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1.
Cell Physiol Biochem ; 53(2): 301-322, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31343125

RESUMO

BACKGROUND/AIMS: Propolis is one of the most promising natural products, exhibiting not only therapeutic but also prophylactic actions. Propolis has several biological and pharmacological properties, including hepatoprotective activities. The present study aimed to investigate the underlying molecular mechanisms of propolis against CCl4-mediated liver fibrosis. METHODS: Three groups of male BALB/c mice (n=15/ group) were used: group 1 comprised control mice; groups 2 and 3 were injected with CCl4 for the induction of liver fibrosis. Group 3 was then orally supplemented with propolis (100 mg/kg body weight) for four weeks. Different techniques were used to monitor the antifibrotic effects of propolis, including histopathological investigations using H&E, Masson's trichrome and Sirius red staining; Western blotting; flow cytometry; and ELISA. RESULTS: We found that the induction of liver fibrosis by CCl4 was associated with a significant increase in hepatic collagen and α-smooth muscle actin (α-SMA) expression. Moreover, CCl4-treated mice also exhibited histopathological alterations in the liver architecture. Additionally, the liver of CCl4-treated mice exhibited a marked increase in proinflammatory signals, such as increased expression of HSP70 and increased levels of proinflammatory cytokines and ROS. Mechanistically, the liver of CCl4-treated mice exhibited a significant increase in the phosphorylation of AKT and mTOR; upregulation of the expression of BAX and cytochrome C; downregulation of the expression of Bcl2; a significant elevation in the levels of TGF-ß followed by increased phosphorylation of SMAD2; and a marked increase in the expression of P53 and iNOS. Interestingly, oral supplementation of CCl4-treated mice with propolis significantly abolished hepatic collagen deposition, abrogated inflammatory signals and oxidative stress, restored CCl4-mediated alterations in the signaling cascades, and hence repaired the hepatic architecture nearly to the normal architecture observed in the control mice. CONCLUSION: Our findings revealed the therapeutic potential and the underlying mechanisms of propolis against liver fibrosis.


Assuntos
Apoptose/efeitos dos fármacos , Cirrose Hepática Experimental/patologia , Própole/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Tetracloreto de Carbono/toxicidade , Citocinas/metabolismo , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Smad2/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo
2.
Nat Commun ; 10(1): 2993, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278269

RESUMO

Activated hepatic stellate cell (aHSC)-mediated liver fibrosis is essential to the development of liver metastasis. Here, we discover intra-hepatic scale-up of relaxin (RLN, an anti-fibrotic peptide) in response to fibrosis along with the upregulation of its primary receptor (RXFP1) on aHSCs. The elevated expression of RLN serves as a natural regulator to deactivate aHSCs and resolve liver fibrosis. Therefore, we hypothesize this endogenous liver fibrosis repair mechanism can be leveraged for liver metastasis treatment via enforced RLN expression. To validate the therapeutic potential, we utilize aminoethyl anisamide-conjugated lipid-calcium-phosphate nanoparticles to deliver plasmid DNA encoding RLN. The nanoparticles preferentially target metastatic tumor cells and aHSCs within the metastatic lesion and convert them as an in situ RLN depot. Expressed RLN reverses the stromal microenvironment, which makes it unfavorable for established liver metastasis to grow. In colorectal, pancreatic, and breast cancer liver metastasis models, we confirm the RLN gene therapy results in significant inhibition of metastatic progression and prolongs survival. In addition, enforced RLN expression reactivates intra-metastasis immune milieu. The combination of the RLN gene therapy with PD-L1 blockade immunotherapy further produces a synergistic anti-metastatic efficacy. Collectively, the targeted RLN gene therapy represents a highly efficient, safe, and versatile anti-metastatic modality, and is promising for clinical translation.


Assuntos
Terapia Genética/métodos , Cirrose Hepática Experimental/terapia , Neoplasias Hepáticas/terapia , Hepatopatia Gordurosa não Alcoólica/terapia , Relaxina/genética , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Tetracloreto de Carbono/administração & dosagem , Tetracloreto de Carbono/toxicidade , Linhagem Celular Tumoral/transplante , Progressão da Doença , Feminino , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Plasmídeos/genética , Receptores Acoplados a Proteínas-G/metabolismo , Relaxina/metabolismo , Resultado do Tratamento , Microambiente Tumoral/genética , Regulação para Cima
3.
Environ Sci Pollut Res Int ; 26(23): 24010-24019, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31222653

RESUMO

Actinomycetes are a group of the Gram-positive bacteria famous for their antimicrobial, anticancer, anti-parasitic, and anti-inflammatory activities. This study aimed to investigate the efficacy of two bacterial extracts derived from two soil actinomycete strains (S19 and G30) against carbon tetrachloride (CCl4)-induced nephrotoxicity in experimental rats. Sixty-four male rats were assigned to four groups of 16 rats in each group. The 1st group was kept as a normal (control) group and given corn oil combined with the used production medium, while the 2nd group received only CCl4 (CCl4 group). On the other hand, the 3rd group (CCl4+S19) was administered CCl4 and the extract of the actinomycete strain S19 and the 4th group (CCl4+G30) received CCl4 and the extract of the actinomycete strain G30, both treatments for 8 weeks. The results revealed that the two actinomycete extracts S19 and G30 could significantly (p < 0.01) lower the elevated levels of serum creatinine, urea, and uric acid caused by the CCl4 administration. Additionally, the two actinomycete extracts improved the decreased serum total protein. Interestingly, treatment of the CCl4-intoxicated rats with S19 and G30 extracts remarkably reversed the lowered renal glutathione (GSH), glutathione peroxidase (GSH-Px), peroxidase (Px) and superoxide dismutase (SOD) activities, and the elevated lipid peroxidation (LPO) levels. The histopathological examination of the treated kidney revealed that the two actinomycete extracts improved rats against CCl4-induced kidney lesions. The present results suggested that the protective effect of the two actinomycete extracts may rely on its effect on reducing the oxidative stress and improving the antioxidant defense system.


Assuntos
Actinobacteria/metabolismo , Fatores Biológicos/metabolismo , Tetracloreto de Carbono/toxicidade , Estresse Oxidativo/fisiologia , Animais , Antioxidantes/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Rim/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Ratos , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
4.
Chem Biol Interact ; 309: 108675, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31150632

RESUMO

Liver fibrosis is a progression of chronic liver disease with lacks effective therapies at present. Schisandrin B (Sch B), a bioactive compound extracted from the traditional Chinese medicine Schisandra chinensis, was reported to benefit liver diseases. This study aimed to investigate the therapeutic effects and molecular mechanisms of Sch B against CCl4-induced liver fibrosis in rats. RNA sequencing and transcriptome analysis were performed collaboratively, including analysis of differential gene expression, gene ontology (GO) analysis, pathway analysis and pathway-act-network analysis. The results demonstrated that Sch B effectively alleviated CCl4-induced liver damage and fibrosis in rats, as evidenced by improved liver function and decreased extracellular matrix deposition. Furthermore, 4440 (1878 up-regulated, 2562 down-regulated) genes in the model group versus (vs) normal group, 4243 (2584 up-regulated, 1659 down-regulated) genes in Sch B-treated group vs model group were identified as differentially expressed genes (DEGs). Subsequently, GO analysis revealed that DEGs were mainly enriched in metabolism, oxidation-reduction, endoplasmic reticulum stress and apoptosis-related biological processes. Pathway analysis suggested that Sch B up-regulated cytochrome P450 drug metabolism, PPAR signaling pathways, and down-regulated glutathione metabolism pathways. In addition, the regulatory patterns of Sch B on key genes and pathways were also confirmed. In conclusion, our study demonstrated Sch B alleviated CCl4-induced liver fibrosis by multiple modulatory mechanisms, which provide new clues for further pharmacological study of Sch B.


Assuntos
Lignanas/farmacologia , Cirrose Hepática/patologia , Fígado/metabolismo , Compostos Policíclicos/farmacologia , Transcriptoma , Animais , Apoptose/efeitos dos fármacos , Tetracloreto de Carbono/toxicidade , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Perfilação da Expressão Gênica , Lignanas/química , Lignanas/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Masculino , Medicina Tradicional Chinesa , Compostos Policíclicos/química , Compostos Policíclicos/uso terapêutico , RNA/química , RNA/isolamento & purificação , RNA/metabolismo , Ratos , Ratos Wistar , Schisandra/química , Schisandra/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Regulação para Cima/efeitos dos fármacos
5.
Food Chem Toxicol ; 131: 110531, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31136780

RESUMO

1-O-(4-hydroxymethylphenyl)-α-L-rhamnopyranoside (MPG) is a phenolic glycoside that exists in Moringa oleifera seeds with various health benefits, whereas its hepatoprotective effect is lacking clarification. Herein, MPG was isolated from Moringa oleifera seeds, and its hepatoprotection against CCl4-induced hepatotoxicity in L02 cells and ICR mice was investigated. Toxicity studies showed that MPG did not induce significant changes in organ coefficients and histological analysis, as well as exhibited no cytotoxicity. In vitro studies indicated that MPG substantially increased cell viability and intracellular SOD activities, and significantly inhibited LDH leakage in CCl4-treated cells. In vivo studies demonstrated that MPG significantly alleviated CCl4-induced hepatotoxicity in mice, as indicated by diagnostic indicators of hepatic injury, as well as the histopathological analysis. Moreover, MPG reduced the lipid peroxidation levels and regulated the inflammatory cytokines. Notably, MPG substantially suppressed the significant elevation of ROS production in hepatocytes of mice intoxicated with CCl4. Moreover, TUNEL assay demonstrated that MPG obviously inhibited hepatic apoptosis induced by CCl4. Altogether, these results suggested that MPG has excellent liver-protecting effects against hepatocytotoxicity induced by CCl4 in mice and L02 cells, which can be further developed as a valuable functional food additive or drug for the treatment of hepatic injury.


Assuntos
Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Glicosídeos/farmacologia , Moringa oleifera/química , Sementes/química , Administração Oral , Animais , Antioxidantes/administração & dosagem , Antioxidantes/isolamento & purificação , Antioxidantes/toxicidade , Tetracloreto de Carbono/toxicidade , Linhagem Celular , Citocinas/metabolismo , Feminino , Glicosídeos/administração & dosagem , Glicosídeos/isolamento & purificação , Glicosídeos/toxicidade , Fígado/patologia , Masculino , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos
7.
Biochim Biophys Acta Mol Basis Dis ; 1865(5): 1031-1039, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31007174

RESUMO

Drug-induced liver injury (DILI) presents unique challenges for consumers, clinicians, and regulators. It is the most common cause of acute liver failure in the US. It is also one of the most common reasons for termination of new drugs during pre-clinical testing and withdrawal of new drugs post-marketing. DILI is generally divided into two forms: intrinsic and idiosyncratic. Many of the challenges with DILI are due in large part to poor understanding of the mechanisms of toxicity. Although useful models of intrinsic DILI are available, they are frequently misused. Modeling idiosyncratic DILI presents greater challenges, but promising new models have recently been developed. The purpose of this manuscript is to provide a critical review of the most popular animal models of DILI, and to discuss the future of DILI research.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Acetaminofen/toxicidade , Animais , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Humanos , Tolerância Imunológica
8.
Biochim Biophys Acta Mol Basis Dis ; 1865(5): 993-1002, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31007176

RESUMO

Hepatocellular carcinoma (HCC) represents ~90% of all cases of primary liver cancer and occurs predominantly in patients with underlying chronic liver disease and cirrhosis. Establishing appropriate animal models for HCC is required for basic and translational studies, especially the models that can recapitulate one of the human disease settings. Current animal models can be categorized as chemically-induced, genetically-engineered, xenograft, or a combination of these with each other or with a metabolic insult. A single approach to resemble human HCC in animals is not sufficient. Combining pathogenic insults in animal models may more realistically recapitulate the multiple etiologic agents occurring in humans. Combining chemical injury with metabolic disorder or alcohol consumption in mice reduces the time taken to hepatocarcinogenesis. Genetically-engineering weak activation of HCC-promoting pathways combined with disease-specific injury models will possibly mimic the pathophysiology of human HCC in distinct clinical settings.


Assuntos
Carcinoma Hepatocelular/etiologia , Modelos Animais de Doenças , Neoplasias Hepáticas/etiologia , Animais , Tetracloreto de Carbono/toxicidade , Carcinoma Hepatocelular/patologia , Edição de Genes/métodos , Humanos , Neoplasias Hepáticas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
9.
FEBS Open Bio ; 9(4): 755-768, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30984549

RESUMO

Liver cirrhosis (LC) is a disease characterized by pathological accumulation and alteration of extracellular matrix (ECM) proteins; the interaction between two such proteins, collagen and vitronectin (VN), is considered to be the key to controlling ECM remodeling in liver cirrhosis. If it is possible to control the modification of oligosaccharides on VN, it may be possible to retard progression of liver cirrhosis. In this study, we examined the relationship between changes in VN glycosylation and activity related to the remodeling of hepatic tissue in human LC and a rat model of LC generated using carbon tetrachloride (CCl4). Plasma concentrations of VN in human LC declined to approximately two-thirds that in normal plasma, but the ratio of active VN, which has collagen-binding activities, increased 2.8 times in LC plasma. In contrast, purified LC-VN exhibited similar binding activities toward type I, IV, and V collagens to those of normal VN. Lectin reactivities and carbohydrate analyses of LC-VN revealed that branching, fucosylation, and sialylation of N-glycans were higher than those of normal VN. On the other hand, the plasma level of rat CCl4-VN increased and the ratio of active molecules to collagen in plasma decreased. Increased fucosylation of LC-VN was not detected in carbohydrates of CCl4-VN. The changes in rat VN due to CCl4 treatment did not correspond to the changes in plasma levels of human VN caused by LC, the ratio of active molecules, or carbohydrate composition, thereby indicating that CCl4-treated rats are not an appropriate model for studying VNs in human LC. Glycosidase treatment of VNs supported the hypothesis that the collagen-binding activity of VN is modulated by alterations of glycosylation during LC, which may contribute to (a) the matrix incorporation of VN and (b) tissue fibrosis.


Assuntos
Colágeno/metabolismo , Glicosilação , Cirrose Hepática/metabolismo , Regeneração Hepática , Vitronectina/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Humanos , Masculino , Ratos , Ratos Wistar
10.
Life Sci ; 225: 20-28, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30928408

RESUMO

AIMS: Increasing nicotinamide adenine dinucleotide (NAD+) by Nicotinamide riboside (NR) provides protective benefits in multiple disorders. However, the role of NR on liver fibrosis is unclear. We performed in vivo and in vitro experiments to test the hepatic protective effects of NR against liver fibrosis and the underlying mechanisms. MATERIALS AND METHODS: Mice were injected with CCl4 to establish liver fibrosis model. NR was given by gavage to explore the hepatic protection of NR. LX-2 cells were given a TGF-ß stimulation ±â€¯NR, the activation of LX-2 cells and the acetylation of Smads were analyzed. To further confirm the role of Sirt1 on the protective pathway of NR, we knockdown Sirt1 in LX-2 cells. KEY FINDINGS: We found NR could prevent liver fibrosis and reverse the existing liver fibrosis. NR inhibited the activation of LX-2 cells induced by TGF-ß, activated Sirt1 and deacetylated Smad2/3. Sirt1 knockdown diminished the inhibiting effect of NR on LX-2 cells activation, and increased expressions of acetylated Smads. In conclusion, NR could prevent liver fibrosis via suppressing activation of hepatic stellate cells (HSCs). This protective effect was mediated by regulating the acetylation of Smads signaling pathway. SIGNIFICANCE: NR protected mice against liver fibrosis induced by CCl4. NR suppressed activation of hepatic stellate cells induced by TGF-ß. NR protects liver fibrosis via increasing the activity of Sirt1 and decreasing the expression of P300, resulting in the deacetylation of Smads in stellate cells.


Assuntos
Tetracloreto de Carbono/toxicidade , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Niacinamida/análogos & derivados , Substâncias Protetoras/farmacologia , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Acetilação , Animais , Proteína p300 Associada a E1A/metabolismo , Regulação da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Niacinamida/farmacologia , Sirtuína 1/metabolismo , Fator de Crescimento Transformador beta/metabolismo
11.
Biomed Environ Sci ; 32(3): 153-161, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30987689

RESUMO

OBJECTIVE: This study was designed to evaluate hematological disorders and the orchestrating roles of hepcidin and IL-6 in rat models of thioacetamide (TAA) and carbon tetrachloride (CCl4) hepatotoxicity. METHODS: Rats were intraperitoneally injected with TAA (10 mg/100 g rat weight dissolved in isosaline) or CCl4 (100 µL/100 g rat weight diluted as 1:4 in corn oil) twice weekly for eight consecutive weeks to induce subchronic liver fibrosis. Blood and tissue samples were collected and analyzed. RESULTS: CCl4 but not TAA significantly decreased the RBCs, Hb, PCV, and MCV values with minimal alterations in other erythrocytic indices. Both hepatotoxins showed leukocytosis, granulocytosis, and thrombocytopenia. By the end of the experiment, the erythropoietin level increased in the CCl4 model. The serum iron, UIBC, TIBC, transferrin saturation%, and serum transferrin concentration values significantly decreased, whereas that of ferritin increased in the CCl4 model. TAA increased the iron parameters toward iron overload. RT-PCR analysis revealed increased expression of hepatic hepcidin and IL-6 mRNAs in the CCl4 model and suppressed hepcidin expression without significant effect on IL-6 in the TAA model. CONCLUSION: These data suggest differences driven by hepcidin and IL-6 expression between CCl4 and TAA liver fibrosis models and are of clinical importance for diagnosis and therapeutics of liver diseases.


Assuntos
Hepcidinas/farmacologia , Interleucina-6/farmacologia , Ferro/metabolismo , Cirrose Hepática/terapia , Transferrina/metabolismo , Animais , Análise Química do Sangue , Tetracloreto de Carbono/toxicidade , Injeções Intraperitoneais , Ferro/sangue , Leucocitose/induzido quimicamente , Leucocitose/terapia , Cirrose Hepática/induzido quimicamente , Masculino , Ratos , Tioacetamida/toxicidade , Trombocitopenia/induzido quimicamente , Trombocitopenia/terapia
12.
Food Chem ; 291: 110-116, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31006448

RESUMO

The objective of this study was to evaluate the effects of the ingestion of different white grape juices: organic, conventional and conventional grape juice with 5% lemon juice during adolescence on biochemical serum profile and oxidative stress level in liver of adult Wistar rats. The phenolic and vitamin C composition of the juices were evaluated. During 32 days the rats were treated with the juices or oral water (gavage) for at a dose of 7 µL/g body weight. The animals were divided into 4 groups (n = 16/each). In the end, half of the animals received an intraperitoneal CCl4 injection of 3.0 mL/kg; the other ones received mineral oil. After euthanasia, biochemical parameters were evaluated in serum and oxidative stress in the liver. It is possible to emphasize that the juices have different phenolic and vitamin C contents. The juice consumption didn't alter the weight body and biochemical parameters in adult life.


Assuntos
Sucos de Frutas e Vegetais/análise , Fígado/metabolismo , Vitis/química , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Ácido Ascórbico/análise , Peso Corporal/efeitos dos fármacos , Tetracloreto de Carbono/toxicidade , Cromatografia Líquida de Alta Pressão , Fígado/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fenóis/análise , Fenóis/farmacologia , Ratos , Ratos Wistar , Superóxido Dismutase , Vitis/metabolismo
13.
Pak J Pharm Sci ; 32(1(Supplementary)): 301-308, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30829207

RESUMO

Carbon tetrachloride (CCl4) is one of the chemicals used in industry reported to accelerate the risk of liver diseases in workers especially in developing countries, if it is not handled carefully. Therefore, the present study conducted to evaluate the liver protective and oxidative stress reducing activities of methanolic (MFEt) and aqueous methanolic fruits (AqMFEt) extracts of Withania coagulans against CCl4-induced liver damage in rats. These fruits extracts in oral doses of 800 mg/kg were found effective in their respective test groups in decreasing weight loss, maintaining hepatic membrane integrity, biosynthetic and conjugative abilities by improving liver and bile duct specific enzymes (alanine and aspartate transferases, alkaline phosphatase, γ-glutamyltranstransferase), total protein and bilirubin profiles, uric acid levels plus uplifting the efficacy of hepatic antioxidant enzymes and protein by minimizing lipid peroxidation. All these beneficial effects confirmed by observing normal anatomical features of liver tissues in test groups. Total phenolic compounds were found high in AqMFEt. Interestingly, for the first time, gallic acid and rutin are identified and quantified in these extracts and thought to improve hepatoprotective potential of W. coagulans.


Assuntos
Ácido Gálico/farmacologia , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rutina/farmacologia , Withania/química , Animais , Bilirrubina/metabolismo , Peso Corporal/efeitos dos fármacos , Tetracloreto de Carbono/toxicidade , Enzimas/metabolismo , Feminino , Fígado/enzimologia , Fígado/patologia , Metanol/química , Fenóis/análise , Extratos Vegetais/química , Plantas Medicinais/química , Substâncias Protetoras/farmacologia , Ratos Wistar
14.
World J Gastroenterol ; 25(11): 1355-1365, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30918428

RESUMO

BACKGROUND: Fatty liver (FL) is now a worldwide disease. For decades, researchers have been kept trying to elucidate the mechanism of FL at the molecular level, but rarely involve the study of morphology and medical physics. Traditionally, it was believed that hemodynamic changes occur only when fibrosis occurs, but it has been proved that these changes already show in steatosis stage, which may help to reveal the pathogenesis and its progress. Because the pseudolobules are not formed during the steatosis stage, this phenomenon may be caused by the compression of the liver microcirculation and changes in the hemodynamics. AIM: To understand the pathogenesis of hepatic steatosis and to study the hemodynamic changes associated with hepatic steatosis. METHODS: Eight-week-old male C57BL/6 mice were divided into three groups randomly (control group, 2-wk group, and 4-wk group), with 16 mice per group. A hepatic steatosis model was established by subcutaneous injection of carbon tetrachloride in mice. After establishing the model, liver tissue from mice was stained with hematoxylin and eosin (HE), and oil red O stains. Blood was collected from the angular vein, and hemorheological parameters were estimated. A two-photon fluorescence microscope was used to examine the flow properties of red blood cells in the hepatic sinusoids. RESULTS: Oil red O staining indicated lipid accumulation in the liver after CCl4 treatment. HE staining indicated narrowing of the hepatic sinusoidal vessels. No significant difference was observed between the 2-wk and 4-wk groups of mice on morphological examination. Hemorheological tests included whole blood viscosity (mPas, γ = 10 s-1/γ = 100 s-1) (8.83 ± 2.22/4.69 ± 1.16, 7.73 ± 2.46/4.22 ± 1.32, and 8.06 ± 2.88/4.22 ± 1.50), red blood cell volume (%) (51.00 ± 4.00, 42.00 ± 5.00, and 40.00 ± 3.00), the content of plasma fibrinase (g/L) (3.80 ± 0.50, 2.90 ± 0.80, and 2.30 ± 0.70), erythrocyte deformation index (%) (44.49 ± 5.81, 48.00 ± 15.29, and 44.36 ± 15.01), erythrocyte electrophoresis rate (mm/s per V/m) (0.55 ± 0.11, 0.50 ± 0.11, and 0.60 ± 0.20), revealing pathological changes in plasma components and red blood cells of hepatic steatosis. Assessment of blood flow velocity in the hepatic sinusoids with a laser Doppler flowmeter (mL/min per 100 g) (94.43 ± 14.64, 80.00 ± 12.12, and 67.26 ± 5.92) and two-photon laser scanning microscope (µm/s) (325.68 ± 112.66, 213.53 ± 65.33, and 173.26 ± 44.02) revealed that as the modeling time increased, the blood flow velocity in the hepatic sinusoids decreased gradually, and the diameter of the hepatic sinusoids became smaller (µm) (10.28 ± 1.40, 6.84 ± 0.93, and 5.82 ± 0.79). CONCLUSION: The inner diameter of the hepatic sinusoids decreases along with the decrease in the blood flow velocity within the sinusoids and the changes in the systemic hemorheology.


Assuntos
Capilares/fisiopatologia , Fígado Gorduroso/fisiopatologia , Imagem Tridimensional/métodos , Microcirculação/fisiologia , Animais , Velocidade do Fluxo Sanguíneo/fisiologia , Capilares/diagnóstico por imagem , Tetracloreto de Carbono/toxicidade , Modelos Animais de Doenças , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/diagnóstico por imagem , Humanos , Fluxometria por Laser-Doppler , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal
15.
J Immunol Res ; 2019: 7657294, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906791

RESUMO

Macrophages are the master regulator of the dynamic fibrogenesis-fibrosis resolution paradigm. TNF-like ligand 1 aberrance (TL1A) was found to be able to induce intestinal inflammation and fibrosis. Furthermore, significantly increased TL1A had been detected in liver tissues and mononuclear cells of patients with primary biliary cirrhosis (PBC). This study was to investigate the effect of myeloid cells with constitutive TL1A expression on liver fibrogenesis. We found that TL1A expressions in liver tissues and macrophages were significantly increased in mice with liver fibrosis induced by injection of carbon tetrachloride (CCl4). TL1A overexpression in myeloid cells induced liver function injury, accelerated the necrosis and apoptosis of hepatocytes, recruited macrophages, and promoted activation of hepatic stellate cells (HSCs) and fibrosis. In vitro results of our study showed that TL1A overexpression in macrophages promoted secretion of platelet-derived growth factor-BB (PDGF-BB), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß). Culturing macrophages with TL1A overexpression could accelerate the activation and proliferation of primary HSCs. These results indicated that constitutive TL1A expression in myeloid cells exacerbated liver fibrosis, probably through macrophage recruitment and secretion of proinflammatory and profibrotic cytokines.


Assuntos
Hepatócitos/fisiologia , Inflamação/metabolismo , Cirrose Hepática Biliar/metabolismo , Fígado/patologia , Macrófagos/imunologia , Células Mieloides/fisiologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Animais , Apoptose , Becaplermina/metabolismo , Tetracloreto de Carbono/toxicidade , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Humanos , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Necrose , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/metabolismo
16.
Molecules ; 24(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897831

RESUMO

The mechanism of hepatoprotective compounds is usually related to its antioxidant or anti-inflammatory effects. Black garlic is produced from garlic by heat treatment and its anti-inflammatory activity has been previously reported. Therefore, the aim of this study was to investigate the hepatoprotective effect of five different extracts of black garlic against carbon tetrachloride (CCl4)-induced acute hepatic injury (AHI). In this study, mice in the control, CCl4, silymarin, and black garlic groups were orally administered distilled water, silymarin, and different fraction extracts of black garlic, respectively, after CCl4 was injected intraperitoneally to induce AHI. The results revealed that the n-butanol layer extract (BA) and water layer extract (WS) demonstrated a hepatoprotective effect by reducing the levels of alanine aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and hepatic malondialdehyde (MDA). Furthermore, the BA and WS fractions of black garlic extract increased the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Rd), tumor necrosis factor alpha (TNF-α), and the interleukin-1 (IL-1ß) level in liver. It was concluded that black garlic exhibited significant protective effects on CCl4-induced acute hepatic injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Alho/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Extratos Vegetais/uso terapêutico , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/metabolismo , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Antioxidantes/metabolismo , Tetracloreto de Carbono/toxicidade , Fermentação/fisiologia , Glutationa Peroxidase/sangue , Glutationa Redutase/sangue , Masculino , Malondialdeído/sangue , Extratos Vegetais/química , Ratos , Silimarina , Superóxido Dismutase/sangue , Fator de Necrose Tumoral alfa/sangue
17.
Molecules ; 24(4)2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30813233

RESUMO

Oxidative stress leads to various diseases, including diabetes, cardiovascular diseases, neurodegenerative diseases, and even cancer. The dietary flavonol glycoside, hyperoside (quercetin-3-O-galactoside), exerts health benefits by preventing oxidative damage. To further understand its antioxidative defence mechanisms, we systemically investigated the regulation of hyperoside on oxidative damage induced by hydrogen peroxide, carbon tetrachloride, and cadmium in Saccharomyces cerevisiae. Hyperoside significantly increased cell viability, decreased lipid peroxidation, and lowered intracellular reactive oxygen species (ROS) levels in the wild-type strain (WT) and mutants gtt1∆ and gtt2∆. However, the strain with ctt1∆ showed variable cell viability and intracellular ROS-scavenging ability in response to the hyperoside treatment upon the stimulation of H2O2 and CCl4. In addition, hyperoside did not confer viability tolerance or intercellular ROS in CdSO4-induced stress to strains of sod1∆ and gsh1∆. The results suggest that the antioxidative reactions of hyperoside in S. cerevisiae depend on the intercellular ROS detoxification system.


Assuntos
Antioxidantes/farmacologia , Flavonoides/farmacologia , Proteínas Fúngicas/genética , Espécies Reativas de Oxigênio/metabolismo , Saccharomyces cerevisiae/crescimento & desenvolvimento , Cádmio/toxicidade , Tetracloreto de Carbono/toxicidade , Peróxido de Hidrogênio/toxicidade , Peroxidação de Lipídeos/efeitos dos fármacos , Viabilidade Microbiana , Modelos Biológicos , Mutação , Estresse Oxidativo/efeitos dos fármacos , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética
18.
Drug Dev Ind Pharm ; 45(6): 946-958, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30767678

RESUMO

OBJECTIVE: To prepare and characterize an optimized phospholipid complex of Ursolic acid (UA) to overcome the poor pharmacokinetic properties and to investigate the impact of the complex on hepatoprotective activity and bioavailability in animal model. SIGNIFICANCE: UA is a potential phytoconstituent obtained from several plant sources, which has been explored for its diverse pharmacological activities including hepatoprotection. Its major limitation is poor absorption, rapid elimination, and hence low bioavailability after administration. METHODS: Response surface methodology was adopted to formulate an optimized (UA) complex. The complex was characterized by differential thermal analysis (DTA), Fourier transform-Infrared Spectroscopy, Powder X ray Diffraction, molecular docking, etc. The physico-chemical profile (solubility, oil/water partition coefficient) and in vitro dissolution profile was estimated. The formulation was then used to study hepatoprotective activity and bioavailability in animal models. RESULTS: Results showed that the phospholipid complex of UA has enhanced the hepatoprotective potential as compared to pure UA at the same dose level. The complex restored the levels of serum hepatic marker enzymes with respect to untreated group and increased the relative bioavailability of UA in rat plasma by 8.49-fold in comparison with pure compound at the same dose level. It enhanced the elimination half-life (t1/2 el) from 0.69 ± 1.76 to 8.28 ± 1.98 h. CONCLUSION: Complexation of UA with phospholipid markedly enhanced the hepatoprotective potential of UA by improving its bioavailability and pharmacokinetic parameters. Novelty statement The present article deals with rational optimization of the formulation parameters for phospholipid complex of ursolic acid by Response Surface Methodology analysis, characterizing the formulation by in silico approach apart from conventional instrumental techniques, and evaluating the in vitro dissolution, pharmacokinetics, and hepatoprotective activity of the complex in animals. Novelty statement The present article deals with rational optimization of the formulation parameters for phospholipid complex of ursolic acid by Response Surface Methodology analysis, characterizing the formulation by in silico approach apart from conventional instrumental techniques, and evaluating the in vitro dissolution, pharmacokinetics, and hepatoprotective activity of the complex in animals.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Excipientes/química , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Triterpenos/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Simulação por Computador , Modelos Animais de Doenças , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Meia-Vida , Humanos , Fígado/patologia , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Tamanho da Partícula , Fosfolipídeos/química , Substâncias Protetoras/química , Substâncias Protetoras/uso terapêutico , Ratos , Ratos Wistar , Solubilidade , Triterpenos/química , Triterpenos/uso terapêutico , Difração de Raios X
19.
Chem Biol Interact ; 302: 53-60, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30703375

RESUMO

The current study was designed to assess the antifibrotic effect of dimethylfumarate (DMF) on CCl4-induced hepatic injury in rats. Hepatic injury was induced by intraperitoneal twice weekly injection of CCl4 for 2 and 3 months. DMF was administered orally during the last 4 weeks in each model. Liver injury was estimated using biochemical parameters such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), total serum bilirubin (TSB), total protein, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Additionally, oxidative stress parameters such as superoxide dismutase (SOD), reduced glutathione (GSH), nitric oxide (NOx), and malondialdehyde (MDA) were studied. Collagen IV (Col IV), alpha-smooth muscle actin (α-SMA), transforming growth factor beta1 (TGF-ß1) and nuclear factor kappa B (NF-κB) were also assessed as markers of fibrosis and inflammation. Histopathological examination of liver tissues was performed and compared with control. The obtained results showed that DMF ameliorated the elevated markers of liver injury and oxidative stress in addition to hepatic necroinflammation scoring induced by CCl4. Furthermore, DMF ameliorated CCl4-induced fibrosis as evidenced by histopathological scoring and collagen IV content. Besides, we investigated the possible underlying mechanisms for these effects which include: (1) attenuating oxidative stress as designated by decreased MDA and NOx as well as increased GSH and SOD levels; (2) anti-inflammatory effect as evidenced by inhibitory effect on NF-κB; (3) preventing hepatic stellate cells (HSCs) activation as indicated by blunting the expression of α-SMA; and (4) downregulating the fibrogenesis response of HSCs as denoted by inhibiting TGF-ß1 secretion and Col IV deposition. In conclusion, this study clarified the antifibrotic effect of DMF that might serve as a new candidate for management of liver fibrosis.


Assuntos
Tetracloreto de Carbono/toxicidade , Fumarato de Dimetilo/uso terapêutico , Cirrose Hepática Experimental/prevenção & controle , Actinas/metabolismo , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Colágeno Tipo IV/metabolismo , Fumarato de Dimetilo/farmacologia , Glutationa/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/patologia , Masculino , Malondialdeído/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
20.
Nutrients ; 11(2)2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30781895

RESUMO

The late stages of liver fibrosis are considered to be irreversible. Red quinoa (Chenopodium formosanum Koidz), a traditional food for Taiwanese aborigines, was gradually developed as a novel supplemental food due to high dietary fibre and polyphenolic compounds. Its bran was usually regarded as the agricultural waste, but it contained a high concentration of rutin known as an antioxidant and anti-inflammatory agent. This study is to explore the effect of red quinoa bran extracts on the prevention of carbon tetrachloride (CCl4)-induced liver fibrosis. BALB/c mice were intraperitoneally injected CCl4 to induce liver fibrosis and treated with red quinoa whole seed powder, bran ethanol extracts, bran water extracts, and rutin. In the results, red quinoa powder provided more protection than rutin against CCl4-induced oxidative stress, pro-inflammatory factor expression and fibrosis development. However, the bran ethanol extract with high rutin content provided the most liver protection and anti-fibrosis effect via blocking the tumor necrosis factor alpha (TNF-α)/interleukin 6 (IL-6) pathway and transforming growth factor beta 1 (TGF-ß1) pathway.


Assuntos
Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Chenopodium quinoa , Cirrose Hepática/induzido quimicamente , Extratos Vegetais/farmacologia , Animais , Antioxidantes/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/química , Sementes , Substâncias Reativas com Ácido Tiobarbitúrico , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
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