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1.
Glia ; 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32003513

RESUMO

Astrogliosis comprises a variety of changes in astrocytes that occur in a context-specific manner, triggered by temporally diverse signaling events that vary with the nature and severity of brain insults. However, most mechanisms underlying astrogliosis were described using animals, which fail to reproduce some aspects of human astroglial signaling. Here, we report an in vitro model to study astrogliosis using human-induced pluripotent stem cells (iPSC)-derived astrocytes which replicate temporally intertwined aspects of reactive astrocytes in vivo. We analyzed the time course of astrogliosis by measuring nuclear translocation of NF-kB, production of cytokines, changes in morphology and function of iPSC-derived astrocytes exposed to TNF-α. We observed NF-kB p65 subunit nuclear translocation and increased gene expression of IL-1ß, IL-6, and TNF-α in the first hours following TNF-α stimulation. After 24 hr, conditioned media from iPSC-derived astrocytes exposed to TNF-α exhibited increased secretion of inflammation-related cytokines. After 5 days, TNF-α-stimulated cells presented a typical phenotype of astrogliosis such as increased immunolabeling of Vimentin and GFAP and nuclei with elongated shape and shrinkage. Moreover, ~50% decrease in aspartate uptake was observed during the time course of astrogliosis with no evident cell damage, suggesting astroglial dysfunction. Together, our results indicate that human iPSC-derived astrocytes reproduce canonical events associated with astrogliosis in a time dependent fashion. The approach described here may contribute to a better understanding of mechanisms governing human astrogliosis with potential applicability as a platform to uncover novel biomarkers and drug targets to prevent or mitigate astrogliosis associated with human brain disorders.

2.
J Cell Mol Med ; 24(1): 88-97, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31654493

RESUMO

We aim to characterize the kinetics of early and late microglial phenotypes after systemic inflammation in an animal model of severe sepsis and the effects of minocycline on these phenotypes. Rats were subjected to CLP, and some animals were treated with minocycline (10 ug/kg) by i.c.v. administration. Animals were killed 24 hours, 5, 10 and 30 days after sepsis induction, and serum and hippocampus were collected for subsequent analyses. Real-time PCR was performed for M1 and M2 markers. TNF-α, IL-1ß, IL-6, IL-10, CCL-22 and nitrite/nitrate levels were measured. Immunofluorescence for IBA-1, CD11b and arginase was also performed. We demonstrated that early after sepsis, there was a preponderant up-regulation of M1 markers, and this was not switched to M2 phenotype markers later on. We found that up-regulation of both M1 and M2 markers co-existed up to 30 days after sepsis induction. In addition, minocycline induced a down-regulation, predominantly, of M1 markers. Our results suggest early activation of M1 microglia that is followed by an overlap of both M1 and M2 phenotypes and that the beneficial effects of minocycline on sepsis-associated brain dysfunction may be related to its effects predominantly on the M1 phenotype.

3.
Food Chem Toxicol ; 133: 110766, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31430511

RESUMO

People with large amounts of adipose tissue are more vulnerable and more likely to develop diseases where oxidative stress and inflammation play a pivotal role, than persons with a healthy weight. Atmospheric contamination is a reality to which a large part of the worldwide population is exposed. Half of today's global electrical energy is derived from coal. Each organism, in its complexity, responds in different ways to dietary compounds and air pollution. The objective of this study was to investigate the effects of obesity and coal ash inhalation within the parameters of oxidative damage and inflammation in different regions of the brain of rats. A diet containing high-fat concentration was administered chronically to rats, along with exposure to coal ash, simulating the contamination that occurs daily throughout human life. High-resolution transmission electron microscopy was performed to identify the particles present in coal ash samples. Our results demonstrated that obese rats exposed to coal ash inhalation were more affected by oxidative damage with subsequent systemic inflammation in the hippocampus. Since there is an inflammatory predisposition caused by obesity, the inhalation of nanoparticles increases the levels of free radicals, resulting in systemic inflammation and oxidative damage, which can lead to chronic neurodegeneration.


Assuntos
Cinza de Carvão/toxicidade , Hipocampo/efeitos dos fármacos , Inflamação/metabolismo , Exposição por Inalação , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poluentes Atmosféricos/toxicidade , Animais , Catalase/metabolismo , Dieta Hiperlipídica , Glutationa Peroxidase/metabolismo , Inflamação/induzido quimicamente , Masculino , Ratos Wistar , Superóxido Dismutase/metabolismo
4.
Mol Cell Biochem ; 462(1-2): 11-23, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446616

RESUMO

BRCA-1 is a nuclear protein involved in DNA repair, transcriptional regulation, and cell cycle control. Its involvement in other cellular processes has been described. Here, we aimed to investigate the role of BRCA-1 in macrophages M(LPS), M(IL-4), and tumor cell-induced differentiation. We used siRNAs to knockdown BRCA-1 in RAW 264.7 macrophages exposed to LPS, IL-4, and C6 glioma cells conditioned medium (CMC6), and evaluated macrophage differentiation markers and functional phagocytic activity as well as DNA damage and cell survival in the presence and absence of BRCA-1. LPS and CMC6, but not by IL-4, increased DNA damage in macrophages, and this effect was more pronounced in BRCA-1-depleted cells, including M(IL-4). BRCA-1 depletion impaired expression of pro-inflammatory cytokines, TNF-α and IL-6, and reduced the phagocytic activity of macrophages in response to LPS. In CMC6-induced differentiation, BRCA-1 knockdown inhibited TNF-α and IL-6 expression which was accompanied by upregulation of the anti-inflammatory markers IL-10 and TGF-ß and reduced phagocytosis. In contrast, M(IL-4) phenotype was not affected by BRCA-1 status. Molecular docking predicted that the conserved BRCA-1 domain BRCT can interact with the p65 subunit of NF-κB. Immunofluorescence assays showed that BRCA-1 and p65 co-localize in the nucleus of LPS-treated macrophages and reporter gene assay showed that depletion of BRCA-1 decreased LPS and CMC6-induced NF-κB transactivation. IL-4 had no effect upon NF-κB. Taken together, our findings suggest a role of BRCA-1 in macrophage differentiation and phagocytosis induced by LPS and tumor cells secretoma, but not IL-4, in a mechanism associated with inhibition of NF-κB.


Assuntos
Proteína BRCA1/metabolismo , Polaridade Celular , Inflamação/patologia , Ativação de Macrófagos , Macrófagos/metabolismo , Macrófagos/patologia , NF-kappa B/metabolismo , Animais , Biomarcadores/metabolismo , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Polaridade Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Dano ao DNA , Inflamação/metabolismo , Lipopolissacarídeos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , Camundongos , Fagocitose/efeitos dos fármacos , Células RAW 264.7 , RNA Interferente Pequeno/metabolismo , Ratos
5.
J Cell Biochem ; 120(12): 19730-19737, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31297896

RESUMO

Tyrosine hydroxylase (TH) is the key enzyme that controls the rate of synthesis of the catecholamines. SH-SY5Y cells with stable transfections of either human tyrosine hydroxylase isoform 1 (hTH1) or human tyrosine hydroxylase isoform 4 (hTH4) were used to determined the subcellular distribution of TH protein and phosphorylated TH, under basal conditions and after muscarine stimulation. Muscarine was previously shown to increase the phosphorylation of only serine 19 and serine 40 in hTH1 cells. Under basal conditions, the hTH1 and hTH4 proteins, their serine 19 phosphorylated forms and hTH1 phosphorylated at serine 40 were all similarly distributed; with ~80% in the cytosolic fraction, ~20% in the membrane fraction, and less than 1%, or not detectable, in the nuclear fraction. However, hTH4 phosphorylated at serine 71 had a significantly different distribution with ~65% cytosolic and ~35% membrane associated. Muscarine stimulation led to hTH1 being redistributed from the cytosol and nuclear fractions to the membrane fraction and hTH4 being redistributed from the cytosol to the nuclear fraction. These muscarine stimulated redistributions were not due to TH phosphorylation at serine 19, serine 40, or serine 71 and were most likely due to TH binding to proteins whose phosphorylation was increased by muscarine. This is the first study to show a difference in subcellular distribution between two human TH isoforms under basal and stimulated conditions.

6.
Cell Signal ; 62: 109356, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31288066

RESUMO

Recent studies have investigated the use of retinoic acid (RA) molecule in combined chemotherapies to cancer cells as an attempt to increase treatment efficiency and circumvent cell resistance. Positive results were obtained in clinical trials from lung cancer patients treated with RA and cisplatin. Meanwhile, the signalling process that results from the interaction of both molecules remains unclear. One of the pathways that RA is able to modulate is the activity of NRF2 transcription factor, which is highly associated with tumour progression and resistance. Therefore, the aim of this work was to investigate molecular mechanism of RA and cisplatin co-treatment in A549 cells, focusing in NRF2 pathway. To this end, we investigated NRF2 and NRF2-target genes expression, cellular redox status, cisplatin-induced apoptosis, autophagy and DNA repair through homologous recombination. RA demonstrated to have an inhibitory effect over NRF2 activation, which regulates the expression of thiol antioxidants enzymes. Moreover, RA increased reactive species production associated with increased oxidation of thiol groups within the cells. The expression of proteins associated with DNA repair through homologous recombination was also suppressed by RA pre-treatment. All combined, these effects appear to create a more sensitive cellular environment to cisplatin treatment, increasing apoptosis frequency. Interestingly, autophagy was also increased by combination therapy, suggesting a resistance mechanism by A549 cells. In conclusion, these results provided new information about molecular mechanisms of RA and cisplatin treatment contributing to chemotherapy optimization.

7.
Int Immunopharmacol ; 75: 105743, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31357087

RESUMO

Macrophages are immune system cells that respond to various pathogenic insults. The recognition of antigens is performed through receptors such as TLR4 and RAGE, which recognize pathogen-associated patterns (PAMPs), including lipopolysaccharide (LPS) from Gram-negative bacteria. Carvacrol (CAR) is a phenolic compound found in some essential oils commonly used in folk medicine for treatment of inflammation-related diseases. Previous works observed strong antioxidant actions and some anti-inflammatory effects by CAR in in vivo and in vitro assays. However, the potential pharmacological application of CAR remains limited as details on its mechanisms of action are still missing. Here we investigated the molecular pathways by which CAR acts on LPS-mediated pro-inflammatory activation of RAW 264.7 macrophages. CAR 100 µM protected cells against loss of cell viability induced by LPS (1 µg/mL). Pre-incubation with CAR prevented LPS-induced ERK1/2 phosphorylation, but it had no effect on p38 and JNK activation. The effect of LPS on NF-kB (p65) translocation from cytoplasm to nucleus was inhibited by CAR, as well as NF-kB transcriptional activation. Moreover, LPS-elicited release of TNF-α and IL-1ß were inhibited by CAR, as well as activation of phagocytic activity. Such effects may be related to the antioxidant effect of CAR, as the LPS-induced increase in reactive species (RS) production (assessed by DCFH oxidation) and nitric oxide (NO) production (assessed by nitrite quantification) were inhibited by CAR. Altogether, these results demonstrate that CAR exerts relevant anti-inflammatory actions through a cellular mechanism involving ERK1/2 and NF-kB inhibition and possibly related to the antioxidant properties of this phenolic compound.

8.
Front Neurol ; 10: 221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930837

RESUMO

The presence of autoantibodies against neuronal cell surface or synaptic proteins and their relationship to autoimmune encephalitis have recently been characterized. These autoantibodies have been also reported in other pathologic conditions; however, their role during sepsis is not known. This study detected the presence of autoantibodies against neuronal cell surface or synaptic proteins in the serum of septic patients and determined their relationship to the occurrence of brain dysfunction and mortality. This prospective, observational cohort study was performed in four Brazilian intensive care units (ICUs). Sixty patients with community-acquired severe sepsis or septic shock admitted to the ICU were included. Blood samples were collected from patients within 24 h of ICU admission. Antibodies to six neuronal proteins were assessed, including glutamate receptors (types NMDA, AMPA1, and AMPA2); voltage-gated potassium channel complex (VGKC) proteins, leucine-rich glioma-inactivated protein 1 (LGI1), and contactin-associated protein-2 (Caspr2), as well as the GABAB1 receptor. There was no independent association between any of the measured autoantibodies and the occurrence of brain dysfunction (delirium or coma). However, there was an independent and significant relationship between anti-NMDAR fluorescence intensity and hospital mortality. In conclusion, anti-NMDAR was independently associated with hospital mortality but none of the measured antibodies were associated with brain dysfunction in septic patients.

9.
Phytother Res ; 33(5): 1394-1403, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30868680

RESUMO

Obesity is a metabolic disorder associated with adverse health consequences that has increased worldwide at an epidemic rate. This has encouraged many people to utilize nonprescription herbal supplements for weight loss without knowledge of their safety or efficacy. However, mounting evidence has shown that some herbal supplements used for weight loss are associated with adverse effects. Guarana seed powder is a popular nonprescription dietary herb supplement marketed for weight loss, but no study has demonstrated its efficacy or safety when administered alone. Wistar rats were fed four different diets (low-fat diet and Western diet with or without guarana supplementation) for 18 weeks. Metabolic parameters, gut microbiota changes, and toxicity were then characterized. Guarana seed powder supplementation prevented weight gain, insulin resistance, and adipokine dysregulation induced by Western diet compared with the control diet. Guarana induced brown adipose tissue expansion, mitochondrial biogenesis, uncoupling protein-1 overexpression, AMPK activation, and minor changes in gut microbiota. Molecular docking suggested a direct activation of AMPK by four guarana compounds tested here. We propose that brown adipose tissue activation is one of the action mechanisms involved in guarana supplementation-induced weight loss and that direct AMPK activation may underlie this mechanism. In summary, guarana is an attractive potential therapeutic agent to treat obesity.


Assuntos
Adipocinas/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Resistência à Insulina , Paullinia/química , Animais , Dieta Hiperlipídica/efeitos adversos , Dieta Ocidental , Suplementos Nutricionais , Humanos , Masculino , Simulação de Acoplamento Molecular , Obesidade/metabolismo , Ratos , Ratos Wistar , Ganho de Peso , Perda de Peso/efeitos dos fármacos
10.
Neurochem Int ; 126: 27-35, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30849398

RESUMO

Carvacrol (CARV) presents valuable biological properties such as anti-inflammatory and antioxidant activities. However, pharmacological uses of CARV are largely limited due to disadvantages related to solubility, bioavailability, preparation and storage processes. The complexation of monoterpenes with ß-cyclodextrin (ß-CD) increases their stability, solubility and oral bioavailability. Here, the protective effect of oral treatment with CARV/ß-CD complex (25 µg/kg/day) against dopaminergic (DA) denervation induced by unilateral intranigral injection of 6-hydroxydopamine (6-OHDA - 10 µg per rat) was analyzed, in order to evaluate a putative application in the development of neuroprotective therapies for Parkinson's disease (PD). Pretreatment with CARV/ß-CD for 15 days prevented the loss of DA neurons induced by 6-OHDA in adult Wistar rats. This effect may occur through CARV anti-inflammatory and antioxidant properties, as the pretreatment with CARV/ß-CD inhibited the release of IL-1ß and TNF-α; besides, CARV prevented the increase of mitochondrial superoxide production induced by 6-OHDA in cultured SH-SY5Y cells. Importantly, hepatotoxicity or alterations in blood cell profile were not observed with oral administration of CARV/ß-CD. Therefore, this study showed a potential pharmacological application of CARV/ß-CD in PD using a non-invasive route of drug delivery, i.e., oral administration.


Assuntos
/administração & dosagem , Denervação/efeitos adversos , Neurônios Dopaminérgicos/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Oxidopamina/toxicidade , beta-Ciclodextrinas/administração & dosagem , Administração Oral , Animais , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Combinação de Medicamentos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar
11.
Neurochem Int ; 125: 25-34, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30739037

RESUMO

Vitamin A (retinol) is involved in signaling pathways regulating gene expression and was postulated to be a major antioxidant and anti-inflammatory compound of the diet. Parkinson's disease (PD) is a progressive neurodegenerative disorder, characterized by loss of nigral dopaminergic neurons, involving oxidative stress and pro-inflammatory activation. The aim of the present study was to evaluate the neuroprotective effects of retinol oral supplementation against 6-hydroxydopamine (6-OHDA, 12 µg per rat) nigrostriatal dopaminergic denervation in Wistar rats. Animals supplemented with retinol (retinyl palmitate, 3000 IU/kg/day) during 28 days exhibited increased retinol content in liver, although circulating retinol levels (serum) were unaltered. Retinol supplementation did not protect against the loss of dopaminergic neurons (assessed through tyrosine hydroxylase immunofluorescence and Western blot). Retinol supplementation prevented the effect of 6-OHDA on Iba-1 levels but had no effect on 6-OHDA-induced GFAP increase. Moreover, GFAP levels were increased by retinol supplementation alone. Rats pre-treated with retinol did not present oxidative damage or thiol redox modifications in liver, and the circulating levels of TNF-α, IL-1ß, IL-6 and IL-10 were unaltered by retinol supplementation, demonstrating that the protocol used here did not cause systemic toxicity to animals. Our results indicate that oral retinol supplementation is not able to protect against 6-OHDA-induced dopaminergic denervation, and it may actually stimulate astrocyte reactivity without altering parameters of systemic toxicity.


Assuntos
Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Degeneração Neural/induzido quimicamente , Degeneração Neural/tratamento farmacológico , Simpatectomia Química/métodos , Vitamina A/administração & dosagem , Administração Oral , Animais , Neurônios Dopaminérgicos/metabolismo , Masculino , Degeneração Neural/metabolismo , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Resultado do Tratamento
12.
Mol Neurobiol ; 56(5): 3079-3089, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30094805

RESUMO

The receptor for advanced glycation endproducts (RAGE) is a transmembrane, immunoglobulin-like receptor that interacts with a broad repertoire of extracellular ligands. RAGE belongs to a family of cell adhesion molecules and is considered a key receptor in the inflammation axis and a potential contributor to the neurodegeneration. The present study aimed to investigate the content and cell localization of RAGE in the brain of Wistar rats subjected to systemic inflammation induced by a single dose of lipopolysaccharide (LPS, 5 mg/kg, i.p.). Fifteen days after LPS administration, the content of RAGE was analyzed in the prefrontal cortex (PFC), hippocampus (HIPP), cerebellum (CB), and substantia nigra (SN) were investigated. RAGE levels increased in all structures, except HIPP; however, immunohistochemistry analysis demonstrated that the cell site of RAGE expression changed from blood vessel-like structures to neuronal cells in all brain areas. Besides, the highest level of RAGE expression was found in SN. Immunofluorescence analysis in SN confirmed that RAGE expression was mainly co-localized in endothelial cells (RAGE/PECAM-1 co-staining) in untreated animals, while LPS-treated animals had RAGE expression predominantly in dopaminergic neurons (RAGE/TH co-staining). Decreased TH levels, as well as increased pro-inflammatory markers (TNF-α, IL-1ß, Iba-1, GFAP, and phosphorylated ERK1/2) in SN, occurred concomitantly to RAGE stimulation in the same site. These results suggest a role for RAGE in the establishment of a neuroinflammation-neurodegeneration axis that develops as a long-term response to systemic inflammation by LPS.


Assuntos
Encéfalo/metabolismo , Encéfalo/patologia , Células Endoteliais/metabolismo , Inflamação/metabolismo , Neurônios/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Animais , Biomarcadores/metabolismo , Neurônios Dopaminérgicos/metabolismo , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Masculino , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos Wistar , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
13.
Biochim Biophys Acta Mol Cell Res ; 1866(3): 317-328, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30529222

RESUMO

Retinoic acid (RA) promotes differentiation in multiple neurogenic cell types by promoting gene reprogramming through retinoid receptors and also by inducing cytosolic signaling events. The nuclear RXR receptors are one of the main mediators of RA cellular effects, classically by joining the direct receptors of RA, the nuclear RAR receptors, in RAR/RXR dimers which act as transcription factors. Distinct RXR genes lead to RXRα, RXRß and RXRγ subtypes, but their specific roles in neuronal differentiation remain unclear. We firstly investigated both RXRs and RARs expression profiles during RA-mediated neuronal differentiation of human neuroblastoma cell line SH-SY5Y, and found varying levels of retinoid receptors transcript and protein contents along the process. In order to understand the roles of the expression of distinct RXR subtypes to RA signal transduction, we performed siRNA-mediated silencing of RXRα and RXRß during the first stages of SH-SY5Y differentiation. Our results showed that RXRα is required for RA-induced neuronal differentiation of SH-SY5Y cells, since its silencing compromised cell cycle arrest and prevented the upregulation of neuronal markers and the adoption of neuronal morphology. Besides, silencing of RXRα affected the phosphorylation of ERK1/2. By contrast, silencing of RXRß improved neurite extension and led to increased expression of tau and synaptophysin, suggesting that RXRß may negatively regulate neuronal parameters related to neurite outgrowth and function. Our results indicate distinct functions for RXR subtypes during RA-dependent neuronal differentiation and reveal new perspectives for studying such receptors as clinical targets in therapies aiming at restoring neuronal function.


Assuntos
Neuritos/metabolismo , Receptor X Retinoide alfa/fisiologia , Receptor X Retinoide beta/fisiologia , Animais , Pontos de Checagem do Ciclo Celular/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Neuroblastoma/genética , Neuroblastoma/metabolismo , Ratos , Receptores Citoplasmáticos e Nucleares/genética , Receptores do Ácido Retinoico/metabolismo , Receptores do Ácido Retinoico/fisiologia , Receptor X Retinoide alfa/metabolismo , Receptor X Retinoide beta/metabolismo , Receptores X Retinoide , Transdução de Sinais/efeitos dos fármacos , Ativação Transcricional , Tretinoína/metabolismo , Tretinoína/farmacologia , Células Tumorais Cultivadas
14.
Neurotoxicology ; 69: 164-180, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30316701

RESUMO

Fish consumption and ubiquitous methylmercury (MeHg) exposure represent a public health problem globally. Micronutrients presented in fish affects MeHg uptake/distribution. Vitamin A (VitA), another fish micronutrient is used in nutritional supplementation, especially during pregnancy. However, there is no information about the health effects arising from their combined exposure. The present study aimed to examine the effects of both MeHg and retinyl palmitate administered to pregnant and lactating rats. Thirty Wistar female rats were orally supplemented with MeHg (0,5 mg/Kg/day) and retinyl palmitate (7500 µg RAE1/Kg/day), either individually or in combination from the gestational day 0 to weaning. In dams, maternal behavior was scored. In neonatal and infant offspring, associative learning and neurodevelopment were evaluated. Further periadolescent male and female pups were assessed for open field, habituation and object recognition using episodic-like memory paradigm. Maternal and offspring redox parameters were evaluated. Our results showed no effects of MeHg-VitA co-administration in the quality of maternal care but showed subtle alterations in the pro-oxidant response of the hippocampus. In offspring, MeHg-VitA co-exposure affected early associative learning in neonatal pups, with no further modifications in neurodevelopment, and no locomotor or exploratory alterations in later developmental stages. Habituation was altered in a sex-dependent manner, but no overall memory disturbances were encountered. Finally, MeHg-VitA co-administration reduced lipoperoxidation in male offspring hippocampus. In conclusion, VitA co-administration in dams, under our exposure protocol, can counteract the deleterious neurodevelopmental effects solely attributed to low-dose MeHg in a tissue-specific mechanism, suggesting a protective effect of VitA against MeHg-induced oxidative damage in the central nervous system, especially in the offspring. Further work is needed to confirm our findings and elucidate the molecular mechanisms of MeHg-VitA modulation. Pre-clinical assays are necessary to demonstrate the potential therapeutical use of VitA in populations directly or indirectly exposed to MeHg.


Assuntos
Lactação/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Compostos de Metilmercúrio/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Vitamina A/análogos & derivados , Animais , Anticarcinógenos/administração & dosagem , Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem por Associação/fisiologia , Diterpenos , Combinação de Medicamentos , Feminino , Lactação/fisiologia , Locomoção/fisiologia , Masculino , Compostos de Metilmercúrio/toxicidade , Odorantes , Estresse Oxidativo/fisiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , Vitamina A/administração & dosagem
15.
Ecotoxicol Environ Saf ; 165: 44-51, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30179764

RESUMO

Obesity is an important nutritional disorder worldwide. Its association with environmental pollution may trigger an increase in oxidative stress and inflammatory parameters. Coal is a resource used throughout the world as an important fuel source for generating electricity. The ashes released by the coal combustion cause serious problems for human health due to their high toxicity and their capacity to bioaccumulate. The aim of this work was to investigate the effects of coal dust inhalation in the organs of obese and non-obese Wistar rats. Pro-inflammatory cytokines, oxidative stress, oxidative damage, histological analysis, comet assay, and micronuclei were investigated. Both obesity and coal dust inhalation increased the pro-inflammatory cytokines IL-1ß and TNF-α and decreased HSP70 levels in serum, however, in obese animals that inhaled coal dust these changes were more pronounced. Liver histological analysis showed severe microvesicular steatosis in obese animals that inhaled coal dust. Lung histologic investigation showed abnormalities in lung structure of animals exposed to coal dust and showed severe lung distensibility in obese animals exposed to coal dust. The comet assay showed DNA damage in animals subjected to coal. In addition, there were modulations in enzymatic activities and damage to protein and lipids. Based on our results, the coal dust inhalation can potentiate the pro-inflammatory profile present in obese rats. We also observed an increase in the protein oxidative damage in obese rats that inhaled coal dust. Taken together, our results suggest that the combination of obesity and coal inhalation increased the risks of the development of diseases related to oxidative stress and inflammation.


Assuntos
Carvão Mineral/toxicidade , Dano ao DNA , Obesidade/patologia , Estresse Oxidativo , Administração por Inalação , Animais , Citocinas/sangue , Poeira , Mediadores da Inflamação/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Obesidade/sangue , Obesidade/metabolismo , Ratos , Ratos Wistar
16.
Food Res Int ; 113: 57-64, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30195546

RESUMO

Rice bran is obtained from the rice polishing process, and this by-product contains many bioactive compounds. In this study, the composition of phenolic compounds from red and black rice brans was determined by HPLC-DAD-MS. Additionally, the neuroprotective ability of these brans in SH-SY5Y cells insulted with hydrogen peroxide (H2O2) was evaluated. The phenolic constituents of rice bran were separated into hydrophilic and pellet fractions. The major phenolic compound in both samples was ferulic acid. Cyanidin 3-glucoside was the main anthocyanin in black rice bran. The hydrophilic and pellet fractions showed a protective effect (38-94%) on SH-SY5Y cells insulted by H2O2 in DCFH-DA assay. No extract showed cytotoxicity in the SRB assay. These results suggest a neuroprotective effect of red and black rice brans extracts due to their high antioxidant capacity, along with the absence of cytotoxicity. Thus, they may potentially be used as sources of bioactive compounds.


Assuntos
Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oryza/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Sementes/química , Antocianinas/análise , Antioxidantes , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão/métodos , Ácidos Cumáricos/análise , Glucosídeos/análise , Humanos , Fenóis/análise , Compostos Fitoquímicos/análise , Extratos Vegetais/química
17.
Ecotoxicol Environ Saf ; 162: 603-615, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30031321

RESUMO

Ubiquitous low-dose methylmercury (MeHg) exposure through an increased fish consumption represents a global public health problem, especially among pregnant women. A plethora of micronutrients presented in fish affects MeHg uptake/distribution, but limited data is available. Vitamin A (VitA), another fish micronutrient is used in nutritional supplementation, especially during pregnancy. However, there is no information about the health effects arising from their combined exposure. Therefore, the present study aimed to examine the effects of both MeHg and retinyl palmitate administered on pregnant and lactating rats in metabolic and redox parameters from dams and their offspring. Thirty Wistar female rats were orally supplemented with MeHg (0,5 mg/kg/day) and retinyl palmitate (7500 µg RAE/kg/day) via gavage, either individually or in combination from the gestational day 0 to weaning. For dams (150 days old) and their offspring (31 days old), glycogen accumulation (hepatic and cardiac) and retinoid contents (plasma and liver) were analyzed. Hg deposition in liver tissue was quantified. Redox parameters (liver, kidney, and heart) were evaluated for both animals. Cytogenetic damage was analyzed with micronucleus test. Our results showed no general toxic or metabolic alterations in dams and their offspring by MeHg-VitA co-administration during pregnancy and lactation. However, increased lipoperoxidation in maternal liver and a disrupted pro-oxidant response in the heart of male pups was encountered, with apparently no particular effects in the antioxidant response in female offspring. GST activity in dam kidney was altered leading to possible redox disruption of this tissue with no alterations in offspring. Finally, the genomic damage was exacerbated in both male and female pups. In conclusion, low-dose MeHg exposure and retinyl palmitate supplementation during gestation and lactation produced a potentiated pro-oxidant effect, which was tissue-specific. Although this is a pre-clinical approach, we recommend precaution for pregnant women regarding food consumption, and we encourage more epidemiological studies to assess possible modulations effects of MeHg-VitA co-administration at safe or inadvertently used doses in humans, which may be related to specific pathologies in mothers and their children.


Assuntos
Antioxidantes/farmacologia , Lactação , Compostos de Metilmercúrio/toxicidade , Vitamina A/análogos & derivados , Animais , Animais Recém-Nascidos , Catalase/metabolismo , Suplementos Nutricionais , Diterpenos , Feminino , Glutationa Peroxidase/metabolismo , Glutationa Transferase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Compostos de Metilmercúrio/sangue , Oxirredução/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Vitamina A/sangue , Vitamina A/metabolismo , Vitamina A/farmacologia
18.
Toxicol In Vitro ; 51: 23-33, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29730415

RESUMO

Achyrocline satureioides, popularly known as "marcela", is a medicinal plant found in South America. This plant is rich in flavonoids, which have been reported to exert numerous biological activities. The aim of this study was to purify, identify and evaluate the mechanisms underlining anticancer activity of A. satureioides flavonoids in glioma cell lines (U87, U251 and C6) as well as their comparative toxicity in normal brain cells (primary astrocytes, neurons and organotypic hippocampal cultures). The main flavonoids present in A. satureioides are luteolin, quercetin, 3-O-methyl-quercetin and achyrobichalcone, the later a very unique metabolite present in this plant. Isolated flavonoids as well as A. satureioides extracts reduced proliferation and clonogenic survival, and induced apoptosis of glioma cell lines. In addition, A. satureioides flavonoids potentiated the cytotoxic effect and apoptosis induction by the glioma chemotherapeutic temozolomide (TMZ). Importantly, A. satureioides flavonoids were less cytotoxic to astrocytes, neuron:astrocytes co-cultures and hippocampal cultures if compared to gliomas. Investigation of 10 cancer-related pathways showed a reduced activation of MYC and the Map kinases ERK and JNK by A. satureioides flavonoid-enriched extract, an effect not observed when individual flavonoids were evaluated. Altogether, the herein presented results show that A. satureioides extract possesses a combination of flavonoids, some unique for this plant, which have synergistic anticancer activity and potential for further studies in vivo.


Assuntos
Achyrocline , Antineoplásicos/farmacologia , Flavonoides/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Flores , Glioma/tratamento farmacológico , Glioma/metabolismo , Hipocampo/efeitos dos fármacos , Humanos , Masculino , Neurônios/efeitos dos fármacos , Ratos Wistar
19.
Neurotoxicology ; 66: 98-106, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29588162

RESUMO

Recent evidence shows that aminochrome induces glial activation related to neuroinflammation. This dopamine derived molecule induces formation and stabilization of alpha-synuclein oligomers, mitochondria dysfunction, oxidative stress, dysfunction of proteasomal and lysosomal systems, endoplasmic reticulum stress and disruption of the microtubule network, but until now there has been no evidence of effects on production of cytokines and neurotrophic factors, that are mechanisms involved in neuronal loss in Parkinson's disease (PD). This study examines the potential role of aminochrome on the regulation of NGF, GDNF, TNF-α and IL-1ß production and microglial activation in organotypic midbrain slice cultures from P8 - P9 Wistar rats. We demonstrated aminochrome (25 µM, for 24 h) induced reduction of GFAP expression, reduction of NGF and GDNF mRNA levels, morphological changes in Iba1+ cells, and increase of both TNF-α, IL-1ß mRNA and protein levels. Moreover, aminochrome (25 µM, for 48 h) induced morphological changes in the edge of slices and reduction of TH expression. These results demonstrate neuroinflammation, as well as negative regulation of neurotrophic factors (GDNF and NGF), may be involved in aminochrome-induced neurodegeneration, and they contribute to a better understanding of PD pathogenesis.


Assuntos
Encefalite/induzido quimicamente , Indolquinonas/toxicidade , Mesencéfalo/efeitos dos fármacos , Doença de Parkinson/metabolismo , Animais , Encefalite/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Interleucina-1beta/metabolismo , Mesencéfalo/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fator de Crescimento Neural/metabolismo , Ratos Wistar , Técnicas de Cultura de Tecidos , Fator de Necrose Tumoral alfa/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
20.
J Biochem ; 163(6): 515-523, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29365096

RESUMO

The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor, which activation amplifies and perpetuates inflammatory reactions. RAGE activation also strongly stimulates the production of reactive oxygen species, leading an imbalance of redox cellular state. The extent of liver damage caused by inflammation is crucial to the systemic response during proinflammatory episodes. To investigate the role of RAGE in liver damage caused by systemic inflammation, we evaluated the effect of RAGE blocking in oxidative stress parameters induced by systemic lipopolysaccharide (LPS) injection. Wistar rats received an intraperitoneal injection of RAGE antibody (50 mg/kg), 1 h prior intraperitoneal injection of LPS (5 mg/kg). Twenty-four hours later, the liver was isolated for analysis. The LPS-induced effect in protein oxidative damage, mitochondrial complex II activity, catalase activity, signal transducer and activator of transcription 3 phosphorylation and caspase 3 activation was prevented by prior treatment with RAGE antibody. However, RAGE blocking was not able to inhibit reactive oxygen species production and the impairment in non-enzymatic antioxidant capacity induced by LPS. The present results indicate that RAGE is an important mediator of liver oxidative damage induced by an acute systemic injection of LPS, although other mechanisms may also be responsible for liver function impairment during inflammation.


Assuntos
Anticorpos/imunologia , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Fígado/metabolismo , Estresse Oxidativo , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Receptor para Produtos Finais de Glicação Avançada/imunologia , Animais , Anticorpos/administração & dosagem , Anticorpos/farmacologia , Inflamação/imunologia , Inflamação/metabolismo , Injeções Intraperitoneais , Fígado/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo
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