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1.
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.

2.
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.

3.
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
4.
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
5.
Aging Cell ; : e12860, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30488644

RESUMO

Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD). Accumulated damaged mitochondria, which are associated with impaired mitophagy, contribute to neurodegeneration in AD. We show levels of Disrupted-in-schizophrenia-1 (DISC1), which is genetically associated with psychiatric disorders and AD, decrease in the brains of AD patients and transgenic model mice and in Aß-treated cultured cells. Disrupted-in-schizophrenia-1 contains a canonical LC3-interacting region (LIR) motif (210 FSFI213 ), through which DISC1 directly binds to LC3-I/II. Overexpression of DISC1 enhances mitophagy through its binding to LC3, whereas knocking-down of DISC1 blocks Aß-induced mitophagy. We further observe overexpression of DISC1, but not its mutant (muFSFI) which abolishes the interaction of DISC1 with LC3, rescues Aß-induced mitochondrial dysfunction, loss of spines, suppressed long-term potentiation (LTP). Overexpression of DISC1 via adeno-associated virus (serotype 8, AAV8) in the hippocampus of 8-month-old APP/PS1 transgenic mice for 4 months rescues cognitive deficits, synaptic loss, and Aß plaque accumulation, in a way dependent on the interaction of DISC1 with LC3. These results indicate that DISC1 is a novel mitophagy receptor, which protects synaptic plasticity from Aß accumulation-induced toxicity through promoting mitophagy.

6.
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
7.
Biochem Biophys Res Commun ; 499(3): 702-710, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29605299

RESUMO

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Recent studies reported that lncRNA LINC00473 (LNC473) was involved in cancer progression. However, the clinical significance and functional role of LNC473 in HCC progression is still unknown. In the present study, we found that the LNC473 expression was markedly elevated in HCC tissues and correlated with bigger tumor size, higher BCLC stage, vascular invasion and poor prognosis. Gain- and loss-of-function assay showed that LNC473 enhanced HCC cell proliferation and invasion and induced epithelial-mesenchymal transition (EMT) process. Mechanistically, LNC473 associated with oncoprotein survivin and regulates its stability. Moreover, LNC473 could recruit deubiquitinase USP9X to inhibit the ubiquitination level of survivin and then increase survivin expression. Therefore, our results suggest that LNC473 exerts its functions as an oncogene in HCC progression and may be a therapeutic target for HCC treatment.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , RNA Longo não Codificante/metabolismo , Ubiquitina Tiolesterase/metabolismo , Ubiquitinação , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estabilidade Proteica , RNA Longo não Codificante/genética , Survivina , Regulação para Cima/genética
8.
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
9.
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.

10.
Chin Med J (Engl) ; 130(22): 2661-2665, 2017 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-29133752

RESUMO

BACKGROUND: The Food and Drug Administration recently announced that the use of morcellation may cause fibroids or pelvic dissemination and metastasis of uterine sarcoma; therefore, the use of morcellation is limited in the USA. A large sample study is necessary to assess the proportion of uterine malignant tumors found in patients with laparoscopic myomectomy. METHODS: A national multicenter study was performed in China. From 2002 to 2014, 33,723 cases were retrospectively selected. We calculated the prevalence and recorded the clinical characteristics of the patients with malignancy after morcellation application. A total of 62 cases were finally pathologically confirmed as malignant postoperatively. Additionally, the medical records of the 62 patients were analyzed in details. RESULTS: The proportion of postoperative malignancy after morcellation application was 0.18% (62/33,723) for patients who underwent laparoscopic myomectomy. Nearly 62.9% (39/62) of patients had demonstrated blood flow signals in the uterine fibroids before surgery. And, 23 (37.1%) patients showed rapid growth at the final preoperative ultrasound. With respect to the pathological types, 38 (61.3%) patients had detectable endometrial stromal sarcoma, 13 (21.0%) had detectable uterine leiomyosarcoma, only 3 (3.2%) had detectable carcinosarcoma, and 5 (8.1%) patients with leiomyoma had an undetermined malignant potential. CONCLUSIONS: The proportion of malignancy is low after using morcellation in patients who undergo laparoscopic myomectomy. Patients with fast-growing uterine fibroids and abnormal ultrasonic tumor blood flow should be considered for malignant potential, and morcellation should be avoided.


Assuntos
Morcelação/efeitos adversos , Miomectomia Uterina/efeitos adversos , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgia , Adulto , China , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos
11.
Cancer Biol Med ; 14(1): 60-65, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28443204

RESUMO

OBJECTIVE: : This study aimed to determine if gastric cardia adenocarcinoma (GCA) risk was associated with the lys (A or *2) allele at the rs671 (glu504lys) polymorphism within the aldehyde dehydrogenase 2 (ALDH2) gene in a Chinese Han population. We also aimed to investigateALDH2 genotypic distributions between subjects from high- and low-incidence areas for both GCA and esophageal squamous cell carcinoma (ESCC). METHODS: : We designed a case-control study including 2,686 patients with GCA and 3,675 control subjects from high- and low-incidence areas for both GCA and ESCC in China. TaqMan allele discrimination assay was used to genotype the rs671 polymorphism.χ2 test and binary logistic regression analysis were used to estimate the odds ratios for the development of GCA, and multivariate ordinal logistic regression was used to analyzeALDH2 genotypic distributions among different groups. RESULTS: : Compared withALDH2*1/*1 homozygotes,ALDH2*1/*2 andALDH2*2/*2 carriers did not increase the risk for GCA in the Chinese Han population (P>0.05). Interestingly, the ratio of homozygous or heterozygousALDH2 *2 carriers in high-incidence areas for both GCA and ESCC was lower than that in low-incidence areas (P<0.001). CONCLUSIONS: : Genotypes of rs671 atALDH2 may not increase GCA susceptibility in Chinese Han populations. In addition, theALDH2 genotypic distribution differs between Chinese Han populations from high- and low-incidence areas for both GCA and ESCC. Our findings may shed light on the possible genetic mechanism for the dramatic geographic differences of GCA occurrence in China.

12.
J Surg Res ; 205(1): 1-10, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27620992

RESUMO

BACKGROUND: Histone deacetylase (HDAC) inhibitors have been widely applied in the clinic as anticancer drugs against multiple neoplasms and proved their anti-inflammation under different pathology recently. Trichostatin A (TSA) is an HDAC inhibitor specific in class I and II HDAC enzymes. The aim of the present study was to elucidate the protective effects of TSA on acute liver failure (ALF) in rats and its potential mechanism. METHODS: A total of 18 female Sprague-Dawley rats were separated into control, model, and TSA groups. We used Western blotting to determine the expression of HDACs, inflammatory cytokines, and acetylation of histone in liver and small intestine. The gene expression of inflammatory factors and Cox-2 was detected by a polymerase chain reaction. Colonic motility was assessed by spatiotemporal mapping. Histologic analysis and immunohistochemistry were performed. Intestinal permeability examination and levels of alanine aminotransferase, aspartate aminotransferase, and total bilirubin were also observed. RESULTS: ALF procedure caused harm to histology of liver and small intestine, increased the intestinal permeability and serum levels of alanine aminotransferase, aspartate aminotransferase, and total bilirubin. It also interrupted the normal organization of colonic motor patterns by hurting enteric nervous system and pacemaker cells. Along with the decrease of inflammatory factors in ALF rats by TSA administration, all the damage to the liver, the small intestine, and the colon was repaired. CONCLUSIONS: TSA alleviates the lesion in liver, as well as in small intestine and colon in ALF rats by directly inhibiting inflammatory response.


Assuntos
Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Enteropatias/prevenção & controle , Falência Hepática Aguda/complicações , Fígado/efeitos dos fármacos , Animais , Citocinas/metabolismo , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Histona Desacetilases/metabolismo , Enteropatias/etiologia , Intestino Delgado/efeitos dos fármacos , Lipopolissacarídeos , Fígado/patologia , Falência Hepática Aguda/enzimologia , Falência Hepática Aguda/patologia , Ratos , Ratos Sprague-Dawley
13.
Inflammation ; 38(3): 1364-73, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25604312

RESUMO

Histone deacetylase inhibitors (HDACi) were recently shown to suppress inflammatory responses in experimental models of autoimmune and inflammatory diseases. In this study, the protective effects of Trichostatin A (TSA), an HDACi, on experimental acute-on-chronic liver failure (ACLF) in rat were explored. An ACLF model was established in rats, and animals were randomly divided into control, model, and TSA-treated groups. The rats in TSA-treated group received TSA (2 mg/kg) at 2 h before induction of ACLF. Samples were obtained at 24 h after ACLF induction. We found that the rats in model group showed severe damage to liver tissue at 24 h after ACLF induction. TSA improved liver injury effectively. Serum tumor necrosis factor-alpha (TNF-α), interferon-γ (IFN-γ), interleukin (IL)-10, and IL-18 levels were significantly increased in model group compared with control group, but TSA reduced serum TNF-α, IFN-γ, IL-10, and IL-18 levels effectively compared with model group. In addition, TSA reduced the total HDAC activity, promoted the acetylation of histone, and decreased the expressions of class I HDAC in liver tissue. TSA also increased the acetylation levels and decreased phosphorylation levels in NF-κB p65. The median survival time of the rats was significantly prolonged in TSA-treated group. To conclude, TSA can inhibit the release of multiple inflammatory cytokines, prolong the survival time, and protect against ACLF in rats. The mechanisms were probably through enhancing the acetylation levels of non-histones rather than histone.


Assuntos
Insuficiência Hepática Crônica Agudizada/prevenção & controle , Inibidores de Histona Desacetilases/farmacologia , Histonas/metabolismo , Ácidos Hidroxâmicos/farmacologia , Fator de Transcrição RelA/metabolismo , Acetilação , Insuficiência Hepática Crônica Agudizada/tratamento farmacológico , Animais , Galactosamina , Histona Desacetilases/metabolismo , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-18/sangue , Lipopolissacarídeos , Fígado/patologia , Distribuição Aleatória , Ratos , Ratos Wistar , Albumina Sérica , Fator de Necrose Tumoral alfa/sangue
14.
Hepatobiliary Pancreat Dis Int ; 13(3): 309-15, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24919615

RESUMO

BACKGROUND: Acute liver failure (ALF) is a serious clinical syndrome with high mortality. Sodium butyrate has been shown to alleviate organ injury in a wide variety of preclinical models of critical diseases. The aim of this study was to investigate the protective effect of sodium butyrate on ALF in rats. METHODS: All rats were randomly divided into control, model and sodium butyrate treatment groups. Except the control group, the rats were induced ALF animal model by subcutaneous injection of human serum albumin+ D-galactosamine+lipopolysaccharide. After induction of ALF, the rats in the treatment group received sodium butyrate (500 mg/kg) at 12-hour or 24-hour time point. Fourty-eight hours after ALF induction, the animals were sacrificed and samples were harvested. Serum endotoxin, high mobility group box-1 (HMGB1), liver function parameters, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were measured. The expression of HMGB1 and nuclear factor-kappa B (NF-kappaB) p65 protein in liver tissue was detected by Western blotting. The histological changes of liver and intestine were examined. The survival duration was also observed. RESULTS: Serum endotoxin, alanine aminotransferase, HMGB1, TNF-alpha and IFN-gamma were significantly increased and the liver histology showed more severe histopathological injury in the model group compared with the control group (P<0.05). Compared to the model group, sodium butyrate treatment significantly improved the histopathological changes in the liver and intestine, reduced serum endotoxin and inflammatory cytokines, suppressed HMGB1 and NF-kappaB p65 proteins in liver tissue, and prolonged the survival duration regardless of treatment at 12 hours or 24 hours after induction of ALF (P<0.05). CONCLUSIONS: Sodium butyrate protected the liver from toxin-induced ALF in rats. The mechanisms may be due to direct hepatoprotection and decreased intestinal permeability.


Assuntos
Ácido Butírico/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Falência Hepática Aguda/prevenção & controle , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citoproteção , Modelos Animais de Doenças , Galactosamina , Proteína HMGB1/sangue , Mediadores da Inflamação/sangue , Interferon gama/sangue , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Lipopolissacarídeos , Fígado/metabolismo , Fígado/ultraestrutura , Falência Hepática Aguda/sangue , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/patologia , Permeabilidade , Ratos Wistar , Albumina Sérica , Albumina Sérica Humana , Fatores de Tempo , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/sangue
15.
Inflammation ; 37(3): 848-57, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24385241

RESUMO

In this study, we induced an acute-on-chronic liver failure (ACLF) model by human serum albumin (HSA), D-galactosamine (D-Gal) and lipopolysaccharide (LPS) in rats. Anti-TNF-α polyclonal antibody (as TNF-α inhibitor) and pyrrolidine dithiocarbamate (PDTC, a NF-κB inhibitor) were used to treat the liver failure animals, respectively. The results showed that TNF-α inhibition was beneficial, but NF-κB inhibition failed to protect the rats in ACLF. However, HMGB1 levels, cytokine production and activation of TLR4-NF-κB signaling pathway were all suppressed by both TNF-α and NF-κB inhibition. In order to verify the effect of PDTC on inflammatory response, we further explored its effect in vitro. Anti-inflammatory activity of PDTC was proved in U937 cell line. To conclude, both inhibitions of TNF-α and NF-κB are able to suppress the activation of TLR4 and NF-κB signaling pathway. However, NF-κB inhibition with PDTC failed to protect the rats in ACLF induced by D-Gal and LPS.


Assuntos
Insuficiência Hepática Crônica Agudizada/imunologia , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Anticorpos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocinas/biossíntese , Feminino , Galactosamina , Proteína HMGB1/metabolismo , Humanos , Inflamação/tratamento farmacológico , Lipopolissacarídeos , Pirrolidinas/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais , Tiocarbamatos/farmacologia , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Células U937
16.
Dig Dis Sci ; 58(11): 3198-206, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23861108

RESUMO

BACKGROUND AND OBJECTIVES: Previous studies have shown that betaine prevents alcohol-induced liver injury and improves liver function. The purpose of this study was to investigate the hepatoprotective effects of betaine on nonalcoholic fatty liver disease (NAFLD) and to observe changes of HMGB1/TLR4 signaling. METHODS: Thirty rats were randomly divided into control, model, and betaine groups. The rats in the model and betaine groups were fed a high-fat diet for 12 weeks to induce an animal model of NAFLD. The rats in the betaine group were then intragastrically administered betaine solution at a dose of 400 mg/kg per day for four weeks. Liver histology was examined. Serum levels of ALT, AST, TC, TG, HDL-C, LDL-C, FFA, HMGB1, NF-κB, TLR4, and tHcy were determined and intrahepatic TC, TG, and Hcy levels were assayed. mRNA expression and protein levels of HMGB1, NF-κB, and TLR4 in liver tissue were also determined. RESULTS: Compared with the control group, rats in the model group developed severe liver injury, accompanied by significant increases in serum levels of ALT, AST, TC, TG, LDL-C, FFA, HMGB1, NF-κB, and TLR4, intrahepatic TC, TG, and Hcy content, histological scores for steatosis, inflammation, and necrosis, and mRNA expression and protein levels of HMGB1, NF-κB, and TLR4, and a significant decrease in serum HDL-C (P < 0.05). Compared with the model group, all these indicators were significantly improved by administration of betaine (P < 0.05). CONCLUSIONS: Betaine effectively protects against high-fat-diet-induced NAFLD and improves liver function; the mechanism is probably related to inhibition of HMGB1/TLR4 signaling pathways.


Assuntos
Betaína/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Gorduras na Dieta/efeitos adversos , Regulação da Expressão Gênica/fisiologia , Domínios HMG-Box/fisiologia , Receptor 4 Toll-Like/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Fígado Gorduroso/prevenção & controle , Feminino , Domínios HMG-Box/genética , Metabolismo dos Lipídeos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica , Ratos , Ratos Sprague-Dawley , Organismos Livres de Patógenos Específicos , Receptor 4 Toll-Like/genética , Ganho de Peso
17.
Int J Mol Sci ; 14(6): 11224-37, 2013 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-23712360

RESUMO

Cisplatin is one of the most widely used chemical drugs for anticancer treatment. Recent studies have focused on the ability of cisplatin to retain the high mobility group box 1 (HMGB1) protein in cisplatin-DNA adducts, thereby preventing its release from the nucleus. Because HMGB1 is a powerful inflammatory mediator in many diseases, the aim of this study is to evaluate the therapeutic effect of cisplatin acute liver failure. In this study, low-dose cisplatin was administered to treat PMA-induced macrophage-like cells induced by PMA and rats with acute liver failure. We found that cell viability and liver injury were greatly improved by cisplatin treatment. The extracellular levels of HMGB1, TNF-α and IFN-γ were also significantly decreased by the administration of cisplatin. During inflammation, nuclear HMGB1 translocates from the nucleus to the cytoplasm. The administration of cisplatin reduced the cytoplasmic levels of HMGB1 and increased nuclear HMGB1 levels in vitro and in vivo. In conclusion, cisplatin can protect against acute liver failure by retaining HMGB1 in the nucleus and preventing its release into the extracellular milieu.


Assuntos
Núcleo Celular/metabolismo , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Citoproteção/efeitos dos fármacos , Proteína HMGB1/metabolismo , Falência Hepática Aguda/tratamento farmacológico , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/biossíntese , Falência Hepática Aguda/sangue , Falência Hepática Aguda/enzimologia , Falência Hepática Aguda/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Ratos Wistar , Análise de Sobrevida , Fatores de Tempo
18.
Inflamm Res ; 62(7): 703-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23591781

RESUMO

OBJECTIVE: High-mobility group box-1 (HMGB1) is identified as an extracellularly released mediator of inflammation. In this study, specific monoclonal anti-HMGB1 antibody was administered to rats with acute on chronic liver failure (ACLF) in order to evaluate the therapeutic efficacy of HMGB1 blockade. METHODS: All animals were randomly divided into control group, model group and anti-HMGB1 antibody group. The changes in liver histology and apoptosis of liver tissue were detected by H&E staining and TUNEL assay, respectively. The serum levels of alanine aminotransferase (ALT), endotoxin, HMGB1, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) were examined. The hepatic levels of HMGB1, caspase3, Toll-like receptor 4 (TLR4) and p65 subunit of NF-κB (P65) were also determined. RESULTS: Changes in liver pathology and liver cell apoptosis were greatly attenuated in the anti-HMGB1 antibody group compared with the model group. The serum levels of ALT, endotoxin, TNF-α, IFN-γ and HMGB1 were also decreased in the anti-HMGB1 antibody group. Furthermore, the hepatic levels of HMGB1, TLR4, caspase3 and P65 were also down-regulated by HMGB1 blockade. CONCLUSION: Blockade of HMGB1 can confer a protective effect against ACLF in rats, even 24 h after induction of ACLF. The protective effect of HMGB1 blockade is associated with interactions of HMGB1 with the TLR4 signaling pathway and cytokine production.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Proteína HMGB1/antagonistas & inibidores , Falência Hepática/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Alanina Transaminase/sangue , Animais , Anticorpos Monoclonais/farmacologia , Antígeno CD24 , Proteína HMGB1/imunologia , Proteína HMGB1/metabolismo , Interferon gama/sangue , Lipopolissacarídeos , Falência Hepática/metabolismo , Masculino , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/sangue
19.
Hepatobiliary Pancreat Dis Int ; 12(2): 180-8, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23558073

RESUMO

BACKGROUND: The pathogenesis and progression of acute liver failure (ALF) are closely associated with intestinal endotoxemia because of the high permeability of the intestinal wall. Treatment with ethyl pyruvate (EP) has been shown to protect liver failure effectively. The current study aimed to explore the relationship between proinflammatory cytokines and intestinal permeability, and to investigate whether EP administration might prevent the release of multiple proinflammatory cytokines and decrease intestinal permeability and therefore, protect the liver from injury. METHODS: The ALF model was induced by D-galactosamine in rats. The rats were randomly divided into control (saline, i.p.), model (D-galactosamine, 1.2 g/kg, i.p.), prevention [EP injection (40 mg/kg) 2 hours ahead of D-galactosamine] and treatment groups (EP injection 2 hours after D-galactosamine). Samples were obtained at 12 and 24 hours after ALF induction, respectively. The histology of liver and intestinal tissue was assessed. Serum alanine aminotransferase, endotoxin, D(-)-lactate, diamine oxidase (DAO), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and high mobility group box-1 (HMGB1) were evaluated. The survival of rats was also recorded. RESULTS: The rats in model group showed severe damage to liver tissue and intestinal mucosa 12 and 24 hours after ALF induction. EP significantly improved liver or intestinal injury. In addition, serum endotoxin, D(-)-lactate, DAO, TNF-alpha, IFN-gamma and HMGB1 levels were significantly increased in the model group compared with the control group. There was a positive correlation between intestinal permeability and proinflammatory cytokines. EP significantly reduced serum endotoxin, D(-)-lactate, DAO, TNF-alpha, IFN-gamma and HMGB1 levels. The median survival time was significantly prolonged in both prevention and treatment groups (126 and 120 hours compared with 54 hours in the model group). CONCLUSIONS: EP has protective and therapeutic effects on intestinal mucosa. EP decreases intestinal permeability, and inhibits the release of multiple proinflammatory cytokines in rats with ALF.


Assuntos
Anti-Inflamatórios/farmacologia , Translocação Bacteriana/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Endotoxinas/sangue , Galactosamina , Mediadores da Inflamação/sangue , Mucosa Intestinal/efeitos dos fármacos , Falência Hepática Aguda/tratamento farmacológico , Piruvatos/farmacologia , Animais , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/microbiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citoproteção , Modelos Animais de Doenças , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/imunologia , Falência Hepática Aguda/microbiologia , Falência Hepática Aguda/patologia , Masculino , Permeabilidade , Ratos , Ratos Wistar , Fatores de Tempo
20.
World J Gastroenterol ; 18(40): 5709-18, 2012 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-23155311

RESUMO

AIM: To investigate the protective effects of ethyl pyruvate (EP) on acute-on-chronic liver failure (ACLF) in rats. METHODS: An ACLF model was established in rats, and animals were randomly divided into normal, model and EP treatment groups. The rats in EP treatment group received EP (40 mg/kg) at 3 h, 6 h, 12 h and 24 h after induction of ACLF. Serum endotoxin, high mobility group box-1 (HMGB1), alanine transaminase (ALT), tumor necrosis factor-α (TNF-α), interferon-α (IFN-γ), interleukin (IL)-10 and IL-18 levels, changes of liver histology and HMGB1 expressions in liver tissues were detected at 48 h after induction of ACLF. The effects of EP on the survival of ACLF rats were also observed. RESULTS: Serum levels of endotoxin (0.394 ± 0.066 EU/mL vs 0.086 ± 0.017 EU/mL, P < 0.001), HMGB1 (35.42 ± 10.86 µg/L vs 2.14 ± 0.27 µg/L, P < 0.001), ALT (8415.87 ± 3567.54 IU/L vs 38.64 ± 8.82 IU/L, P < 0.001), TNF-α (190.77 ± 12.34 ng/L vs 124.40 ± 4.12 ng/L, P < 0.001), IFN-γ (715.38 ± 86.03 ng/L vs 398.66 ± 32.91 ng/L, P < 0.001), IL-10 (6.85 ± 0.64 ng/L vs 3.49 ± 0.24 ng/L, P < 0.001) and IL-18 (85.19 ± 3.49 ng/L vs 55.38 ± 1.25 ng/L, P < 0.001) were significantly increased, and liver tissues presented severe pathological injury in the model group compared with the normal group. However, EP administration significantly improved hepatic histopathology and reduced the serum levels of endotoxin (0.155 ± 0.045 EU/mL vs 0.394 ± 0.066 EU/mL, P < 0.001) and inflammatory cytokines (11.13 ± 2.58 µg/L vs 35.42 ± 10.86 µg/L for HMGB1, 3512.86 ± 972.67 IU/L vs 8415.87 ± 3567.54 IU/L for ALT, 128.55 ± 5.76 ng/L vs 190.77 ± 12.34 ng/L for TNF-α, 438.16 ± 38.10 ng/L vs 715.38 ± 86.03 ng/L for IFN-γ, 3.55 ± 0.36 ng/L vs 6.85 ± 0.64 ng/L for IL-10, and 60.35 ± 1.63 ng/L vs 85.19 ± 3.49 ng/L for IL-18, respectively, P < 0.001), and the levels of HMGB1 in liver tissues regardless of treatment time after induction of ACLF. EP treatment at the four time points prolonged the median survival time of ACLF rats (60 h) to 162 h, 120 h, 102 h and 78 h, respectively (χ(2) = 41.17, P < 0.0001). CONCLUSION: EP administration can protect against ACLF in rats, and is a potential and novel therapeutic agent for severe liver injury.


Assuntos
Doença Hepática Terminal/tratamento farmacológico , Falência Hepática Aguda/tratamento farmacológico , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Piruvatos/farmacologia , Animais , Biomarcadores/sangue , Citocinas/sangue , Citoproteção , Modelos Animais de Doenças , Doença Hepática Terminal/sangue , Doença Hepática Terminal/patologia , Endotoxinas/sangue , Feminino , Proteína HMGB1/sangue , Mediadores da Inflamação/sangue , Fígado/metabolismo , Fígado/patologia , Falência Hepática Aguda/sangue , Falência Hepática Aguda/patologia , Ratos , Ratos Wistar , Índice de Gravidade de Doença , Fatores de Tempo
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