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1.
Mar Drugs ; 18(5)2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32380741

RESUMO

Increased interest in natural antioxidants has brought to light the fucoidans (sulfated polysaccharides present in brown marine algae) as highly valued nutrients as well as effective and safe therapeutics against several diseases. Based on their satisfactory in vitro antioxidant potency, researchers have identified this molecule as an efficient remedy for neuropathological as well as metabolic disorders. Some of this therapeutic activity is accomplished by upregulation of cytoprotective molecular pathways capable of restoring the enzymatic antioxidant activity and normal mitochondrial functions. Sirtuin-3 has been discovered as a key player for achieving the neuroprotective role of fucoidan by managing these pathways, whose ultimate goal is retrieving the entirety of the antioxidant response and preventing apoptosis of neurons, thereby averting neurodegeneration and brain injuries. Another pathway whereby fucoidan exerts neuroprotective capabilities is by interactions with P-selectin on endothelial cells, thereby preventing macrophages from entering the brain proper. Furthermore, beneficial influences of fucoidan have been established in hepatocytes after xenobiotic induced liver injury by decreasing transaminase leakage and autophagy as well as obtaining optimal levels of intracellular fiber, which ultimately prevents fibrosis. The hepatoprotective role of this marine polysaccharide also includes a sirtuin, namely sirtuin-1 overexpression, which alleviates obesity and insulin resistance through suppression of hyperglycemia, reducing inflammation and stimulation of enzymatic antioxidant response. While fucoidan is very effective in animal models for brain injury and neuronal degeneration, in general, it is accepted that fucoidan shows somewhat limited potency in liver. Thus far, it has been used in large doses for treatment of acute liver injuries. Thus, it appears that further optimization of fucoidan derivatives may establish enhanced versatility for treatments of various disorders, in addition to brain injury and disease.


Assuntos
Antioxidantes/farmacologia , Lesões Encefálicas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Polissacarídeos/farmacologia , Sirtuínas/metabolismo , Animais , Antioxidantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Lesões Encefálicas/patologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Fármacos Neuroprotetores/uso terapêutico , Phaeophyceae/química , Polissacarídeos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
2.
Toxicol Mech Methods ; 30(8): 570-579, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32623939

RESUMO

Toxicological studies have identified polycyclic aromatic hydrocarbons (PAH) in human breast milk, smoked and barbequed food, although the largest contribution of PAH intake into the body are cereals and cereals products. The major effects attributable to PAH appeared to occur in the liver, lungs, the hematopoietic system, and the kidney. Nevertheless, more precise mechanisms by which PAH initiates its pathological features are not fully understood. In the present study, we evaluated levels of myeloperoxidase activity, its association with nitric oxide synthesis (NO), levels of uric acid (UA) in circulating blood and glucose in female rats exposed to environmental toxicants. A higher concentration of hydrogen peroxide activates myeloperoxidase, which acts as a leucocyte attractant, contributing to enhanced iNOS activity. In parallel, uric acid in addition to its pro-inflammatory effects aggravates insulin resistance and hyperglycemia, which worsens the process. Our findings suggest potential intermediate mechanisms involved in the inflammatory effects of PAH, which might give insight for the involvement of environmental toxicants not only in carcinogenesis but also in its association with acute cardiovascular disease and induction of multi-organ damage. The development of iNOS inhibitors might be beneficial in certain inflammatory disorders.


Assuntos
9,10-Dimetil-1,2-benzantraceno/toxicidade , Poluentes Ambientais/toxicidade , Mediadores da Inflamação/metabolismo , Inflamação/induzido quimicamente , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Feminino , Inflamação/sangue , Inflamação/metabolismo , Rim/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Óxido Nítrico/metabolismo , Peroxidase/metabolismo , Carbonilação Proteica/efeitos dos fármacos , Ratos Wistar , Ácido Úrico/sangue
3.
J Cell Mol Med ; 20(2): 204-16, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26648452

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and lifestyle, while exercise is beneficial for NAFLD. Dysregulated microRNAs (miRs) control the pathogenesis of NAFLD. However, whether exercise could prevent NAFLD via targeting microRNA is unknown. In this study, normal or high-fat diet (HF) mice were either subjected to a 16-week running program or kept sedentary. Exercise attenuated liver steatosis in HF mice. MicroRNA array and qRT-PCR demonstrated that miR-212 was overexpressed in HF liver, while reduced by exercise. Next, we investigated the role of miR-212 in lipogenesis using HepG2 cells with/without long-chain fatty acid treatment (± FFA). FFA increased miR-212 in HepG2 cells. Moreover, miR-212 promoted lipogenesis in HepG2 cells (± FFA). Fibroblast growth factor (FGF)-21, a key regulator for lipid metabolism, was negatively regulated by miR-212 at protein level in HepG2 cells. Meanwhile, FFA downregulated FGF-21 both at mRNA and protein levels in HepG2 cells. Also, FGF-21 protein level was reduced in HF liver, while reversed by exercise in vivo. Furthermore, siRNA-FGF-21 abolished the lipogenesis-reducing effect of miR-212 inhibitor in HepG2 cells (± FFA), validating FGF-21 as a target gene of miR-212. These data link the benefit of exercise and miR-212 downregulation in preventing NAFLD via targeting FGF-21.


Assuntos
Regulação para Baixo/genética , Fatores de Crescimento de Fibroblastos/genética , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Condicionamento Físico Animal/fisiologia , Animais , Linhagem Celular Tumoral , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , RNA Mensageiro/genética
4.
Clin Sci (Lond) ; 130(13): 1125-36, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27129182

RESUMO

Hepatocellular carcinoma (HCC) represents a leading cause of deaths worldwide. Novel therapeutic targets for HCC are needed. Phospholipase D (PD) is involved in cell proliferation and migration, but its role in HCC remains unclear. In the present study, we show that PLD1, but not PLD2, was overexpressed in HCC cell lines (HepG2, Bel-7402 and Bel-7404) compared with the normal human L-02 hepatocytes. PLD1 was required for the proliferation, migration and invasion of HCC cells without affecting apoptosis and necrosis, and PLD1 overexpression was sufficient to promote those effects. By using HCC xenograft models, we demonstrated that therapeutic inhibition of PLD1 attenuated tumour growth and epithelial-mesenchymal transition (EMT) in HCC mice. Moreover, PLD1 was found to be highly expressed in tumour tissues of HCC patients. Finally, mTOR (mechanistic target of rapamycin) and Akt (protein kinase B) were identified as critical pathways responsible for the role of PLD1 in HCC cells. Taken together, the present study indicates that PLD1 activation contributes to HCC development via regulation of the proliferation, migration and invasion of HCC cells, as well as promoting the EMT process. These observations suggest that inhibition of PLD1 represents an attractive and novel therapeutic modality for HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Fosfolipase D/metabolismo , Animais , Carcinoma Hepatocelular/enzimologia , Regulação para Baixo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/fisiologia , Neoplasias Hepáticas/enzimologia , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos
5.
Med Sci Monit ; 22: 83-91, 2016 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-26744142

RESUMO

BACKGROUND: Multiple microRNAs (miRNAs, miRs), including miR-21, have been documented to be critical regulators of liver regeneration, but the mechanism underlying their roles in hepatocyte proliferation and cell cycle progression is still far from understood. MATERIAL/METHODS: miR-21 levels were determined using qRT-PCRs in mouse livers at 48 h after 70% partial hepatectomy (PH-48 h). Cell proliferation was determined by use of a cell-counting kit-8 (CCK-8), EdU incorporation staining, and flow cytometry. Phosphatase and tensin homolog (PTEN) expressions were determined using qRT-PCR and Western blot analysis. PTEN siRNA was used to perform the rescue experiment. RESULTS: A marked upregulation of miR-21 was observed in mouse livers at 48 h after 70% partial hepatectomy (PH-48 h) compared to 0 h after PH (PH-0 h). Overexpression of miR-21 was associated with increased proliferation and a rapid G1-to-S phase transition of the cell cycle in BNL CL.2 normal liver cells in vitro. In addition, we showed that PTEN expression was inversely correlated with miR-21 in BNL CL.2 cells and demonstrated that PTEN expression is lower in mouse livers at PH-48 h. Moreover, the presence of PTEN siRNA significantly abolished the suppressive effect of miR-21 inhibitor on hepatocyte proliferation. CONCLUSIONS: miR-21 overexpression contributes to liver regeneration and hepatocyte proliferation by targeting PTEN. Upregulation of miR-21 might be a useful therapeutic strategy to promote liver regeneration.


Assuntos
Hepatócitos/citologia , Regeneração Hepática , Fígado/fisiologia , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Animais , Ciclo Celular , Proliferação de Células , Tamanho Celular , Perfilação da Expressão Gênica , Hepatectomia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transfecção , Regulação para Cima
6.
J Food Biochem ; 46(10): e14364, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35929368

RESUMO

In light of the powerful therapeutic features of Phellinus species and due to the absence of toxic compounds, our investigations were aimed at screening of the antioxidant profile of fortified yogurts with hot water extracts from Phellinus torulosus and Phellinus igniarius leveled to 10%, 5%, and 1% final fortification concentrations after acknowledging their superior bioactive content and radical scavenging capacities (59.77% and 56.73% of DPPH inhibition, respectively) versus cold water extracts (29.87% and 33.18% inhibition rates). Fortified samples signified dose-dependent increases in their inhibition rates during the storage period, with significant differences between 10% fortifications on the 7 day of storage in favor of the samples fortified with P. torulosus. Explicitly, P. torulosus showed 16% higher DPPH and 62.5% higher LPO neutralizing activity than yogurt enriched with P. igniarius. However, prolonged refrigeration tended to equalize antioxidant profiles in both fortified yogurts. Total titratable acidity and pH levels of the fortified yogurts as most important parameters for consumer acceptance were unaltered during storage. PRACTICAL APPLICATIONS: It is a common scientific perception that bioactive compounds present in wild medicinal fungi are the main contributors for their in vitro antioxidant efficiency. On account of these attributes, Phellinus species have been exploited in Far East Asia as safe remedies for many disorders thus making them attractive fortifying ingredients; however, according to our knowledge these mushrooms have never been used as natural additives in beverages. Given the current popularity of yogurt consumption as seen from the global market profits, as well as experimental evidences of enhanced potency of extract in comparison with powder due to maximal bioavailability of antioxidants, it is our belief that this study will increase the interest in the manufacture of functional foods with extracts from wild mushrooms.


Assuntos
Agaricales , Iogurte , Antioxidantes/farmacologia , Phellinus , Pós , Água , Iogurte/microbiologia
7.
Toxicol Pathol ; 38(6): 957-68, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21037200

RESUMO

7,12-Dimethylbenz[a]anthracene (DMBA) presents a pollutant implicated in various toxicological effects. The aim of this experiment was to study the effects of DMBA administration on oxidative stress, histopathological signs, and 18 kDa translocator protein (TSPO) binding characteristics in rat liver. We also studied the effects of dose stoichiometry, dose frequency, and duration of protocol of DMBA administration. In this study, rats surviving eighteen weeks after DMBA exposure showed mild to moderate histopathological changes in the liver, mainly characterized by glossy appearance of hepatocytes, heterochromatic nuclei, and glycogen overload in the midzonal region of the hepatic lobe. These changes were accompanied by significant rises in oxidant levels, along with declines in nonenzymic antioxidants, indicating that DMBA induced oxidative stress in the liver. This finding correlated well with decreases in TSPO binding capacity in the liver of the rats in our study. Other studies have shown that TSPO can be affected by oxidative stress, as well as contribute to oxidative stress at mitochondrial levels. Further studies are needed to assay whether the decreases in TSPO density in the liver are part of the damaging effects caused by DMBA or a compensatory response to the oxidative stress induced by DMBA.


Assuntos
9,10-Dimetil-1,2-benzantraceno/toxicidade , Carcinógenos/toxicidade , Proteínas de Transporte/efeitos dos fármacos , Fígado/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Receptores de GABA-A/efeitos dos fármacos , Animais , Proteínas de Transporte/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Mitocôndrias Hepáticas/metabolismo , Proteínas Mitocondriais/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de GABA-A/metabolismo
8.
Drug Chem Toxicol ; 33(4): 337-47, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20550435

RESUMO

In this study, rats surviving 18 weeks after 7,12-dimethylbenz[a]anthracene (DMBA) exposure showed robust pathological changes in the aorta. This correlated well with decreases in 18-kDa translocator protein (TSPO) binding capacity in this tissue. As expected, markers for oxidative stress, including thiobarbituric-acid-reactive substances, and advanced oxidation protein products, showed that the applied DMBA exposure increased oxidative stress in the aorta. Our study suggests that TSPO may be involved in toxic DMBA effects in the aorta, including inflammatory responses and reactive oxygen species generation.


Assuntos
9,10-Dimetil-1,2-benzantraceno/toxicidade , Aorta/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Ligantes , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , Ligação Proteica , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fatores de Tempo
9.
Cells ; 9(4)2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32252470

RESUMO

Neuroinflammation and cell death are among the common symptoms of many central nervous system diseases and injuries. Neuroinflammation and programmed cell death of the various cell types in the brain appear to be part of these disorders, and characteristic for each cell type, including neurons and glia cells. Concerning the effects of 18-kDa translocator protein (TSPO) on glial activation, as well as being associated with neuronal cell death, as a response mechanism to oxidative stress, the changes of its expression assayed with the aid of TSPO-specific positron emission tomography (PET) tracers' uptake could also offer evidence for following the pathogenesis of these disorders. This could potentially increase the number of diagnostic tests to accurately establish the stadium and development of the disease in question. Nonetheless, the differences in results regarding TSPO PET signals of first and second generations of tracers measured in patients with neurological disorders versus healthy controls indicate that we still have to understand more regarding TSPO characteristics. Expanding on investigations regarding the neuroprotective and healing effects of TSPO ligands could also contribute to a better understanding of the therapeutic potential of TSPO activity for brain damage due to brain injury and disease. Studies so far have directed attention to the effects on neurons and glia, and processes, such as death, inflammation, and regeneration. It is definitely worthwhile to drive such studies forward. From recent research it also appears that TSPO ligands, such as PK11195, Etifoxine, Emapunil, and 2-Cl-MGV-1, demonstrate the potential of targeting TSPO for treatments of brain diseases and disorders.


Assuntos
Alcoolismo/genética , Lesões Encefálicas Traumáticas/genética , Encéfalo/patologia , Transtornos Mentais/genética , Doenças Neurodegenerativas/genética , Receptores de GABA/uso terapêutico , Acidente Vascular Cerebral/genética , Humanos
10.
Oncotarget ; 7(2): 1584-97, 2016 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-26636539

RESUMO

Liver regeneration is a highly orchestrated process which can be regulated by microRNAs (miRNAs, miRs), though the mechanisms are largely unclear. This study was aimed to identify miRNAs responsible for hepatocyte proliferation during liver regeneration. Here we detected a marked elevation of miR-382 in the mouse liver at 48 hrs after partial hepatectomy (PH-48h) using microarray analysis and qRT-PCRs. miR-382 overexpression accelerated the proliferation and the G1 to S phase transition of the cell cycle both in mouse NCTC1469 and human HL7702 normal liver cells, while miR-382 downregulation had inverse effects. Moreover, miR-382 negatively regulated PTEN expression and increased Akt phosphorylation both in vitro and in vivo. Using PTEN siRNA and Akt activator/inhibitor, we further found that PTEN inhibition and Akt phosphorylation were essential for mediating the promotive effect of miR-382 in the proliferation and cell growth of hepatocytes. Collectively, our findings identify miR-382 as a promoter for hepatocyte proliferation and cell growth via targeting PTEN-Akt axis which might be a novel therapeutic target to enhance liver regeneration capability.


Assuntos
Hepatócitos/enzimologia , Regeneração Hepática , Fígado/enzimologia , MicroRNAs/genética , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Ciclo Celular , Linhagem Celular , Proliferação de Células , Ativadores de Enzimas/farmacologia , Hepatectomia , Hepatócitos/patologia , Humanos , Fígado/patologia , Fígado/cirurgia , Masculino , Camundongos Endogâmicos C57BL , Modelos Animais , PTEN Fosfo-Hidrolase/genética , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/agonistas , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Interferência de RNA , Transdução de Sinais , Transfecção , Regulação para Cima
11.
Food Chem Toxicol ; 48(3): 910-21, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20060027

RESUMO

It is well known that high fat and high cholesterol levels present a contributing factor to pathologies including fatty liver and atherosclerosis. Oxidative stress is also considered to play a role in these pathologies. The 18 kDa Translocator Protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, is known to be involved in cholesterol metabolism, oxidative stress, and cardiovascular pathology. We applied a high fat high cholesterol atherogenic (HFHC) diet to rats to study correlations between cardiovascular and liver pathology, oxidative stress, and TSPO expression in the liver and the cardiovascular system. This study corroborates the presence of increased oxidative stress markers and decreased anti-oxidants in liver and aorta. In addition, it appeared that induction of oxidative stress in the liver and aorta by atherogenic HFHC diet was accompanied by a reduction in TSPO binding density in both these tissues. Our data suggest that involvement of TSPO in oxidative stress and ROS generation, as reported in other studies, may also take part in atherogenesis as induced by HFHC diet. Presently, it is not clear whether this TSPO response is compensatory for the stress induced by HFHC diet or is a participant in the induction of oxidative stress.


Assuntos
Aorta Torácica/metabolismo , Proteínas de Transporte/metabolismo , Colesterol na Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Fígado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Animais , Antioxidantes/metabolismo , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Biomarcadores , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Dieta , Dieta Aterogênica , Endotélio Vascular/patologia , Produtos Finais de Glicação Avançada/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Oxirredução , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar
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