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1.
Can J Gastroenterol Hepatol ; 2021: 5581816, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34557455

RESUMO

Both oxidative stress (OS) and inflammation are two fundamental pathological processes of acute liver injury (ALI). The current work is to investigate the effect and possible mechanism of Uncaria rhynchophylla (UR) on thioacetamide- (TAA-) induced ALI in rats. UR (100 and 200 mg/kg) was orally administrated with TAA (200 mg/kg of bodyweight, intraperitoneal injection) for 3 consecutive days. ALI was confirmed using histological examination and the factors associated with OS and liver function activity measured in serum. Moreover, expressions of inflammation and collagen-related proteins were measured by the Western blot analysis. Myeloperoxidase (MPO), which mediates OS in the ALI control group, was manifested by a significant rise compared with the normal group. UR significantly reduced AST, ALT, and ammonia levels in serum. The nuclear factor-κB (NF-κB) activation induced by TAA led to increase both inflammatory mediators and cytokines. Whereas, UR administration remarkably suppressed such an overexpression. UR supplementation improved matrix metalloproteinases (MMPs) such as MMP-1, -2, and -8. In contrast, tissue inhibitors of metalloproteinases- (TIMP-) 1 level increased significantly by UR treatment. In addition, the histopathological analysis showed that the liver tissue lesions were improved obviously by UR treatment. UR may ameliorate the effects of TAA-induced ALI in rats by suppressing both OS through MPO activation and proinflammatory factors through NF-κB activation. In conclusion, UR exhibited a potent hepatoprotective effect on ALI through the suppression of OS.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Uncaria , Animais , Fígado , NF-kappa B , Ratos , Tioacetamida/toxicidade
2.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443423

RESUMO

Chronic liver inflammation has become a major global health concern. In the absence of clinical surrogate markers to diagnose inflammatory liver disease, the intervention with effective drugs in modern medicine tends to be late. In Sri Lanka, traditional medical practitioners prescribe herbal preparations from Osbeckia octandra for the prevention and treatment of liver disorders. To test the efficacy of such treatments, we have administered thioacetamide (TAA) to male Wistar rats to induce chronic liver damage (disease control; DC) and examined how various leaf extracts: crude leaf suspension (CLS), boiled leaf extract (BLE), sonicated leaf extract (SLE), methanol leaf extract (MLE) and hexane leaf extract (HLE) of O. octandra ameliorate TAA-induced liver disease. The CLS, BLE and SLE treatments in cirrhotic rats significantly attenuated disease-related changes, such as liver weight and hepato-enzymes. The mRNA levels of Tnf-α were significantly decreased by 3.6, 10 and 3.9 times in CLS, BLE and SLE compared to DC. The same treatments resulted in significantly lower (19.5, 4.2 and 2.4 times) α-Sma levels compared to DC. In addition, Tgf-ß1 and Vegf-R2 mRNA expressions were significantly lower with the treatments. Moreover, BLE expressed a strong anti-angiogenic effect. We conclude that CLS, BLE and SLE from O. octandra have potent hepatic anti-fibrotic effects in TAA-induced liver cirrhosis.


Assuntos
Cirrose Hepática Experimental/tratamento farmacológico , Melastomataceae/química , Neovascularização Patológica/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Citocinas/genética , Citocinas/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática Experimental/sangue , Neovascularização Patológica/sangue , Tamanho do Órgão/efeitos dos fármacos , Extratos Vegetais/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tioacetamida , Regulação para Cima/efeitos dos fármacos , Água , Perda de Peso/efeitos dos fármacos
3.
Environ Toxicol ; 36(10): 2062-2072, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34227734

RESUMO

Quercetin is a flavonoid compound with a variety of biological properties that is widely distributed throughout the plant kingdom. Studies have found that quercetin has anti-inflammatory, antioxidant, and liver-protective effects, while thioacetamide (TAA) can cause inflammation and liver damage in zebrafish larvae. The purpose of this study was to evaluate whether quercetin can prevent TAA-induced inflammation and liver damage in zebrafish larvae and to investigate the molecular mechanisms involved. Zebrafish Tg transgenic lines were used as the experimental animals. Behavioral, oxidative stress level, proliferative antigen chromogenic antibody, and western blot analyses were carried out on zebrafish larvae in the control group and groups treated with TAA and 12 µM quercetin. The results indicated that quercetin promoted the development of zebrafish larvae damaged by TAA, exhibited antioxidant and anti-inflammatory properties, and promoted cell proliferation. Quercetin reduced the expression of p53 protein in zebrafish larvae injured by TAA, resulting in decreased levels of Bax and increased levels of Bcl-2. The findings suggested quercetin has antiapoptotic action. Quercetin reduced the expression of DKK1 and DKK2 genes related to the Wnt signaling pathway in zebrafish larvae damaged by TAA and increased the expression of Lef1 and wnt2bb. Quercetin may regulate the development of zebrafish larvae damaged by TAA through the Wnt signaling pathway. This study provides the scientific basis for the development and utilization of quercetin and the development of new related drugs.


Assuntos
Quercetina , Tioacetamida , Animais , Antioxidantes/metabolismo , Larva , Fígado/metabolismo , Estresse Oxidativo , Quercetina/farmacologia , Tioacetamida/toxicidade , Peixe-Zebra
4.
J Org Chem ; 86(15): 10360-10367, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34281342

RESUMO

A novel and efficient synthetic method for the preparation of various pyrroloindolines from 2-alkynyl arylazides and thioacetamides was developed. The reaction was carried out in a one-pot process under mild reaction conditions to afford the products in moderate to good yields, which has the potential to be used in organic synthesis.


Assuntos
Paládio , Tioacetamida , Catálise , Técnicas de Química Sintética
5.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206365

RESUMO

Acute liver failure (ALF) is associated with deregulated nitric oxide (NO) signaling in the brain, which is one of the key molecular abnormalities leading to the neuropsychiatric disorder called hepatic encephalopathy (HE). This study focuses on the effect of ALF on the relatively unexplored endothelial NOS isoform (eNOS). The cerebral prefrontal cortices of rats with thioacetamide (TAA)-induced ALF showed decreased eNOS expression, which resulted in an overall reduction of NOS activity. ALF also decreased the content of the NOS cofactor, tetrahydro-L-biopterin (BH4), and evoked eNOS uncoupling (reduction of the eNOS dimer/monomer ratio). The addition of the NO precursor L-arginine in the absence of BH4 potentiated ROS accumulation, whereas nonspecific NOS inhibitor L-NAME or EDTA attenuated ROS increase. The ALF-induced decrease of eNOS content and its uncoupling concurred with, and was likely causally related to, both increased brain content of reactive oxidative species (ROS) and decreased cerebral cortical blood flow (CBF) in the same model.


Assuntos
Biopterina/análogos & derivados , Córtex Cerebral/enzimologia , Encefalopatia Hepática/enzimologia , Falência Hepática Aguda/enzimologia , Óxido Nítrico Sintase Tipo III/genética , Animais , Arginina/metabolismo , Biopterina/análise , Biopterina/metabolismo , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/metabolismo , Circulação Cerebrovascular , Regulação da Expressão Gênica , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/genética , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/complicações , Falência Hepática Aguda/genética , Masculino , Ratos , Ratos Sprague-Dawley , Tioacetamida/toxicidade
6.
Analyst ; 146(16): 5198-5203, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34308456

RESUMO

Thioacetamide (TAA) is a well-known hepatotoxic substance, so it is important to determine its presence and content in food and environmental samples. Herein, we report a highly sensitive determination method for TAA based on the electrochemiluminescence (ECL) of tris(2,2'-bipyridyl)ruthenium(ii) (Ru(bpy)32+) for the first time by using TAA as a new coreactant for Ru(bpy)32+ ECL via an anodic route. The developed Ru(bpy)32+-TAA ECL system allows the determination of TAA with a good dynamic linear range and low limit of detection (LOD) of 0.1 µM to 1000 µM and 0.035 µM (3σ/m), respectively. In addition, the established ECL system can be applied to detect TAA in fruit juice and waste water samples with outstanding recoveries.


Assuntos
Compostos Organometálicos , Rutênio , 2,2'-Dipiridil/toxicidade , Medições Luminescentes , Tioacetamida/toxicidade
7.
Commun Biol ; 4(1): 824, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193972

RESUMO

Demand for a cure of liver fibrosis is rising with its increasing morbidity and mortality. Therefore, it is an urgent issue to investigate its therapeutic candidates. Liver fibrosis progresses following 'multi-hit' processes involving hepatic stellate cells, macrophages, and hepatocytes. The NOD-like receptor protein 3 (NLRP3) inflammasome is emerging as a therapeutic target in liver fibrosis. Previous studies showed that the anti-rheumatic agent auranofin inhibits the NLRP3 inflammasome; thus, this study evaluates the antifibrotic effect of auranofin in vivo and explores the underlying molecular mechanism. The antifibrotic effect of auranofin is assessed in thioacetamide- and carbon tetrachloride-induced liver fibrosis models. Moreover, hepatic stellate cell (HSC), bone marrow-derived macrophage (BMDM), kupffer cell, and hepatocyte are used to examine the underlying mechanism of auranofin. Auranofin potently inhibits activation of the NLRP3 inflammasome in BMDM and kupffer cell. It also reduces the migration of HSC. The underlying molecular mechanism was inhibition of cystine-glutamate antiporter, system Xc. Auranofin inhibits system Xc activity and instantly induced oxidative burst, which mediated inhibition of the NLRP3 inflammasome in macrophages and HSCs. Therefore, to the best of our knowledge, we propose the use of auranofin as an anti-liver fibrotic agent.


Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Auranofina/farmacologia , Inflamassomos/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Tetracloreto de Carbono , Células Cultivadas , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Piroptose/efeitos dos fármacos , Tioacetamida
8.
Sci Rep ; 11(1): 12296, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112866

RESUMO

Liver fibrosis is a significant health problem that can cause serious illness and death. Unfortunately, a standard treatment for liver fibrosis has not been approved yet due to its complicated pathogenesis. The current study aimed at assessing the anti-fibrotic effect of taurine against thioacetamide induced liver fibrosis in rats through the modulation of toll like receptor 4/nuclear factor kappa B signaling pathway. Both concomitant and late taurine treatment (100 mg/kg, IP, daily) significantly reduced the rise in serum ALT and AST activities and significantly reversed the decrease in serum albumin and total protein. These results were confirmed by histopathological examinations and immunehistochemical inspection of α-SMA, caspase-3 and NF-κB. The antioxidant potential of taurine was verified by a marked increase of GSH content and a reduction of MDA level in liver tissue. The anti-fibrotic effects of taurine were evaluated by investigating the expression of TLR4, NF-κB. The protein levels of IL-6, LPS, MyD88, MD2, CD14, TGF-ß1 and TNF-α were determined. Docking studies were carried out to understand how taurine interacts inside TLR4-MD2 complex and it showed good binding with the hydrophobic binding site of MD2. We concluded that the anti-fibrotic effect of taurine was attributable to the modulation of the TLR4/NF-κB signaling.


Assuntos
Antioxidantes/farmacologia , Cirrose Hepática/tratamento farmacológico , Antígeno 96 de Linfócito/genética , Taurina/farmacologia , Receptor 4 Toll-Like/genética , Actinas/genética , Animais , Caspase 3/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/patologia , Simulação de Acoplamento Molecular , NF-kappa B/genética , Ligação Proteica/efeitos dos fármacos , Ratos , Albumina Sérica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Taurina/genética , Tioacetamida/toxicidade
9.
Int J Mol Sci ; 22(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064584

RESUMO

Liver fibrosis results from many chronic injuries and may often progress to cirrhosis and hepatocellular carcinoma (HCC). In fact, up to 90% of HCC arise in a cirrhotic liver. Conversely, stress is implicated in liver damage, worsening disease outcome. Hence, stress could play a role in disrupting liver homeostasis, a concept that has not been fully explored. Here, in a murine model of TAA-induced liver fibrosis we identified nerve growth factor (NGF) to be a crucial regulator of the stress-induced fibrogenesis signaling pathway as it activates its receptor p75 neurotrophin receptor (p75NTR), increasing liver damage. Additionally, blocking the NGF decreased liver fibrosis whereas treatment with recombinant NGF accelerated the fibrotic process to a similar extent than stress challenge. We further show that the fibrogenesis induced by stress is characterized by specific changes in the hepatoglycocode (increased ß1,6GlcNAc-branched complex N-glycans and decreased core 1 O-glycans expression) which are also observed in patients with advanced fibrosis compared to patients with a low level of fibrosis. Our study facilitates an understanding of stress-induced liver injury and identify NGF signaling pathway in early stages of the disease, which contributes to the established fibrogenesis.


Assuntos
Regulação da Expressão Gênica , Cirrose Hepática/patologia , Fator de Crescimento Neural/metabolismo , Polissacarídeos/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Estresse Fisiológico , Tioacetamida/toxicidade , Animais , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/genética
10.
Phytomedicine ; 88: 153609, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34126414

RESUMO

BACKGROUD: Schisandra chinensis, a traditional Chinese medicine for liver protection, can significantly improve liver fibrosis. However, it is still unclear which active components in Schisandra chinensis play an anti-fibrosis role. PURPOSE: The purpose of present study was to observe the anti-fibrosis effect of schisantherin A (SCA) on liver fibrosis and explore its underlying mechanism. METHODS: The liver fibrosis model of mice was constructed by the progressive intraperitoneal injection of thioacetamide (TAA), and SCA (1, 2, and 4 mg/kg) was administered by gavage for 5 weeks. The biochemical indicators and inflammatory cytokines were measured, changes in the pathology of the mice liver were observed by hematoxylin & eosin (H&E) and Masson stainings for studying the anti-fibrosis effect of SCA. A hepatic stellate cell (HSCs) activation model induced by transforming growth factor-ß1 (TGF-ß1) was established, and the effect of SCA on the HSCs proliferation was observed by MTT assay. The expressions of target proteins related to transforming growth factor-ß-activated kinase 1 (TAK1)/mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways were evaluated by western blotting, immunohistochemistry or immunofluorescence analysis, to explore the potential mechanism of SCA. RESULTS: SCA could significantly ameliorate the pathological changes of liver tissue induced by TAA, and reduce the serum transaminase level, the hydroxyproline level and the expression of α-smooth muscle actin (α-SMA) and collagen 1A1 (COL1A1) proteins in the liver tissue. SCA could significantly lower the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in the serum and liver tissue, and down-regulate the expression of target proteins related to TAK1/MAPK and NF-κB pathways in the liver tissue. The in vitro studies demonstrated that SCA significantly inhibited the proliferation and activation of HCS-T6 cells induced by TGF-ß1, decreased TNF-α and IL-6 levels, and inhibited the TAK1 activation induced by TGF-ß1 and then the expression of MAPK and NF-κB signaling pathway-related proteins. CONCLUSION: Together, SCA can ameliorate the liver fibrosis induced by TAA and the HSC-T6 cell activation induced by TGF-ß1 in mice, and its mechanism may be to inhibit the HSCs activation and inflammatory response by inhibiting TGF-ß1 mediated TAK1/MAPK and signal pathways.


Assuntos
Ciclo-Octanos/farmacologia , Dioxóis/farmacologia , Lignanas/farmacologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Linhagem Celular , Citocinas/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/patologia , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos Endogâmicos ICR , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Tioacetamida/toxicidade
11.
Cell Prolif ; 54(7): e13072, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34031939

RESUMO

OBJECTIVES: Induction of deactivation and apoptosis of hepatic stellate cells (HSCs) are principal therapeutic strategies for liver fibrosis. Krüppel-like factor 14 (KLF14) regulates various biological processes, however, roles, mechanisms and implications of KLF14 in liver fibrosis are unknown. MATERIALS AND METHODS: KLF14 expression was detected in human, rat and mouse fibrotic models, and its effects on HSCs were assessed. Chromatin immunoprecipitation assays were utilized to investigate the binding of KLF14 to peroxisome proliferator-activated receptor γ (PPARγ) promoter, and the binding of enhancer of zeste homolog 2 (EZH2) to KLF14 promoter. In vivo, KLF14-overexpressing adenovirus was injected via tail vein to thioacetamide (TAA)-treated rats to investigate the role of KLF14 in liver fibrosis progression. EZH2 inhibitor EPZ-6438 was utilized to treat TAA-induced rat liver fibrosis. RESULTS: KLF14 expression was remarkably decreased in human, rat and mouse fibrotic liver tissues. Overexpression of KLF14 increased LD accumulation, inhibited HSCs activation, proliferation, migration and induced G2/M arrest and apoptosis. Mechanistically, KLF14 transactivated PPARγ promoter activity. Inhibition of PPARγ blocked the suppressive role of KLF14 overexpression in HSCs. Downregulation of KLF14 in activated HSCs was mediated by EZH2-regulated histone H3 lysine 27 trimethylation. Adenovirus-mediated KLF14 overexpression ameliorated TAA-induced rat liver fibrosis in PPARγ-dependent manner. Furthermore, EPZ-6438 dramatically alleviated TAA-induced rat liver fibrosis. Importantly, KLF14 expression was decreased in human with liver fibrosis, which was significantly correlated with EZH2 upregulation and PPARγ downregulation. CONCLUSIONS: KLF14 exerts a critical anti-fibrotic role in liver fibrosis, and targeting the EZH2/KLF14/PPARγ axis might be a novel therapeutic strategy for liver fibrosis.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Cirrose Hepática/patologia , PPAR gama/metabolismo , Animais , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , Fatores de Transcrição Kruppel-Like/genética , Cirrose Hepática/metabolismo , Camundongos , Morfolinas/farmacologia , PPAR gama/antagonistas & inibidores , PPAR gama/genética , Regiões Promotoras Genéticas , Piridonas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Tioacetamida/farmacologia
12.
Environ Toxicol Pharmacol ; 86: 103668, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33945853

RESUMO

AIM: Hepatocellular carcinoma (HCC) is a highly invasive form of hepatic cancer. It is a highly intricate disease with multiple pathophysiological mechanisms underlying its pathogenesis. MATERIALS AND METHODS: The results of the current investigation shed light on the ability of saxagliptin (SAXA) (12.5 mg/kg) to defer HCC progression in an experimental model of thioacetamide (TAA)-induced hepatocarcinogenesis. RESULTS: SAXA administration improved liver function biomarkers, with a concomitant histopathological recovery. Mechanistically, the observed hepatoprotective impact was associated with significant suppression of the hepatic content of Wnt3a, ß-catenin, Notch1, Smo, and Gli2 and enhanced expression of GSK 3ß. Nevertheless, the hepatic expression of PCNA, P53, and cyclin D1 was significantly enhanced, with a parallel increase in the tumor expression of caspase-3. Thus, it appears that SAXA significantly enhanced tumor apoptosis, with concomitant suppression of HCC proliferation. CONCLUSION: SAXA deferred experimentally-induced HCC via suppressing Wnt/Hedgehog/Notch1 Signaling, with enhanced tumor apoptosis and suppressed proliferation.


Assuntos
Adamantano/análogos & derivados , Carcinoma Hepatocelular/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adamantano/farmacologia , Adamantano/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Dipeptídeos/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Proteínas Hedgehog/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Masculino , Ratos Sprague-Dawley , Receptor Notch1/metabolismo , Tioacetamida , Via de Sinalização Wnt/efeitos dos fármacos
13.
Methods Mol Biol ; 2299: 339-356, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34028753

RESUMO

Liver fibrosis is defined as excessive accumulation of extracellular matrix, and results from maladaptive wound healing processes that occur in response to chronic liver injury and inflammation. The main etiologies of liver fibrosis include nonalcoholic fatty liver disease (NAFLD), chronic viral hepatitis, as well as alcoholic and cholestatic liver disease. In patients, liver fibrosis typically develops over several decades and can progress to cirrhosis, and liver failure due to replacement of functional liver tissue with scar tissue. Additionally, advanced fibrosis and cirrhosis are associated with an increased risk for the development of hepatocellular carcinoma. On a cellular level, hepatic fibrosis is mediated by activated hepatic stellate cells, the primary fibrogenic cell type of the liver. Murine models are employed to recapitulate, understand, and therapeutically target mechanisms of fibrosis and hepatic stellate cell activation. Here, we summarize different mouse models of liver fibrosis focusing on the most commonly used models of toxic, biliary, and metabolically induced liver fibrosis, triggered by treatment with carbon tetrachloride (CCl4), thioacetamide (TAA), bile duct ligation (BDL), 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), and high-fat diets.


Assuntos
Células Estreladas do Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Animais , Tetracloreto de Carbono/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Piridinas/efeitos adversos , Tioacetamida/efeitos adversos
14.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805788

RESUMO

Persistent chronic liver diseases increase the scar formation and extracellular matrix accumulation that further progress to liver fibrosis and cirrhosis. Nevertheless, there is no antifibrotic therapy to date. The ketogenic diet is composed of high fat, moderate to low-protein, and very low carbohydrate content. It is mainly used in epilepsy and Alzheimer's disease. However, the effects of the ketogenic diet on liver fibrosis remains unknown. Through ketogenic diet consumption, ß-hydroxybutyrate (bHB) and acetoacetate (AcAc) are two ketone bodies that are mainly produced in the liver. It is reported that bHB and AcAc treatment decreases cancer cell proliferation and promotes apoptosis. However, the influence of bHB and AcAc in hepatic stellate cell (HSC) activation and liver fibrosis are still unclear. Therefore, this study aimed to investigate the effect of the ketogenic diet and ketone bodies in affecting liver fibrosis progression. Our study revealed that feeding a high-fat ketogenic diet increased cholesterol accumulation in the liver, which further enhanced the carbon tetrachloride (CCl4)- and thioacetamide (TAA)-induced liver fibrosis. In addition, more severe liver inflammation and the loss of hepatic antioxidant and detoxification ability were also found in ketogenic diet-fed fibrotic mouse groups. However, the treatment with ketone bodies (bHB and AcAc) did not suppress transforming growth factor-ß (TGF-ß)-induced HSC activation, platelet-derived growth factor (PDGF)-BB-triggered proliferation, and the severity of CCl4-induced liver fibrosis in mice. In conclusion, our study demonstrated that feeding a high-fat ketogenic diet may trigger severe steatohepatitis and thereby promote liver fibrosis progression. Since a different ketogenic diet composition may exert different metabolic effects, more evidence is necessary to clarify the effects of a ketogenic diet on disease treatment.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Acetoacetatos/farmacologia , Colesterol/biossíntese , Dieta Cetogênica/efeitos adversos , Cirrose Hepática/metabolismo , Fígado/efeitos dos fármacos , Ácido 3-Hidroxibutírico/biossíntese , Acetoacetatos/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Becaplermina/farmacologia , Tetracloreto de Carbono/administração & dosagem , Catalase/genética , Catalase/metabolismo , Proliferação de Células/efeitos dos fármacos , Colesterol/sangue , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Desmina/genética , Desmina/metabolismo , Progressão da Doença , Regulação da Expressão Gênica/efeitos dos fármacos , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Cultura Primária de Células , Índice de Gravidade de Doença , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Tioacetamida/administração & dosagem , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/farmacologia
15.
J Food Sci ; 86(6): 2753-2765, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33928646

RESUMO

25-Hydroxylprotopanaxadiol-3ß, 12ß, 20-triol (25-OH-PPD or AD-2) belongs to dammarane ginsenoside, and is commonly obtained from the acidic hydrolysate of total ginsensides of Panax ginseng. This study investigated the potential mechanism of AD-2 toward improving thioacetamide (TAA)-induced hepatic fibrosis in mice. Mice were divided into seven groups: control group, TAA model group, TAA + AD-2 (5, 10, and 20 mg/kg) groups, TAA + silymarin (100 mg/kg) group, and TAA + Fu Fang Biejia (FFBj; 300 mg/kg) group. All mice were treated to intraperitoneal TAA injection to establish a hepatic fibrosis model, and drugs were administered orally. The mechanism and related pathways underlying the AD-2-mediated action against hepatic fibrosis were explored by Western blotting and immunohistochemical staining. After AD-2 treatment, the expression levels of Lipin-1, SREBP1, and F4/80 significantly decreased, meanwhile the protein expressions levels of IL1ß, IL1R1, IL18, Bax, Bid, Bcl-2, and cFlips also decreased. Furthermore, AD-2 inhibited RAF and MEK pathways. The results demonstrate that AD-2 can alleviate hepatic fibrosis. The mechanism is likely related to the regulation of lipid accumulation, inflammatory response, apoptosis pathway, and Raf-MEK signaling pathways, which provide a basis for clinical research for the treatment of hepatic fibrosis. PRACTICAL APPLICATION: Ginsenoside is one of the main active ingredients of ginseng, and can alleviate the symptoms of various diseases, for example, hepatic fibrosis. This paper mainly used Western blotting to explore its possible mechanism of action. The goal was to provide a reference for the development of traditional Chinese medicines for hepatic fibrosis.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Ginsenosídeos/farmacologia , Inflamação/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Tioacetamida/toxicidade , Quinases raf/metabolismo , Animais , Doença Hepática Crônica Induzida por Substâncias e Drogas/etiologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos , Panax/química , Transdução de Sinais/efeitos dos fármacos
16.
Molecules ; 26(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808318

RESUMO

Liver disorders have been recognized as one major health concern. Fucoidan, a sulfated polysaccharide extracted from the brown seaweed Fucus serratus, has previously been reported as an anti-inflammatory and antioxidant. However, the discovery and validation of its hepatoprotective properties and elucidation of its mechanisms of action are still unknown. The objective of the current study was to investigate the effect and possible modes of action of a treatment of fucoidan against thioacetamide (TAA)-induced liver injury in male C57BL/6 mice by serum biochemical and histological analyses. The mouse model for liver damage was developed by the administration of TAA thrice a week for six weeks. The mice with TAA-induced liver injury were orally administered fucoidan once a day for 42 days. The treated mice showed significantly higher body weights; food intakes; hepatic antioxidative enzymes (catalase, glutathione peroxidase (GPx), and superoxide dismutase (SOD)); and a lower serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and C-reactive protein (CRP) levels. Additionally, a reduced hepatic IL-6 level and a decreased expression of inflammatory-related genes, such as cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) mRNA was observed. These results demonstrated that fucoidan had a hepatoprotective effect on liver injury through the suppression of the inflammatory responses and acting as an antioxidant. In addition, here, we validated the use of fucoidan against liver disorders with supporting molecular data.


Assuntos
Anti-Inflamatórios , Antioxidantes , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Fígado/efeitos dos fármacos , Polissacarídeos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Citocinas/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/administração & dosagem , Polissacarídeos/farmacologia , Tioacetamida/toxicidade
17.
Life Sci ; 277: 119460, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33811899

RESUMO

BACKGROUND AND AIMS: The normal functioning of Kelch-like ECH-associated protein-1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) complex is necessary for the cellular protection against oxidative stress. We investigated the effect of chlorogenic acid (CGA), quercetin (Qt), coenzyme Q10 (Q10) and silymarin on the expression of Keap1/Nrf2 complex and its downstream target; heme oxygenase-1 (HO-1) as well as inflammation and apoptosis in an acute liver toxicity model induced by thioacetamide (TAA). MAIN METHODS: Wistar rats were divided into 13 groups: Control, silymarin, CGA, Qt, Q10, TAA (single dose 50 mg/kg, i.p.), TAA + silymarin (400 mg/kg, p.o.), TAA + CGA (100 & 200 mg/kg, p.o.), TAA + Qt (200 &300 mg/kg, p.o.) and TAA+ Q10 (30&50 mg/kg, p.o.) and treated for 8 days. KEY FINDINGS: The results showed improved liver functions and hepatic tissue integrity in all tested doses of TAA + silymarin, TAA + CGA, TAA + Qt and TAA + Q10 groups compared to the TAA group. Furthermore, these groups showed significantly lower ROS, malondialdehyde and nitric oxide levels but higher glutathione content and superoxide dismutase activity compared to the TAA group, p < 0.05. In these groups, Keap1 expression was significantly decreased while Nrf2 expression and HO-1 activity were increased. In addition, the number of apoptotic cells and the expression level of TNF-α in the liver tissues were significantly decreased compared to the TAA group. SIGNIFICANCE: CGA, Qt, Q10 and silymarin protect against TAA-induced acute liver toxicity via antioxidant, anti-inflammatory, anti-apoptotic activities and regulating Keap1-Nrf2/HO-1 expression.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Ácido Clorogênico/metabolismo , Ácido Clorogênico/farmacologia , Heme Oxigenase (Desciclizante)/fisiologia , Heme Oxigenase-1/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/fisiologia , Fígado/metabolismo , Fígado/patologia , Masculino , Fator 2 Relacionado a NF-E2/fisiologia , Quercetina/metabolismo , Quercetina/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Silimarina/metabolismo , Silimarina/farmacologia , Tioacetamida/efeitos adversos , Tioacetamida/farmacologia , Tioacetamida/toxicidade , Ubiquinona/análogos & derivados , Ubiquinona/metabolismo , Ubiquinona/farmacologia
18.
J Biochem Mol Toxicol ; 35(5): e22745, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33749060

RESUMO

Liver fibrosis is a public health burden that is highly associated with morbidity and mortality. Therefore, this study aims to explore the anti-fibrotic effects of low dose of paclitaxel (PTX) against thioacetamide (TAA)-induced liver fibrosis in rats and the possible mechanisms involved. TAA was administered at a dose of 200 mg/kg twice weekly for 6 weeks in rats to induce liver fibrosis similar to that in humans. Liver dysfunction was shown by increased alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transferase, along with histopathological changes. Liver fibrosis was confirmed by Masson's Trichome staining, increased collagen content, and elevated α-smooth muscle actin (α-SMA) protein expression. In addition, TAA induced liver apoptosis as indicated by the increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in liver tissues. This study demonstrated that the administration of PTX (0.3 mg/kg/i.p.) three times a week for 6 weeks significantly alleviated functional and biochemical changes induced by TAA in addition to improving the liver architecture. PTX attenuated liver fibrosis as reflected by the decreased collagen content and α-SMA protein expression. Additionally, PTX attenuated liver apoptosis as indicated by the decreased TUNEL-positive cells. Moreover, PTX prevented TAA-induced elevation of transforming growth factor-ß1 (TGF-ß1), platelet-derived growth factor-BB (PDGF-BB), and tissue inhibitor of metalloproteinase 1 (TIMP-1) levels in liver tissues. These findings suggest that the low dose of PTX prevented TAA-induced liver fibrosis in rats, possibly by inhibiting the expression of TGF-ß1 and PDGF-BB and subsequently suppressing the apoptosis and the expression of TIMP-1.


Assuntos
Cirrose Hepática , Paclitaxel/farmacologia , Tioacetamida/toxicidade , Animais , Modelos Animais de Doenças , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Masculino , Ratos , Ratos Sprague-Dawley
19.
Biomed Pharmacother ; 138: 111502, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33756156

RESUMO

The water-soluble acidic polysaccharide from Thalassodendron ciliatum (Forss.) den Hartog was successfully extracted, fractionated and purified. The phytochemical profile of the two water-soluble fractions (F1 and F2), were detected using different analytic techniques. GC-MS analysis revealed the presence of 22 saccharide. Acidic polysaccharide, galacturonic and glucuronic acid were the most abundant. Moreover, paper chromatography and electrophoresis also performed as a preliminary chemical characterization of the polymer. The hepatoprotective activity of the fractions against thioacetamide (TAA) induced liver failure; antioxidant potential and preliminary immunomodulatory activity were assigned in-vivo. The results revealed a potent competence to improve the liver function profile (ALT, AST, total bilirubin, total glyceride, etc.) and a remarkable improvement in liver architecture in comparison to the challenged intoxicated groups. Moreover, they showed high anti-oxidative properties and a promising immunomodulatory influence via Il6. These findings provide new insight into the possible role of polysaccharide purified two fractions in the treatment of acute liver injury.


Assuntos
Chalconas/análise , Chalconas/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Glicosídeos/análise , Glicosídeos/uso terapêutico , Falência Hepática/tratamento farmacológico , Polissacarídeos/uso terapêutico , Tioacetamida/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Relação Dose-Resposta a Droga , Cromatografia Gasosa-Espectrometria de Massas/métodos , Falência Hepática/induzido quimicamente , Falência Hepática/patologia , Masculino , Polissacarídeos/análise , Ratos , Ratos Wistar
20.
Int J Biochem Cell Biol ; 134: 105933, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33540107

RESUMO

Chronic liver injury is characterised by continuous or repeated epithelial cell loss and inflammation. Hepatic wound healing involves matrix deposition through activated hepatic stellate cells (HSCs) and the expansion of closely associated Ductular Reactions and liver progenitor cells (LPCs), which are thought to give rise to new epithelial cells. In this study, we used the murine thioacetamide (TAA) model to reliably mimic these injury and regeneration dynamics and assess the impact of a recovery phase on subsequent liver injury and fibrosis. Age-matched naïve or 6-week TAA-treated/4-week recovered mice (C57BL/6 J, n = 5-9) were administered TAA for six weeks (C57BL/6 J, n = 5-9). Sera and liver tissues were harvested at key time points to assess liver injury biochemically, by real-time PCR for fibrotic mediators, Sirius Red staining and hydroxyproline assessment for collagen deposition as well as immunofluorescence for inflammatory, HSC and LPC markers. In addition, primary HSCs and the HSC cell line LX-2 were co-cultured with the well-characterised LPC line BMOL and analysed for potential changes in expression of fibrogenic mediators. Our data demonstrate that recovery from a previous TAA insult, with LPCs still present on day 0 of the second treatment, led to a reduced TAA-induced disease progression with less severe fibrosis than in naïve TAA-treated animals. Importantly, primary activated HSCs significantly reduced pro-fibrogenic gene expression when co-cultured with LPCs. Taken together, previous TAA injury established a fibro-protective molecular and cellular microenvironment. Our proof-of principle HSC/LPC co-culture data demonstrate that LPCs communicate with HSCs to regulate fibrogenesis, highlighting a key role for LPCs as regulatory cells during chronic liver disease.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/patologia , Células Estreladas do Fígado/citologia , Cirrose Hepática/patologia , Regeneração Hepática/fisiologia , Fígado/citologia , Células-Tronco/citologia , Tioacetamida/toxicidade , Animais , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Técnicas de Cocultura , Modelos Animais de Doenças , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco/metabolismo
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