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1.
Eur Rev Med Pharmacol Sci ; 25(19): 6077-6092, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34661268

RESUMO

OBJECTIVE: Obstructive jaundice (OJ) is a common clinical pathological syndrome in hepatobiliary surgery. High incidence of multiple organ injuries during perioperative period and its associated mortality remains challenging in clinical practice. Omega-3 polyunsaturated fatty acids (ω-3 PUFA) is an important enteral immune nutrition. This study investigated the protective role of ω-3 PUFA in the regulation of inflammatory response in OJ. MATERIALS AND METHODS: Seventy-two rats were randomly divided into obstructive jaundice (OJ) group, obstructive jaundice + ω-3 PUFA group (OJPUFA) group, and sham group. OJ model was created by ligation of the bile duct. Abdominal thoracic catheter was placed to collect lymph. Body weight, liver function, serum and lymphatic levels of TNF-α, IL-1ß, IL-10, HMGB1, and nitric oxide (NO) were measured on day 3, day 7, and day 14 after operation. Hematoxylin staining and Alcian blue-periodic acid-Shiff (AB-PAS) staining were performed on the ileum tissue. Protein and mRNA expression of HMGB1, TLR4, and NF-κB p65 were measured at the aforementioned time points. RESULTS: The general condition, including body weight and liver function, were worse in the OJ and the OJPUFA group compared to that in the sham group. On day 14, the body weight recovery and liver function were significantly better in the OJPUFA group than those in the OJ group were (p<0.05 for all). No marked change in the serum and lymphatic levels of TNF-α, IL-1ß, IL-10, HMGB1 and NO was observed in the sham group after operation, while corresponding levels in the OJ and the OJPUFA groups were significantly higher. Compared with the OJPUFA group, serum and lymphatic levels of the above factors were consistently higher in the OJ group and were significantly higher on day 14 (p<0.05 for all). At the same time, ω-3 PUFA lowered the damage of intestinal villi and intestinal mucosal epithelium. It also improved the number and function of goblet cells in intestinal mucosal epithelium. The protein and mRNA expression of HMGB1, TLR4, and NF-κB p65 were significantly higher in the OJ group than those in the OJPUFA group (p<0.05 for all). CONCLUSIONS: ω-3 PUFA has protective effect in the management of obstructive jaundice. It can regulate the inflammatory response and reduce its damage to intestinal structure. Reducing the activation of HMGB1/TLR4/ NF-κB pathway might be a mechanism for its protective effect. We suggested that ω-3 PUFA and drugs targeted HMGB1/TLR4/NF-κB pathway might be potential treatment strategies in obstructive jaundice.


Assuntos
Ácidos Graxos Ômega-3/farmacologia , Inflamação/prevenção & controle , Icterícia Obstrutiva/tratamento farmacológico , Animais , Modelos Animais de Doenças , Proteína HMGB1/metabolismo , Inflamação/etiologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Icterícia Obstrutiva/fisiopatologia , Masculino , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Receptor 4 Toll-Like/metabolismo
4.
Cancer Gene Ther ; 20(6): 366-74, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23703473

RESUMO

STAT1 has a key role in exerting the antiproliferative and proapoptotic effects of interferon (IFN)-α on tumors, and its defects in expression is associated with IFN-α resistance. In this study we want to investigate whether aspirin can improve the antitumor efficiency of IFN-α on hepatocellular carcinoma (HCC) through the activation of STAT1. We found that aspirin not only significantly enhanced IFN-α-induced antiproliferation and apoptosis of HCC in vitro study but also enhanced tumor growth inhibition in nude mice. Although IFN-α alone resulted in significant phosphorylation of both STAT1 and STAT3, aspirin only prompted the IFN-α-induced phosphorylation of STAT1. Further study revealed that aspirin-prompted phosphorylation of STAT1 was activated through phosphorylation of JAK1. Furthermore, aspirin-activated STAT1 upregulated the transcription of proapoptotic IFN-stimulated gene (ISG) of X-linked inhibitor of apoptosis-associated factor-1 and downregulated the transcription of antiapoptotic ISG of G1P3, which in turn promoted the expression of Bax and activation of caspase-9 and caspase-3, thereby sensitizing HCC cells to IFN-α-induced apoptosis. Taken together, our findings suggest a novel strategy of using aspirin to overcome tumor resistance and enhance the effectiveness of IFN-α in HCC treatment through activating STAT1 gene, and have potential implications for improving future IFN-α protein and gene therapy.


Assuntos
Aspirina/administração & dosagem , Carcinoma Hepatocelular/patologia , Janus Quinase 1/biossíntese , Neoplasias Hepáticas/patologia , Fator de Transcrição STAT1/biossíntese , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interferon-alfa/administração & dosagem , Interferon-alfa/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Camundongos , Transdução de Sinais
5.
Cancer Gene Ther ; 18(9): 617-26, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21637307

RESUMO

Recurrence and metastasis are frequently observed after radiotherapy for hepatocellular carcinoma (HCC), although upregulation of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) induced by radiation has been claimed to be involved, the mechanism is not clarified yet. In the present study, by using MHCC97L, a human HCC cell line with metastatic potential, and its xenograft in nude mice, we found that radiation induced a 48- to 72-h temporary increase in the expression of MMP-2 and VEGF both in vitro and in vivo, but only the in vitro invasiveness of MHCC97L cells was enhanced, while the in vivo metastatic potential of tumors was suppressed. Whereas, 30 days after radiation, when the expression of MMP-2 and VEGF decreased to unirradiated control levels, the in vivo dissemination and metastatic potential of residual tumors have just begun to increase with overexpression of TMPRSS4, which induced loss of E-cadherin through induction of Smad-Interacting Protein 1 (SIP1), an E-cadherin transcriptional repressor, and led to epithelial-mesenchymal transition (EMT). This process was blocked by treatment of siRNA-TMPRSS4. In conclusion, our study revealed novel findings regarding the biphasic effect of radiation on the metastatic potential of residual HCC. Overexpression of TMPRSS4 has a critical role in radiation-induced long-term dissemination and metastasis of residual HCC by facilitating EMT. These findings may provide new clues to suppress the radiation-induced dissemination and metastasis, thereby improve the prognosis of HCC patients.


Assuntos
Carcinoma Hepatocelular/complicações , Transição Epitelial-Mesenquimal/efeitos da radiação , Proteínas de Membrana/metabolismo , Metástase Neoplásica , Serina Endopeptidases/metabolismo , Animais , Western Blotting , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Imuno-Histoquímica , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina Endopeptidases/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Raios X , Ensaios Antitumorais Modelo de Xenoenxerto
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