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1.
J Cell Mol Med ; 24(9): 5304-5316, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32243714

RESUMO

A growing number of studies recognize that long non-coding RNAs (lncRNAs) are essential to mediate multiple tumorigenic processes, including hepatic tumorigenesis. However, the pathological mechanism of lncRNA-regulated liver cancer cell growth remains poorly understood. In this study, we identified a novel function lncRNA, named polo-like kinase 4 associated lncRNA (lncRNA PLK4, GenBank Accession No. RP11-50D9.3), whose expression was dramatically down-regulated in hepatocellular carcinoma (HCC) tissues and cells. Interestingly, talazoparib, a novel and highly potent poly-ADP-ribose polymerase 1/2 (PARP1/2) inhibitor, could increase lncRNA PLK4 expression in HepG2 cells. Importantly, we showed that talazoparib-induced lncRNA PLK4 could function as a tumour suppressor gene by Yes-associated protein (YAP) inactivation and induction of cellular senescence to inhibit liver cancer cell viability and growth. In summary, our findings reveal the molecular mechanism of talazoparib-induced anti-tumor effect, and suggest a potential clinical use of talazoparib-targeted lncRNA PLK4/YAP-dependent cellular senescence for the treatment of HCC.

2.
Apoptosis ; 24(11-12): 905-920, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31538267

RESUMO

Hepatic stellate cell (HSC) activation plays an indispensable role in hepatic fibrosis. Inducing apoptosis of activated HSCs can attenuate or reverse fibrogenesis. In this study, we initially found that oroxylin A (OA) protected CCl4-induced liver injury accompanied by endoplasmic reticulum stress (ERS) activation of HSCs in mice. In vitro, OA treatment markedly reduced fibrogenesis by modulating extracellular matrix synthesis and degradation. OA inhibited cell proliferation and induced cell cycle arrest of HSCs at S phase. Further, OA was observed to induce HSC apoptosis, as indicated by caspase activation. Using the eIF2α dephosphorylation inhibitor salubrinal, we found that ERS pathway activation was required for OA to induce HSC apoptosis. ERS-related proteins were significantly upregulated by OA treatment, and salubrinal abrogated the effects of OA on HSCs. Thus, we inferred that OA attenuated HSC activation by promoting ERS. In vivo, inhibition of ERS by salubrinal partly abrogated the hepatoprotective effect of OA in CCl4-treated mice. In conclusion, our findings suggest a role for ERS in the mechanism underlying amelioration of hepatic fibrosis by OA.

3.
Int Immunopharmacol ; 75: 105816, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31437794

RESUMO

Docosahexaenoic acid (DHA) has been found to have a hepatoprotective effect. In this study, we investigated the role of peroxisome proliferator-activated receptor γ (PPARγ) in DHA regulation of liver fibrosis. DHA was found to inhibit hepatic stellate cell (HSC)-LX2 cell viability and downregulate marker proteins of HSC activation. Furthermore, DHA induced cell cycle arrest at G1 phase in HSCs. Antagonism of PPARγ by GW9662 abrogated the effects of DHA on HSCs. Computer-aided molecular docking predicted that DHA bound to PPARγ via hydrogen bonding with residues Ser289, His323, Tyr473, and His499. We overexpressed Ser289 mutant PPARγ in HSC-LX2 cells and investigated fibrotic marker modulation, and found that DHA effects on HSCs were diminished. Thus, bonding with the Ser289 residue might be indispensable for DHA to activate PPARγ to exert its inhibiting effect on activated HSCs. Last, data from a CCl4-treated mouse model confirmed that PPARγ activation was required for DHA to attenuate liver fibrosis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , PPAR gama/imunologia , Animais , Tetracloreto de Carbono , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ácidos Docosa-Hexaenoicos/farmacologia , Células Estreladas do Fígado/imunologia , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos ICR
4.
IUBMB Life ; 71(11): 1740-1750, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31265202

RESUMO

Alcoholic liver disease (ALD) is generated from excessive alcohol consumption, characterized by hepatic steatosis. Mechanistically, excessive hepatic lipid accumulation was attributed to the aberrant lipin-1 signaling during the development of alcoholic steatosis in rodent species and human. Dihydroartemisinin (DHA) has been recently identified to relieve hepatocytes necrosis and prevent from hepatic steatosis in alcohol-induced liver diseases; however, the role of DHA in ALD has not been elucidated completely. Therefore, this study was aimed to further identify the potential mechanisms of pharmacological effects of DHA on ALD. Results demonstrated that DHA regulated the expression and nucleocytoplasmic shuttling of lipin-1 in mice with chronic ethanol exposure. Results confirmed that the disruption of lipin-1 signaling abolished the suppression of DHA on alcohol-induced hepatic steatosis. Interestingly, DHA also significantly improved liver injury, and inflammation mediated by lipin-1 signaling in chronic alcohol-fed mice. in vivo experiments further consolidated the concept that DHA protected against hepatocyte lipoapoptosis dependent on the regulation of nucleocytoplasmic shuttling of lipin-1 signaling, resulting in attenuated ratio of Lpin1 ß/α. Obvious increases in cell apoptosis were observed in alcohol-treated lipin1ß-overexpressed mice. Although DHA attenuated cell apoptosis, overexpression of lipin-1ß neutralized DHA action. DHA ameliorated activation of endoplasmic reticulum stress through inhibiting activation of JNK and CHOP, which was abrogated by overexpression of lipin-1ß. In summary, DHA significantly improved liver injury, steatosis and hepatocyte lipoapoptosis in chronic alcohol-fed mice via regulation of lipin-1 signaling.

5.
Trends Plant Sci ; 24(7): 569-571, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31101402

RESUMO

It is well known that E3 ubiquitin ligase COP1 is a negative regulator of plant photomorphogenesis. However, COP1 acts as a positive regulator under UV-B light. A recent study (Ren et al. Proc. Natl. Acad. Sci. U. S. A. 2019;116:4722-4731) proposes a two-step protein degradation model to explain how COP1 switches its role in response to UV-B light.

6.
Plant Physiol ; 180(4): 1793-1802, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31113832
7.
Life Sci ; 226: 91-97, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30978348

RESUMO

The liver is importantly metabolic and detoxifying organ in the body. When various pathogenic factors affect the liver, the normal physiological and biochemical functions are weakened, resulting in liver diseases. Liver fibrosis is a common pathological process of chronic liver disease. During hepatic fibrosis the changes in the components of the extracellular matrix (ECM) provide an environment that facilitates tissue remodeling. Among these ECM components, periostin, a glycoprotein that is predominantly secreted by osteoblasts and their precursors, playing an important role in bone formation, has attracted great attention. Periostin not only involves in bone metabolism, but also functions in modulating the cell fate determination, proliferation, inflammatory responses, even tumorigenesis of many other tissues and organs including liver. In different categories of liver disease patients, the serum and liver tissue levels of periostin were closely related to the decline of liver function, and the pathological stage. Numerous animal studies and experiments in vitro subsequently demonstrated that the abnormal expression of periostin resulted in metabolic disorders, liver inflammation, fibrosis and even tumorigenesis. Here we review the current progress on the role of periostin in pathologic pathways of liver system to explore whether periostin is a potential therapeutic target for the treatment of different liver diseases.


Assuntos
Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/fisiologia , Hepatopatias/metabolismo , Animais , Diferenciação Celular , Doença Crônica , Matriz Extracelular , Células Estreladas do Fígado , Hepatite , Humanos , Fígado/metabolismo , Fígado/fisiologia , Cirrose Hepática , Hepatopatias/fisiopatologia , Transdução de Sinais
8.
Toxicol In Vitro ; 57: 226-232, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30853489

RESUMO

Alcoholic liver disease (ALD), featured by excessive hepatocyte death and inflammation, is a prevalent disease that causes heavy health burdens worldwide. Hepatocyte necroptosis is a central event that promotes inflammation in ALD. At molecular levels, inhibition of nuclear factor (erythroid - derived 2) - like 2 (NRF2) was an important trigger for cell necroptosis. The protective effects of gallic acid (GA) on liver diseases caused by multiple factors have been elucidated, however, the role of GA in ALD remained unclear. Therefore, this study was aimed to investigate the anti-ALD effects of GA and further reveal the molecular mechanisms. Results showed that GA could effectively recover cell viability and reduce the release of aspartate transaminase, alanine transaminase, and lactic dehydrogenase by ethanol-stimulated hepatocytes. More importantly, GA limited hepatocyte necroptosis under ethanol stimulation, which was characterized by reduced expression of distinct necroptotic signals receptor-interacting protein 1 (RIP1) and RIP3 and release of high mobility group box protein 1. Mechanistically, GA could induce NRF2 expression in ethanol-incubated hepatocytes, which was a molecular basis for GA to suppress ethanol-induced hepatocyte necroptosis. In conclusion, this study demonstrated that GA improved ethanol-induced hepatocyte necroptosis in vitro. Further, NRF2 activation might be requisite for GA to exert its protective effects.


Assuntos
Etanol/toxicidade , Ácido Gálico/farmacologia , Hepatócitos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Substâncias Protetoras/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fator 2 Relacionado a NF-E2/genética , Necrose/induzido quimicamente , Necrose/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Ligação a RNA/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética
9.
Sci China Life Sci ; 62(3): 423-425, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30547348
10.
Redox Biol ; 19: 375-387, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30237126

RESUMO

It is generally recognized that hepatic fibrogenesis is an end result of increased extracellular matrix (ECM) production from the activation and proliferation of hepatic stellate cells (HSCs). An in-depth understanding of the mechanisms of HSC necroptosis might provide a new therapeutic strategy for prevention and treatment of hepatic fibrosis. In this study, we attempted to investigate the effect of curcumol on necroptosis in HSCs, and further to explore the molecular mechanisms. We found that curcumol ameliorated the carbon tetrachloride (CCl4)-induced mice liver fibrosis and suppressed HSC proliferation and activation, which was associated with regulating HSC necroptosis through increasing the phosphorylation of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3). Moreover, curcumol promoted the migration of RIPK1 and RIPK3 into necrosome in HSCs. RIPK3 depletion impaired the anti-fibrotic effect of curcumol. Importantly, we showed that curcumol-induced RIPK3 up-regulation significantly increased mitochondrial reactive oxygen species (ROS) production and mitochondrial depolarization. ROS scavenger, N-acetyl-L-cysteine (NAC) impaired RIPK3-mediated necroptosis. In addition, our study also identified that the activation of c-Jun N-terminal kinase1/2 (JNK1/2) was regulated by RIPK3, which mediated curcumol-induced ROS production. Down-regulation of RIPK3 expression, using siRIPK3, markedly abrogated JNK1/2 expression. The use of specific JNK1/2 inhibitor (SP600125) resulted in the suppression of curcumol-induced ROS production and mitochondrial depolarization, which in turn, contributed to the inhibition of curcumol-triggered necroptosis. In summary, our study results reveal the molecular mechanism of curcumol-induced HSC necroptosis, and suggest a potential clinical use of curcumol-targeted RIPK1/RIPK3 complex-dependent necroptosis via JNK1/2-ROS signaling for the treatment of hepatic fibrosis.


Assuntos
Células Estreladas do Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Necrose/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Sesquiterpenos/farmacologia , Acetilcisteína/farmacologia , Animais , Tetracloreto de Carbono/toxicidade , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/genética , Distribuição Aleatória , Espécies Reativas de Oxigênio/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética
11.
Plant Cell Environ ; 41(12): 2858-2868, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30088270

RESUMO

Ethylene stimulates the exaggerated hook formation in etiolated seedlings. It has been reported that other phytohormones, such as jasmonate or gibberellins, could inhibit or coordinate hook formation, respectively. However, whether any environmental factors participate in this process is unknown. Here, we show that in darkness, high ambient temperature suppresses the ethylene-triggered exaggerated hook formation in wild-type plants and reduces the hook curvatures in constitutively ethylene responsive mutants. Interestingly, high temperature does not abrogate the activity of the central transcription factor EIN3, suggesting that high temperature acts downstream of ethylene signaling. Next, we show that the natural auxin levels in the hook regions are reduced and their asymmetric distributions are disturbed upon high temperature treatment. To explore the mechanisms for reducing auxin accumulation, we monitor the transcription of several genes encoding auxin biosynthesis related enzymes and find that most YUCCA genes are transcriptionally down-regulated. Finally, we show that the currently reported plant thermo-sensory components in light-grown plants (phytochrome or PIF4) are not sufficient for thermo-sensing in etiolated seedlings. We speculate that in darkness, plants sense high ambient temperature through a distinct mechanism. Taken together, we demonstrate that high temperature suppresses ethylene-induced exaggerated hook formation via the inhibition of local auxin activities.


Assuntos
Arabidopsis/crescimento & desenvolvimento , Etilenos/metabolismo , Reguladores de Crescimento de Planta/metabolismo , Plântula/crescimento & desenvolvimento , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Ligação a DNA , Temperatura Alta , Ácidos Indolacéticos/metabolismo , Microscopia Confocal , Proteínas Nucleares/metabolismo , Plântula/metabolismo , Fatores de Transcrição/metabolismo
12.
Chem Biol Interact ; 285: 14-20, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29476730

RESUMO

Accumulating data reveal that oroxylin A has beneficial effects against chronic liver disease. The previously studies showed oroxylin A, a flavonoid extracted from Scutellariae radix, improved acute liver injury and accelerated liver regeneration in vivo. However, it's unclear that the effect of oroxylin A on alcoholic liver disease. The present study was aimed at elucidating the effect of oroxylin A on alcohol-induced hepatic steatosis and the underlying mechanisms. Human hepatocyte LO2 were cultured and stimulated with ethanol for inducing LO2 damage. We examined the effects of oroxylin A on the accumulation of lipid droplets in ethanol-treated LO2. The results showed that oroxylin A reduced the accumulation of lipid droplets associated with regulating the lipid metabolism genes. Moreover, oroxylin A significantly suppressed the nuclear translocation of HIF-1α in ethanol-treated LO2. Furthermore, activation of HIF-1α significantly attenuated the effect of oroxylin A on lipid droplets accumulation and genes related to lipid metabolism in vitro and in vivo. Altogether, we demonstrated a HIF-1α-associated mechanism underlying oroxylin A inhibition of lipid deposition in ethanol-stimulated LO2. Oroxylin A modulation of HIF-1α level may represent a therapeutic remedy for ALD.


Assuntos
Etanol/toxicidade , Flavonoides/farmacologia , Hepatócitos/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Células Cultivadas , Fígado Gorduroso/prevenção & controle , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Extratos Vegetais/farmacologia
13.
Theranostics ; 8(3): 610-626, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29344293

RESUMO

Rationale: Hepatic stellate cells (HSCs) are liver-specific pericytes regulating vascular remodeling during hepatic fibrosis. Here, we investigated how ligustrazine affects HSC pericyte functions. Methods: Rat HSC-T6 and human HSC-LX2 cells were cultured, and multiple molecular experiments including real-time PCR, Western blot, flow cytometry, immunofluorescence, electrophoretic mobility shift assay and co-immunoprecipitation were used to elucidate the underlying mechanisms. Molecular simulation and site-directed mutagenesis were performed to uncover the target molecule of ligustrazine. Rats were intoxicated with CCl4 for evaluating ligustrazine's effects in vivo. Results: Ligustrazine inhibited angiogenic cytokine production, migration, adhesion and contraction in HSCs, and activated PPARγ. Selective PPARγ inhibitor GW9662 potently abrogated ligustrazine suppression of HSC pericyte functions. Additionally, HIF-1α inhibitor PX-478 repressed HSC pericyte functions, and ligustrazine inhibited the transcription of HIF-1α, which was diminished by GW9662. Moreover, ligustrazine downregulation of HIF-1α was rescued by knockdown of SMRT, and ligustrazine increased PPARγ physical interaction with SMRT, which was abolished by GW9662. These findings collectively indicated that activation of PPARγ by ligustrazine led to transrepression of HIF-1α via a SMRT-dependent mechanism. Furthermore, molecular docking evidence revealed that ligustrazine bound to PPARγ in a unique double-molecule manner via hydrogen bonding with the residues Ser289 and Ser342. Site-directed mutation of Ser289 and/or Ser342 resulted in the loss of ligustrazine transrepression of HIF-1α in HSCs, indicating that interactions with both the residues were indispensable for ligustrazine effects. Finally, ligustrazine improved hepatic injury, angiogenesis and vascular remodeling in CCl4-induced liver fibrosis in rats. Conclusions: We discovered a novel ligand activation pattern for PPARγ transrepression of the target gene with therapeutic implications in HSC pericyte biology and liver fibrosis.


Assuntos
Células Estreladas do Fígado/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , PPAR gama/agonistas , Pericitos/metabolismo , Pirazinas/farmacologia , Vasodilatadores/farmacologia , Animais , Sítios de Ligação , Linhagem Celular , Humanos , Ligantes , Masculino , Correpressor 2 de Receptor Nuclear/metabolismo , PPAR gama/química , PPAR gama/metabolismo , Ligação Proteica , Ratos , Ratos Sprague-Dawley
14.
Cell Prolif ; 51(3): e12431, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29318697

RESUMO

OBJECTIVES: Oroxylin A, a natural flavonoid isolated from Scutellaria baicalensis, has been reported to have anti-hepatic injury effects. However, the effects of oroxylin A on alcoholic liver disease (ALD) remains unclear. The aim of this study was to elucidate the effects of oroxylin A on ALD and the potential mechanisms. MATERIALS AND METHODS: Male ICR mice and human hepatocyte cell line LO2 were used. Yes-associated protein (YAP) overexpression and knockdown were achieved using plasmid and siRNA technique. Cellular senescence was assessed by analyses of the senescence-associated ß-galactosidase (SA-ß-gal), senescence marker p16, p21, Hmga1, cell cycle and telomerase activity. RESULTS: Oroxylin A alleviated ethanol-induced hepatocyte damage by suppressing activities of supernatant marker enzymes. We found that oroxylin A inhibited ethanol-induced hepatocyte senescence by decreasing the number of SA-ß-gal-positive LO2 cells and reducing the expression of senescence markers p16, p21 and Hmga1 in vitro. Moreover, oroxylin A affected the cell cycle and telomerase activity. Of importance, we revealed that YAP pharmacological inhibitor verteporfin or YAP siRNA eliminated the effect of oroxylin A on ethanol-induced hepatocyte senescence in vitro, and this was further supported by the evidence in vivo experiments. CONCLUSION: Therefore, these aggregated data suggested that oroxylin A relieved alcoholic liver injury possibly by inhibiting the senescence of hepatocyte, which was dependent on its activation of YAP in hepatocytes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Senescência Celular/efeitos dos fármacos , Etanol/toxicidade , Flavonoides/farmacologia , Fosfoproteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Expressão Gênica , Hepatócitos/efeitos dos fármacos , Hepatócitos/fisiologia , Humanos , Fígado/patologia , Hepatopatias Alcoólicas/tratamento farmacológico , Masculino , Camundongos Endogâmicos ICR , Fosfoproteínas/genética , Transdução de Sinais , Fatores de Transcrição
15.
Biomed Pharmacother ; 97: 975-984, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29136776

RESUMO

Alcoholic liver disease (ALD), characterized by accumulation of fatty acids in liver cells, is usually caused by Chronic alcohol consumption. Our previous study has identified that DA protects against alcoholic liver injury in alcohol-fed rats through alleviating hepatocyte steatosis. It has emerged that saturated fatty acids could provoke endoplasmic reticulum (ER) stress and apoptosis in hepatocytes. This study was aimed to explore the impact of DA on ALD and further elaborate the underlying mechanisms. Results demonstrated that DA attenuates alcoholic liver injury in mice. Our results also indicated that DA attenuated lipid accumulation in hepatocytes exposed to ethanol. DA attenuates ethanol-induced hepatocyte apoptosis. Results demonstrated that DA dose-dependently ameliorated activation of mitochondrial pathway activation, which plays a critical role in apoptosis attributed to lipotoxicity. Further, DA suppressed the activation of JNK and the expression of CHOP, attributed to the inhibition of ER stress. It has emerged that activation of ER stress-JNK/CHOP-mitochondria cascade is considered as the key mechanisms underlying hepatocyte lipoapoptosis. In addition, DA attenuates PI3K/Akt Pathway in hepatocytes, consistent with our previous finding in HSCs. DA effects were reinforced by PI3K specific inhibitor LY294002. In summary, DA significantly protected hepatocytes against lipoapoptosis via a PI3K/Akt Pathway inhibition-dependent mechanism.


Assuntos
Apoptose/efeitos dos fármacos , Artemisininas/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Animais , Cromonas/farmacologia , Etanol/toxicidade , Hepatócitos/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Hepatopatias Alcoólicas/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
16.
J Cell Biochem ; 119(2): 2258-2268, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28857294

RESUMO

Angiogenesis of liver sinusoidal endothelial cells (LSECs) accompanies with hypoxia in liver fibrosis and they are of mutual promotion, which has raised wide concern. Here we established murine model of liver fibrosis and found that oroxylin A (40 mg/kg) could ameliorate angiogenesis in liver fibrosis may related to hypoxia inducible factor 1α (HIF-1α). The underlying mechanism was further investigated by isolating and culturing murine primary LSECs. Hypoxia induced vascular endothelial growth factor A (VEGF-A), angiopoietin 2 (Ang-2), and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) elevated in LSECs were reduced by oroxylin A or acriflavine (ACF, an HIF-1α inhibitor), indicating HIF-1α involved the angiogenesis of LSECs. Additionally, interference with Yes-associated protein (YAP) significant downregulated the protein expression of HIF-1α and VEGF-A, while YAP plasmid exhibited an opposite effect. We next found that oroxylin A inhibited hypoxia-induced nuclear translocation of YAP, which may influence the accumulation of HIF-1α and subsequently decrease transcription of downstream target gene including VEGF-A and Ang-2, thereby exerting an anti-angiogenic activity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Flavonoides/administração & dosagem , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Cirrose Hepática/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Fosfoproteínas/metabolismo , Angiopoietina-2/genética , Angiopoietina-2/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Proteínas de Ciclo Celular , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Flavonoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Masculino , Camundongos , Neovascularização Patológica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
Biofactors ; 43(6): 836-846, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29048780

RESUMO

Varied pathogenetic elements have been touched upon the liver fibrosis, including inflammatory, stress, apoptosis and unfolded proteins aggregation. Magnesium Isoglycyrrhizinate (MgIG) has been accepted to be a neuroprotective effect, hepatoprotective and anti-inflammatory molecule. In our vitro researches, MgIG was considered to activate hepatic stellate cells (HSCs) apoptosis by promoting endoplasmic reticulum stress (ERS) detrimental response to a certain extent. Consequently, MgIG showed its potential therapeutic capacity in fibrogenesis and counteracted the pathogenetic aspects, which were involved in integrating current treatments correcting liver fibrosis. In addition, we further verificated the behavior and pathogenic mechanisms in the CCl4 -induced liver fibrosis in male mice. What surprised us was that with the treatment of MgIG caused the activation of ERS and resisted the activated HSCs in the protective effects on liver damage. We found MgIG significantly promoted the apoptosis of activated HSCs and protected the CCl4 -induced liver fibrosis. Main molecules came down to the unfolded protein response signaling pathway. Furthermore, MgIG inhibited the levels of the downstream inflammatory cytokines, which were triggered by CCl4 -induced liver fibrosis. Here, we reported that MgIG improved behavioral impairments induced by intraperitoneal injection of CCl4 and decreased the expression of proinflammatory factor, which indicated the preserving effects on liver fibrosis. © 2017 BioFactors, 43(6):836-846, 2017.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Apoptose/genética , Tetracloreto de Carbono , Linhagem Celular , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclina E/genética , Ciclina E/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Regulação da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Transdução de Sinais , Resposta a Proteínas não Dobradas/efeitos dos fármacos , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
19.
Trends Plant Sci ; 22(6): 451-454, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28420557

RESUMO

The jasmonate signaling pathway has been established for 10 years. Nonetheless, two recent reports suggest that its temporal and spatial regulation is worth further investigation. These reports show that jasmonate responses decay gradually with increasing plant age and that signaling components vary between different tissues.


Assuntos
Ciclopentanos/metabolismo , Regulação da Expressão Gênica de Plantas/fisiologia , Oxilipinas/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
20.
Oxid Med Cell Longev ; 2017: 1406726, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28303169

RESUMO

Accumulating data reveal that garlic has beneficial effects against chronic liver disease. We previously reported that diallyl trisulfide (DATS), the primary organosulfur compound in garlic, reduced fibrosis and attenuated oxidative stress in rat fibrotic liver. The present study was aimed at elucidating the underlying mechanisms. The primary rat hepatic stellate cells (HSCs) were cultured and stimulated with hydrogen peroxide (H2O2) for inducing HSC activation under oxidative stress. We examined the effects of DATS on the profibrogenic properties and oxidative stress in H2O2-treated HSCs. The results showed that DATS suppressed and reduced fibrotic marker expression in HSCs. DATS arrested cell cycle at G2/M checkpoint associated with downregulating cyclin B1 and cyclin-dependent kinase 1, induced caspase-dependent apoptosis, and reduced migration in HSCs. Moreover, intracellular levels of reactive oxygen species and lipid peroxide were decreased by DATS, but intracellular levels of glutathione were increased in HSCs. Furthermore, DATS significantly elevated hydrogen sulfide (H2S) levels within HSCs, but iodoacetamide (IAM) reduced H2S levels and significantly abrogated DATS production of H2S within HSCs. IAM also abolished all the inhibitory effects of DATS on the profibrogenic properties and oxidative stress in HSCs. Altogether, we demonstrated an H2S-associated mechanism underlying DATS inhibition of profibrogenic properties and alleviation of oxidative stress in HSCs. Modulation of H2S production may represent a therapeutic remedy for liver fibrosis.


Assuntos
Compostos Alílicos/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Sulfeto de Hidrogênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sulfetos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Cirrose Hepática/patologia , Ratos
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