RESUMO
Liver fibrosis, a consequence of unhealthy modern lifestyles, has a growing impact on human health, particularly in developed countries. Here, we have explored the anti-fibrotic effects of propylene glycol alginate sodium sulphate (PSS), a natural extract from brown algae, in fibrotic mice and cell models. Thus, we established bile duct ligature and carbon tetrachloride mouse models and LX-2 cell models with or without PSS treatment. Liver pathological sections and the relevant indicators in serum and liver tissues were examined. PSS prevented hepatic injury and fibrosis to a significant extent, and induced up-regulation of matrix metalloproteinase-2 and down-regulation of tissue inhibitor of metalloproteinase-1 through suppressing the transforming growth factor ß1 (TGF-ß1)/Smad pathway. PSS additionally exerted an anti-autophagy effect through suppressing the Janus kinase (JAK) 2/transducer and activator of transcription 3 (STAT3) pathway. In conclusion, PSS prevents hepatic fibrosis by suppressing inflammation, promoting extracellular matrix (ECM) decomposition and inactivating hepatic stellate cells through mechanisms involving the TGF-ß1/Smad2/3 and JAK2/STAT3 pathways in vivo and in vitro.
Assuntos
Alginatos/uso terapêutico , Janus Quinases/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Alginatos/farmacologia , Animais , Autofagia/efeitos dos fármacos , Ductos Biliares/patologia , Tetracloreto de Carbono , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Ligadura , Cirrose Hepática/enzimologia , Cirrose Hepática/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND AND AIM: Liver fibrosis is a worldwide clinical challenge during the progression of chronic liver disease to liver cirrhosis. Shikonin is extracted from the root of Lithospermum erythrorhizon with antioxidant, anti-inflammatory, anticancer, and wound-healing properties. The study aims to investigate the protective effect of shikonin on liver fibrosis and its underlying mechanism. METHODS: Two liver fibrosis models were established in male C57 mice by intraperitoneal injection of CCl4 or bile duct ligation. Shikonin was administered orally three times weekly at a dose of 2.5 or 5 mg/kg. Protein and mRNA expressions were assayed by quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemical staining. RESULTS: Shikonin significantly inhibited activation of hepatic stellate cells and extracellular matrix formation by downregulating the transforming growth factor-ß1 expression and maintaining the normal balance between metalloproteinase-2 and tissue inhibitor of metalloproteinase-1. Shikonin also decreased hepatic stellate cell energy production by inhibiting autophagy. CONCLUSIONS: The results confirmed that shikonin attenuated liver fibrosis by downregulating the transforming growth factor-ß1/Smads pathway and inhibiting autophagy.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Naftoquinonas/farmacologia , Proteínas Smad Reguladas por Receptor/antagonistas & inibidores , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Alanina Transaminase/sangue , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspartato Aminotransferases/sangue , Autofagia/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Matriz Extracelular/metabolismo , Células Estreladas do Fígado/fisiologia , Cirrose Hepática/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Naftoquinonas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-1/metabolismoRESUMO
Hepatocellular carcinoma (HCC) is one of the few cancers with a continuous increase in incidence and mortality. Drug resistance is a major problem in the treatment of HCC. In this study, two sorafenib-resistant HCC cell lines and a nude mouse subcutaneously tumor model were used to explore the possible mechanisms leading to sorafenib resistance, and to investigate whether aspirin could increase the sensitivity of hepatoma cells to sorafenib. The combination of aspirin and sorafenib resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. High glycolysis and PFKFB3 overexpression occupied a dominant position in sorafenib resistance, and can be targeted and overcome by aspirin. Aspirin plus sorafenib induced apoptosis in tumors without inducing weight loss, hepatotoxicity or inflammation. Our results suggest that aspirin overcomes sorafenib resistance and their combination may be an effective treatment approach for HCC.
Assuntos
Aspirina/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Fosfofrutoquinase-2/genética , Animais , Aspirina/farmacologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Nus , Niacinamida/administração & dosagem , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Fosfofrutoquinase-2/metabolismo , Sorafenibe , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Genistein is a natural isoflavone with many health benefits, including antitumour effects. Increased hypoxia-inducible factor 1 α (HIF-1α) levels and glycolysis in tumour cells are associated with an increased risk of mortality, cancer progression, and resistance to therapy. However, the effect of genistein on HIF-1α and glycolysis in hepatocellular carcinoma (HCC) is still unclear. METHODS: Cell viability, apoptosis rate, lactate production, and glucose uptake were measured in HCC cell lines with genistein incubation. Lentivirus-expressed glucose transporter 1 (GLUT1) or/and hexokinase 2 (HK2) and siRNA of HIF-1α were used to test the direct target of genistein. Subcutaneous xenograft mouse models were used to measure in vivo efficacy of genistein and its combination with sorafenib. RESULTS: Genistein inhibited aerobic glycolysis and induced mitochondrial apoptosis in HCC cells. Neither inhibitors nor overexpression of HK2 or GLUTs enhance or alleviate this effect. Although stabiliser of HIF-1α reversed the effect of genistein, genistein no longer has effects on HIF-1α siRNA knockdown HCC cells. In addition, genistein enhanced the antitumour effect of sorafenib in sorafenib-resistant HCC cells and HCC-bearing mice. CONCLUSIONS: Genistein sensitised aerobic glycolytic HCC cells to apoptosis by directly downregulating HIF-1α, therefore inactivating GLUT1 and HK2 to suppress aerobic glycolysis. The inhibitory effect of genistein on tumour cell growth and glycolysis may help identify effective treatments for HCC patients at advanced stages.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Genisteína/farmacologia , Glicólise/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: Shikonin possesses anti-inflammatory effects. However, its function in concanavalin A-induced acute liver injury remains uncertain. The aim of the present study was to investigate the functions of shikonin and its mechanism of protection on ConA-induced acute liver injury. MATERIALS AND METHODS: Balb/C mice were exposed to ConA (20 mg/kg) via tail vein injection to establish acute liver injury; shikonin (7.5 mg/kg and 12.5 mg/kg) was intraperitoneally administered 2 h before the ConA injection. The serum liver enzyme levels and the inflammatory cytokine levels were determined at 3, 6, and 24 h after ConA injection. RESULTS: After the injection of ConA, inflammatory cytokines IL-1ß, TNF-α, and IFN-γ were significantly increased. Shikonin significantly ameliorated liver injury and histopathological changes and suppressed the release of inflammatory cytokines. The expressions of Bcl-2 and Bax were markedly affected by shikonin pretreatment. LC3, Beclin-1, and p-JNK expression levels were decreased in the shikonin-pretreated groups compared with the ConA-treated groups. Shikonin attenuated ConA-induced liver injury by reducing apoptosis and autophagy through the inhibition of the JNK pathway. CONCLUSION: Our results indicated that shikonin pretreatment attenuates ConA-induced acute liver injury by inhibiting apoptosis and autophagy through the suppression of the JNK pathway.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Concanavalina A/toxicidade , Naftoquinonas/uso terapêutico , Animais , Western Blotting , Imuno-Histoquímica , Interferon gama/metabolismo , Interleucina-1beta/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Objective: Non-alcoholic fatty liver disease (NAFLD) can be attributed to the dysregulation of hepatic lipid metabolism; however, its cellular and molecular mechanisms remain unclear. This study aims to explore the effect of long non-coding RNA growth arrest specific 5 (GAS5) on hepatic lipid metabolism in fatty liver models. Methods: Obese mice, high fat diet-fed mice and free fatty acid-stimulated cells were used for GAS5 expression detection. GAS5 overexpression or knockdown models were established to elucidate the regulatory function of GAS5 in de novo lipogenesis (DNL) and mitochondrial function. Bioinformatic analyses and dual luciferase assays were used to investigate the interaction between GAS5, miR-26a-5p and phosphodiesterase (PDE) 4B. The involvement of the cyclic adenosine monophosphate (cAMP)/cAMP-response element-binding protein (CREB) pathway was evaluated using H89 and forskolin treatment. Results: GAS5 was activated in vitro and in vivo fatty liver models. Knockdown of GAS5 reduced lipid droplet accumulation, DNL associated enzymes and preserved mitochondrial function, while GAS5 overexpression exacerbated hepatic lipid accumulation. Mechanistically, GAS5 sponged miR-26a-5p to increase PDE4B expression and subsequently modulated DNL and mitochondrial function via the cAMP/CREB pathway. Conclusion: Downregulation of GAS5 can activate the cAMP/CREB pathway through miR-26a-5p/PDE4B axis to mitigate hepatic lipid accumulation. This study provides evidence that downregulation of GAS5 may be a potential therapeutic option for the treatment of NAFLD.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , MicroRNAs , Hepatopatia Gordurosa não Alcoólica , RNA Longo não Codificante , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Ácidos Graxos não Esterificados , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
Long non-coding RNAs (lncRNAs) play critical functions in various cancers. Firre intergenic repeating RNA element (FIRRE), a lncRNA located in the nucleus, was overexpressed in colorectal cancer (CRC). However, the detailed mechanism of FIRRE in CRC remains elusive. Results of RNA sequence and qPCR illustrated overexpression of FIRRE in CRC cell lines and tissues. The aberrant expression of FIRRE was correlated with the migration, invasion, and proliferation in cell lines. In accordance, it was also associated with lymphatic metastasis and distant metastasis in patients with CRC. FIRRE was identified to physically interact with Polypyrimidine tract-binding protein (PTBP1) by RNA pull-down and RNA immunoprecipitation (RIP). Overexpression of FIRRE induced the translocation of PTBP1 from nucleus to cytoplasm, which was displayed by immunofluorescence and western blot. In turn, delocalization of FIRRE from nucleus to cytoplasm is observed after the loss of PTBP1. The RNA-protein complex in the cytoplasm directly bound to BECN1 mRNA, and the binding site was at the 3' end of the mRNA. Cells with FIRRE and PTBP1 depletion alone or in combination were treated by Actinomycin D (ACD). Results of qPCR showed FIRRE stabilized BECN1 mRNA in a PTBP1-medieated manner. In addition, FIRRE contributed to autophagy activity. These findings indicate FIRRE acts as an oncogenic factor in CRC, which induces tumor development through stabilizing BECN1 mRNA and facilitating autophagy in a PTBP1-mediated manner.
Assuntos
Autofagia , Proteína Beclina-1/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Oncogenes/fisiologia , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , RNA Longo não Codificante/fisiologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
OBJECTIVE: The study was aimed to explore the hepatocellular protective functions of cafestol during hepatic ischemia-reperfusion injury and the possible mechanisms. METHODS: Ninety male Balb/c mice were randomly divided into seven groups, including normal control group, L-cafestol(20mg/kg) group, H-cafestol(40mg/kg) group, sham group, IR group, L-cafestol(20mg/kg) + IR group, H-cafestol(40mg/kg) + IR group. Serum liver enzymes (ALT, AST), inflammation mediators, proteins associated with apoptosis and autophagy, indicators linked with ERK/PPARγ pathway, and liver histopathology were measured using ELISA, qRT-PCR, immunohistochemical staining, and western blotting at 2, 8, and 24 hours after reperfusion. RESULTS: Our findings confirmed that cafestol preconditioning groups could reduce the levels of ALT and AST, alleviate liver pathological damage, suppress the release of inflammation mediators, inhibit the production of pro-apoptosis protein including caspase-3, caspase-9 and Bax, decrease the expression of autophagy-linked protein including Beclin-1 and LC3, increase anti-apoptosis protein Bcl-2, and restrain the activation of ERK and PPARγ. CONCLUSION: Cafestol preconditioning could attenuate inflammatory response, apoptosis and autophagy on hepatic ischemia reperfusion injury by suppressing ERK/PPARγ pathway.
Assuntos
Diterpenos/administração & dosagem , Hepatopatias/tratamento farmacológico , Substâncias Protetoras/administração & dosagem , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Células Cultivadas , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , PPAR gama/genética , PPAR gama/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Isorhamnetin, a flavonoid compound extracted from plants' fruit or leaves, like sea buckthorn (Hippophae rhamnoides L.), has many biological functions, including anti-tumor, anti-oxidant and anti-inflammatory effect. The present study is in order to explore the hepatoprotective effect of isorhamnetin on concanavalin A (ConA)-induced acute fulminant hepatitis and the underlying mechanism. Mice were injected with ConA (25â¯mg/kg) to induce acute fulminant hepatitis, three doses of isorhamnetin (10/30/90â¯mg/kg) was intraperitoneally administrated about 1â¯h previously. The serum and liver tissues were harvested at 2, 8, and 24â¯h after ConA injection. The levels of serum liver enzymes and proinflammatory cytokines were significantly reduced in isorhamnetin administration groups. Besides, isorhamnetin improved pathological damage. Furthermore, isorhamnetin affected P38/PPAR-α pathway, and subsequently regulated the expression of apoptosis and autophagy related proteins. The present study investigated that isorhamnetin inhibits apoptosis and autophagy via P38/PPAR-α pathway in mice.
Assuntos
Autofagia/fisiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Sistema de Sinalização das MAP Quinases/fisiologia , PPAR alfa/metabolismo , Quercetina/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Autofagia/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Concanavalina A/toxicidade , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , PPAR alfa/antagonistas & inibidores , Quercetina/farmacologia , Quercetina/uso terapêuticoRESUMO
Salidroside (Sal) is a glycoside extract from Rhodiola rosea L. with anti-inflammatory, antioxidant, anticancer and cardioprotective properties. The present study explored the protective effects and the possible mechanisms of Sal on concanavalin A (ConA)-induced liver injury in mice. Balb/C mice were divided into five groups: Normal control (injected with normal saline), ConA (25 mg/kg), Sal (10 mg/kg) +ConA, Sal (20 mg/kg) + ConA (Sal injected 2 h prior to ConA injection) and Sal (20 mg/kg) only. The serum levels of liver enzymes, pro-inflammatory cytokines, and apoptosis- and autophagy-associated marker proteins were determined at 2, 8 and 24 h after ConA injection. LY294002 was further used to verify whether the phosphoinositide 3-kinase (PI3K)/Akt pathway was activated. Primary hepatocytes were isolated to verify the effect of Sal in vitro. The results indicated that Sal was a safe agent to reduce pathological damage and serum liver enzymes in ConA-induced liver injury. Sal suppressed inflammatory reactions in serum and liver tissues, and activated the PI3K/Akt signaling pathway to inhibit apoptosis and autophagy in vivo and in vitro, which could be reversed by LY294002. In conclusion, Sal attenuated ConA-induced liver injury by modulating PI3K/Akt pathway-mediated apoptosis and autophagy in mice.
RESUMO
Portulaca oleracea L. is a traditional Chinese medicine, which has been used as adjuvant therapy for inflammatory bowel disease (IBD). However, the mechanism of its activity in IBD still remains unclear. Since previous studies have documented the anti-inflammatory effect of peroxisome proliferator activated receptors-γ (PPAR-γ), Portulaca regulation of PPAR-γ in inflammation was examined in current study. Ulcerative colitis (UC) was generated by 5% dextran sulfate sodium (DSS) in mice and four groups were established as normal control, DSS alone, DSS plus mesalamine, and DSS plus Portulaca. Severity of UC was evaluated by body weight, stool blood form, and length of colorectum. Inflammation was examined by determination of inflammatory cytokines (TNF-a, IL-6, and IL-1a). Portulaca extract was able to attenuate development of UC in DSS model similar to the treatment of mesalazine. Moreover, Portulaca extract inhibited proinflammatory cytokines release and reduced the level of DSS-induced NF-κB phosphorylation. Furthermore, Portulaca extract restored PPAR-γ level, which was reduced by DSS. In addition, Portulaca extract protected DSS induced apoptosis in mice. In conclusion, Portulaca extract can alleviate colitis in mice through regulation of inflammatory reaction, apoptosis, and PPAR-γ level; therefore, Portulaca extract can be a potential candidate for the treatment of IBD.
RESUMO
Ischemia-reperfusion injury (IRI) contributes to liver damage in many clinical situations, such as liver resection and liver transplantation. In the present study, we investigated the effects of the antioxidant, anti-inflammatory, and anticancer agent salidroside (Sal) on hepatic IRI in mice. The mice were randomly divided into six groups: normal control, Sham, Sal (20 mg/kg), IRI, IRI + Sal (10 mg/kg), and IRI + Sal (20 mg/kg). We measured liver enzymes, proinflammatory cytokines, TNF-α and interleukin-6, and apoptosis- and autophagy-related marker proteins at 2, 8, and 24 hours after reperfusion. Components of mitogen-activated protein kinase (MAPK) signaling, including P-38, jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK), were also measured using an MAPK activator anisomycin to deduce their roles in hepatic IRI. Our results show that Sal safely protects hepatocytes from IRI by reducing levels of liver enzymes in the serum. These findings were confirmed by histopathology. We concluded that Sal protects hepatocytes from IRI partly by inhibiting the activation of MAPK signaling, including the phosphorylation of P38, JNK, and ERK. This ameliorates inflammatory reactions, apoptosis, and autophagy in the mouse liver.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Glucosídeos/farmacologia , Fígado/irrigação sanguínea , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fenóis/farmacologia , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Anisomicina/farmacologia , Citocinas/análise , Citocinas/metabolismo , Ativadores de Enzimas/farmacologia , Hepatócitos/efeitos dos fármacos , Testes de Função Renal , Fígado/patologia , Testes de Função Hepática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação/efeitos dos fármacos , Traumatismo por Reperfusão/patologiaRESUMO
Quercetin, as a member of the flavonoids family, has many beneficial properties. The aim of our study was to evaluate the protective effect of quercetin in ConA-induced hepatitis in mice, and to clarify its mechanism of action. Hepatitis was induced by using ConA (25 mg/kg), and quercetin was administered intragastrically at the dose of 100 mg/kg or 200 mg/kg for 5 days before ConA injection. The serum levels of liver enzymes, inflammatory cytokines and other marker proteins were determined at 2 h, 8 h and 24 h after ConA injection. Following ConA injection, serum levels of liver enzymes and inflammatory cytokines were significantly increased. Quercetin ameliorated liver damage and histopathological changes, and suppressed the release of inflammatory cytokines. The expression of Bax, Bcl-2, Beclin-1, LC3, P62 and caspase 9 were markedly affected by quercetin pretreatment. The expression of TRAF6 and p-JNK were decreased in the quercetin groups. Quercetin attenuated apoptosis and autophagy in ConA-induced autoimmune hepatitis by inhibiting TRAF6/JNK pathway.
Assuntos
Antioxidantes/uso terapêutico , Hepatite/metabolismo , Hepatite/prevenção & controle , Sistema de Sinalização das MAP Quinases/fisiologia , Quercetina/uso terapêutico , Fator 6 Associado a Receptor de TNF/metabolismo , Doença Aguda , Animais , Antioxidantes/farmacologia , Hepatite/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Quercetina/farmacologia , Fator 6 Associado a Receptor de TNF/antagonistas & inibidores , Resultado do TratamentoRESUMO
Methyl jasmonate has recently been found to have anti-cancer activity. Methyl jasmonate detached hexokinase 2 from a voltage dependent anion channel causing a reduction in mitochondrial transmembrane potential that led to the release of cytochrome C and apoptosis inducing factor resulting in intrinsic apoptosis. Blocked adenosine triphosphate synthesis caused by mitochondrial injury hampered oxidative phosphorylation and led to cell necrosis. The results were applied to the in vivo treatment of nude mice with a satisfactory effect. Collectively, our results suggest that methyl jasmonate may be an adjuvant therapy for liver tumors due to its mechanism in cancer cells compared to that in normal cells: The major function is to inhibit glycolysis instead of changing aerobic metabolism.
Assuntos
Acetatos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Ciclopentanos/farmacologia , Neoplasias Hepáticas/metabolismo , Oxilipinas/farmacologia , Reguladores de Crescimento de Plantas/farmacologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Metabolismo Energético/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Hexoquinase/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Necrose/tratamento farmacológico , Necrose/metabolismo , Necrose/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIMS: Propylene glycol alginate sodium sulfate (PSS), a sulfated polysaccharide possesses anti-inflammatory effects. Here, we investigated the effect of PSS on concanavalin A (Con A)-induced liver injury in mice and examined the underlying mechanisms. MAIN METHODS: Balb/C mice were injected intravenously with Con A (25mg/kg) to generate a model of acute liver injury. PSS (25 or 50mg/kg) was injected intraperitoneally 1h before the Con A administration. The levels of serum liver enzymes, inflammatory cytokines, and other marker proteins were determined, and liver injury was assessed histopathologically 2, 8, and 24h after Con A injection. KEY FINDINGS: Pretreatment with PSS reduced the levels of serum liver enzymes, inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, and attenuated histopathological damage in Con A-induced liver injury in mice. The effects of Con A were mediated by apoptosis and autophagy, as indicated by changes in protein and gene expression of related factors after Con A injection. PSS activated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway and showed a protective function against apoptosis and autophagy. SIGNIFICANCE: PSS ameliorated Con A-induced liver injury by downregulating inflammatory cytokines including TNF-α and IL-1ß and regulating apoptosis and autophagy via the PI3K/Akt pathway.
Assuntos
Alginatos/farmacologia , Citocinas/metabolismo , Hepatite Autoimune/prevenção & controle , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Alginatos/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Concanavalina A/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hepatite Autoimune/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The aim of this study was to investigate the effect of quercetin on hepatic fibrosis, a characteristic response to acute or chronic liver injury. Mice were randomized to bile duct ligation (BDL) or carbon tetrachloride (CCl4) cirrhosis models. Quercetin (100 mg/kg or 200 mg/kg daily) was administered by gavage for 2 or 4 weeks. Liver tissue and blood samples were collected for histological and molecular analysis. The results of our experiments showed that quercetin reduced BDL or CCl4 liver fibrosis, inhibited extracellular matrix formation, and regulated matrix metallopeptidase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1. Quercetin attenuated liver damage by suppressing the TGF-ß1/Smads signaling pathway and activating the PI3K/Akt signaling pathway to inhibit autophagy in BDL- or CCl4- induced liver fibrosis. Quercetin prevented hepatic fibrosis by attenuating hepatic stellate cell activation and reducing autophagy through regulating crosstalk between the TGF-ß1/Smads and PI3K/Akt pathways.
Assuntos
Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Autofagia/efeitos dos fármacos , Biópsia , Tetracloreto de Carbono/efeitos adversos , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Expressão Gênica , Cirrose Hepática/patologia , Cirrose Hepática/prevenção & controle , Testes de Função Hepática , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Quercetina/farmacologia , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismoRESUMO
BACKGROUND: Hepatic ischemia reperfusion (IR) injury is a common phenomenon in transplantation or trauma. The aim of the present study was to determine the protective effect of quercetin (QE) on hepatic IR injury via the ERK/NF-κB pathway. METHODS: Mice were randomized into the sham, IR, QE100 + IR, and QE200 + IR groups. Quercetin was administered intragastrically daily at two doses (100 mg/kg and 200 mg/kg) for 5 days prior to IR injury. The expression levels of liver enzymes, inflammatory cytokines, and other marker proteins were determined at 2, 8, and 24 hours after IR. And they were compared among these groups. RESULTS: Compared with the IR group, the treatment of QE reduced the release of cytokines, leading to inhibition of apoptosis and autophagy via downregulation of the ERK/NF-κB pathway in this model of hepatic IR injury. CONCLUSION: Apoptosis and autophagy caused by hepatic IR injury were inhibited by QE following a reduction in the release of inflammatory cytokines, and the relationship between the two may be associated with inactivation of the ERK/NF-κB pathway.
RESUMO
Objective. The present study was conducted to compare the efficacy of metformin combined with diammonium glycyrrhizinate enteric-coated capsule (DGEC) versus metformin alone versus DGEC alone for the treatment of nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). Subjects and Methods. 163 patients with NAFLD and T2DM were enrolled in this 24-week study and were randomized to one of three groups: group 1 was treated with metformin alone; group 2 was treated with DGEC alone; group 3 received metformin plus DGEC combination therapy. Anthropometric parameters, liver function, lipid profile, serum ferritin (SF), metabolic parameters, liver/spleen computed tomography (CT) ratio, and fibroscan value were evaluated at baseline and after 8, 16, and 24 weeks of treatment. Results. After 24 weeks, significant improvements in all measured parameters were observed in three groups (P < 0.05) except for the improvements in low density lipoprotein cholesterol (LDL-C) and metabolic parameters in group 2 which did not reach statistical significance (P > 0.05). Compared with group 1 and group 2, the patients in group 3 had greater reductions in observed parameters apart from CB and TB (P < 0.05). Conclusions. This study showed that metformin plus DGEC was more effective than metformin alone or DGEC alone in reducing liver enzymes, lipid levels, and metabolic parameters and ameliorating the degree of hepatic fibrosis in patients with NAFLD and T2DM.
RESUMO
Hepatic ischemia/reperfusion (I/R) injury, which can result in severe liver injury and dysfunction, occurs in a variety of conditions such as liver transplantation, shock, and trauma. Cell death in hepatic I/R injury has been linked to apoptosis and autophagy. Shikonin plays a significant protective role in ischemia/reperfusion injury. The purpose of the present study was to investigate the protective effect of shikonin on hepatic I/R injury and explore the underlying mechanism. Mice were subjected to segmental (70%) hepatic warm ischemia to induce hepatic I/R injury. Two doses of shikonin (7.5 and 12.5 mg/kg) were administered 2 h before surgery. Balb/c mice were randomly divided into four groups: normal control, I/R, and shikonin preconditioning at two doses (7.5 and 12.5 mg/kg). The serum and liver tissues were collected at three time points (3, 6, and 24 h). Shikonin significantly reduced serum AST and ALT levels and improved pathological features. Shikonin affected the expression of Bcl-2, Bax, caspase 3, caspase 9, Beclin-1, and LC3, and upregulated PI3K and p-Akt compared with the levels in the I/R group. Shikonin attenuated hepatic I/R injury by inhibiting apoptosis and autophagy through a mechanism involving the activation of PI3K/Akt signaling.
Assuntos
Fígado/patologia , Naftoquinonas/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Substâncias Protetoras/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/enzimologia , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Citocinas/metabolismo , Dimetil Sulfóxido , Ativação Enzimática/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Mediadores da Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Fígado/ultraestrutura , Testes de Função Hepática , Masculino , Camundongos Endogâmicos BALB C , Modelos Biológicos , Naftoquinonas/farmacologia , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologiaRESUMO
Emerging evidence shows that the Hedgehog pathway and the long noncoding RNA TUG1 play pivotal roles in cell proliferation, migration, and invasion in tumors. However, the mechanism underlying the effect of TUG1 and the Hedgehog pathway in hepatoma remains undefined. In the present study, we showed that the expression of TUG1 was negatively correlated with that of microRNA (miR)-132, and depletion of TUG1 inhibited the activation of the Hedgehog pathway in vitro and in vivo. We showed that TUG1 functions as a competing endogenous (ceRNA) by competing with miR-132 for binding to the sonic hedgehog protein in HCC, thereby suppressing the activation of Hedgehog signaling and its tumorigenic effect. These data indicate that targeting the TUG1-miR132-Hedgehog network could be a new strategy for the treatment of HCC.