receptores Notch/antagonistas & inibidores , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos
18.
Vascul Pharmacol ; 58(1-2): 64-70, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22820258

RESUMO

Evidence has indicated that resveratrol (Res) produces vasorelaxation and may decrease the coronary heart disease mortality. However, several pathways involved in the mechanism of vasorelaxation are still unclear. This study was designed, therefore, to test the probable ion channels or receptors involved in the mechanism. The abdominal aortic rings from the male Sprague-Dawley rats were perfused in the organ chambers filled with Kreb's solution, where the tension of each ring was measured. Treatment with L-NAME (a nitric oxide synthase inhibitor), glibenclamide and tetraethylammonium (TEA) significantly attenuated the vasorelaxing effect of Res. In lower concentration Res relaxed the ring in an endothelium-dependent manner, while in higher concentration the endothelium-independent manner could be observed. In calcium-free Kreb's solution, Res inhibited vasoconstriction induced by NE. With intracellular calcium depleted by thapsigargin, Res also inhibited vasoconstriction induced by Kreb's solution with high potassium via L-Ca(2+) channel. In a word, Res decreased both extracellular calcium influx and intracellular calcium release. These results suggest that: (1) Res may exert its relaxing effect on abdominal aorta by opening K(+) channel to hyperpolarize vascular smooth muscle.(2) Res relaxes the abdominal aorta in both endothelium-dependent and endothelium-independent manners. (3) Finally, Res attenuates both extracellular calcium influx and intracellular calcium release, which results in vasorelaxation.


Assuntos
Cálcio/metabolismo , Estilbenos/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Glibureto/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Ratos , Ratos Sprague-Dawley , Resveratrol , Tetraetilamônio/farmacologia , Vasoconstrição/efeitos dos fármacos
19.
World J Gastroenterol ; 18(10): 1048-58, 2012 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-22416179

RESUMO

AIM: To compare the influence of different transplant sites in bone marrow mesenchymal stem cell (MSC)-based therapy for liver fibrosis. METHODS: MSCs isolated from Sprague Dawley (SD) rats were induced into hepatocyte-like cells. Liver fibrosis in SD rats was induced with carbon tetrachloride. Following hepatocyte induction in vitro, 4',6-diamidino-2-phenylindole (DAPI)-labeled MSCs were transplanted by intravenous, intrahepatic, and intraperitoneal injection. Histopathological staining, immunohistochemistry, and biochemical analysis were used to compare the morphological and functional liver regeneration among different MSC injection modalities. The expression differences of interleukins, growth factor, extracellular matrix, matrix metalloproteinases, and tissue inhibitor of metalloproteinase were examined by real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA). RESULTS: Four days after exposure to hepatocyte differentiation medium, MSCs that did not express hepatocyte markers could express α-fetoprotein, albumin, and cytokeratin 18. The results of histopathological staining, immunohistochemistry, and biochemical analysis indicated that intravenous injection is more effective at rescuing liver failure than other injection modalities. DAPI-labeled cells were found around liver lobules in all three injection site groups, but the intravenous group had the highest number of cells. PCR and ELISA analysis indicated that interleukin-10 (IL-10) was highest in the intravenous group, whereas il1ß, il6, tnfα and tgfß, which can be regulated by IL10 and are promoters of liver fibrosis, were significantly lower than in the other groups. CONCLUSION: MSC administration is able to protect against liver fibrosis. Intravenous injection is the most favorable treatment modality through promotion of IL10 expression.


Assuntos
Cirrose Hepática/cirurgia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/fisiologia , Animais , Transdiferenciação Celular/fisiologia , Células Cultivadas , Citocinas/metabolismo , Hepatócitos/citologia , Hepatócitos/metabolismo , Injeções Intravenosas , Masculino , Células-Tronco Mesenquimais/citologia , Ratos , Ratos Sprague-Dawley
20.
PLoS One ; 7(12): e51223, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23284668

RESUMO

This study was designed to investigate whether Resveratrol (Res) could be a prophylactic factor in the prevention of I/R injury and to shed light on its underlying mechanism. Primary culture of neonatal rat cardiomyocytes were randomly distributed into three groups: the normal group (cultured cardiomyocytes were in normal conditions), the I/R group (cultured cardiomyocytes were subjected to 2 h simulated ischemia followed by 4 h reperfusion), and the Res+I/R group (100 µmol/L Res was administered before cardiomyocytes were subjected to 2 h simulated ischemia followed by 4 h reperfusion). To test the extent of cardiomyocyte injury, several indices were detected including cell viability, LDH activity, Na(+)-K(+)-ATPase and Ca(2+)-ATPase activity. To test apoptotic cell death, caspase-3 activity and the expression of Bcl-2/Bax were detected. To explore the underlying mechanism, several inhibitors, intracellular calcium, SOD activity and MDA content were used to identify some key molecules involved. Res increased cell viability, Na(+)-K(+)-ATPase and Ca(2+)-ATPase activity, Bcl-2 expression, and SOD level. While LDH activity, capase-3 activity, Bax expression, intracellular calcium and MDA content were decreased by Res. And the effect of Res was blocked completely by either L-NAME (an eNOS inhibitor) or MB (a cGMP inhibitor), and partly by either DS (a PKC inhibitor) or Glybenclamide (a K(ATP) inhibitor). Our results suggest that Res attenuates I/R injury in cardiomyocytes by preventing cell apoptosis, decreasing LDH release and increasing ATPase activity. NO, cGMP, PKC and K(ATP) may play an important role in the protective role of Res. Moreover, Res enhances the capacity of anti-oxygen free radical and alleviates intracellular calcium overload in cardiomyocytes.


Assuntos
Cardiotônicos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle , Estilbenos/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , ATPases Transportadoras de Cálcio/metabolismo , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , L-Lactato Desidrogenase/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Resveratrol , ATPase Trocadora de Sódio-Potássio/metabolismo , Proteína X Associada a bcl-2/metabolismo
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