RESUMO
Pyrrolizidine alkaloids (PAs) are secondary plant metabolites playing an important role as phytotoxins in the plant defense mechanisms and can be present as contaminant in the food of humans and animals. The PA monocrotaline (MCT), one of the major plant derived toxin that affect humans and animals, is present in a high concentration in Crotalaria spp. (Leguminosae) seeds and can induce toxicity after consumption, characterized mainly by hepatotoxicity and pneumotoxicity. However, the effects of the ingestion of MCT in the central nervous system (CNS) are still poorly elucidated. Here we investigated the effects of MCT oral acute administration on the behavior and CNS toxicity in rats. Male adult Wistar were treated with MCT (109 mg/Kg, oral gavage) and three days later the Elevated Pluz Maze test demonstrated that MCT induced an anxiolytic-like effect, without changes in novelty habituation and in operational and spatial memory profiles. Histopathology revealed that the brain of MCT-intoxicated animals presented hyperemic vascular structures in the hippocampus, parahippocampal cortex and neocortex, mild perivascular edema in the neocortex, hemorrhagic focal area in the brain stem, hemorrhage and edema in the thalamus. MCT also induced neurotoxicity in the cortex and hippocampus, as revealed by Fluoro Jade-B and Cresyl Violet staining, as well astrocyte reactivity, revealed by immunocytochemistry for glial fibrillary acidic protein. Additionally, it was demonstrated by RT-qPCR that MCT induced up-regulation on mRNA expression of neuroinflammatory mediator, especially IL1ß and CCL2 in the hippocampus and cortex, and down-regulation on mRNA expression of neurotrophins HGDF and BDNF in the cortex. Together, these results demonstrate that the ingestion of MCT induces cerebrovascular lesions and toxicity to neurons that are associated to astroglial cell response and neuroinflammation in the cortex and hippocampus of rats, highlighting CNS damages after acute intoxication, also putting in perspective it uses as a model for cerebrovascular damage.
Assuntos
Gliose , Monocrotalina , Humanos , Ratos , Animais , Monocrotalina/toxicidade , Monocrotalina/metabolismo , Gliose/induzido quimicamente , Ratos Wistar , Astrócitos/metabolismo , RNA Mensageiro/metabolismoRESUMO
Rutin is an important flavonoid consumed in the daily diet. It is also known as vitamin P and has been extensively investigated due to its pharmacological properties. On the other hand, neuronal death induced by glutamate excitotoxicity is present in several diseases including neurodegenerative diseases. The neuroprotective properties of rutin have been under investigation, although its mechanism of action is still poorly understood. We hypothesized that the mechanisms of neuroprotection of rutin are associated with the increase in glutamate metabolism in astrocytes. This study aimed to evaluate the protective effects of rutin with a focus on the modulation of glutamate detoxification. We used brain organotypic cultures from post-natal Wistar rats (P7-P9) treated with rutin to evaluate neural cell protection and levels of proteins involved in the glutamate metabolism. Moreover, we used cerebral cortex slices from adult Wistar rats to evaluate glutamate uptake. We showed that rutin inhibited the cell death and loss of glutamine synthetase (GS) induced by glutamate that was associated with an increase in glutamate-aspartate transporter (GLAST) in brain organotypic cultures from post-natal Wistar rats. Additionally, it was observed that rutin increased the glutamate uptake in cerebral cortex slices from adult Wistar rats. We conclude that rutin is a neuroprotective agent that prevents glutamate excitotoxicity and thereof suggest that this effect involves the regulation of astrocytic metabolism.
Assuntos
Morte Celular/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Neurônios/efeitos dos fármacos , Rutina/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Transportador 1 de Aminoácido Excitatório , Glutamato-Amônia Ligase/genética , Ácido Glutâmico/toxicidade , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/metabolismo , Neurotoxinas/toxicidade , Ratos , Ratos WistarRESUMO
OBJECTIVE: JM-20, a novel hybrid synthetic molecule, has been reported to have antioxidant, mitoprotective, anti-excitotoxic, anti-apoptotic and anti-inflammatory properties. However, the neuroprotective effect of JM-20 against memory impairment in preclinical AD-like models has not been analyzed. The aim of this study was to evaluate the potential neuroprotection of JM-20 that preserves essential memory process from cholinergic dysfunction and other molecular damages. METHODS: The effects of JM-20 on scopolamine (1 mg/kg)-induced cognitive disorders were studied. Male Wistar rats (220-230 g) were treated with JM-20 and/or scopolamine, and behavioral tasks were performed. The AChE activity, superoxide dismutase activity, catalase activity, MDA and T-SH level on brain tissue were determined by spectrophotometric methods. Mitochondrial functionality parameters were measured after behavioral tests. Histological analyses on hippocampus and prefrontal cortex were processed with hematoxylin and eosin, and neuronal and axonal damage were determined. RESULTS: The behavioral, biochemical and histopathological studies revealed that oral pre-treatment with JM-20 (8 mg/kg) significantly attenuated the scopolamine-induced memory deficits, mitochondrial malfunction, oxidative stress, and prevented AChE hyperactivity probably due to specific inhibition of AChE enzyme. It was also observed marked histological protection on hippocampal and prefrontal-cortex regions. CONCLUSIONS: The multimodal action of this molecule could mediate the memory protection here observed and suggest that it may modulate different pathological aspects of memory deï¬cits associated with AD in humans.
Assuntos
Benzodiazepinas/farmacologia , Inibidores da Colinesterase/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Memória/efeitos dos fármacos , Niacina/análogos & derivados , Nootrópicos/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Memória/fisiologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Niacina/farmacologia , Distribuição Aleatória , Ratos Wistar , EscopolaminaRESUMO
This study was performed to evaluate the bilateral effects of focal permanent ischemia (FPI) on glial metabolism in the cerebral cortex. Two and 9 days after FPI induction, we analyze [18F]FDG metabolism by micro-PET, astrocyte morphology and reactivity by immunohistochemistry, cytokines and trophic factors by ELISA, glutamate transporters by RT-PCR, monocarboxylate transporters (MCTs) by western blot, and substrate uptake and oxidation by ex vivo slices model. The FPI was induced surgically by thermocoagulation of the blood in the pial vessels of the motor and sensorimotor cortices in adult (90 days old) male Wistar rats. Neurochemical analyses were performed separately on both ipsilateral and contralateral cortical hemispheres. In both cortical hemispheres, we observed an increase in tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), and glutamate transporter 1 (GLT-1) mRNA levels; lactate oxidation; and glutamate uptake and a decrease in brain-derived neurotrophic factor (BDNF) after 2 days of FPI. Nine days after FPI, we observed an increase in TNF-α levels and a decrease in BDNF, GLT-1, and glutamate aspartate transporter (GLAST) mRNA levels in both hemispheres. Additionally, most of the unilateral alterations were found only in the ipsilateral hemisphere and persisted until 9 days post-FPI. They include diminished in vivo glucose uptake and GLAST expression, followed by increased glial fibrillary acidic protein (GFAP) gray values, astrocyte reactivity, and glutamate oxidation. Astrocytes presented signs of long-lasting reactivity, showing a radial morphology. In the intact hemisphere, there was a decrease in MCT2 levels, which did not persist. Our study shows the bilateralism of glial modifications following FPI, highlighting the role of energy metabolism adaptations on brain recovery post-ischemia.
Assuntos
Adaptação Fisiológica/fisiologia , Isquemia Encefálica/metabolismo , Córtex Cerebral/metabolismo , Neuroglia/metabolismo , Animais , Isquemia Encefálica/patologia , Córtex Cerebral/patologia , Transportador 1 de Aminoácido Excitatório/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Masculino , Neuroglia/patologia , Ratos , Ratos WistarRESUMO
Astrocytes are dynamic glial cells associated to neurotransmitter systems, metabolic functions, antioxidant defense, and inflammatory response, maintaining the brain homeostasis. Elevated concentrations of homocysteine (Hcy) are involved in the pathogenesis of age-related neurodegenerative disorders, such as Parkinson and Alzheimer diseases. In line with this, our hypothesis was that Hcy could promote glial reactivity in a model of cortical primary astrocyte cultures from adult Wistar rats. Thus, cortical astrocytes were incubated with different concentrations of Hcy (10, 30, and 100 µM) during 24 h. After the treatment, we analyzed cell viability, morphological parameters, antioxidant defenses, and inflammatory response. Hcy did not induce any alteration in cell viability; however, it was able to induce cytoskeleton rearrangement. The treatment with Hcy also promoted a significant decrease in the activities of Na+, K+ ATPase, superoxide dismutase (SOD), and glutathione peroxidase (GPx), as well as in the glutathione (GSH) content. Additionally, Hcy induced an increase in the pro-inflammatory cytokine release. In an attempt to elucidate the putative mechanisms involved in the Hcy-induced glial reactivity, we measured the nuclear factor kappa B (NFκB) transcriptional activity and heme oxygenase 1 (HO-1) expression, which were activated and inhibited by Hcy, respectively. In summary, our findings provide important evidences that Hcy modulates critical astrocyte parameters from adult rats, which might be associated to the aging process.
Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Homocisteína/toxicidade , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Fatores Etários , Animais , Antioxidantes/metabolismo , Astrócitos/patologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Relação Dose-Resposta a Droga , Mediadores da Inflamação/metabolismo , Masculino , Neuroglia/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos WistarRESUMO
Zika virus (ZIKV) has become a major challenge for scientists and health agencies. ZIKV's involvement with human fetal microcephaly and Guillain-Barré syndrome and its transmission through Aedes africanus and Aedes aegypti mosquitos highlighted the epidemiological and neurological risks associated to ZIKV infection. In 2013, ZIKV arrives in Brazil but the first outbreak in the country was reported in 2015. Here, we used the Web of Science as a search tool for comparing the evolution of world and Brazilian scientific research on dengue virus (DENV)-also present in mosquito-, ZIKV and microcephaly. The association between ZIKV and microcephaly was only evidenced in 2015. Interestingly, Brazil and the USA are the responsible for most of these reports. Furthermore, the level of double-counted articles indicates a high degree of international collaborative effort in studying ZIKV and microcephaly. The ZIKV research clearly requires multidisciplinary expertise including epidemiologic, clinical, virological, and neurochemical backgrounds. This letter intends to emphasize the need of multidisciplinary studies and put forward some as yet unanswered questions in attempting to contribute to the understanding of this multifaceted health problem. In line with this, we recently constituted a collaborative and multidisciplinary taskforce encompassing eight Brazilian scientific institutions of excellence, The ZIKV translational research taskforce. This taskforce comprises a vast international network of collaborators and welcomes additional collaborators. We intend to advance fast in terms of mechanisms, which can potentially contribute to treat or halt ZIKV spreading around the world.
Assuntos
Infecção por Zika virus , Zika virus , Animais , Brasil , Surtos de Doenças , Humanos , Neurociências , Pesquisa Translacional BiomédicaRESUMO
OBJECTIVES: Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a polyglutamine disorder with no current disease-modifying treatment. Conformational changes in mutant ataxin-3 trigger different pathogenic cascades, including reactive oxygen species (ROS) generation; however, the clinical relevance of oxidative stress elements as peripheral biomarkers of SCA3/MJD remains unknown. We aimed to evaluate ROS production and antioxidant defense capacity in symptomatic and presymptomatic SCA3/MJD individuals and correlate these markers with clinical and molecular data with the goal of assessing their properties as disease biomarkers. METHODS: Molecularly confirmed SCA3/MJD carriers and controls were included in an exploratory case-control study. Serum ROS, measured by 2',7'-dichlorofluorescein diacetate (DCFH-DA) as well as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) antioxidant enzyme activities, levels were assessed. RESULTS: Fifty-eight early/moderate stage symptomatic SCA3/MJD, 12 presymptomatic SCA3/MJD, and 47 control individuals were assessed. The DCFH-DA levels in the symptomatic group were 152.82 nmol/mg of protein [95% confidence interval (CI), 82.57-223.08, p < 0.001] higher than in the control and 243.80 nmol/mg of protein (95% CI, 130.64-356.96, p < 0.001) higher than in the presymptomatic group. The SOD activity in the symptomatic group was 3 U/mg of protein (95% CI, 0.015-6.00, p = 0.048) lower than in the presymptomatic group. The GSH-Px activity in the symptomatic group was 13.96 U/mg of protein (95% CI, 5.90-22.03, p < 0.001) lower than in the control group and 20.52 U/mg of protein (95% CI, 6.79-34.24, p < 0.001) lower than in the presymptomatic group and was inversely correlated with the neurological examination score for spinocerebellar ataxias (R = -0.309, p = 0.049). CONCLUSION: Early/moderate stage SCA3/MJD patients presented a decreased antioxidant capacity and increased ROS generation. GSH-Px activity was the most promising oxidative stress disease biomarker in SCA3/MJD. Further longitudinal studies are necessary to identify both the roles of redox parameters in SCA3/MJD pathophysiology and as surrogate outcomes for clinical trials.
RESUMO
OBJECTIVE: Scopolamine (SCO) administration to rats induces molecular features of AD and other dementias, including impaired cognition, increased oxidative stress, and imbalanced cholinergic transmission. Although mitochondrial dysfunction is involved in different types of dementias, its role in cognitive impairment induced by SCO has not been well elucidated. The aim of this work was to evaluate the in vivo effect of SCO on different brain mitochondrial parameters in rats to explore its neurotoxic mechanisms of action. METHODS: Saline (Control) or SCO (1 mg/kg) was administered intraperitoneally 30 min prior to neurobehavioral and biochemical evaluations. Novel object recognition and Y-maze paradigms were used to evaluate the impact on memory, while redox profiles in different brain regions and the acetylcholinesterase (AChE) activity of the whole brain were assessed to elucidate the amnesic mechanism of SCO. Finally, the effects of SCO on brain mitochondria were evaluated both ex vivo and in vitro, the latter to determine whether SCO could directly interfere with mitochondrial function. RESULTS: SCO administration induced memory deficit, increased oxidative stress, and increased AChE activities in the hippocampus and prefrontal cortex. Isolated brain mitochondria from rats administered with SCO were more vulnerable to mitochondrial swelling, membrane potential dissipation, H2O2 generation and calcium efflux, all likely resulting from oxidative damage. The in vitro mitochondrial assays suggest that SCO did not affect the organelle function directly. CONCLUSION: In conclusion, the present results indicate that SCO induced cognitive dysfunction and oxidative stress may involve brain mitochondrial impairment, an important target for new neuroprotective compounds against AD and other dementias.
Assuntos
Transtornos da Memória/metabolismo , Mitocôndrias/metabolismo , Acetilcolinesterase/metabolismo , Animais , Encéfalo/metabolismo , Cálcio/metabolismo , Cátions Bivalentes/metabolismo , Modelos Animais de Doenças , Peróxido de Hidrogênio/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Potencial da Membrana Mitocondrial/fisiologia , Dilatação Mitocondrial/fisiologia , Estresse Oxidativo/fisiologia , Distribuição Aleatória , Ratos Wistar , Reconhecimento Psicológico/fisiologia , EscopolaminaRESUMO
Diabetes mellitus (DM) causes important modifications in the availability and use of different energy substrates in various organs and tissues. Similarly, dietary manipulations such as high fat diets also affect systemic energy metabolism. However, how the brain adapts to these situations remains unclear. To investigate these issues, control and alloxan-induced type I diabetic rats were fed either a standard or a high fat diet enriched with advanced glycation end products (AGEs) (HAGE diet). The HAGE diet increased their levels of blood ketone bodies, and this effect was exacerbated by DM induction. To determine the effects of diet and/or DM induction on key cerebral bioenergetic parameters, both ketone bodies (ß-hydroxybutyric acid) and lactate oxidation were measured. In parallel, the expression of Monocarboxylate Transporter 1 (MCT1) and 2 (MCT2) isoforms in hippocampal and cortical slices from rats submitted to these diets was assessed. Ketone body oxidation increased while lactate oxidation decreased in hippocampal and cortical slices in both control and diabetic rats fed a HAGE diet. In parallel, the expression of both MCT1 and MCT2 increased only in the cerebral cortex in diabetic rats fed a HAGE diet. These results suggest a shift in the preferential cerebral energy substrate utilization in favor of ketone bodies in animals fed a HAGE diet, an effect that, in DM animals, is accompanied by the enhanced expression of the related transporters.
RESUMO
Elevated plasma homocysteine (Hcy) levels have been detected in patients with various neurodegenerative conditions. Studies of brain tissue have revealed that hyperhomocysteinemia may impair energy metabolism, resulting in neuronal damage. In addition, new evidence has indicated that vitamin D plays crucial roles in brain development, brain metabolism and neuroprotection. The aim of this study was to investigate the neuroprotective effects of 1,25-dihydroxivitamin D3 (calcitriol) in cerebral cortex slices that were incubated with a mild concentration of Hcy. Cerebral cortex slices from adult rats were first pre-treated for 30 min with one of three different concentrations of calcitriol (50 nM, 100 nM and 250 nM), followed by Hcy for 1h to promote cellular dysfunction. Hcy caused changes in bioenergetics parameters (e.g., respiratory chain enzymes) and mitochondrial functions by inducing changes in mitochondrial mass and swelling. Here, we used flow cytometry to analyze neurons that were double-labelled with Propidium Iodide (PI) and found that Hcy induced an increase in NeuN(+)/PI cells but did not affect GFAP(+)/Pi cells. Hcy also induced oxidative stress by increasing reactive oxygen species generation, lipid peroxidation and protein damage and reducing the activity of antioxidant enzymes (e.g., SOD, CAT and GPx). Calcitriol (50 nM) prevented these alterations by increasing the level of the vitamin D receptor. Our findings suggest that using calcitriol may be a therapeutic strategy for treating the cerebral complications caused by Hcy.
Assuntos
Calcitriol/farmacologia , Córtex Cerebral/efeitos dos fármacos , Homocisteína/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Antioxidantes/metabolismo , Relação Dose-Resposta a Droga , Complexo II de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Citometria de Fluxo , Proteína Glial Fibrilar Ácida/metabolismo , Técnicas In Vitro , Masculino , Fosfopiruvato Hidratase/metabolismo , Propídio/metabolismo , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
Lesions with great loss of skin and extensive burns are usually treated with heterologous skin grafts, which may lead rejection. Cell therapy with mesenchymal stem cells is arising as a new proposal to accelerate the healing process. We tested a new therapy consisting of sodium carboxymethylcellulose (CMC) as a biomaterial, in combination with adipose-derived stem cells (ADSCs), to treat skin lesions in an in vivo rat model. This biomaterial did not affect membrane viability and induced a small and transient genotoxicity, only at the highest concentration tested (40 mg/mL). In a rat wound model, CMC at 10 mg/mL associated with ADSCs increased the rate of cell proliferation of the granulation tissue and epithelium thickness when compared to untreated lesions (Sham), but did not increase collagen fibers nor alter the overall speed of wound closure. Taken together, the results show that the CMC is capable to allow the growth of ADSCs and is safe for this biological application up to the concentration of 20 mg/mL. These findings suggest that CMC is a promising biomaterial to be used in cell therapy.
Assuntos
Carboximetilcelulose Sódica/farmacologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/efeitos dos fármacos , Pele/lesões , Ferimentos e Lesões/terapia , Tecido Adiposo/citologia , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células Cultivadas , Colágeno/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Queratinas/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Ratos Wistar , Pele/metabolismo , Pele/fisiopatologia , Engenharia Tecidual/métodos , Alicerces Teciduais/química , Cicatrização , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/fisiopatologiaRESUMO
INTRODUCTION: In this study we examined oxidative stress and skeletal muscle damage resulting from acute strength, aerobic, or concurrent exercise in rats. METHODS: The animals were divided into control (C), strength (SE), aerobic (AE), and combined (CE) exercise groups. They were euthanized at 3 different time-points (6, 24, and 48 h) after acute exercise. RESULTS: SE exercise rats had increased dichlorofluorescein oxidation at 6 h post-exercise and decreased superoxide dismutase activity at all time-points. Glutathione peroxidase activity and sulfhydryl levels were increased in the AE group at 48 h post-exercise. Serum lactate dehydrogenase activity was increased in the SE and CE groups at 24 h and in the AE group at 48 h. Echo intensity was elevated at 24 h for all groups. CONCLUSIONS: Forty-eight hours was sufficient for complete recovery from oxidative stress and muscle damage in the SE and CE groups, but not in the AE group.
Assuntos
Força Muscular/fisiologia , Músculo Esquelético/lesões , Condicionamento Físico Animal/fisiologia , Aerobiose , Animais , Catalase/metabolismo , Fluoresceínas , Corantes Fluorescentes , Glutationa Peroxidase/metabolismo , L-Lactato Desidrogenase/metabolismo , Masculino , Músculo Esquelético/diagnóstico por imagem , Oxirredução , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Treinamento Resistido , Compostos de Sulfidrila/metabolismo , Superóxido Dismutase/metabolismo , UltrassonografiaRESUMO
Long-chain polyunsaturated n-3 fatty acids (n-3 LCPUFAs) have hypolipidemic effects and modulate intermediary metabolism to prevent or reverse insulin resistance in a way that is not completely elucidated. Here, effects of these fatty acids on the lipid profile, phosphoenolpyruvate carboxykinase (PEPCK) activity, lipid synthesis from glucose in epididymal adipose tissue (Ep-AT) and liver were investigated. Male rats were fed a high-sucrose diet (SU diet), containing either sunflower oil or a mixture of sunflower and fish oil (SU-FO diet), and the control group was fed a standard diet. After 13 weeks, liver, adipose tissue and blood were harvested and analysed. The dietary n-3 LCPUFAs prevented sucrose-induced increase in adiposity and serum free fat acids, serum and hepatic triacylglycerol and insulin levels. Furthermore, these n-3 LCPUFAs decreased lipid synthesis from glucose and increased PEPCK activity in the Ep-AT of rats fed the SU-FO diet compared to those fed the SU diet, besides reducing lipid synthesis from glucose in hepatic tissue. Thus, the inclusion of n-3 LCPUFAs in the diet may be beneficial for the prevention or attenuation of dyslipidemia and insulin resistance, and for reducing the risk of related chronic diseases.
Assuntos
Tecido Adiposo/metabolismo , Sacarose Alimentar/administração & dosagem , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/farmacologia , Glucose/metabolismo , Lipídeos/biossíntese , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Tecido Adiposo/efeitos dos fármacos , Animais , Sacarose Alimentar/farmacologia , Suplementos Nutricionais , Ativação Enzimática/efeitos dos fármacos , Glucose/química , Masculino , Ratos , Ratos WistarRESUMO
The present study investigated the effects of chronic hyperprolinemia on oxidative and metabolic status in liver and serum of rats. Wistar rats received daily subcutaneous injections of proline from their 6th to 28th day of life. Twelve hours after the last injection the rats were sacrificed and liver and serum were collected. Results showed that hyperprolinemia induced a significant reduction in total antioxidant potential and thiobarbituric acid-reactive substances. The activities of the antioxidant enzymes catalase and superoxide dismutase were significantly increased after chronic proline administration, while glutathione (GSH) peroxidase activity, dichlorofluorescin oxidation, GSH, sulfhydryl, and carbonyl content remained unaltered. Histological analyses of the liver revealed that proline treatment induced changes of the hepatic microarchitecture and increased the number of inflammatory cells and the glycogen content. Biochemical determination also demonstrated an increase in glycogen concentration, as well as a higher synthesis of glycogen in liver of hyperprolinemic rats. Regarding to hepatic metabolism, it was observed an increase on glucose oxidation and a decrease on lipid synthesis from glucose. However, hepatic lipid content and serum glucose levels were not changed. Proline administration did not alter the aminotransferases activities and serum markers of hepatic injury. Our findings suggest that hyperprolinemia alters the liver homeostasis possibly by induction of a mild degree of oxidative stress and metabolic changes. The hepatic alterations caused by proline probably do not implicate in substantial hepatic tissue damage, but rather demonstrate a process of adaptation of this tissue to oxidative stress. However, the biological significance of these findings requires additional investigation.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/induzido quimicamente , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Fígado/metabolismo , Estresse Oxidativo , Prolina/administração & dosagem , 1-Pirrolina-5-Carboxilato Desidrogenase/deficiência , Animais , Antioxidantes/análise , Glicemia/análise , Catalase/metabolismo , Feminino , Fluoresceínas/metabolismo , Glutationa/análise , Glutationa Peroxidase/metabolismo , Glicogênio/biossíntese , Lipídeos/biossíntese , Masculino , Prolina Oxidase/deficiência , Prolina Oxidase/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/análiseRESUMO
Ω3-Polyunsaturated fatty acids (Ω3-PUFAs) are known to act as hypolipidaemics, but the literature is unclear about the effects that Ω3-PUFAs have on oxidative stress in obese and diabetic patients. In this study, our aim was to investigate the effects of Ω3-PUFAs on oxidative stress, including antioxidant enzyme activity and hepatic lipid and glycogen metabolism in the livers of diabetic and non-diabetic rats fed on a high fat thermolyzed diet. Rats were divided into six groups: (1) the control group (C), (2) the control diabetic group (D), (3) the high fat thermolyzed diet group (HFTD), which were fed a diet that was enriched in fat that was heated for 60 min at 180°C, (4) the high fat thermolyzed diet diabetic group (D + HFTD), (5) the high fat thermolyzed diet + Ω3 polyunsaturated fatty acid group (HFTD + Ω3), and (6) the high fat thermolyzed diet + Ω3 polyunsaturated fatty acid diabetic group (D + HFTD + Ω3). The most important finding of this study was that Ω3-PUFAs are able to reduce triglycerides, non-esterified fatty acid, lipoperoxidation levels, advanced glycation end products, SOD/CAT enzymatic ratio, and CAT immunocontent and increase SOD2 levels in the livers of diabetic rats fed with a HFTD. However, Ω3-PUFAs did not alter the observed levels of protein damage, blood glucose, or glycogen metabolism in the liver. These findings suggest that Ω3-PUFAs may represent an important auxiliary adjuvant in combating some diseases like diabetes mellitus, insulin resistance, and non-alcoholic fatty liver disease.
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Diabetes Mellitus Experimental/metabolismo , Ácidos Graxos Ômega-3/administração & dosagem , Glicogênio/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos , Fígado/metabolismo , Adiposidade , Animais , Catalase/metabolismo , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/fisiopatologia , Dieta Hiperlipídica , Produtos Finais de Glicação Avançada/sangue , Fígado/enzimologia , Fígado/fisiopatologia , Lisina/análogos & derivados , Lisina/sangue , Masculino , Estresse Oxidativo , Carbonilação Proteica , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Nutrition during pregnancy and lactation can program an offspring's metabolism with regard to glucose and lipid homeostasis. A suboptimal environment during fetal, neonatal and infant development is associated with impaired glucose tolerance, type 2 diabetes and insulin resistance in later adult life. However, studies on the effects of a low protein diet imposed from the beginning of gestation until adulthood are scarce. This study's objective was to investigate the effects of a low protein diet imposed from the gestational period until 4 months of age on the parameters of glucose tolerance and insulin responsiveness in Wistar rats. The rats were divided into a low protein diet group and a control group and received a diet with either 7% or 25% protein, respectively. After birth, the rats received the same diet as their mothers, until 4 months of age. In the low protein diet group it was observed that: (i) the hepatic glycogen concentration and hepatic glycogen synthesis from glycerol were significantly greater than in the control group; (ii) the disposal of 2-deoxyglucose in soleum skeletal muscle slices was 29.8% higher than in the control group; (iii) there was both a higher glucose tolerance in the glucose tolerance test; and (iv) a higher insulin responsiveness in than in the control group. The results suggest that the low protein diet animals show higher glucose tolerance and insulin responsiveness relative to normally nourished rats. These findings were supported by the higher hepatic glycogen synthesis and the higher disposal of 2-deoxyglucose in soleum skeletal muscle found in the low protein diet rats.
Assuntos
Envelhecimento/metabolismo , Resistência à Insulina , Complicações na Gravidez/metabolismo , Deficiência de Proteína/metabolismo , Animais , Desoxiglucose/metabolismo , Proteínas Alimentares , Feminino , Idade Gestacional , Teste de Tolerância a Glucose , Glicerol/metabolismo , Glicogênio/biossíntese , Lactação/metabolismo , Fígado/metabolismo , Masculino , Músculo Esquelético/metabolismo , Gravidez , Ratos , Ratos WistarRESUMO
Many studies have demonstrated that DNA damage may be associated with type 2 diabetes mellitus (T2DM) and its complications. The goal of this study was to evaluate the effects of the potential relationship between fat (thermolyzed) intake, glucose dyshomeostasis and DNA injury in rats. Biochemical parameters related to glucose metabolism (i.e., blood glucose levels, insulin tolerance tests, glucose tolerance tests and fat cell glucose oxidation) and general health parameters (i.e., body weight, retroperitoneal and epididymal adipose tissue) were evaluated in rats after a 12-month treatment with either a high fat or a high thermolyzed fat diet. The high fat diet (HFD) and high fat thermolyzed diet (HFTD) showed increased body weight and impaired insulin sensitivity at the studied time-points in insulin tolerance test (ITT) and glucose tolerance test (GTT). Interestingly, only animals subjected to the HFTD diet showed decreased epididymal fat cell glucose oxidation. We show which high fat diets have the capacity to reduce glycogen synthesis by direct and indirect pathways. HFTD promoted an increase in lipid peroxidation in the liver, demonstrating significant damage in lipids in relation to other groups. Blood and hippocampus DNA damage was significantly higher in animals subjected to HFDs, and the highest damage was observed in animals from the HFTD group. Striatum DNA damage was significantly higher in animals subjected to HFDs, compared with the control group. These results show a positive correlation between high fat diet, glucose dyshomeostasis, oxidative stress and DNA damage.
Assuntos
Dano ao DNA , Gorduras na Dieta/farmacologia , Resistência à Insulina , Temperatura , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Gorduras na Dieta/administração & dosagem , Glucose/metabolismo , Teste de Tolerância a Glucose , Glicogênio/biossíntese , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Oxirredução/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
In the present study we evaluated the effect of chronic methionine administration on oxidative stress and biochemical parameters in liver and serum of rats, respectively. We also performed histological analysis in liver. Results showed that hypermethioninemia increased chemiluminescence, carbonyl content and glutathione peroxidase activity, decreased total antioxidant potential, as well as altered catalase activity. Hypermethioninemia increased synthesis and concentration of glycogen, besides histological studies showed morphological alterations and reduction in the glycogen/glycoprotein content in liver. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and glucose were increased in hypermethioninemic rats. These findings suggest that oxidative damage and histological changes caused by methionine may be related to the hepatic injury observed in hypermethioninemia.
Assuntos
Fígado/efeitos dos fármacos , Fígado/patologia , Metionina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Glutationa/metabolismo , Glicogênio/biossíntese , Humanos , Fígado/enzimologia , Fígado/metabolismo , Luminescência , Metionina/administração & dosagem , Ratos , Ratos Wistar , Compostos de Sulfidrila/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
The aim of this study was to investigate the potential relationship between hypothyroidism and delta-aminolevulinate dehydratase (delta-ALA-D) activity in rat blood and liver. Experimental hypothyroidism was induced in weanling rats by exposing their mothers to propylthiouracil (PTU) diluted in tap water (0.05% w/ v), ad libitum, during the lactational period (PTU group). Control (euthyroid) group included weanling rats whose mothers received just tap water, ad libitum, during the lactational period. Reverted-hypothyroid group (PTU + 3,3',5-triiodo-L-thyronine [T(3)]) included weanling rats whose mothers were exposed to PTU similarly to those in the hypothyroid group, but pups received daily subcutaneous injections of T(3) (20 microg/kg, from Postnatal Days 2-20). After the treatment, serum T(3) levels were drastically decreased (around 70%) in the PTU group, and this phenomenon was almost reverted by exogenous T(3). PTU decreased blood delta-ALA-D activity by 75%, and T(3) treatment prevented such phenomena. Erythrocytes and hemoglobin levels were increased by 10% in PTU-treated animals and higher increments (around 25%) were observed in these parameters when exogenous T(3) was coadministered. Dithiothreitol did not change blood delta-ALA-D activity of PTU-exposed animals when present in the reaction medium, suggesting no involvement of the enzyme's essential thiol groups in PTU-induced delta-ALA-D inhibition. PTU did not affect blood delta-ALA-D activity in vitro. These results are the first to show a correlation between hypothyroidism and decreased delta-ALA-D activity and point to this enzyme as a potential molecule involved with hypothyroidism-related hematological changes.