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1.
Hereditas ; 159(1): 39, 2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36253874

RESUMO

BACKGROUND: Liver ischemia reperfusion injury (LIRI) is not only a common injury during liver transplantation and major hepatic surgery, but also one of the primary factors that affect the outcome of postoperative diseases. However, there are still no reliable ways to tackle the problem. Our study aimed to find some characteristic genes associated with immune infiltration that affect LIRI, which can provide some insights for future research in the future. Therefore, it is essential for the treatment of LIRI, the elucidation of the mechanisms of LIRI, and exploring the potential biomarkers. Efficient microarray and bioinformatics analyses can promote the understanding of the molecular mechanisms of disease occurrence and development. METHOD: Data from GSE151648 were downloaded from GEO data sets, and we performed a comprehensive analysis of the differential expression, biological functions and interactions of LIRI-associated genes. Then we performed Gene ontology (GO) analysis and Kyotoencydlopedia of genes and genomes (KEGG) enrichment analysis of DEGs. At last, we performed a protein-protein interaction network to screen out hub genes. RESULTS: A total of 161 differentially expressed genes (DEGs) were identified. GO analysis results revealed that the changes in the modules were mostly enriched in the neutrophil degranulation, neutrophil activation involved in immune response, and neutrophil mediated immunity. KEGG enrichment analysis of DEGs demonstrated that LIRI mainly involved the cytokine-cytokine receptor interaction. Our data indicated that macrophages and neutrophils are closely related to LIRI. 9 hub genes were screened out in the protein-protein interaction network. CONCLUSIONS: In summary, our data indicated that neutrophil degranulation, neutrophil activation involved in immune response, neutrophil mediated immunity and cytokine-cytokine receptor interaction may play a key role in LIRI, HRH1, LRP2, P2RY6, PKD1L1, SLC8A3 and TNFRSF8, which were identified as potential biomarkers in the occurrence and development of LIRI. However, further studies are needed to validate these findings and explore the molecular mechanism of these biomarkers in LIRI.


Assuntos
Redes Reguladoras de Genes , Traumatismo por Reperfusão , Biomarcadores , Citocinas/genética , Perfilação da Expressão Gênica/métodos , Humanos , Fígado , Proteínas de Membrana/genética , Receptores de Citocinas/genética , Traumatismo por Reperfusão/genética
2.
Hepatobiliary Pancreat Dis Int ; 20(6): 551-560, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33947635

RESUMO

BACKGROUND: The sterile inflammatory response is one of the key mechanisms leading to hepatic ischemia-reperfusion injury. Melatonin has been shown to prevent organ injuries, but its roles in the inflammatory response after hepatic ischemia-reperfusion injury have not been fully explored, especially in late ischemia-reperfusion injury. The present study aimed to investigate the roles and possible mechanisms of melatonin in the inflammatory response after hepatic ischemia-reperfusion injury. METHODS: Sixty Sprague-Dawley rats were randomly divided into a sham group, ischemia-reperfusion injury group (I/R group), and melatonin-treated group (M + I/R group). The rats in the I/R group were subjected to 70% hepatic ischemia for 45 min, followed by 5 or 24 h of reperfusion. The rats in the M + I/R group were injected with melatonin (10 mg/kg, intravenous injection) 15 min prior to ischemia and immediately before reperfusion. Serum and samples of ischemic liver lobes were harvested for future analysis, and the 7-day survival rate was assessed after hepatic ischemia-reperfusion surgery. RESULTS: In comparison with the I/R group, the M + I/R group showed markedly decreased expression levels of inflammatory cytokines (IL-6 and TNF-α) and numbers of apoptotic hepatocytes (P < 0.05). Immunoblotting showed that the expression levels of IL-6, p-NF-κBp65/t-NF-κBp65 and p-IκB-α/t-IκB-α in the M + I/R group were significantly lower than those in the I/R group, and immunofluorescence staining showed that the expression level of p-NF-κBp65 in the M + I/R group was lower than that in the I/R group (P < 0.05). The 7-day survival rates were 20% in the I/R group and 50% in the M + I/R group (P < 0.05). CONCLUSIONS: Melatonin downregulated the activity of the NF-κB signaling pathway in the early and late stages of hepatic ischemia-reperfusion injury, alleviated the inflammatory response, protected the liver from ischemia-reperfusion injury, and increased the survival rate.


Assuntos
Melatonina , Traumatismo por Reperfusão , Animais , Humanos , Fígado/metabolismo , Melatonina/metabolismo , Melatonina/farmacologia , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais
3.
Hepatogastroenterology ; 59(116): 1251-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22440189

RESUMO

Kupffer cells, the resident macrophages of the liver, not only exert phagocytosis but also excrete proinflammatory cytokines. Large amounts of cytokines, produced by activated Kupffer cells, can induce aggravate liver ischemia/reperfusion (I/R) injury. Also, Kupffer cells that express protective genes protect from I/R injury after liver transplantation. Due to their key location, Kupffer cells might function as antigen-presenting cells and participate in transplantation immunity. They also seem to play a key role in innate immune responses and host defence through the expression and secretion of soluble inflammatory mediators. With this review we want to assist in improving the understanding of the contribution of Kupffer cells in liver I/R injury and the development of the transplantation immune. We hope that the delineation of the complex mechanisms of dysregulation may inspire the design and development of novel treatment approaches.


Assuntos
Células de Kupffer/fisiologia , Transplante de Fígado , Animais , Rejeição de Enxerto/imunologia , Heme Oxigenase-1/fisiologia , Humanos , Tolerância Imunológica , Fígado/irrigação sanguínea , Transplante de Fígado/imunologia , Traumatismo por Reperfusão/etiologia
4.
World J Clin Cases ; 9(32): 9699-9710, 2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34877309

RESUMO

Hepatocellular carcinoma (HCC) remains one of the most frequent types of liver cancer and is characterized by a high recurrence rate. Recent studies have proposed that long non-coding RNAs (lncRNAs) are potential biomarkers in several recurrent tumor types. It is now well understood that invasion, migration, and metastasis are important factors for tumor recurrence. Moreover, some of the known risk factors for HCC may affect the expression levels of several types of lncRNAs and thus affect the recurrence of liver cancer through lncRNA regulation. In this paper, we review the biological functions, molecular mechanisms, and roles of lncRNAs in HCC and summarize current knowledge about lncRNAs as potential biomarkers in recurrent HCC.

5.
Hepatogastroenterology ; 57(101): 875-81, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21033245

RESUMO

BACKGROUND/AIMS: Ischemic postconditioning (Postcon) is a phenomenon that intermittent interruptions of blood flow in the early phase of reperfusion can protect organ against ischemia/ reperfusion (I/R) injury. The potential application of postconditioning to liver is not available. In the present study, we investigated the effects of Postcon in liver I/R injury in rat liver transplantation models. METHODOLOGY: Adult male Sprague-Dawley rats were randomly allocated to three groups including sham group without I/R, I/R group with 24h cold ischemic donor liver before orthotopic liver transplantation, and Postcon group treated the same as I/R group and 6 cycles of 60s ischemia and 60s reperfusion at the onset of reperfusion. Peripheral blood samples were collected after reperfusion. Serum transaminases level, plasma cytokines concentration, histopathology, liver tissues malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were measured. The heme oxygenase-1 (HO-1) expression levels of liver were evaluated. RESULTS: Serum transaminases level and plasma cytokines concentration significantly decreased in Postcon group as compared to I/R group. Postcon treatment reduced MDA production and increased SOD activity compared with the I/R group. The HO-1 expression levels of liver were significantly higher in Postcon rats than in the I/R group at the end of reperfusion. CONCLUSIONS: These results indicate that Post-con ameliorates liver I/R injury. This protective effect is likely mediated by up-regulation of HO-1 expression.


Assuntos
Pós-Condicionamento Isquêmico , Transplante de Fígado/fisiologia , Fígado/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Animais , Heme Oxigenase-1/metabolismo , Interleucina-6/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/sangue , Regulação para Cima/fisiologia
6.
Biomed Pharmacother ; 129: 110398, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32603889

RESUMO

Hepatic ischemia reperfusion (I/R) injury (HIRI) HIRI is a complex, multifactorial pathophysiological process and in liver surgery has been known to significantly affect disease prognosis, surgical success rates, and patient survival. Ginsenoside Rgl (Rgl) monomer is one of the main active ingredients of ginseng. Previous studies have demonstrated that Rgl exerts various pharmacological effects through several mechanisms including suppression of apoptosis-related proteins levels, downregulation of inflammatory mediators and as well as antioxidant, which effectively exerts an organ protective effect I/R-induced damage. However, the exact mechanisms of Rg1 on HIRI remain to be elucidated. In the present study, we investigated the protective effect of Rg1 on hepatic ischemia-reperfusion (I/R) injury (HIRI) and explored its underlying molecular mechanism. A rat warm I/R injury model in vivo and an oxygen-glucose deprivation/reperfusion (OGD/R)-treated BRL-3A cell model in vitro were established after pretreating with Rg1(20 mg/kg). The results showed that Rg1 reduced the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). TUNEL staining showed that pretreated with Rg1 inhibited the apoptosis rate compared with the I/R group. Moreover, pretreated with Rg1 significantly reduced the expression of Cyt-C, Caspase-9 and Caspase-3 to inhibit the cell apoptosis. Flow cytometry analysis showed the MMP in the I/R group was significantly increased, whereas pretreated with Rg1 effectively stabilized the MMP compared with the I/R group. in vitro, the proliferation of BRL-3A cells was significantly decreased by the OGD/R treatment, while Rg1 effectively reversed this phenomenon. In addition, western blotting showed that the increase of Cyt-C, Caspase-9 and Caspase-3 was inhibited by H2O2. These observations suggest that Rg1 exerts the protective effect by inhibiting the CypD protein-mediated mitochondrial apoptotic pathway.


Assuntos
Apoptose/efeitos dos fármacos , Ginsenosídeos/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatopatias/prevenção & controle , Fígado/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Peptidil-Prolil Isomerase F/genética , Peptidil-Prolil Isomerase F/metabolismo , Modelos Animais de Doenças , Hepatócitos/metabolismo , Hepatócitos/ultraestrutura , Fígado/metabolismo , Fígado/ultraestrutura , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/ultraestrutura , Ratos Sprague-Dawley , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
7.
Zhonghua Wai Ke Za Zhi ; 47(17): 1343-6, 2009 Sep 01.
Artigo em Zh | MEDLINE | ID: mdl-20092734

RESUMO

OBJECTIVE: To investigate the effects of ischemic postconditioning on the expression of HO-1 in the liver graft ischemia and reperfusion injury in rats. METHODS: Fifty-six male SD rats were randomly divided into four groups: sham-operation group (sham) (n = 8), ischemia and reperfusion group (I/R)(n = 16), ischemic postconditioning group (IPo) (n = 16) and inhibitor of HO-1 group (ZnPP) (n = 16). Donor livers were preserved in 0 - 4 degrees C normal saline, and the period of cold preservation and anhepatic phase were 90 min and 15 min. At 6 h after portal vein reperfusion, blood samples were obtained from the abdominal aorta to determine the level of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), simultaneously liver tissues were taken to determine the level of malondialdehyde (MDA), superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) mRNA. The changes of liver tissues were observed by HE staining and electron microscope. RESULTS: SOD activity was significantly lower whereas MDA content was significantly higher in I/R group than that in Sham group (P < 0.05). The expression of HO-1 in I/R group was higher than that in Sham group (P < 0.05). MDA content was significantly lower whereas SOD activity was significantly higher in IPO group than that in I/R group (P < 0.05), and the expression of HO-1 in IPO group was significantly stronger than that in I/R group (P < 0.05). SOD activity and the expression of HO-1 were significantly lower whereas MDA content was significantly higher in ZnPP group than that in I/R group (P < 0.05). The changes of liver tissues also proved the previous results. CONCLUSIONS: Ischemic postconditioning attenuates liver graft injury induced by I/R in rats. The mechanism might be related with the induction of HO-1 and enhancement of liver graft antioxidation.


Assuntos
Heme Oxigenase (Desciclizante)/metabolismo , Fígado/irrigação sanguínea , Traumatismo por Reperfusão/metabolismo , Animais , Modelos Animais de Doenças , Fígado/metabolismo , Fígado/patologia , Transplante de Fígado , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia
8.
World J Gastroenterol ; 21(10): 2937-48, 2015 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-25780291

RESUMO

AIM: To investigate the efficacy and molecular mechanisms of induced heme oxygenase (HO)-1 in protecting liver from warm ischemia/reperfusion (I/R) injury. METHODS: Partial warm ischemia was produced in the left and middle hepatic lobes of SD rats for 75 min, followed by 6 h of reperfusion. Rats were treated with saline, cobalt protoporphyrin (CoPP) or zinc protoporphyrin (ZnPP) at 24 h prior to the ischemia insult. Blood and samples of ischemic lobes subjected to ischemia were collected at 6 h after reperfusion. Serum transaminases level, plasma lactate dehydrogenase and myeloperoxidase activity in liver were measured. Liver histological injury and inflammatory cell infiltration were evaluated by tissue section and liver immunohistochemical analysis. We used quantitative reverse transcription polymerase chain reaction to analyze liver expression of inflammatory cytokines and chemokines. The cell lysates were subjected to immunoprecipitation with anti-Toll-IL-1R-containing adaptor inducing interferon-ß (TRIF) and anti-myeloid differentiation factor 88 (MyD88), and then the immunoprecipitates were analyzed by SDS-PAGE and immunoblotted with the indicated antibodies. RESULTS: HO-1 protected livers from I/R injury, as evidenced by diminished liver enzymes and well-preserved tissue architecture. In comparison with ZnPP livers 6 h after surgery, CoPP treatment livers showed a significant increase inflammatory cell infiltration of lymphocytes, plasma cells, neutrophils and macrophages. The Toll-like receptor (TLR)-4 and TANK binding kinase 1 protein levels of rats treated with CoPP significantly reduced in TRIF-immunoprecipitated complex, as compared with ZnPP treatment. In addition, pretreatment with CoPP reduced the expression levels of TLR2, TLR4, IL-1R-associated kinase (IRAK)-1 and tumor necrosis factor receptor-associated factor 6 in MyD88-immunoprecipitated complex. The inflammatory cytokines and chemokines mRNA expression rapidly decreased in CoPP-pretreated liver, compared with the ZnPP-treated group. However, the expression of negative regulators Toll-interacting protein, suppressor of cytokine signaling-1, IRAK-M and Src homology 2 domain-containing inositol-5-phosphatase-1 in CoPP treatment rats were markedly up-regulated as compared with ZnPP-treated rats. CONCLUSION: HO-1 protects liver against I/R injury by inhibiting TLR2/TLR4-triggered MyD88- and TRIF-dependent signaling pathways and increasing expression of negative regulators of TLR signaling in rats.


Assuntos
Heme Oxigenase (Desciclizante)/metabolismo , Fígado/efeitos dos fármacos , Protoporfirinas/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Receptor 2 Toll-Like/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Isquemia Quente/efeitos adversos , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Citoproteção , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Fígado/enzimologia , Fígado/imunologia , Fígado/patologia , Masculino , Fator 88 de Diferenciação Mieloide/metabolismo , Ratos Sprague-Dawley , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo
9.
World J Gastroenterol ; 18(15): 1765-72, 2012 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-22553400

RESUMO

AIM: To evaluate the effects of diazoxide on ischemia/reperfusion (I/R)-injured hepatocytes and further elucidate its underlying mechanisms. METHODS: Male Sprague-Dawley rats were randomized (8 for donor and recipient per group) into five groups: I/R group (4 h of liver cold ischemia followed by 6 h of reperfusion); heme oxygenase-1 (HO-1) small interfering RNA (siRNA) group (injection of siRNA via donor portal vein 48 h prior to harvest); diazoxide (DZ) group (injection of DZ via donor portal vein 10 min prior to harvest); HO-1 siRNA + DZ group; and siRNA control group. Blood and liver samples were collected at 6 h after reperfusion. The mRNA expressions and protein levels of HO-1 were determined by reverse transcription polymerase chain reaction and Western blotting, and tissue morphology was examined by light and transmission electron microscopy. Serum transaminases level and cytokines concentration were also measured. RESULTS: We observed that a significant reduction of HO-1 mRNA and protein levels in HO-1 siRNA and HO-1 siRNA + DZ group when compared with I/R group, while the increases were prominent in the DZ group. Light and transmission electron microscopy indicated severe disruption of tissue with lobular distortion and mitochondrial cristae damage in the HO-1 siRNA and HO-1 siRNA + DZ groups compared with DZ group. Serum alanine aminotransferase, aspartate transaminase, tumor necrosis factor-α and interleukin-6 levels increased in the HO-1 siRNA and HO-1 siRNA + DZ groups, and decreased in the DZ group. CONCLUSION: The protective effect of DZ may be induced by upregulation of HO-1. By inhibiting expression of HO-1, this protection pretreated with DZ was abolished.


Assuntos
Diazóxido/farmacologia , Heme Oxigenase (Desciclizante)/fisiologia , Transplante de Fígado/efeitos adversos , Fígado/irrigação sanguínea , Traumatismo por Reperfusão/tratamento farmacológico , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Citocinas/sangue , Diazóxido/uso terapêutico , Heme Oxigenase (Desciclizante)/análise , Heme Oxigenase (Desciclizante)/genética , Fígado/patologia , Fígado/ultraestrutura , Masculino , Microscopia Eletrônica de Transmissão , Canais de Potássio/fisiologia , Ratos , Ratos Sprague-Dawley , Regulação para Cima
10.
World J Gastroenterol ; 16(10): 1285-92, 2010 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-20222175

RESUMO

AIM: To examine whether heme oxygenase (HO)-1 overexpression would exert direct or indirect effects on Kupffer cells activation, which lead to aggravation of reperfusion injury. METHODS: Donors were pretreated with cobalt protoporphyrin (CoPP) or zinc protoporphyrin (ZnPP), HO-1 inducer and antagonist, respectively. Livers were stored at 4 degrees C for 24 h before transplantation. Kupffer cells were isolated and cultured for 6 h after liver reperfusion. RESULTS: Postoperatively, serum transaminases were significantly lower and associated with less liver injury when donors were pretreated with CoPP, as compared with the ZnPP group. Production of the cytokines tumor necrosis factor-alpha and interleukin-6 generated by Kupffer cells decreased in the CoPP group. The CD14 expression levels (RT-PCR/Western blots) of Kupffer cells from CoPP-pretreated liver grafts reduced. CONCLUSION: The study suggests that the potential utility of HO-1 overexpression in preventing ischemia/reperfusion injury results from inhibition of Kupffer cells activation.


Assuntos
Heme Oxigenase-1/metabolismo , Células de Kupffer/fisiologia , Transplante de Fígado , Traumatismo por Reperfusão/metabolismo , Animais , Células Cultivadas , Citoproteção , Interleucina-6/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Fígado/metabolismo , Testes de Função Hepática , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismo
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