Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Life Sci ; 238: 116976, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31634464

RESUMO

AIM: The purpose of the present study was to elucidate the protective effect of histone deacetylase 6 inhibitor ACY1215 on autophagy pathway in acute liver failure (ALF). MAIN METHODS: Lipopolysaccharide (LPS) and d-galactosamine (D-Gal) were used to induce ALF model in C57BL/6 mice. D-Gal and tumor necrosis factor alpha (TNF-α) were applied in L02 cell. Autophagy inhibitor 3-MA and ACY1215 were conducted to induce 3-MA group, ACY1215 group and ACY1215+3-MA group. RESULTS: ACY1215 improved liver histological and functional changes in ALF mice model, whereas the autophagy inhibitor 3-MA aggravated liver tissue pathological and functional damage in ALF mice model group. The apoptotic levels (including apoptotic index/rate and apoptotic proteins) in ALF mice and L02 cell were ameliorated with treatment ACY1215. 3-MA accentuated the apoptotic levels in ACY1215 group. D-Gal/TNF-α could reduce L02 cell mitochondrial membrane potential (ΔΨm) in control group. ACY1215 increased the ΔΨm in ALF model. 3-MA also further reduced the ΔΨm in ACY1215 group. ACY1215 could induce autophagy in ALF mice and cell model group accompanied with an increase in expression of LC3-II and beclin-1 proteins and down-regulation of p62 protein. Moreover, the expression of LC3-II and beclin1 proteins were greatly reduced and the expression of p62 protein was ascended after intervention with 3-MA in ACY1215 group. SIGNIFICANCE: Histone deacetylase 6 inhibitor ACY1215 could protect acute liver failure mice and L02 cell by inhibiting apoptosis pathway through enhancing autophagy way.

2.
Biomed Pharmacother ; 117: 109166, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31255993

RESUMO

BACKGROUND: Histone deacetylase 6 (HDAC6) has been considered as an important regulator in the development of inflammatory diseases. However, the mechanism of HDAC6 in regulating inflammatory responses has not been fully determined. In the present study, we aim to investigate the role and mechanisms of HDAC6 in regulating inflammation in lipopolysaccharide (LPS)-activated macrophages. METHODS: Flow cytometry was used to determine a suitable treatment dosage of ACY-1215 on lipopolysaccharide (LPS)-activated macrophages for the present study. The RAW264.7 macrophages were divided into normal, LPS-treated, and ACY-1215 treated groups, respectively. For the ACY-1215 group, ACY-1215 (10 µM) was added to the medium 2 h prior to treatment with LPS (1 µg/ml) for 24 h. In this study, ROS, inflammatory cytokines, the ultrastructure of mitochondria, mitochondrial membrane potential, RNA and protein expression assay were detected respectively. Subsequently, the effect of HDAC6 knockdown on inflammatory response in LPS-activated RAW264.7 macrophages was also detected. RESULTS: Inhibition of HDAC6 inhibited the overproduction of ROS and suppressed the expression of pro-inflammatory cytokines such as TNF-α, IL-1ß, and IL-6 in LPS-activated RAW264.7 cells. Pretreatment with ACY-1215 could normalize the ultrastructure of mitochondria and mitochondrial membrane potential in LPS-activated macrophages. Moreover, the protein expression of TLR4, Nrf2, HO-1 and the activation of MAPK and NF-κB signaling pathways were normalized by the inhibition of HDAC6. CONCLUSIONS: Inhibition of HDAC6 exhibited protective role against LPS-induced inflammation in RAW264.7 cells by regulating oxidative stress and suppressing the activation of TLR4- MAPK/NF-κB signaling pathway.

3.
Oxid Med Cell Longev ; 2019: 8173016, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183000

RESUMO

The purpose of this study was to investigate the modulation of histone deacetylase 2 (HDAC2) on mitochondrial apoptosis in acute liver failure (ALF). The cellular model was established with LO2 cells stimulated by tumor necrosis factor alpha (TNF-α)/D-galactosamine (D-gal). Rats were administrated by lipopolysaccharide (LPS)/D-gal as animal model. The cell and animal models were then treated by HDAC2 inhibitor CAY10683. HDAC2 was regulated up or down by lentiviral vector transfection in LO2 cells. The mRNA levels of bcl2 and bax were detected by real-time PCR. The protein levels of HDAC2, bcl2, bax, cytochrome c (cyt c) in mitochondrion and cytosol, apoptosis protease activating factor 1 (apaf1), caspase 3, cleaved-caspase 3, caspase 9, cleaved-caspase 9, acetylated histone H3 (AH3), and histone H3 (H3) were assayed by western blot. Apoptosis was detected by flow cytometry. The serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) levels were also assayed. The openness degree of the mitochondrial permeability transition pore (MPTP) was detected by ultraviolet spectrophotometry. The apoptosis of hepatocytes in liver tissues was determined by tunnel staining. The liver tissue pathology was detected by hematoxylin eosin (HE) staining. The ultrastructure of liver tissue was observed by electron microscopy. Compared with cell and rat model groups, the bax mRNA level was decreased, and bcl2 mRNA was increased in the CAY10683 treatment group. The protein levels of HDAC2, bax, cyt c in cytosol, apaf1, cleaved-caspase 3, and cleaved-caspase 9 were decreased, and the apoptosis rate was decreased (P < 0.05), whereas the protein level of bcl2 and cyt c in the mitochondrion was elevated (P < 0.05) in the CAY10683 treatment group. In the HDAC2 down- or upregulated LO2 cells, the mitochondrial apoptosis pathway was inhibited or activated, respectively. After being treated with TNF-α/D-gal in HDAC2 down- or upregulated LO2 cells, the mitochondrial apoptosis pathway was further suppressed or activated, respectively. The MPTP value was elevated in CAY10683-treated groups compared with the rat model group (P < 0.05). Liver tissue pathological damage and apoptotic index in the CAY10683-treated group were significantly reduced. In addition, AH3 was elevated in both cell and animal model groups (P < 0.05). Downregulated or overexpressed HDAC2 could accordingly increase or decrease the AH3 level, and TNF-α/D-gal could enhance the acetylation effect. These results suggested that modulations of histone deacetylase 2 offer a protective effect through the mitochondrial apoptosis pathway in acute liver failure.

4.
Life Sci ; 230: 68-75, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129140

RESUMO

AIMS: The aim of the present study was to investigate the protective effects of AGK2 as a selective SIRT2 inhibitor on thioacetamide (TAA)-induced acute liver failure (ALF) in mice and its potential mechanism. MAIN METHODS: All male C57BL/6 mice were separated into control, TAA, AGK2 + TAA, and AGK2 groups. The histological changes were observed by hematoxylin and eosin (HE) staining. The apoptosis cells of liver tissues were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were used to evaluate the damage of liver function. The inflammatory cytokines of iNOS, TNF-α, IL-1ß was detected by Western blotting and RT-PCR assay. The expression of mitogen-activated protein kinase (MAPK), NF-κB, and apoptosis pathways was determined by Western blotting. KEY FINDINGS: AGK2 improved the damage of TAA-induced liver pathology and function. AGK2 pretreatment also reduced the levels of pro-inflammatory cytokines in ALF liver tissues. AGK2 improved the TAA-induced survival rate. Moreover, AGK2 administration suppressed the increase of phosphorylation NF-κB-p65 and the activation of MAPK pathway. In addition, pretreatment alleviated TAA-induced the liver cells apoptosis. SIGNIFICANCE: AGK2 improve TAA-induced survival rate in mice with ALF, suppress the inflammatory responses by inhibition of MAPK and NF-κB signaling pathways, and decrease the hepatocyte necrosis by inhibition of apoptosis. Pharmacologic inhibition of SIRT2 may be a promising approach for the treatment of ALF.


Assuntos
Furanos/farmacologia , Falência Hepática Aguda/tratamento farmacológico , Fígado/patologia , Quinolinas/farmacologia , Alanina Transaminase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/metabolismo , Citocinas/metabolismo , Furanos/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Fígado/metabolismo , Falência Hepática Aguda/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Quinolinas/metabolismo , Transdução de Sinais , Sirtuína 2/antagonistas & inibidores , Tioacetamida/farmacologia , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Life Sci ; 223: 1-8, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30862568

RESUMO

AIMS: The aim of this study was to investigate the relationship between anti-HBV treatment and the regulation of HDACs during HBV DNA replication. METHODS: HDAC activities and HBV DNA levels in CHB patients' sera were measured and correlation analysis was made. The changes of HDAC2, HDAC6, AH3 and histone H3 levels in normal control and 4 CHB patient liver tissue samples before and after antiviral treatment were examined. The HDAC inhibitor, TSA, anti-HBV agents, ETV and IFN-α were used to stimulate HepG2.2.15 cells. The levels of HBV DNA, pgRNA in supernatants, and cccDNA in the cells were determined by PCR. The HDAC activity, HDAC6, HDAC2, AH3 and H3 protein levels in cells were tested at days 3, 6, and 9 after treatments. KEY FINDINGS: HDAC activity was positively correlated with HBV DNA in the HBV patients' sera. The levels of HDAC2, HDAC6 and AH3 were notably decreased after antiviral treatment. When compared with antiviral treatment group, the normal liver tissue showed obviously decreased HDAC2, HDAC6 and AH3 protein levels. In vitro study, the level of HBV DNA, the HDAC activity, and the HDAC2, HDAC6 and AH3 protein levels decreased in the ETV, IFN-α and TSA groups compared with the control group. The pgRNA level in supernatants was declined in the IFN-α group and increased in the ETV and TSA groups. cccDNA expression was suppressed by IFN-α. SIGNIFICANCE: The changes of HBV replicative products during antiviral treatment are associated with histone deacetylation. Acetylated histone H3 is involved in the process of hepatitis B virus DNA replication.


Assuntos
Replicação do DNA/efeitos dos fármacos , DNA Viral/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Histona Desacetilases/metabolismo , Histonas/genética , Adulto , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Técnicas de Cultura de Células , Replicação do DNA/genética , Feminino , Células Hep G2 , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/enzimologia , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/genética , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/virologia , Masculino , Pessoa de Meia-Idade , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética
6.
Hepatobiliary Pancreat Dis Int ; 17(5): 423-429, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30249543

RESUMO

BACKGROUND: Histone deacetylases (HDACs) inhibitors are new anti-fibrotic drugs that inhibit the activity of hepatic stellate cells. The present study focused on the anti-fibrotic function of HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) by suppressing transforming growth factor-ß1 (TGF-ß1) signaling. METHODS: Male Sprague-Dawley rats were used to induce liver fibrosis with carbon tetrachloride (CCl4) and LX2 cell (human hepatic stellate cell line) was stimulated by TGF-ß1. Both animals and cells were treated with SAHA. The Smad7 and connective tissue growth factor (CTGF) mRNA levels were detected by real-time polymerase chain reaction (PCR). Western blotting was used to examine the protein levels of CTGF, Histone H3 (H3), Smad7, Smad2/3, Acetyl-Histone H3 (AH3), HDAC2, α-smooth muscle actin (α-SMA), HDAC6, p-Smad2/3 and HDAC8. In addition, the TGF-ß1 and liver enzyme levels from rat serum were detected. Histopathological changes were examined by hematoxylin and eosin (HE), Sirius red and Masson trichrome staining. The α-SMA expression was detected by immumohistochemical staining. RESULTS: Compared with control group, the TGF-ß1 and liver enzyme levels from rat serum, together with the mRNA levels of CTGF and protein levels of CTGF, HDAC2, α-SMA, HDAC6, p-Smad2/3 and HDAC8 were elevated in fibrotic rats (P < 0.01). But the Smad7 mRNA and AH3 protein levels were notably suppressed in the fibrotic rats (P < 0.01). Pathological examination showed the typical changes of liver fibrosis in the fibrotic rats. After the treatment with SAHA, the levels of liver enzymes, TGF-ß1, CTGF, HDAC2, α-SMA, HDAC6, p-Smad2/3 and HDAC8 were reduced (P < 0.01) and Smad7 and AH3 protein contents were elevated in liver fibrotic rats (P < 0.01). Moreover, immumohistochemistry showed that SAHA significantly suppressed the α-SMA protein content in fibrotic liver (P < 0.01). CONCLUSION: The HDAC inhibitor SAHA alleviated liver fibrosis by suppressing the TGF-ß1 signaling.

7.
Mediators Inflamm ; 2018: 7859601, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29725271

RESUMO

The purpose of this study was to investigate the protective mechanism of HDAC2 inhibitor CAY10683 on intestinal mucosal barrier in acute liver failure (ALF). In order to establish ALF-induced intestinal epithelial barrier disruption models, D-galactosamine/LPS and LPS were, respectively, used with rats and NCM460 cell and then administrated with CAY10683. Transepithelial electrical resistance (TEER) was measured to detect the permeability of cells. Real-time PCR and Western blotting were employed to detect the key mRNA and protein levels. The intestinal epithelial tissue pathology was detected. After interfering with CAY10683, the mRNA and protein levels of TLR4, MyD88, TRIF, and TRAF6 were decreased compared with model group (P < 0.05), whereas the levels of ZO-1 and occluding were elevated (P < 0.05). The permeability was elevated in CAY10683-interfered groups, when compared with model group (P < 0.05). And the degree of intestinal epithelial tissue pathological damage in CAY10683 group was significantly reduced. Moreover, CAY10683 significantly decreased the TLR4 staining in animal tissue. The HDAC2 inhibitor CAY10683 could promote the damage of intestinal mucosal barrier in ALF through inhibiting LPS/TLR4/MyD88 pathway.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Lipopolissacarídeos/toxicidade , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Galactosamina/toxicidade , Histona Desacetilase 2/antagonistas & inibidores , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Falência Hepática Aguda/induzido quimicamente , Ratos , Reação em Cadeia da Polimerase em Tempo Real
8.
Neurochem Res ; 43(6): 1161-1170, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29675728

RESUMO

Neuroinflammation involves in the progression of many central nervous system diseases. Several studies have shown that histone deacetylase (HDAC) inhibitors modulated inflammatory responses in lipopolysaccharide (LPS) stimulated microglia. While, the mechanism is still unclear. The aim of present study was to investigate the effect of HDAC2 inhibitor CAY10683 on inflammatory responses and TLR4/NF-κB signaling pathways in LPS activated BV2 microglial cells and LPS induced mice neuroinflammation. The effect of CAY10683 on cell viability of BV2 microglial cells was detected by CCK-8 assay. The expressions of inflammatory cytokines were analyzed by western blotting and RT-PCR respectively. The TLR4 protein expression was measured by western blotting, immunofluorescence, immunohistochemistry respectively. The protein expressions of MYD88, phospho-NF-κB p65, NF-κB-p65, acetyl-H3 (AH3), H3, and HDAC2 were analyzed by western blotting. We found that CAY10683 could inhibit expression levels of inflammatory cytokine TNF-α and IL-1ß in LPS activated BV2 microglial cells and LPS induced mice neuroinflammation. It could induce TLR4, MYD88, phospho-NF-κB p65, and HDAC2 expressions. Moreover, CAY10683 increased the acetylation of histones H3 in LPS activated BV2 microglial cells and LPS induced mice neuroinflammation. Taken together, our findings suggested that HDAC2 inhibitor CAY10683 could suppress neuroinflammatory responses and TLR4/NF-κB signaling pathways by acetylation after LPS stimulation.


Assuntos
Histona Desacetilase 2/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Mediadores da Inflamação/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , NF-kappa B/antagonistas & inibidores , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Linhagem Celular , Histona Desacetilase 2/metabolismo , Mediadores da Inflamação/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , NF-kappa B/metabolismo , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/metabolismo
9.
Biomed Pharmacother ; 97: 818-824, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29112935

RESUMO

Histone deacetylase 6 (HDAC6) is considered a new target for anticancer, anti-inflammatory, and neurodegenerative treatment. ACY-1215 is a selective histone deacetylase 6 inhibitor, and it has been recognized as a potential anticancer and anti-inflammation drug. The aim of our study was to investigate whether ACY-1215 has protective effects on acute liver failure (ALF) in mice and explore its potential mechanism. Male C57/BL6 mice were divided into normal, model, and ACY-1215 groups. ACY-1215 (25mg/kg) and same amounts of saline were given to mice. After 2h, the ALF models were induced by lipopolysaccharide (LPS, 100µg/kg) combined with D-galactosamine (D-gal, 400mg/kg). All animals were killed after 24h. The expressions of HDAC6 were determined by western blotting and RT-PCR assay. The expression levels of inflammatory cytokines were detected by ELISA and RT-PCR. The protein expression of Toll-like receptor 4 (TLR4), mitogen-activated protein kinase (MAPK), and nuclear factor κB (NF-κB) species were determined by western blot. The mortality of mice with ALF induced by LPS and D-gal was significantly decreased by ACY-1215 pretreatment. Procedures to manage ALF caused adversely affected liver histology and function; this damage was repaired by pretreatment of ACY-1215. ACY-1215 treatment also attenuated the serum and messenger RNA levels of the proinflammatory cytokines. Pretreatment of ACY-1215 significantly decreased the protein expression of TLR4 and the activation of MAPK and NF-κB signalling pathways. ACY-1215 has potential therapeutic value in mice with ALF by directly inhibiting inflammatory response via regulation of the TLR4-MAPK/NF-kB pathway.


Assuntos
Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Falência Hepática Aguda/prevenção & controle , Pirimidinas/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Western Blotting , Citocinas/metabolismo , Modelos Animais de Doenças , Galactosamina/administração & dosagem , Inflamação/tratamento farmacológico , Inflamação/patologia , Lipopolissacarídeos/administração & dosagem , Falência Hepática Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
10.
Exp Ther Med ; 14(6): 5825-5832, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29285127

RESUMO

The inflammatory response of sepsis induced by lipopolysaccharide (LPS) may result in irreversible cardiac dysfunction. Glutamine (GLN) has a multitude of pharmacological effects, including anti-inflammatory abilities. Previous studies have reported that GLN attenuated LPS-induced acute lung injury and intestinal mucosal injury. The present study investigated whether GLN exerts potential protective effects on LPS-induced cardiac dysfunction. Male Sprague-Dawley rats were divided into three groups (15 rats per group), including the control (saline-treated), LPS and LPS+GLN groups. Pretreatment with 1 g/kg GLN was provided via gavage for 5 days in the LPS+GLN group, while the control and LPS groups received the same volume of normal saline. On day 6, a cardiac dysfunction model was induced by administration of LPS (10 mg/kg). After 24 h, the cardiac functions of the rats that survived were detected by echocardiography and catheter-based measurements. The serum levels of tumor necrosis factor α (TNF-α), interleukin (IL)-1ß and IL-6 were detected by enzyme-linked immunosorbent assay, while the mRNA levels of toll-like receptor (TLR)4, TNF-α, IL-1ß and IL-6 were examined by reverse transcription-quantitative polymerase chain reaction. The protein expression of TLR4, mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) were also determined by western blot analysis. The results of echocardiography and catheter-based measurements revealed that GLN treatment attenuated cardiac dysfunction. GLN treatment also attenuated the serum and mRNA levels of the pro-inflammatory cytokines. In addition, the protein levels of TLR4, phosphorylated (p-)extracellular signal-regulated kinase, p-c-Jun N-terminal kinase and p-P38 were reduced upon GLN pretreatment. Furthermore, GLN pretreatment resulted in decreased activation of the NF-κB signaling pathway. In conclusion, GLN has a potential therapeutic effect in the protection against cardiac dysfunction mediated by sepsis through regulating the TLR4/MAPK/NF-κB signaling pathway.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA