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1.
PLoS One ; 15(8): e0231234, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804947

RESUMO

Cardiometabolic syndrome has become a global health issue. Heart failure is a common comorbidity of cardiometabolic syndrome. Successful drug development to prevent cardiometabolic syndrome and associated comorbidities requires preclinical models predictive of human conditions. To characterize the heart failure component of cardiometabolic syndrome, cardiometabolic, metabolic, and renal biomarkers were evaluated in lean and obese ZSF1 19- to 32-week-old male rats. Histopathological assessment of kidneys and hearts was performed. Cardiac function, exercise capacity, and left ventricular gene expression were also analyzed. Obese ZSF1 rats exhibited multiple features of human cardiometabolic syndrome by pathological changes in systemic renal, metabolic, and cardiovascular disease circulating biomarkers. Hemodynamic assessment, echocardiography, and decreased exercise capacity confirmed heart failure with preserved ejection fraction. RNA-seq results demonstrated changes in left ventricular gene expression associated with fatty acid and branched chain amino acid metabolism, cardiomyopathy, cardiac hypertrophy, and heart failure. Twelve weeks of growth differentiation factor 15 (GDF15) treatment significantly decreased body weight, food intake, blood glucose, and triglycerides and improved exercise capacity in obese ZSF1 males. Systemic cardiovascular injury markers were significantly lower in GDF15-treated obese ZSF1 rats. Obese ZSF1 male rats represent a preclinical model for human cardiometabolic syndrome with established heart failure with preserved ejection fraction. GDF15 treatment mediated dietary response and demonstrated a cardioprotective effect in obese ZSF1 rats.


Assuntos
Fator 15 de Diferenciação de Crescimento/metabolismo , Fator 15 de Diferenciação de Crescimento/farmacologia , Síndrome Metabólica/metabolismo , Animais , Biomarcadores/metabolismo , Coração/fisiologia , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/fisiopatologia , Rim/metabolismo , Masculino , Síndrome Metabólica/complicações , Miocárdio/metabolismo , Obesidade/complicações , Ratos , Ratos Endogâmicos , Ratos Zucker , Volume Sistólico/fisiologia , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologia
2.
J Oleo Sci ; 69(7): 771-782, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32522946

RESUMO

The role of fish oil, primrose oil and their mixture in ameliorating the changes in Alzheimer's like model was evaluated in rats. Primrose oil and primrose/fish oil mixture fatty acids composition was assessed by gas chromatography. The rat experiment consisted of 5 groups; the first fed on balanced diet as control normal (CN); the other four groups treated with intraperitoneal aluminum lactate and consumed dyslipidemic diet; one group served as control Alzheimer's like disease (CA) while the other three groups (test groups) received daily oral dose from primrose oil, fish oil and primrose/fish oil mixture separately for 5 weeks. Results showed primrose oil and primrose/ fish oil mixture to contain gamma linolenic acid as 9.15 and 4.3% of total fatty acids, respectively. Eicosapentaenoic and docosahexaenoic were present as 10.9 and 6.5 %, respectively in the oil mixture. Dyslipidemia and increased erythrocyte sedimentation rate (ESR), plasma butyrylcholinesterase (BChE), brain malondialdehyde (MDA) and NO with decrease in plasma magnesium, brain catalase, reduced glutathione, body weight gain and brain weight were demonstrated in CA compared to CN. Brain histopathology and immuno-histochemistry showed neuronal degeneration and neurofibrillary tangles with elevated myeloperoxidase and nuclear factor-kappa B in CA compared to CN. The tested oils demonstrated neuro-protection reflected in the variable significant improvement of biochemical parameters, immuno-histochemistry and brain histopathology. Primrose/fish oil mixture was superior in reducing ESR, brain MDA, plasma activity of BChE and brain histopathological changes along with elevating plasma magnesium. Primrose/fish oil mixture and fish oil were more promising in improving plasma high density lipoprotein cholesterol (HDL-C) than primrose. Fish oil was the most efficient in improving plasma total cholesterol (T-C), low density lipoprotein cholesterol and T-C /HDL-C. Primrose/fish oil mixture and primrose oil were superior in elevating brain catalase compared to fish oil. Other parameters were equally improved by the different oil treatments. Primrose oil, fish oil and their mixture reduced the progression of Alzheimer's disease in rats with superiority to primrose/fish oil mixture.


Assuntos
Compostos de Alumínio/efeitos adversos , Doença de Alzheimer/prevenção & controle , Doença de Alzheimer/terapia , Óleos de Peixe/administração & dosagem , Lactatos/efeitos adversos , Óleos Vegetais/administração & dosagem , Primula , Ácido gama-Linolênico/análise , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Butirilcolinesterase/metabolismo , Catalase/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Progressão da Doença , Ácidos Docosa-Hexaenoicos/análise , Ácido Eicosapentaenoico/análise , Óleos de Peixe/química , Masculino , Malondialdeído/metabolismo , Óleos Vegetais/química , Ratos , Ratos Endogâmicos
3.
Int J Mol Sci ; 21(6)2020 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32245205

RESUMO

Hepatocellular carcinoma (HCC) is the strongest independent predictor of mortality in non-alcoholic steatohepatitis (NASH)-related cirrhosis. The effects and mechanisms of combination of sodium-dependent glucose cotransporter inhibitor and canagliflozin (CA) and dipeptidyl peptidase-4 inhibitor and teneligliptin (TE) on non-diabetic NASH progression were examined. CA and TE suppressed choline-deficient, L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. CA alone or with TE significantly decreased proinflammatory cytokine expression. CA and TE significantly attenuated hepatic lipid peroxidation. In vitro studies showed that TE alone or with CA inhibited cell proliferation and TGF-ß1 and α1 (I)-procollagen mRNA expression in Ac-HSCs. CA+TE inhibited liver fibrogenesis by attenuating hepatic lipid peroxidation and inflammation and by inhibiting Ac-HSC proliferation with concomitant attenuation of hepatic lipid peroxidation. Moreover, CA+TE suppressed in vivo angiogenesis and oxidative DNA damage. CA or CA+TE inhibited HCC cells and human umbilical vein endothelial cell (HUVEC) proliferation. CA+TE suppressed vascular endothelial growth factor expression and promoted increased E-cadherin expression in HUVECs. CA+TE potentially exerts synergistic effects on hepatocarcinogenesis prevention by suppressing HCC cell proliferation and angiogenesis and concomitantly reducing oxidative stress and by inhibiting angiogenesis with attenuation of oxidative stress. CA+TE showed chemopreventive effects on NASH progression compared with single agent in non-diabetic rat model of NASH, concurrent with Ac-HSC and HCC cell proliferation, angiogenesis oxidative stress, and inflammation. Both agents are widely, safely used in clinical practice; combined treatment may represent a potential strategy against NASH.


Assuntos
Canagliflozina/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pirazóis/farmacologia , Tiazolidinas/farmacologia , Animais , Caderinas/genética , Caderinas/metabolismo , Canagliflozina/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinoma Hepatocelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Citocinas/metabolismo , Dano ao DNA/efeitos dos fármacos , Progressão da Doença , Sinergismo Farmacológico , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Pirazóis/uso terapêutico , Ratos , Ratos Endogâmicos , Tiazolidinas/uso terapêutico , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Int Immunopharmacol ; 81: 106283, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32044655

RESUMO

BACKGROUND: Rheumatoid arthritis (RA), a primary chronic articular disease with wide range of extra-articular and systemic effects. The spleen is one of the most affected organs in RA. CD4+ T cells play an important role in initiation, maintenance and control of the disease. AIM OF THE WORK: This work was designed to study the histological changes occurring in the spleen in a rat model of RA and to assess the effect of treatment with omega-3 alone, with special refer to the role of CD4+ T-cells. MATERIALS AND METHODS: Thirty male albino rats were divided into four groups; control group, early and progressive RA groups and omega-3 treated group. RA was induced in rats of groups II, III and IV by a single subcutaneous injection of complete Freund's adjuvant (CFA). Samples were taken after two and four weeks of the CFA injection (in early and progressive RA groups respectively). Treatment with omega-3 (300 mg/kg/day in a single, daily oral dose) started two weeks after CFA injection in rats of group IV and continued for another two weeks. Spleen specimens were collected at the appropriate times and processed to obtain paraffin blocks. Sections were then stained for histological and immunofluorescence studies. RESULTS: Both, early and progressive RA induced noticeable structural changes in the spleen. Thickened capsule and trabeculae and marked congestion of the blood sinusoids of the red pulp were evident. Expansion of the white pulp and areas of mononuclear cellular infiltration were seen, especially in progressive RA. Affection of blood vessel walls was also noticed. Immunofluorescence study showed extensive expression of Anti-CD4 Monoclonal Antibodies especially in progressive RA. Treatment with omega-3 significantly improved the structure of the spleen as detected by both histological and immunofluorescence studies. CONCLUSION: Omega-3 treatment ameliorated the structural damage of the spleen caused by experimental induction of RA.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Experimental/terapia , Artrite Reumatoide/terapia , Linfócitos T CD4-Positivos/imunologia , Ácidos Graxos Ômega-3/uso terapêutico , Baço/patologia , Animais , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Progressão da Doença , Imunofluorescência , Adjuvante de Freund , Humanos , Masculino , Metotrexato/uso terapêutico , Ratos , Ratos Endogâmicos
5.
Phytomedicine ; 67: 153158, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31999981

RESUMO

Background Shengui Sansheng Pulvis (SSP) has about 300 years history used for stroke treatment, and evidences suggest it has beneficial effects on neuro-angiogenesis and cerebral energy metabolic amelioration post-stroke. However, its protective action and mechanisms on blood-brain barrier (BBB) is still unknown. Purpose Based on multiple neuroprotective properties of vasoactive intestinal peptide (VIP) in neurological disorders, we investigate if SSP maintaining BBB integrity is associated with VIP pathway in rat permanent middle cerebral artery occlusion (MCAo) model. Methods Three doses of SSP extraction were administered orally. Evaluations of motor and balance abilities and detection of brain edema were performed, and BBB permeability were assessed by Evans blue (EB) staining. Primary brain microvascular endothelial cells (BMECs) were subjected to oxygen-glucose deprivation, and incubated with high dose SSP drug-containing serum and VIP-antagonist respectively. Transendothelial electrical resistance (TEER) assay and Tetramethylrhodamine isothiocyanate (TRITC)-dextran (4.4 kDa) and fluorescein isothiocyanate (FITC)-dextran (70 kDa) were used to evaluate the features of paracellular junction. Western blot detected the expressions of Claudin-5, ZO-1, Occludin and VE-cadherin, matrix metalloproteinase (MMP) 2/9 and VIP receptors 1/2, and immunofluorescence staining tested VIP and Claudin-5 expressions. Results Our results show that SSP significantly reduces EB infiltration in dose-dependent manner in vivo and attenuates TRITC- dextran and FITC-dextran diffusion in vitro, and strengthens endothelial junctional complexes as represented by decreasing Claudin-5, ZO-1, Occludin and VE-cadherin degradations and MMP 2/9 expression, as well as promoting TEER in BMECs after ischemia. Moreover, it suggests that SSP notably enhances VIP and its receptors 1/2 expressions. VIP-antagonist exacerbates paracellular barrier of BMECs, while the result is reversed after incubation with high dose SSP drug-containing serum. Additionally, SSP also improve brain edema and motor and balance abilities after ischemic stroke. Conclusions we firstly demonstrate that the ameliorated efficacy of SSP on BBB permeability is related to the enhancements of VIP and its receptors, suggesting SSP might be an effective therapeutic agent on maintaining BBB integrity post-stroke.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Claudina-5/metabolismo , Medicamentos de Ervas Chinesas/química , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Permeabilidade , Ratos Endogâmicos , Receptores Tipo II de Peptídeo Intestinal Vasoativo/metabolismo , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/metabolismo , Acidente Vascular Cerebral/fisiopatologia
6.
Biosci. j. (Online) ; 36(1): 245-255, jan./feb. 2020. tab, ilus
Artigo em Inglês | LILACS | ID: biblio-1049246

RESUMO

Paracetamol (PCM) overdose can cause hepatotoxicity with oxidative stress; the present study was carried out to establish the possible protective effect of olive leaves extract (OLE) on toxicity induced by paracetamol in adult male rats. Twenty four adult male rats were divided into four equal groups; control, olive leaves extract group, paracetamol group and olive leaves extract plus paracetamol group. Some biochemical parameters and liver histopathology were evaluated. PCM treatment significantly increased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, gamma-glutamyltransferase (GGT), lactate dehydrogenase (LDH), urea, creatinine and alpha-fetoprotein. Paracetamol was found to significantly increase malonaldehyde (MDA) and decrease glutathione reductase (GR) activity in tissue and significantly decrease total antioxidant capacity (TAC) and superoxide dismutase (SOD) in serum. Administration of OLE caused a significant decrease serum AST, ALT enzyme, total bilirubin, GGT, LDH, creatinine, urea, alpha-fetoprotein. Also, amelioration of oxidant ­ antioxidant status with olive leaves extract was observed in addition to a significant decrease in MDA and a significant increase in TAC in liver tissue with a significant increase in glutathione reductase (GR) and SOD in serum compared to paracetamol treated group The chemical pathological changes were in step with histopathological observation suggesting marked hepatoprotective result of olive leaves extract. It could be concluded that olive leaves extract (OLE) treatment may be effective in decreasing hepatic injury and oxidative stress induced by paracetamol overdose in male albino rats


A sobredosagem de paracetamol (PCM) pode causar hepatotoxicidade com estresse oxidativo; o presente estudo foi realizado para estabelecer o possível efeito protetor do extrato de folhas de oliveira (OLE) na toxicidade induzida pelo paracetamol em ratos machos adultos. Vinte e quatro ratos machos adultos foram divididos em quatro grupos iguais: controle, grupo extrato de folhas de oliveira, grupo paracetamol e extrato de folhas de oliveira mais grupo paracetamol. Alguns parâmetros bioquímicos e histopatologia hepática foram avaliados. O tratamento com PCM aumentou significativamente aspartato aminotransferase sérica (AST), alanina aminotransferase (ALT), bilirrubina total, gama-glutamiltransferase (GGT), lactato desidrogenase (LDH), uréia, creatinina e alfa-fetoproteína. Verificou-se que o paracetamol aumenta significativamente o malonaldeído (MDA) e diminui a atividade da glutationa redutase (GR) no tecido e diminui significativamente a capacidade antioxidante total (TAC) e a superóxido dismutase (SOD) no soro. A administração de OLE causou uma diminuição significativa de AST, enzima ALT, bilirrubina total, GGT, LDH, creatinina, uréia, alfa-fetoproteína. Também foi observada melhora do status oxidante - antioxidante com extrato de folhas de oliveira, além de uma diminuição significativa no MDA e um aumento significativo no TAC no tecido hepático, com um aumento significativo na glutationa redutase (GR) e SOD no soro em comparação ao grupo tratado com paracetamol. As alterações patológicas químicas acompanharam a observação histopatológica, sugerindo resultado hepatoprotetor acentuado do extrato de folhas de oliveira. Pode-se concluir que o tratamento com extrato de folhas de oliveira (OLE) pode ser eficaz na diminuição da lesão hepática e do estresse oxidativo induzido pela overdose de paracetamol em ratos albinos machos


Assuntos
Animais , Ratos , Extratos Vegetais/farmacologia , Olea , Medicamentos Hepatoprotetores , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Acetaminofen/toxicidade , Ratos Endogâmicos , Extratos Vegetais/química , Distribuição Aleatória , Oxidantes , Ratos Wistar , Folhas de Planta , Estresse Oxidativo/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Fígado/patologia , Antioxidantes/farmacologia
7.
Behav Pharmacol ; 31(1): 81-96, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31923036

RESUMO

Cognitive decline and neurodegenerative diseases pose a significant burden on healthcare resources both in developed and developing countries which is a major socio-economic and healthcare concern. Alzheimer's disease is the most common form of progressive neurodegenerative dementia of the aged brain. Aluminum is a constituent of antacids, deodorants, kitchenware and food additives which allows easy access into the body posing risk to development of senile dementia of Alzheimer's type. Virgin coconut oil was declared as a potential cognitive strengthener. Assessment of cognitive and memory-enhancing effects of virgin coconut oil in senile and young rats to gain vital insights into its effective use in the prevention of neurodegeneration in dementia/Alzheimer's disease-like manifestations and alleviate cognitive dysfunction and learning impairment with neuronal damage imparted by daily oral intake of aluminum. Alzheimer's disease-like symptoms and memory impairment were experimentally induced using oral anhydrous aluminum chloride given daily for five successive weeks in young and old age albino rats. Treatment groups received virgin coconut oil to assess protection during the experimental period. Behavioral test, Morris water maze was conducted before/after induction/treatment. At the end of the experimental period, cholinergic, dopaminergic, noradrenergic and serotonergic neurotransmission as well as brain-derived neurotrophic factor were being investigated, in addition to immunochemical and histopathological examination of targeted brain regions. Virgin coconut oil significantly improved cholinergic activity and monoaminergic neurotransmission. Moreover, immunochemical and histopathological examination revealed marked protection with virgin coconut oil against aluminum-induced Alzheimer's disease-like pathology and cognitive deficit.


Assuntos
Doença de Alzheimer/dietoterapia , Óleo de Coco/farmacologia , Disfunção Cognitiva/dietoterapia , Fatores Etários , Cloreto de Alumínio/efeitos adversos , Doença de Alzheimer/fisiopatologia , Animais , Encéfalo/patologia , Cognição/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Alimento Funcional/análise , Masculino , Memória/efeitos dos fármacos , Neurônios/patologia , Ratos , Ratos Endogâmicos
8.
Theriogenology ; 144: 146-151, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31940506

RESUMO

In vitro fertilization (IVF) is an established technology that is widely used in reproductive engineering. However, in rats, successful application of IVF is difficult to achieve, and it has had poor reproducibility. In a previous study on the critical issues associated with successful IVF in Wistar rats, we investigated the influence of oocyte collection duration on fertilization rates by dividing the procedure into three steps (oviduct extraction from euthanized animals, oocyte collection from the ampullae of oviducts, and oocyte preincubation until insemination), and identified the appropriate times for each. Here we show that use of the same defined duration for oviduct extraction from superovulated Wistar rats and for oocyte collection from the oviducts also produced highly reproducible fertilization rates of more than 90% in other rat strains. Furthermore, the versatility of these criteria was demonstrated using another IVF protocol. Thus, this simple procedure has enabled the standardization of IVF in rats and will enhance further experimental studies.


Assuntos
Criopreservação , Fertilização In Vitro/normas , Oócitos/fisiologia , Coleta de Tecidos e Órgãos/métodos , Animais , Técnicas de Cultura Embrionária , Embrião de Mamíferos , Eutanásia Animal , Feminino , Congelamento , Ratos , Ratos Endogâmicos
9.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165688, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31987840

RESUMO

In recent years, the prevalence of obesity, metabolic syndrome and type 2 diabetes is increasing dramatically. They share pathophysiological mechanisms and often lead to cardiovascular diseases. The ZDSD rat was suggested as a new animal model to study diabetes and the metabolic syndrome. In the current study, we have further characterized metabolic and hepatic gene expression changes in ZDSD rats. Immuno-histochemical staining of insulin and glucagon on pancreas sections of ZDSD and control SD rats revealed that ZDSD rats have severe damage to their islet structures as early as 15 weeks of age. Animals were followed till they were 26 weeks old, where they exhibited obesity, hypertension, hyperglycemia, dyslipidemia, insulin resistance and diabetes. We found that gene expressions involved in glucose metabolism, lipid metabolism and amino acid metabolism were changed significantly in ZDSD rats. Elevated levels of ER stress markers correlated with the dysregulation of hepatic lipid metabolism in ZDSD rats. Key proteins participating in unfolded protein response pathways were also upregulated and likely contribute to the pathogenesis of dyslipidemia and insulin resistance. Based on its intact leptin system, its insulin deficiency, as well as its timeline of disease development without diet manipulation, this insulin resistant, dyslipidemic, hypertensive, and diabetic rat represents an additional, unique polygenic animal model that could be very useful to study human diabetes.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Hipertensão/metabolismo , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Aminoácidos/metabolismo , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Glucagon/análise , Glucagon/metabolismo , Humanos , Hipertensão/genética , Hipertensão/patologia , Insulina/análise , Insulina/metabolismo , Metabolismo dos Lipídeos/genética , Fígado/patologia , Masculino , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , Herança Multifatorial , Obesidade/genética , Obesidade/patologia , Pâncreas/patologia , Ratos , Ratos Endogâmicos , Ratos Sprague-Dawley , Ratos Zucker
10.
Brain Pathol ; 30(1): 137-150, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31267597

RESUMO

Experimental autoimmune encephalomyelitis (EAE) is the primary disease model of multiple sclerosis (MS), one of the most diffused neurological diseases characterized by fatigue, muscle weakness, vision loss, anxiety and depression. EAE can be induced through injection of myelin peptides to susceptible mouse or rat strains. In particular, EAE elicited by the autoimmune reaction against myelin oligodendrocyte glycoprotein (MOG) presents the common features of human MS: inflammation, demyelination and axonal loss. Optic neuritis affects visual pathways in both MS and in several EAE models. Neurophysiological evaluation through visual evoked potential (VEP) recording is useful to check visual pathway dysfunctions and to test the efficacy of innovative treatments against optic neuritis. For this purpose, we investigate the extent of VEP abnormalities in the dark agouti (DA) rat immunized with MOG, which develops a relapsing-remitting disease course. Together with the detection of motor signs, we acquired VEPs during both early and late stages of EAE, taking advantage of a non-invasive recording procedure that allows long follow-up studies. The validation of VEP outcomes was determined by comparison with ON histopathology, aimed at revealing inflammation, demyelination and nerve fiber loss. Our results indicate that the first VEP latency delay in MOG-EAE DA rats appeared before motor deficits and were mainly related to an inflammatory state. Subsequent VEP delays, detected during relapsing EAE phases, were associated with a combination of inflammation, demyelination and axonal loss. Moreover, DA rats with atypical EAE clinical course tested at extremely late time points, manifested abnormal VEPs although motor signs were mild. Overall, our data demonstrated that non-invasive VEPs are a powerful tool to detect visual involvement at different stages of EAE, prompting their validation as biomarkers to test novel treatments against MS optic neuritis.


Assuntos
Encefalomielite Autoimune Experimental/fisiopatologia , Potenciais Evocados Visuais/fisiologia , Nervo Óptico/metabolismo , Animais , Feminino , Inflamação/patologia , Esclerose Múltipla/patologia , Bainha de Mielina/patologia , Glicoproteína Mielina-Oligodendrócito/metabolismo , Ratos , Ratos Endogâmicos , Medula Espinal/patologia
11.
Epilepsy Behav ; 103(Pt A): 106847, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31864946

RESUMO

AIM: Psychiatric disorders, especially depression and anxiety, are among the most disabling comorbidities in patients with epilepsy, and they are difficult to treat because many antidepressants cause proconvulsive effects. Thus, it is important to identify the seizure risks associated with antidepressants. Trazodone is one of the most frequently prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant drugs for the treatment of depression and anxiety. The aim of the present study was to evaluate the effects of trazodone on epileptiform activity in a penicillin-evoked focal seizure model in Wistar rats and in a genetic absence epilepsy model in Wistar Albino Glaxo/Rijswijk strain (WAG/Rij) rats. METHODS: Trazodone at 5-, 10-, and 30-mg/kg doses was injected intraperitoneally in Wistar rats 30 min after penicillin injection, and spike frequency and amplitude of penicillin-induced epileptiform activity were evaluated. In a separate experimental model, the same trazodone doses were injected in WAG/Rij rats to elucidate their effects on number, duration, and amplitude of spike-and-wave discharges (SWDs) and on depression-anxiety like behavior. In both experimental groups, after trazodone injections recordings were made for 3 h. Depression-anxiety like behaviors in WAG/Rij rats were examined using forced swim test and open-field test. RESULTS: Trazodone at 10- and 30-mg/kg doses significantly reduced the frequency of penicillin-induced epileptiform activity without changing the amplitude. Trazodone at a 5-mg/kg dose had no effect on either frequency or amplitude of epileptiform activity. Trazodone at all doses significantly increased number and duration of SWDs without changing the amplitude. In addition, all doses of trazodone decreased the number of squares crossed and duration of grooming in open-field test, and reduced swimming time activity and increased immobility time in forced swim test. CONCLUSION: Our results suggest that depending on the dose used, trazodone had an anticonvulsant effect or no effect on penicillin-evoked focal seizure model, but all trazodone doses resulted in proconvulsant and depression-anxiety like behavior in WAG/Rij rats, which represent a genetic absence model of epilepsy.


Assuntos
Epilepsia Tipo Ausência/induzido quimicamente , Epilepsia Tipo Ausência/tratamento farmacológico , Penicilinas/toxicidade , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Trazodona/administração & dosagem , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletroencefalografia/métodos , Epilepsia Tipo Ausência/fisiopatologia , Injeções Intraperitoneais , Masculino , Ratos , Ratos Endogâmicos , Ratos Transgênicos , Ratos Wistar , Convulsões/fisiopatologia , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/efeitos adversos , Inibidores de Captação de Serotonina/uso terapêutico , Trazodona/efeitos adversos
12.
Bull Exp Biol Med ; 167(5): 698-701, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31630301

RESUMO

The expression of JNK1 isoform of cJun-N-terminal kinase in hepatocytes of rats receiving excess of simple carbohydrates dissolved in drinking water was studied by immunohisto-chemical staining and confocal microscopy. In experiment I (60 days), the highest expression of JNK1 was observed in female Wistar rats receiving fructose (the difference with the group receiving a mixture of glucose and fructose was significant, p<0.05, the difference with the control group at the trend level, p=0.077; Mann-Whitney U test). In experiment II (120 days), an increase in JNK1 expression was observed in Wistar rats (males and females) receiving 30% fructose. In Dark Aguti rats (females and males) of comparable age, increased basal level of JNK1 expression was observed in comparison with Wistar rats. Three-way ANOVA showed that JNK1 expression was significantly (p<0.05) associated with consumption of fructose and animal line, but not sex. The level of JNK1 expression corresponded to previously identified changes in the biochemical markers of the metabolic syndrome.


Assuntos
Dieta da Carga de Carboidratos , Frutose/metabolismo , Glucose/metabolismo , Hepatócitos/efeitos dos fármacos , Síndrome Metabólica/genética , Proteína Quinase 8 Ativada por Mitógeno/genética , Animais , Feminino , Frutose/administração & dosagem , Regulação da Expressão Gênica , Glucose/administração & dosagem , Hepatócitos/enzimologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/enzimologia , Síndrome Metabólica/patologia , Microscopia Confocal , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Ratos , Ratos Endogâmicos , Ratos Wistar , Especificidade da Espécie
13.
Brain Connect ; 9(9): 703-710, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31591912

RESUMO

The thalamo-cortical circuit is important in the genesis of absence epilepsy. This circuit can be influenced by connecting pathways from various parts of central nervous system. The aim of the present study is to define the dento-thalamic connections in Wistar animals and compare the results with genetic absence epilepsy rats from Strasbourg (GAERS) using the biotinylated dextran amine (BDA) tracer. We injected BDA into the dentate nucleus of 13 (n = 6 Wistar and n = 7 GAERS) animals. The dento-thalamic connections in the Wistar animals were denser and were connected to a wider range of thalamic nuclei compared with GAERS. The dentate nucleus was bilaterally connected to the central (central medial [CM], paracentral [PC]), ventral (ventral medial [VM], ventral lateral [VL], and ventral posterior lateral [VPL]), and posterior (Po) thalamic nuclei in Wistar animals. The majority of these connections were dense contralaterally and scarce ipsilaterally. Contralateral connections were present with the parafascicular (PF), ventral posterior medial, ventral anterior (VA), and central lateral (CL) thalamic nuclei in Wistar animals. Whereas in GAERS, bilateral connections were observed with the VL and CM. Contralateral connections were present with the PC, VM, VA, and PF thalamic nuclei in GAERS. The CL, VPL, and Po thalamic nucleus connections were not observed in GAERS. The present study showed weak/deficit dento-thalamic connections in GAERS compared with control Wistar animals. The scarce information flow from the dentate nucleus to thalamus in GAERS may have a deficient modulatory role on the thalamus and thus may affect modulation of the thalamo-cortical circuit.


Assuntos
Córtex Cerebral/fisiopatologia , Epilepsia Tipo Ausência/fisiopatologia , Tálamo/fisiopatologia , Animais , Biotina/análogos & derivados , Núcleos Cerebelares/diagnóstico por imagem , Dextranos , Modelos Animais de Doenças , Epilepsia/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Ratos , Ratos Endogâmicos , Ratos Wistar
14.
Behav Neurosci ; 133(6): 602-613, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31580093

RESUMO

Previous results suggest that directional information from the head direction cell circuit may inform hippocampal place cell firing when an animal is confronted with visually identical environments. To investigate whether such information might also be essential for spatial behavior, we tested adult, male Lister Hooded rats that had received either bilateral lateral mammillary nuclei (LMN) lesions or sham lesions on a four-way, conditional odor-location discrimination in compartments arranged at 60° to one another. We found that significantly fewer rats in the LMN lesion group were able to learn the task compared to the Sham group. We also found that the extent of the behavioral impairment was highly correlated with the degree of tissue loss in the LMN resulting from the lesion. Animals with LMN lesions were also impaired in a nonmatching-to-sample task in a T maze, and the extent of impairment likewise depended on the extent of the lesion. Performance in the odor-location and T-maze tasks was not affected by tissue loss in the medial mammillary nuclei. Together, these results indicate that the LMN, a key node in the head direction circuit, is critical for solving a spatial task that requires a directional discrimination. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Comportamento Espacial/fisiologia , Processamento Espacial/fisiologia , Potenciais de Ação , Animais , Cabeça/fisiologia , Masculino , Corpos Mamilares/lesões , Corpos Mamilares/fisiopatologia , Vias Neurais/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Ratos , Ratos Endogâmicos , Tálamo/lesões
15.
Am J Physiol Renal Physiol ; 317(5): F1359-F1374, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31566433

RESUMO

The function of actin is regulated by various posttranslational modifications. We have previously shown that in the kidneys of nonobese type 2 diabetes model Goto-Kakizaki rats, increased O-GlcNAcylation of ß-actin protein is observed. It has also been reported that both O-GlcNAcylation and phosphorylation occur on Ser199 of ß-actin. However, their roles are not known. To elucidate their roles in diabetic nephropathy, we examined the rat kidney for changes in O-GlcNAcylation of Ser199 (gS199)-actin and in the phosphorylation of Ser199 (pS199)-actin. Both gS199- and pS199-actin molecules had an apparent molecular weight of 40 kDa and were localized as nonfilamentous actin in both the cytoplasm and nucleus. Compared with the normal kidney, the immunostaining intensity of gS199-actin increased in podocytes of the glomeruli and in proximal tubules of the diabetic kidney, whereas that of pS199-actin did not change in podocytes but decreased in proximal tubules. We confirmed that the same results could be observed in the glomeruli of the human diabetic kidney. In podocytes of glomeruli cultured in the presence of the O-GlcNAcase inhibitor Thiamet G, increased O-GlcNAcylation was accompanied by a concomitant decrease in the amount of filamentous actin and in morphological changes. Our present results demonstrate that dysregulation of O-GlcNAcylation and phosphorylation of Ser199 occurred in diabetes, which may contribute partially to the causes of the morphological changes in the glomeruli and tubules. gS199- and pS199-actin will thus be useful for the pathological evaluation of diabetic nephropathy.


Assuntos
Actinas/metabolismo , Nefropatias Diabéticas/metabolismo , Acilação , Sequência de Aminoácidos , Animais , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas/patologia , Humanos , Rim/metabolismo , Rim/patologia , Masculino , Modelos Moleculares , Fosforilação , Podócitos/metabolismo , Conformação Proteica , Ratos , Ratos Endogâmicos
16.
Medicina (Kaunas) ; 55(9)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480729

RESUMO

Background and Objectives: Side effects of anti-cancer drugs are usually accompanied by oxidative stress, including myelotoxicity. We evaluated the potential of oral highly activated micro-/macroporous carbon adsorbents (bulk density of 0.16 g/cm3, surface area calculation by Brunauer-Emmett-Teller model (SBET) > 2200 m2/g, derived from proprietary phenolic resin beads) to alleviate oxidative stress and myelotoxicity in rats. Materials and Methods: A single injection of cytostatic melphalan (L-PAM) at a dose of 4 mg/kg was used for modelling. Two forms of activated carbon were used: AC1-primary beads with the particle size range of 125-250 µm, and AC2-micronized AC1 with a mean particle size of ~1 µm. We measured haematological parameters white blood cells, red blood cells, platelet count, and haemoglobin level. Oxidative stress intensity was evaluated using the following markers: total levels of reactive oxygen species (ROS) in blood plasma; catalase activity (CAT) and pro-oxidant/antioxidant ratio in blood haemolysate samples; level of reduced glutathione (GSH) in liver tissues; oxidative modification of proteins, OPM (APHD, aldehyde-dinitrophenylhydrazone derivatives and KPHD, ketone dinitrophenylhydrazone derivatives) and malonic dialdehyde (MDA) in blood plasma and liver samples. Results: AC2 administration promoted significant myeloprotective effect: 1.5-fold increase in leukocytes, 2-fold in neutrophils, 1.5-fold in lymphocytes, and 1.23-fold in platelet count compared to the experimental Melphalan Group. At the same time, AC1 administration resulted in a slight increase in haematological parameters. Both ACs positively corrected important, but diverse, components of oxidative stress. They significantly reduced oxidative modification of blood and liver proteins (especially the AC1 form), normalized the level of reduced glutathione, pro-oxidant/antioxidant ratio and other markers. For some markers, such as ROS production in blood plasma, the use of enterosorbents resulted in non-significant a shift towards normal parameters. Conclusions: Oral activated carbon adsorbents reduce oxidative stress intensity and myelotoxicity; they can be promising means to combat the adverse effects of chemotherapy in clinical practice.


Assuntos
Antineoplásicos Alquilantes/toxicidade , Medula Óssea/efeitos dos fármacos , Carvão Vegetal/farmacologia , Enteroadsorção , Melfalan/toxicidade , Microesferas , Estresse Oxidativo/efeitos dos fármacos , Adsorção , Animais , Contagem de Células Sanguíneas , Peso Corporal , Portadores de Fármacos , Feminino , Ratos , Ratos Endogâmicos , Espécies Reativas de Oxigênio/sangue
17.
PLoS One ; 14(9): e0221566, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31479468

RESUMO

Sex-based differences in susceptibility have been reported for a number of neovascular ocular diseases. We quantified corneal neovascularization, induced by superficial silver nitrate cautery, in male and female inbred albino Sprague-Dawley, inbred albino Fischer 344, outbred pigmented Hooded Wistar and inbred pigmented Dark Agouti rats of a range of ages. Corneal neovascular area was quantified on haematoxylin-stained corneal flatmounts by image analysis. Pro-and anti-angiogenic gene expression was measured early in the neovascular response by quantitative real-time polymerase chain reaction. Androgen and estrogen receptor expression was assessed by immunohistochemistry. Male rats from all strains, with or without ocular pigmentation, exhibited significantly greater corneal neovascular area than females: Sprague-Dawley males 43±12% (n = 8), females 25±5% (n = 12), p = 0.001; Fischer 344 males 38±10% (n = 12) females 27±8% (n = 8) p = 0.043; Hooded Wistar males 32±6% (n = 8) females 22±5% (n = 12) p = 0.002; Dark Agouti males 37±11% (n = 9) females 26±7% (n = 9) p = 0.015. Corneal vascular endothelial cells expressed neither androgen nor estrogen receptor. The expression in cornea post-cautery of Cox-2, Vegf-a and Vegf-r2 was significantly higher in males compared with females and Vegf-r1 was significantly lower in the cornea of males compared to females, p<0.001 for each comparison. These data suggest that male corneas are primed for angiogenesis through a signalling nexus involving Cox-2, Vegf-a, and Vegf receptors 1 and 2. Our findings re-enforce that pre-clinical animal models of human diseases should account for sex-based differences in their design and highlight the need for well characterized and reproducible pre-clinical studies that include both male and female animals.


Assuntos
Córnea/irrigação sanguínea , Córnea/metabolismo , Neovascularização da Córnea/etiologia , Animais , Córnea/patologia , Neovascularização da Córnea/genética , Neovascularização da Córnea/metabolismo , Ciclo-Oxigenase 2/genética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Expressão Gênica , Masculino , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos , Ratos Sprague-Dawley , Ratos Wistar , Receptores Androgênicos/metabolismo , Receptores Estrogênicos/metabolismo , Caracteres Sexuais , Especificidade da Espécie , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
18.
Endocrinology ; 160(10): 2339-2352, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504411

RESUMO

Osteoporosis is a complication of diabetes mellitus (DM). The pathology of diabetic osteoporosis is distinct from postmenopausal osteoporosis, and there are no specific treatment guidelines for diabetic osteoporosis. In the current study, this issue was addressed by evaluating the effect of osteoporosis medications, such as the anabolic agent PTH [teriparatide (TPTD)] and the antiresorptive agents calcitonin [elcatonin (ECT)] and bisphosphonate [risedronate (RIS)], on bone metabolism as well as on glucose and lipid metabolism in spontaneously diabetic Torii (SDT) fatty rats, which are a model of type 2 DM (T2DM). The medicines were injected subcutaneously into 8-week-old male SDT fatty rats three times weekly for 8 weeks. TPTD treatment in SDT fatty rats increased the osteoblast number and function on trabecular bone in vertebrae, and increased the trabecular bone mass, bone mineral density (BMD), and mechanical strength of vertebrae. Additionally, TPTD improved cortical bone structure and increased BMD. RIS decreased the osteoclast number and function, which led to an increase in vertebral bone mineral content and BMD in the femoral diaphysis, and mechanical strength was increased in the vertebrae. ECT showed no clear effects on bone mass or metabolism. Similar to diabetic lesions, all of the drugs had no effects on hyperglycemia, pancreas morphology, or serum insulin and glucagon levels. However, triglyceride levels and lipid droplets in fatty liver were decreased in the TPTD group. These results suggest that TPTD may be useful for treating fatty liver in addition to osteoporosis in T2DM.


Assuntos
Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Teriparatida/farmacologia , Animais , Glicemia , Densidade Óssea/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Fígado/metabolismo , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos
19.
Auton Neurosci ; 221: 102577, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31445407

RESUMO

The present study aimed to compare linear and symbolic dynamics (SD) indices for detecting the autonomic cardiac changes produced by endotoxemia in freely-moving rats. In this context, we analyzed ECG-derived R-R time series in freely moving Dark Agouti rats, which received lipopolysaccharide (LPS, n = 9), or vehicle (V, n = 7). Five minutes R-R time series were assessed every hour up to +12 h and + 24 h post-LPS injection. We found that SD indices showed significant differences at +7 h between V vs. LPS groups and at +9 h between basal levels of LPS (-3 h) and post-LPS injection (pre-LPS vs. post-LPS). In general, SD seems more appropriate than linear indices to evaluate the autonomic changes of endotoxemic rats. Overall, the symbolic parameters detected decreased R-R variability and complexity, which indicate a modification of the autonomic regulation during LPS-induced endotoxemia. This modification is probably related to a reduced activity of the cholinergic anti-inflammatory pathway at the long term.


Assuntos
Endotoxemia/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca/fisiologia , Nervo Vago/fisiopatologia , Animais , Endotoxemia/induzido quimicamente , Lipopolissacarídeos/toxicidade , Masculino , Dinâmica não Linear , Ratos , Ratos Endogâmicos
20.
PLoS One ; 14(8): e0220377, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31404079

RESUMO

BACKGROUND: Troxerutin (TRX) has a beneficial effect on blood viscosity and platelet aggregation, and is currently used for the treatment of chronic varicosity. Recently, TRX can improve lipid abnormalities, glucose intolerance and oxidative stress in high-fat diet-induced metabolic disorders. In this study, we tested the effect of TRX on metabolic syndrome-associated disorders using a non-obese model of metabolic syndrome-the Hereditary Hypertriglyceridaemic rats (HHTg). METHODS: Adult male HHTg rats were fed standard diet without or with TRX (150 mg/kg bwt/day for 4 weeks). RESULTS: Compared to untreated rats, TRX supplementation in HHTg rats decreased serum glucose (p<0.05) and insulin (p<0.05). Although blood lipids were not affected, TRX decreased hepatic cholesterol concentrations (p<0.01) and reduced gene expression of HMGCR, SREBP2 and SCD1 (p<0.01), involved in cholesterol synthesis and lipid homeostasis. TRX-treated rats exhibited decreased lipoperoxidation and increased activity of antioxidant enzymes SOD and GPx (p<0.05) in the liver. In addition, TRX supplementation increased insulin sensitivity in muscles and epididymal adipose tissue (p<0.05). Elevated serum adiponectin (p<0.05) and decreased muscle triglyceride (p<0.05) helped improve insulin sensitivity. Among the beneficial effects of TRX were changes to cytochrome P450 family enzymes. Hepatic gene expression of CYP4A1, CYP4A3 and CYP5A1 (p<0.01) decreased, while there was a marked elevation in gene expression of CYP1A1 (p<0.01). CONCLUSION: Our results indicate that TRX improves hepatic lipid metabolism and insulin sensitivity in peripheral tissues. As well as ameliorating oxidative stress, TRX can reduce ectopic lipid deposition, affect genes involved in lipid metabolism, and influence the activity of CYP family enzymes.


Assuntos
Hidroxietilrutosídeo/análogos & derivados , Hipolipemiantes/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Animais , Modelos Animais de Doenças , Glucose/metabolismo , Glicogênio/metabolismo , Hidroxietilrutosídeo/uso terapêutico , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Músculo Esquelético/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma/efeitos dos fármacos
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