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1.
Life Sci ; 253: 117684, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32315728

RESUMO

Brain oxidative stress and neuroinflammation have been implicated in various psychiatric disorders. The current study investigated the effect and mechanism of 25-Methoxyhispidol A (25-MHA) against CCl4-induced anxiety and depression. Mice were challenged with CCl4 (1 ml/kg; i.p.) after 30 min of 25-MHA (1, 5 and 10 mg/kg; i.p.) administration. Pretreatment with 25-MHA (10 mg/kg) significantly attenuated the anxiety and depression-like behavior in testing models. The oxidative stress induced by CCl4 was significantly attenuated by pretreatment with 25-MHA. The immunohistochemical (IHC) analysis showed a reduction in kelch-like ECH-associated protein 1 (Keap1) and improvement in expression of nuclear factor erythroid-2-related factor (Nrf-2) and heme oxygenase (HO)-1. In addition, 25-MHA significantly attenuated the CCl4-mediated depletion of antioxidant enzymes in hippocampus (HC) and prefrontal cortex (PFC) region and reduced the expression of toll-like receptor (TLR)-4 and nuclear factor kappa B (NF-κB), along with a decreased production of pro-inflammatory cytokines in HC and PFC region. Pretreatment with 25-MHA also showed an improved expression of neurotrophic factors i.e., brain derived growth factor (BDNF) and vascular endothelial growth factor (VEGF). Furthermore, 25-MHA inhibited malondialdehyde (MDA) and ammonia level in plasma, liver, HC and PFC regions of mice brain. 25-MHA also exhibited anti-apoptotic effect evident from the reduced expression of caspase-3 and decreased hippocampal DNA damage in comet assay. Furthermore, decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and corticosterone level, along with prevention of CCl4-induced alterations in thickness of dentate gyrus and intact hepatic cells morphology, represented by hippocampal and liver histopathology, indicated the neuroprotective effect of 25-MHA.


Assuntos
Comportamento Animal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Tetracloreto de Carbono/toxicidade , Caspase 3/metabolismo , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fármacos Neuroprotetores/administração & dosagem , Triterpenos/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
Zhonghua Gan Zang Bing Za Zhi ; 28(2): 135-140, 2020 Feb 20.
Artigo em Chinês | MEDLINE | ID: mdl-32164064

RESUMO

Objective: To investigate the mechanism of occurrence and development of zinc-alpha-2-glycoprotein (AZGP1) in the activated hepatic stellate cells (HSCs) and liver fibrosis. Methods: The activated human hepatic stellate cell line LX2 was induced by the stimulation of transforming growth factor - ß1 to construct carbon tetrachloride liver fibrosis mice model. The situation expression of AZGP1 in liver cells and tissues were observed. Plasmid transfection method was used to detect the activation, proliferation, apoptotic functions and changes in related factors of LX2 cells, respectively, after the overexpression and inhibition of AZGP1expression. Univariate analysis of variance was used for multiple group comparison. Results: The results of immunofluorescence staining showed that AZGP1 protein was decreased and α-smooth muscle actin was increased in the activated LX2 cells, and the two were negatively correlated. AZGP1 gene and protein were significantly under-expressed in activated LX2 cells and liver tissues of mice with carbon tetrachloride liver fibrosis. Collagen I, matrix metalloproteinase-2, and α-smooth muscle actin genes and proteins were significantly down-regulated in LX2 cells after over-expression of AZGP1. Cell fluorescence showed that AZGP1-overexpressing cells were activated and α-smooth muscle actin protein was reduced. In addition, the proliferative activity and G1/S-specific cyclin D1 protein of LX2 cells were significantly reduced after overexpression of AZGP1, while cell cycle experiments showed that the proportion of cells overexpressing AZGP1 was significantly increased in the G0/G1 phase, and the proportion of S phase was significantly reduced. AZGP1 had no significant effect on the apoptosis of LX2 cells. Conclusion: AZGP1 can reverse liver fibrosis by inhibiting the activation and proliferation of hepatic stellate cells, and thereby overexpression of AZGP1 is expected to become a new target for liver fibrosis treatment.


Assuntos
Tetracloreto de Carbono/toxicidade , Proliferação de Células/efeitos dos fármacos , Glicoproteínas/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Actinas , Animais , Glicoproteínas/genética , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática , Metaloproteinase 2 da Matriz , Camundongos , Zinco
3.
Mol Med Rep ; 21(3): 1390-1398, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31922209

RESUMO

Carbon tetrachloride (CCl4) is widely used to induce hepatic fibrosis. Therapeutic agents alleviate hepatic fibrosis by inhibiting signal transducer and activator of transcription 3 (STAT3) activation. To understand the direct effects of CCl4 on STAT3 expression in the liver, the present study incubated cultured hepatocytes expressing connective tissue growth factor (CTGF) with CCl4. Rats exposed to CCl4 for 8 weeks exhibited hepatic fibrosis, which was confirmed through the assessment of plasma biomarkers. Isolated liver samples were used to determine the protein levels of CTGF and STAT3 using western blotting. In addition, STAT3 expression was silenced in α mouse liver 12 (AML­12) cells using small interfering RNA transfection. In addition, a pharmacological inhibitor, stattic, was used to inhibit STAT3 expression. The incubation of AML­12 cells with CCl4 induced a dose­dependent increase in CTGF expression and STAT3 activation. Notably, silymarin, an extract from milk thistle, inhibited these changes in AML­12 cells and the antioxidant tiron produced similar effects. Silencing of STAT3 reduced the CTGF expression promoted by CCl4 in the hepatocytes. Additionally, similar to tiron, stattic inhibited CTGF expression induced by CCl4. In conclusion, CCl4 may activate STAT3 through oxidative stress to promote CTGF expression, which is one of the main factors contributing to the risk of hepatic fibrosis.


Assuntos
Intoxicação por Tetracloreto de Carbono/metabolismo , Tetracloreto de Carbono/toxicidade , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Hepatócitos/metabolismo , Cirrose Hepática/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Intoxicação por Tetracloreto de Carbono/patologia , Linhagem Celular , Hepatócitos/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Ratos , Ratos Sprague-Dawley
4.
Food Chem Toxicol ; 137: 111126, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31954714

RESUMO

Syringic acid (SA), a natural polyphenol found in fruits and vegetables, is claimed to show notable hepatoprotection. Nevertheless, low solubility and bioavailability hamper the application of SA. This study aimed to investigate the potential of TPGS/F127/F68 mixed polymeric micelles as a sustained and liver-targeting nanocarrier for SA. Herein, the prepared SA-loaded TPGS/F127/F68 mixed polymeric micelles (SA-TPGS-Ms) were spherically-shaped and homogeneously-distributed nanoparticles with high entrapment efficiency (94.67 ± 2.05%) and sustained release. Besides, in-vitro cell culture studies revealed that SA-TPGS-Ms substantially promoted cellular uptake with excellent biocompatibility. After oral administration, SA-TPGS-Ms demonstrated an increased bioavailability (2.3-fold) and delayed in-vivo elimination compared with the free SA. Furthermore, the alleviation of oxidative stress and amelioration of hepatic injury in CCl4-induced hepatotoxicity mice further demonstrated the excellent hepatoprotection of SA-TPGS-Ms. Collectively, SA-TPGS-Ms could be a promising nanocarrier for the utilization of SA in functional foods, with enhanced bioavailability and hepatoprotection.


Assuntos
Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Ácido Gálico/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/instrumentação , Ácido Gálico/administração & dosagem , Ácido Gálico/química , Ácido Gálico/farmacocinética , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Micelas , Nanopartículas/química , Estresse Oxidativo/efeitos dos fármacos , Polietilenoglicóis/química , Polietilenos/química , Polipropilenos/química , Propilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Vitamina E/química
5.
Immunity ; 52(1): 96-108.e9, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31810881

RESUMO

Although type 1 innate lymphoid cells (ILC1s) have been originally found as liver-resident ILCs, their pathophysiological role in the liver remains poorly investigated. Here, we demonstrated that carbon tetrachloride (CCl4) injection into mice activated ILC1s, but not natural killer (NK) cells, in the liver. Activated ILC1s produced interferon-γ (IFN-γ) and protected mice from CCl4-induced acute liver injury. IFN-γ released from activated ILC1s promoted the survival of hepatocytes through upregulation of Bcl-xL. An activating NK receptor, DNAM-1, was required for the optimal activation and IFN-γ production of liver ILC1s. Extracellular adenosine triphosphate accelerated interleukin-12-driven IFN-γ production by liver ILC1s. These findings suggest that ILC1s are critical for tissue protection during acute liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Hepatócitos/metabolismo , Interferon gama/imunologia , Fígado/citologia , Linfócitos/imunologia , Proteína bcl-X/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/metabolismo , Tetracloreto de Carbono/toxicidade , Células Cultivadas , Feminino , Subunidade p35 da Interleucina-12/imunologia , Células Matadoras Naturais/imunologia , Fígado/imunologia , Fígado/lesões , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
6.
Cell Prolif ; 53(1): e12731, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31755616

RESUMO

OBJECTIVES: T-cell immunoglobulin domain and mucin domain-4 (TIM-4) is selectively expressed on antigen-presenting cells (APCs) and modulates various immune responses. However, the role of TIM-4 expressed by Kupffer cells (KCs) in liver fibrosis remains unclear. The present study aimed to explore whether and how TIM-4 expressed by KCs is involved in liver fibrosis. MATERIALS AND METHODS: Mice chronic liver fibrosis models were established and divided into the olive-induced control group, CCL4-induced control group, olive-induced TIM-4 interference group and CCL4-induced TIM-4 interference group. Different techniques were used to monitor the fibrotic effects of TIM-4, including histopathological assays, Western blotting, ELISA and transmission electron microscopy. Additionally, mice liver transplant models were established to determine the fibrotic effects of TIM-4 on fibrosis after liver transplantation (LT). RESULTS: We found that the induction of liver fibrosis by CCL4 was associated with TIM-4 expression in KCs. TIM-4 interference essentially contributed to liver fibrosis resolution. KCs from the TIM-4 interference group had decreased levels of pro-fibrotic markers, reduced TGF-ß1 secretion and inhibited hepatic stellate cell (HSC) differentiation into myofibroblast-like cells. In addition, we used GdCl3 to verify that KCs are the primary source of TGF-ß1 during fibrosis progression. Moreover, KCs from CCL4-induced mice showed increased ROS production, mitophagy activation and TGF-ß1 secretion. However, TIM-4 interference in the KCs inhibited Akt1-mediated ROS production, resulting in the suppression of PINK1, Parkin and LC3-II/I activation and the reduction of TGF-ß1 secretion during liver fibrosis. Additionally, TIM-4 interference potentially attenuated development of fibrosis after LT. CONCLUSIONS: Our findings revealed the underlying mechanisms of TIM-4 interference in KCs to mitigate liver fibrosis.


Assuntos
Intoxicação por Tetracloreto de Carbono/metabolismo , Macrófagos do Fígado/metabolismo , Cirrose Hepática/metabolismo , Proteínas de Membrana/metabolismo , Mitofagia/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Tetracloreto de Carbono/toxicidade , Intoxicação por Tetracloreto de Carbono/patologia , Modelos Animais de Doenças , Macrófagos do Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Camundongos
7.
Food Chem Toxicol ; 135: 111014, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31794804

RESUMO

Chemical liver and kidney injury have become a serious concern to human. Side effects occur when they are treated with medicine. The present study evaluated the preventive effect of Cyclocarya paliurus polysaccharides (CP) on hepatic and renal injury in carbon tetrachloride (CCl4) induced mice. The results showed that CP treatment could effectively prevent H2O2-induced oxidative damage of NCTC-1469 cells. Administrated with CP could ameliorate the body weight loss and organ swelling of mice induced by the 0.2% CCl4. Compared with the model group, CP groups have beneficial effects in decreasing ALT, AST, TBA and CRE levels in serum. In addition, the expression of CYP2E1 in the liver was also significantly decline after continuous administration of CP. Moreover, pre-administration of CP can improve the antioxidant status of liver and kidney (MDA and SOD, GSH-Px). Histopathological studies also supported the improvement of CP on liver and kidney of CCl4-induced mice. These results indicate that CP may be of therapeutic value in ameliorating the hepatic and renal oxidative stress caused by CCl4, through its antioxidant properties.


Assuntos
Tetracloreto de Carbono/toxicidade , Juglandaceae/química , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/farmacologia , Animais , Linhagem Celular , Citocromo P-450 CYP2E1/metabolismo , Glutationa Peroxidase/metabolismo , Hepatócitos/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Rim/metabolismo , Rim/patologia , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Superóxido Dismutase/metabolismo
8.
Scand J Immunol ; 91(4): e12851, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31733121

RESUMO

Acute liver injury is a common pathological basis for a variety of acute liver diseases in the clinic, which can eventually lead to liver fibrosis and even liver failure. In this study, we found that T cell Ig and mucin domain protein 3 (Tim-3) and TLR4 receptors play important roles in CCl4-induced acute liver injury. Tim-3 is a negative regulator that is expressed by T cells and macrophages. Using antibodies against Tim-3 (anti-Tim-3 Ab), we studied the Tim-3 signal in an animal model of acute liver injury and found that a large number of inflammatory factors were upregulated. In vitro experimental data shown that anti-Tim-3 Ab treatment increased interferon-É£ production by concanavalin A (ConA)-stimulated spleen T cells, and we found that the expression level of interleukin (IL)-6 was increased in a macrophage/spleen T cell coculture system, while administration of galectin-9 (Gal-9, a Tim-3 ligand) reduced the IL-6 production. This indicates the importance of the Tim-3/Gal-9 signalling pathway in maintaining hepatic homeostasis. The Tim-3 signalling pathway inhibits TLR4-mediated NF-κB activity, and an anti-Tim-3 Ab does not affect the liver injury in TLR4-deficient mice. Regulation between Tim-3 and TLR4 determines the severity of liver damage. The negative regulation of Tim-3 reflects the protective mechanisms of patients with impaired liver function, and these results provide important information about innate and adaptive responses in the regulation of liver damage. This finding is potentially important for the study of early liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 4 Toll-Like/imunologia
9.
J Dairy Sci ; 103(2): 1884-1893, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31837790

RESUMO

Buffalo skim milk retentate was hydrolyzed with papain for 4 h (enzyme:substrate, 1:200), resulting in a retentate hydrolysate (RH) with a degree of hydrolysis of 23%. We then investigated the potential hepatoprotective activity of RH at 250 and 500 mg/kg of body weight per day on carbon tetrachloride (CCl4)-induced oxidative stress in albino rats. Liver biomarkers (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase), kidney biomarkers (urea, creatinine), and serum lipid profile (total lipids and triglycerides) were measured, in addition to histopathological status. Injection of CCl4 significantly increased all liver and kidney biomarkers compared with the negative control. In contrast, CCl4 injection significantly reduced hepatic antioxidant enzyme activities; that is, glutathione peroxidase and superoxide dismutase. Oral administration of RH for 28 d effectively maintained a physiologically normal range of liver and kidney biomarkers compared with the positive control. Furthermore, RH administration significantly increased activities of glutathione peroxidase and superoxide dismutase. Histopathological sections of CCl4-stressed rats treated with RH were different from that of the positive control and were similar to those of the negative control, in a concentration-dependent manner. Our results demonstrated the antihepatotoxic activities of buffalo milk RH and demonstrated that the higher RH concentration (500 mg/kg of body weight per day) could maintain the healthy biological status of the CCl4-injected rats.


Assuntos
Antioxidantes/metabolismo , Biomarcadores/metabolismo , Búfalos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Proteínas do Leite/química , Papaína/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Hidrólise , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos
10.
Arch Physiol Biochem ; 126(1): 49-60, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30269598

RESUMO

The objective of this study was to evaluate the potential protective effect of Atriplex halimus aqueous leaves extract (AHAE) against acute carbon tetrachloride (CCl4)-induced oxidative stress in rats. Rats were randomly divided into four groups: group (C) served as a control treated with 1 ml/(kg bw) of olive oil, and group (CCl4) was treated with 1 ml CCl4/(kg bw) dissolved in olive oil administered by intraperitoneal way. Rats of group (CCl4+AHAE) have received CCl4 and treated with 200 mg AHAE/(kg bw). Animals of group (AHAE) were treated with 200 mg/(kg bw) of AHAE. A significant increase in malondialdehyde levels in liver associated with a decrease in antioxidant enzyme activities and reduced glutathione content was observed in CCl4 group compared to controls. The administration of AHAE to CCl4+AHAE group improved all parameters studied. We conclude that CCl4 induces oxidative stress and modifies biochemical parameters and histological aspects of liver. Administration of AHAE alleviates the toxicity induced by this organic compound.


Assuntos
Antioxidantes/farmacologia , Atriplex/química , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Tetracloreto de Carbono/toxicidade , Catalase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Esquema de Medicação , Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Transferase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Picratos/antagonistas & inibidores , Extratos Vegetais/química , Folhas de Planta/química , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
11.
Anal Chim Acta ; 1094: 113-121, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761037

RESUMO

Alkaline phosphatase (ALP), an enzyme that catalyzes the hydrolysis of phosphate groups, is closely associated with many diseases, including bone disease, prostate cancer, and diabetes. Thus, new assays for ALP detection in live cells are needed to better understand its role in related biological processes. In this study, we constructed a novel near-infrared ratiometric fluorescent probe for detecting ALP activity with high sensitivity. The probe uses a new self-immolative mechanism that can achieve a rapid response (within 10 min) to ALP, detected as a spectral shift (from 580 to 650 nm). This method effectively avoids issues related to instrument variability, and the near-infrared fluorescence emission (650 nm) makes it more suitable for biological detection. Moreover, the high sensitivity (14-fold enhancement of the fluorescence ratio F650/F580) and low detection limit (0.89 U L-1) for ALP allows the probe to be adapted to complex biological environments. The assay was successfully performed using serum samples with a linear range of ALP of up to 150 U L-1. We used the developed probe to detect and image endogenous ALP in cells with satisfactory results, and we successfully used the probes to detect changes in endogenous ALP levels in zebrafish caused by drug-induced organ damage.


Assuntos
Fosfatase Alcalina/análise , Carbamatos/química , Corantes Fluorescentes/química , Organofosfatos/química , Acetaminofen/farmacologia , Animais , Carbamatos/síntese química , Carbamatos/toxicidade , Tetracloreto de Carbono/toxicidade , Bovinos , Teoria da Densidade Funcional , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Limite de Detecção , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Modelos Químicos , Organofosfatos/síntese química , Organofosfatos/toxicidade , Peixe-Zebra
12.
Dev Cell ; 52(2): 196-209.e9, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31866205

RESUMO

Saturated fatty acids (SFAs) (the "bad" fat), especially palmitate (PA), in the human diet are blamed for potential health risks such as obesity and cancer because of SFA-induced lipotoxicity. However, epidemiological results demonstrate a latent benefit of SFAs, and it remains elusive whether a certain low level of SFAs is physiologically essential for maintaining cell metabolic hemostasis. Here, we demonstrate that although high-level PA (HPA) indeed induces lipotoxic effects in liver cells, low-level PA (LPA) increases mitochondrial functions and alleviates the injuries induced by HPA or hepatoxic agent carbon tetrachloride (CCl4). LPA treatment in mice enhanced liver mitochondrial activity and reduced CCl4 hepatotoxicity with improved blood levels of aspartate aminotransferase (AST), alanine transaminase (ALT), and mitochondrial aspartate transaminase (m-AST). LPA-mediated mitochondrial homeostasis is regulated by CDK1-mediated SIRT3 phosphorylation, which in turn deacetylates and dimerizes CPT2 to enhance fatty acid oxidation. Thus, an advantageous effect is suggested by the consumption of LPA that augments mitochondrial metabolic homeostasis via CDK1-SIRT3-CPT2 cascade.


Assuntos
Proteína Quinase CDC2/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Hepatócitos/citologia , Mitocôndrias/metabolismo , Palmitatos/farmacologia , Sirtuína 3/metabolismo , Animais , Proteína Quinase CDC2/genética , Tetracloreto de Carbono/toxicidade , Carnitina O-Palmitoiltransferase/genética , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Sirtuína 3/genética
13.
Int J Mol Sci ; 20(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640181

RESUMO

The current study aimed to investigate, for the first time, the beneficial effects of 3,5-dihydroxy-4',7-dimethoxyflavone isolated from Tamarix aphylla L. against liver injury in mice. Liver injury was induced by intraperitoneal (i.p.) injection of carbon tetrachloride (CCl4) at a dose of 0.4 mL/kg mixed in olive oil at ratio (1:4) twice a week for 6 consecutive weeks. The administration of CCl4 caused significant histopathological changes in liver tissues while the pre-treatment with the flavone at dose of 10 and 25 mg/kg ameliorated the observed liver damages. Also, it markedly reduced hepatic malondialdehyde (MDA) level as well as increased the activities of liver superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (Gpx) compared with their recorded levels in CCl4 model group. Moreover, the immunohistochemical analysis demonstrated the enhancement in the protein level of B-cell lymphoma-2 (Bcl-2) while the protein levels of cysteine-aspartic acid protease-3 (caspase-3), Bcl-2-associated x protein (Bax), transforming growth factor-ß1 (TGF-ß1) and CD31 were suppressed following the flavone treatement. These results suggest that the flavone can inhibit liver injury induced in mice owning to its impact on the oxidation, apoptotic and angiogenesis mechanisms. Further pharmacological investigations are essential to determine the effectiveness of the flavone in human.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Flavonas/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Tamaricaceae/química , Inibidores da Angiogênese/farmacologia , Animais , Apoptose , Tetracloreto de Carbono/toxicidade , Catalase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Flavonas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Humanos , Injeções Intraperitoneais , Masculino , Malondialdeído/metabolismo , Camundongos , Superóxido Dismutase/metabolismo
14.
Int J Mol Med ; 44(6): 2256-2264, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638172

RESUMO

The Wnt/ß­catenin pathway confers a chain of molecular events in livers affected by non­alcoholic steatohepatitis (NASH). Namodenoson, a selective agonist of the A3 adenosine receptor (A3AR), which is highly expressed in pathological liver cells, induces a robust anti­inflammatory effect in the liver, mediated via the de­regulation of the Wnt/ß­catenin pathway. Namodenoson also acts as a liver protective agent by inhibiting ischemia/reperfusion injury. Based on these unique characteristics, we investigated the anti­NASH effect of Namodenoson in murine models of steatohepatitis and in the LX2 human hepatic stellate cell line (HSC). In the STAM model, Namodenoson significantly decreased the non­alcoholic fatty liver disease (NAFLD) activity score, NAS, demonstrating anti­inflammatory and anti­steatotic effects. In the carbon tetrachloride (CCl4) model, Namodenoson reversed alanine aminotransferase (ALT) to normal values and significantly improved liver inflammation and fibrosis, as well as the adiponectin and leptin levels. Namodenoson de­regulated the Wnt/ß­catenin pathway in the liver extracts of the CCl4 model mice and in the LX2 HSCs, manifested by a decrease in the expression of phosphoinositide 3­kinase (PI3K), nuclear factor κ­light­chain­enhancer of activated B cells (NF­κB), ß­catenin, lymphoid enhancer­binding factor 1 (Lef­1) and cyclin D1, and an increase in the expression level of glycogen synthase kinase 3ß (GSK­3ß). The fibrosis marker, α­smooth muscle actin (α­SMA) was also de­regulated, supporting the anti­fibrotic effect of Namodenoson. On the whole, the findings of this study demonstrate that Namodenoson exerts an anti­NASH effect mediated via the de­regulation of the PI3K/NF­κB/Wnt/ß­catenin signaling pathway. Thus, targeting A3AR may prove to be a novel direction in the pharmacotherapy of NAFLD/NASH.


Assuntos
Agonistas do Receptor A3 de Adenosina/farmacologia , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptor A3 de Adenosina/genética , Actinas/genética , Adiponectina/genética , Animais , Tetracloreto de Carbono/toxicidade , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Leptina/genética , Fígado/metabolismo , Fígado/patologia , Camundongos , NF-kappa B/genética , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Fosfatidilinositol 3-Quinases/genética , Via de Sinalização Wnt/efeitos dos fármacos
15.
World J Gastroenterol ; 25(39): 5953-5960, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31660032

RESUMO

BACKGROUND: Portal hypertension (PHT) is primarily caused by an increase in resistance to portal outflow and secondarily by an increase in splanchnic blood flow. Vascular hyporeactivity both in systemic circulation and in the mesenteric artery plays a role in the hyperdynamic circulatory syndrome. AIM: To explore gender differences and the role of endogenous sex hormones in PHT and vascular reactivity of mesenteric arterioles in rats. METHODS: Cirrhosis and PHT were established by subcutaneous injection of carbon tetrachloride (CCl4) in both male and female integral and castrated rats (ovariectomized [OVX] in female rats, orchiectomy [ORX] in male rats). The third-order branch of the mensenteric artery was divided and used to measure vascular reactivity to vasoconstrictors. RESULTS: No significant difference in portal pressure was observed between integral and castrated male PHT rats (15.2 ± 2.1 mmHg vs 16.7 ± 2.7 mmHg, P > 0.05). The portal pressure in integral female PHT rats was lower than that in OVX female PHT rats (12.7 ± 2.7 mmHg vs 16.5 ± 2.4 mmHg, P < 0.05). In PHT rats, the concentration response curves of the mesenteric arterioles to norepinephrine were shifted to the right, and the maximal responses (Emax) values were decreased and effective concentrations causing half maximum responses (EC50) values were increased, compared to those of non-PHT rats, both in male and female rats. Compared to non-PHT integral male rats, the sensitivity of the mesenteric arterioles of non-PHT ORX male rats to norepinephrine was decreased (P > 0.05). However, there was no difference between integral and ORX male rats with PHT. In integral female PHT rats, the concentration response curves were shifted to the left (P < 0.05), and the Emax values were increased and EC50 values were decreased compared to OVX female PHT rats. CONCLUSION: Clear gender differences were observed in mesenteric vascular reactivity in CCl4-induced cirrhotic and PHT rats. Conservation of estrogen can retain the sensitivity of the mesenteric arterioles to vasoconstrictors and has a protective effect on splanchnic vascular function in PHT.


Assuntos
Arteríolas/fisiologia , Hormônios Esteroides Gonadais/metabolismo , Hipertensão Portal/fisiopatologia , Cirrose Hepática Experimental/fisiopatologia , Resistência Vascular/fisiologia , Animais , Arteríolas/efeitos dos fármacos , Tetracloreto de Carbono/toxicidade , Feminino , Humanos , Hipertensão Portal/induzido quimicamente , Hipertensão Portal/metabolismo , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , Pressão na Veia Porta/efeitos dos fármacos , Pressão na Veia Porta/fisiologia , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Circulação Esplâncnica/efeitos dos fármacos , Circulação Esplâncnica/fisiologia , Resistência Vascular/efeitos dos fármacos , Vasoconstritores/administração & dosagem
16.
Pak J Pharm Sci ; 32(4): 1649-1653, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31608886

RESUMO

In vitro hepatoprotective activity of Sargassum wightii methanolic extract was checked using established cell culture (Hep G2) and primary rat hepatocytes. In Hep G2 cells, the extract concentrations varying from 31.25-500 µg/ml were studied using 1% CCl4 as toxicant. All the extracts showed moderate protectivity against toxicity induced by CCl4 in Hep G2 cells. All the biochemical constraints were determined and compared with that of the control. In this study, an innovator product (silymarin) was used along with the test extracts. In vitro hepatoprotective activity was evaluated by analyzing various parameters such as ALAT, ASAT, ALP, total protein, total bilirubin, TGL and albumin. The results stated that the hepatoprotective potential exhibited by the methanolic extract of Sargassum wightii (SWMH) is active and comparable with the standard.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Hepatócitos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Sargassum/química , Animais , Bilirrubina/metabolismo , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Chlorocebus aethiops , Enzimas/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/química , Ratos , Silimarina/farmacologia , Células Vero
17.
Int J Biol Sci ; 15(11): 2296-2307, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31595148

RESUMO

Liver is one of the most vital organs to maintain homeostasis because of its peculiar detoxification functionalities to detoxify chemicals and metabolize drugs and toxins. Due to its crucial functions, the liver is also prone to various diseases, i.e., hepatitis, cirrhosis and hepatoma, etc. Additionally, long non-coding RNAs (lncRNAs) has emerged as key regulators which are found to play important roles in transcription, splicing, translation, replication, chromatin shaping and post translational modification of proteins in living cells. However, the underlying mechanisms of biological processes mediated by lncRNA remain unclear. Here, with the aim of disclosing potential lncRNAs implicated in the biological processes in liver in response to cytotoxicity, we performed a co-expression network analysis based on the transcriptome data of the damaged liver tissue of Rattus norvegicus induced by three cytotoxic compounds (carbon tetrachloride, chloroform and thioacetamide). Our analysis unveils that many biological processes and pathways were collectively affected by the three cytotoxic compounds, including drug metabolism, oxidation-reduction process, oxidative stress, glucuronidation, liver development and flavonoid biosynthetic process, etc. Also, our network analysis has identified several highly conserved lncRNA-mRNA interactions participating in those correlated processes and pathways, implying their potential roles in response to the induced cytotoxicity in liver. Our study provides new insights into lncRNA-mRNA regulatory mechanisms in response to pathogenic cytotoxic damaging in liver and facilitates the development of lncRNA-oriented therapies for hepatic diseases in the future.


Assuntos
Fígado/efeitos dos fármacos , Fígado/metabolismo , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Clorofórmio/toxicidade , Ratos , Tioacetamida/toxicidade , Transcriptoma/efeitos dos fármacos
18.
World J Gastroenterol ; 25(36): 5451-5468, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31576092

RESUMO

BACKGROUND: Zinc-α2-glycoprotein 1 (AZGP1) plays important roles in metabolism-related diseases. The underlying molecular mechanisms and therapeutic effects of AZGP1 remain unknown in non-alcoholic fatty liver disease (NAFLD). AIM: To explore the effects and potential mechanism of AZGP1 on NAFLD in vivo and in vitro. METHODS: The expression of AZGP1 and its effects on hepatocytes were examined in NAFLD patients, CCl4-treated mice fed a high fat diet (HFD), and human LO2 cells. RESULTS: AZGP1 levels were significantly decreased in liver tissues of NAFLD patients and mice. AZGP1 knockdown was found to activate inflammation; enhance steatogenesis, including promoting lipogenesis [sterol regulatory element-binding protein (SREBP)-1c, liver X receptor (LXR), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl CoA desaturase 1 (SCD)-1], increasing lipid transport and accumulation [fatty acid transport protein (FATP), carnitine palmitoyl transferase (CPT)-1A, and adiponectin], and reducing fatty acid ß-oxidation [farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)-α]; accelerate proliferation; and reverse apoptosis in LO2 cells. AZGP1 overexpression (OV-AZGP1) had the opposite effects. Furthermore, AZGP1 alleviated NAFLD by blocking TNF-α-mediated inflammation and intracellular lipid deposition, promoting proliferation, and inhibiting apoptosis in LO2 cells. Finally, treatment with OV-AZGP1 plasmid dramatically improved liver injury and eliminated liver fat in NAFLD mice. CONCLUSION: AZGP1 attenuates NAFLD with regard to ameliorating inflammation, accelerating lipolysis, promoting proliferation, and reducing apoptosis by negatively regulating TNF-α. AZGP1 is suggested to be a novel promising therapeutic target for NAFLD.


Assuntos
Proteínas de Transporte/metabolismo , Glicoproteínas/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Proteínas de Transporte/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Regulação para Baixo , Técnicas de Silenciamento de Genes , Glicoproteínas/genética , Humanos , Lipogênese , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Oxirredução , Transdução de Sinais
19.
World J Gastroenterol ; 25(31): 4468-4480, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31496625

RESUMO

BACKGROUND: Activation of hepatic stellate cells (HSCs) is a pivotal event in the onset and progression of liver fibrosis. Loss of microRNA-194 (miR-194) has been reported in activated HSCs, but the actual role of miR-194 in liver fibrosis remains uncertain. AIM: To explore the role and potential mechanism of miR-194-mediated regulation of liver fibrosis in vitro and in vivo. METHODS: The expression of miR-194 was examined in human fibrotic liver tissues, activated HSCs, and a carbon tetrachloride (CCl4) mouse model by qPCR. The effects of AKT2 regulation by miR-194 on the activation and proliferation of HSCs were assessed in vitro. For in vivo experiments, we reintroduced miR-194 in mice using a miR-194 agomir to investigate the functions of miR-194 in liver fibrosis. RESULTS: MiR-194 expression was notably lacking in activated HSCs from both humans and mice. Overexpression of miR-194 (OV-miR-194) inhibited α-smooth muscle actin (α-SMA) and type I collagen (Col I) expression and suppressed cell proliferation in HSCs by causing cell cycle arrest in G0/G1 phase. AKT2 was predicted to be a target of miR-194. Notably, the effects of miR-194 knockdown in HSCs were almost blocked by AKT2 deletion, indicating that miR-194 plays a role in HSCs via regulation of AKT2. Finally, miR-194 agomir treatment dramatically ameliorated liver fibrosis in CCl4-treated mice. CONCLUSION: We revealed that miR-194 plays a protective role by inhibiting the activation and proliferation of HSCs via AKT2 suppression. Our results further propose miR-194 as a potential therapeutic target for liver fibrosis.


Assuntos
Células Estreladas do Fígado/patologia , Cirrose Hepática Experimental/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Animais , Tetracloreto de Carbono/toxicidade , Linhagem Celular , Proliferação de Células/genética , Estudos de Coortes , Regulação para Baixo , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/patologia , Masculino , Camundongos , MicroRNAs/agonistas , MicroRNAs/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/genética
20.
Artigo em Inglês | MEDLINE | ID: mdl-31494630

RESUMO

Background Short-term memory impairment is a neurodegenerative disease associated with oxidative stress. Bryophyllum pinnatum (Lam.) Oken of the family Crassulaceae is traditionally used in the treatment of diseases, such as cough, wounds, and kidney diseases. This study evaluates the effect of the aqueous extract of B. pinnatum (AEBP) leaves on acetylcholinesterase activity in carbon tetrachloride (CCl4)-induced short-term memory impairment in rats. Methods Thirty male Wistar albino rats were used in this study and were divided into six groups (n=5). Group I served as control, group II rats were induced with CCl4, while groups III-V animals were pretreated with silymarin (25 mg/kg body weight), 25 and 50 mg/kg body weight AEBP leaves, respectively, once daily by oral gavage for 14 days prior to a single intraperitoneal injection of CCl4. Animals in group VI received 50 mg/kg body weight AEBP only by oral gavage. Results Administration of carbon tetrachloride significantly increased (p<0.05) spontaneous alternation and locomotor function in rats when compared with the control group. Also, the levels of acetylcholinesterase, adenosine deaminase, and malondialdehyde were increased in CCl4-administered rats, with reduction in both enzymatic and nonenzymatic antioxidant levels. However, pretreatment of rats with AEBP leaves, at tested doses, prevented these changes. Conclusions The increased antioxidant status and the inhibition of acetylcholinesterase activity show that AEBP leaves improve learning memory and stabilizes memory impairment caused by CCl4.


Assuntos
Tetracloreto de Carbono/toxicidade , Kalanchoe , Transtornos da Memória/prevenção & controle , Extratos Vegetais/farmacologia , Acetilcolinesterase/metabolismo , Adenosina Desaminase/metabolismo , Animais , Antioxidantes/metabolismo , Encéfalo/metabolismo , Masculino , Malondialdeído/metabolismo , Transtornos da Memória/induzido quimicamente , Atividade Motora/efeitos dos fármacos , Extratos Vegetais/química , Folhas de Planta/química , Ratos , Silimarina/farmacologia , Água/química
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