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1.
Chem Biol Interact ; 347: 109617, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34391751

RESUMO

PURPOSE: This study was designed to investigate the mechanism of Dapagliflozin (Dapa) cardioprotection against diabetic cardiomyopathy (DCM). Structural and functional changes in the heart as well as decrease of erythropoietin (EPO) levels were reported in DCM. EPO simultaneously activates three pathways: the Janus-activated kinase-signal transducer and activator of transcription (JAK2/STAT5), phosphatidylinositol-3-kinase-Akt (PI3K/Akt), and extracellular signal-related kinase (ERK/MAPK) cascades, that result in proliferation and differentiation of cardiac cells. METHODS AND RESULTS: DCM was induced by a high fat diet for 10 weeks followed by administration of streptozotocin. After confirmation of diabetes, rats were divided randomly to 5 groups: Group 1; normal control group, Group 2; untreated diabetic group and Groups (3-5); diabetic groups received Dapa daily (0.75 mg, 1.5 or 3 mg/Kg, p.o) respectively for a month. At the end of the experiment, full anaesthesia was induced in all rats using ether inhalation and ECG was recorded. Blood samples were collected then rats were sacrificed and their heart were dissected out and processed for biochemical and histopathological studies. Untreated diabetic rats showed abnormal ECG pattern, elevation of serum cardiac enzymes, decrease EPO levels, downregulation of P-Akt, P-JAK2 and pMAPK pathways, abnormal histological structure of the heart and increase immunostaining intensity of P53 and TNF α in the cardiomyocytes. Dapa in a dose dependent manner attenuated the alterations in the previously mentioned parameters. CONCLUSION: The cardioprotective effect of Dapa could be mediated by increasing EPO levels and activation of P-Akt, P-JAK2 and pMAPK signalling cascades which in turn decrease apoptosis.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Cardiotônicos/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/tratamento farmacológico , Glucosídeos/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/complicações , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Eletrocardiografia/efeitos dos fármacos , Eritropoetina/sangue , Eritropoetina/metabolismo , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Ratos Wistar , Estreptozocina
2.
Antioxidants (Basel) ; 9(11)2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33238601

RESUMO

Cyclophosphamide (CP) was found to have a potential toxic effect on lung tissues. Raspberry ketones (RKs) are natural antioxidant chemicals isolated from red raspberries (Rubus ideaus). They are commonly used for weight loss and obesity. The current study aimed to evaluate the possible protective effects of RKs against lung toxicity induced by CP. Mice were allocated into six groups: (1) control group; (2) CP group: received a single intraperitoneal dose of CP (150 mg/kg, i.p.); and (3-6) mice were pre-treated orally with different doses of RKs (25, 50, 100, and 200 mg/kg) for 14 consecutive days, respectively, before the administration of an intraperitoneal dose of CP (150 mg/kg, i.p.). Mice were then sacrificed under anesthesia, then lungs were removed for histopathological and biochemical investigations. A single dose of CP markedly altered the levels of some oxidative stress biomarkers and resulted in the fragmentation of DNA in lung homogenates. Histological examination of CP-treated mice demonstrated diffuse alveolar damage that involved apparent hyalinization of membranes, thickening of inter alveolar septa, and proliferation of type II pneumocytes. The immunohistochemical results of CP-treated mice revealed strongly positive Bax and weakly positive proliferating cell nuclear antigen (PCNA) staining reactivity of the nuclei of the lining epithelium of the bronchioles and alveoli. CP activated the cyclooxygenase-2/nuclear factor-kappa B pathway. However, pre-treatment with RKs significantly attenuated CP-evoked alterations in the previously mentioned parameters, highlighting their antioxidant, anti-inflammatory, and anti-apoptotic potential. RKs may be suggested to be a potential candidate to ameliorate CP-induced pulmonary toxicity.

3.
Plants (Basel) ; 9(8)2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32823927

RESUMO

Phytochemical study of Chiliadenus montanus aerial parts afforded six compounds; Intermedeol (1), 5α-hydroperoxy-ß-eudesmol (2), 5,7-dihydroxy-3,3',4'-trimethoxyflavone (3), 5,7,4'-trihydroxy-3,6,3'-trimethoxyflavone (jaceidin) (4), eudesm-11,13-ene-1ß,4ß,7α-triol (5) and 1ß,4ß,7ß,11-tetrahydroxyeudesmane (6). These compounds were identified based on their NMR spectral data. The isolated compounds were tested for their cytotoxicity against liver cancer cell line (HepG2) and breast cancer cell line (MCF-7). Jaceidin flavonoid (4) exhibited the highest cytotoxic effect in vitro. Therefore, both of jaceidin and C. montanus extract were evaluated for their in vivo anti-tumor activity against Ehrlich's ascites carcinoma (EAC). Compared to control group, jaceidin and C. montanus extract decreased the tumor weight, improved the histological picture of tumor cells, lowered the levels of VEGF and ameliorate the oxidative stress. Molecular docking and in silico studies suggested that jaceidin was a selective inhibitor of VEGF-mediated angiogenesis with excellent membrane permeability and oral bioavailability.

4.
Ecotoxicol Environ Saf ; 195: 110479, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32199213

RESUMO

Cypermethrin (CYP), a class II synthetic pyrethroid, is used to control household insects. CYP can cross the blood-brain barrier to exert neurotoxicity through changes in sodium ion channels. Selenium is an essential component of glutathione peroxidise enzyme; in addition, it shows a potential anti-inflammatory property. The present study aimed to investigate the neuroprotective role of Nano-Se on CYP-induced neurotoxicity. Twenty-four adult male Wister rats were randomly divided into three groups: a) control, b) CYP (1mg/kg) administered orally for 21 days, c) CYP (1mg/kg) administered orally for 21 days and Nano-Se (2.5 mg/kg) given once a day three times a week for three weeks). Locomotor activity was assessed using open field test then rats were sacrificed under anaesthesia, and their brains were dissected out and processed for biochemical and histopathological studies. Histological examination of CYP-treated rats demonstrated some degenerative changes; besides, CYP affected rat locomotor activity. CYP-treated rats showed increased levels of malondialdehyde (MDA), TNF-α and IL-1ß in addition to the reduction of glutathione (GSH) levels and gamma-Aminobutyric acid (GABA). Nano-Se restored normal behavioural function and significantly attenuated CYP-evoked degenerative changes. Nano-Se increased levels of GABA and glutathione; on the other hand, it significantly prevented the rise in the levels of MDA, TNF-α and IL-1ß. Therefore, Nano-Se demonstrated both anti-oxidant and anti-inflammatory potential. Nano-Se may be suggested to be a prospective candidate to ameliorate CYP-induced neurotoxicity.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Inseticidas/toxicidade , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Piretrinas/toxicidade , Selênio/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/metabolismo , Glutationa/metabolismo , Masculino , Malondialdeído/metabolismo , Nanopartículas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Ratos , Ratos Wistar , Selênio/uso terapêutico , Ácido gama-Aminobutírico/metabolismo
5.
Bioorg Chem ; 86: 322-338, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30743173

RESUMO

Targeting of protein tyrosine phosphatase-1B (PTP1B) has emerged as a promising strategy for therapeutic intervention of diabetes and obesity. Investigation of new inhibitors with good bioavailability and high selectivity is the major challenge of drug discovery program targeting PTP1B. Therefore, herein, new neutral benzene-sulfonamide containing compounds were designed, synthesized and biologically evaluated as potent PTP1B inhibitors. New series of thiazolidine, oxazolidine, thiazinan, oxazinan, oxazole, thiazole, tetrazole, cyanopyridine, chromenone, and iminochromene of benzene-sulfonamide derivatives (MSE-1 to MSE-15) were synthesized in a good yield under mild condition using sulfadiazine as a starting material. Among the synthesized compounds, MSE-13 and MSE-14 showed the most in vitro potent PTP-1B inhibitory activity (IC50 of 0.88 µM and 3.33 µM, respectively). Animal treatment by the target compounds significantly improved the insulin resistance, diminished plasma glucose level, decreased initial body weight, and normalized the serum lipid profile compared to pioglitazone, a standard PTP1B inhibitor. The molecular modeling study showed a high affinity and selectivity of our synthesized compounds to the active site and B-site of PTP1B holding hydrogen bonding, hydrophobic, and electrostatic interactions. Furthermore, Electrostatic Surface Potential (ESP) and HOMO/LUMO analysis indicated the importance of sulfamoyl moiety for PTP1B binding. In silico ADME predictions of such compounds also showed the promising pharmacokinetic and physicochemical properties. The proposed compounds could be considered a lead inhibitory scaffold to PTP1B.


Assuntos
Derivados de Benzeno/farmacologia , Diabetes Mellitus/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Diabetes Mellitus/metabolismo , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Fígado/química , Fígado/metabolismo , Masculino , Modelos Moleculares , Estrutura Molecular , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
6.
Biochem Pharmacol ; 159: 1-10, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30414938

RESUMO

Diabetic neuropathy (DN) is a common complication of diabetes mellitus and is associated with structural changes in the nerves. However, the molecular basis for DN is poorly understood. Adenosine monophosphate activated protein kinase (AMPK) has been shown to regulate the activity of some kinases including protein kinase B (AKT), mitogen-activated protein kinases (MAPK) and mammalian target of rapamycin complex 1 (mTORC1) that represent important signalling pathways modulating the function of peripheral nociceptive neuron. Donepezil can activate AMPK and exerts neuroprotective effects. In this study, streptozotocin (45 mg/kg for 5 Day, i.p.) was used to induce experimental DN. After confirmation of development of neuropathy, mice were randomly distributed into five groups: Group 1; negative control group received saline (0.9%NaCl), Group 2; diabetic mice received saline, Group (3-5); diabetic mice received daily donepezil (1, 2 or 4 mg/kg, p.o.) respectively for 20 days. Mice were then sacrificed under anesthesia then their sciatic nerve and spinal cord were dissected out and processed for biochemical and histopathological studies. Diabetic mice revealed severe histological abnormalities including degenerated neurons in the spinal cord and swollen myelin sheath with inflammatory edema observed in sciatic nerves. In addition, diabetic mice showed reduced expression of p-AMPK in sciatic nerves with consequent activation of AKT/MAPK/4EBP1. A significant upregulation of the N-Methyl-d-aspartate (NMDA) receptors in both cervical and lumbar regions of spinal cord of diabetic mice was also demonstrated. Donepezil, an AMPK activator, blocked the phosphorylation of AKT/MAPK/4EBP1, down regulate the expression of NMDA receptors and reversed hyperalgesia developed in diabetic mice. Therefore, Donepezil could be a potential pharmacological agent for management of DN.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Donepezila/farmacologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Ativação Enzimática/efeitos dos fármacos , Fatores de Iniciação em Eucariotos , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfoproteínas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Estreptozocina
7.
Biomed Pharmacother ; 108: 1253-1258, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30372826

RESUMO

BACKGROUND: Cuscuta pedicellata and some of its isolated compounds were suggested previously to have an anti-obesity effect in rats. This study aimed to investigate the effect of ten isolated compounds from C. pedicellata on insulin resistance, some oxidative stress markers and expression of the mitochondrial uncoupling protein-1 (UCP-1) and Carnitine palmitoyltransferase-I (CPT-1) genes in brown adipose tissue of high fat diet (HFD) rats. METHODS: One hundred and four male albino rats were divided into 13 groups. Group (1) was considered as normal untreated rats. Obesity was induced in all other groups by HFD. Group (2) served as obese control group and groups (3-11) were treated for four weeks with C. pedicellata extract or one of its isolated compounds (naringenin, kaempferol, aromadenderin, quercetin, 3,5,7,30,50-pentahydroxy flavanone, naringenin-7-O-b-d-glucoside, aromadenderin-7-O-b-d-glucoside, taxifolin 7-O-b-d-glucoside, kaempferol-3-O-b-d-glucoside [astragalin], and quercitin-3-O-b-d-glucoside [isoquercitrin]). At the end of the experiment, rats were then sacrificed under anesthesia and their brown adipose tissues were dissected out for determination of UCP-1 and CPT-1 genes using quantitative PCR. Blood samples were collected for determination of blood glucose, insulin, thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD) and catalase. RESULTS: A significant reduction in homeostasis model assessment-insulin resistance (HOMA-IR) and TBARS levels was observed in rats treated with C. pedicellata crude extract and some of its isolated compounds, with a significant increase in SOD and catalase levels and upregulation of UCP-1 and CPT-1 genes expression compared to the obese control group. CONCLUSIONS: This study suggests a beneficiary role of C. pedicellata in reducing insulin resistance, oxidative stress and enhancing energy expenditure.


Assuntos
Cuscuta/química , Metabolismo Energético/genética , Obesidade/genética , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Regulação para Cima/genética , Animais , Catalase/metabolismo , Dieta Hiperlipídica , Metabolismo Energético/efeitos dos fármacos , Glucose , Homeostase , Masculino , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Ratos , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Regulação para Cima/efeitos dos fármacos
8.
Environ Sci Pollut Res Int ; 25(12): 12072-12082, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29453720

RESUMO

Repeated administration of chlorpyrifos (CPF), an organophosphate pesticide, can increase the risk of oral cytotoxicity. The current study was designed to assess the mechanism by which CPF mediates its cytotoxic effect on lingual mucosa of rats. Twenty-four male Wistar rats were used in the present study and divided into three groups: group I: healthy rats (negative control), group II: rats treated with CPF 1/40 LD50 (3.375 mg/kg, orally/daily) for 28 days, group III: rats treated with CPF 1/10 LD50 (13.5 mg/kg, orally/daily) for 28 days. At the end of the experiment, all rats were sacrificed by cervical dislocation under ketamine anesthesia. Tongue samples were dissected out at their base for detection of heme oxygenase-1 (HO-1) and nuclear erythroid 2-related factor 2 (Nrf-2) by western blotting and histopathological and electron microscopic studies. Immunostaining was used to determine cleaved caspase 3 and the nuclear factor kappa B (NF-κB) localization. Structural and ultrastructural examination of treated lingual mucosa with CPF demonstrated degenerative changes that involved both the dorsal and ventral surfaces of the tongue as well as the lingual glands. CPF-treated rats demonstrated a significant increase in the levels of pro-inflammatory cytokines such as interleukin-1ß (IL-1ß) and tumor necrosis factor (TNF-α) in addition to a significant dose-dependent activation of NF-κB and cleaved caspase 3. Furthermore, CPF activated HO-1 and Nrf-2 pathway in a dose-dependent manner. In conclusion, this data suggests that the CPF-induced cytotoxicity may be explained by NF-κB activated inflammatory cascade. In addition, CPF triggers an adaptive activation of Nrf-2/HO-1 pathway.


Assuntos
Clorpirifos/toxicidade , Heme Oxigenase-1/metabolismo , Inseticidas/toxicidade , Mucosa Bucal/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Língua/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Inflamação , Masculino , Mucosa Bucal/imunologia , Mucosa Bucal/ultraestrutura , NF-kappa B/metabolismo , Ratos Wistar , Língua/imunologia , Língua/ultraestrutura , Fator de Necrose Tumoral alfa/metabolismo
9.
Pharmacol Rep ; 70(2): 233-242, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29475006

RESUMO

BACKGROUND: Glutamine aminoacid regulates insulin exocytosis from pancreatic ß-cells. Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has fascinated function in inhibiting ß-cell apoptosis and preserving pancreatic ß-cell mass. The present study investigated the benefit of adding glutamine to a regimen of liraglutide in diabetic rats focusing on their role in increasing insulin production and upregulation of the expression of sodium-dependent neutral aminoacid transporter-2 (SNAT2). METHODS: In the present study, diabetes mellitus was induced in rats using streptozotocin (STZ, 50mg/kg, ip). Male rats were allocated into 5 groups, (i) vehicle group, (ii) STZ-diabetic rats, (iii) STZ-diabetic rats treated with liraglutide (150µg/kg, sc), (iv) STZ-diabetic rats treated with glutamine (po) and (v) STZ-diabetic rats treated with a combination of liraglutide and glutamine for four weeks. After finishing the therapeutic courses, the fasting blood glucose value was determined and rats were sacrificed. Pancreases were used for quantification of mRNA expression for SNAT2. Paraffin fixed samples were used for histologic staining and immunohistochemistry for insulin and apoptosis markers (activated caspase-3, BCL2 and BAX). RESULTS: Treatment with liraglutide and/or glutamine enhanced insulin production and hence glycemic control in diabetic male rats with favorable effects on apoptosis markers. Treatment with glutamine and its combination with liraglutide significantly increased pancreatic expression of SNAT2 by approximately 30-35 folds. CONCLUSION: Addition of glutamine to liraglutide regimen enhances the glycemic control and may have utility in clinical settings.


Assuntos
Sistemas de Transporte de Aminoácidos/metabolismo , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Glutamina/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Sistema A de Transporte de Aminoácidos , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Liraglutida/farmacologia , Masculino , Pâncreas/metabolismo , Ratos , Estreptozocina/farmacologia
10.
J Cardiovasc Pharmacol ; 71(3): 160-173, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29256971

RESUMO

Myocardial infarction (MI) is one of the main causes of morbidity and mortality in diabetic patients. The antidiabetic glucagon-like polypeptide-1 receptor (GLP-1R) agonists, such as exenatide, proved to confer cardioprotection; however, their exact mechanisms are not fully elucidated. Although the cardioprotective effect of α-estrogen receptor (ERα) activation is well established, its involvement in exenatide-induced cardioprotection has never been investigated. Moreover, modulation of insulin-like growth factor-1/2 (IGF-1/IGF-2) system by exenatide, and the consequent effect on cardiomyocyte apoptosis, is yet to be established. Current study aimed to investigate the cardioprotective potential of exenatide versus the standard cardioprotective agent, 17ß-estradiol, against isoprenaline (ISO)-induced MI in rats. MI-insulted group showed electrocardiographic abnormalities, elevated serum cardiac markers, higher serum IGF-2 level along with histopathological abnormalities. Treatment with exenatide and/or 17ß-estradiol, commenced 8 weeks before ISO insult, ameliorated these anomalies with maximum cardioprotection achieved with combined treatment. This was associated with upregulation of both ERα and IGF-1R, and downregulation of IGF-2R in left ventricles. Inhibition of ERs in Langendorff preparations confirmed their involvement in mediating exenatide-induced cardioprotective effect. Current study showed that the GLP-1R agonist exenatide exerted cardioprotection associated with upregulation of ERα and modulation of IGF-1/IGF-2 signaling in favor of antiapoptosis.


Assuntos
Receptor alfa de Estrogênio/metabolismo , Exenatida/farmacologia , Fator de Crescimento Insulin-Like II/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Isoproterenol , Infarto do Miocárdio/prevenção & controle , Miocárdio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Citoproteção , Modelos Animais de Doenças , Estradiol/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Preparação de Coração Isolado , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Ratos Wistar , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
11.
Bioorg Chem ; 71: 110-119, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28162233

RESUMO

The synthesis, pharmacological evaluation and molecular modelling study of novel naphthalen-2-yl acetate and 1,6-dithia-4,9-diazaspiro [4.4]nonane-3,8-dione derivatives as potential anticonvulsant agents are described. The newly synthesized compounds were characterized by both analytical and spectral data. Alkylation of 1H-imidazole or substituted piperazine with 1-(2-naphthyl)-2-bromoethanone (2) gave naphthalen-2-yl 2-(1H-imidazol-1-yl) acetate (3) and naphthalen-2-yl 2-(substituted piperazin-1-yl) acetate (4-8). Moreover, condensation of naphthalen-2-yl 2-bromoacetate or 2-bromo-1-(naphthalen-2-yl) ethanone with hydrazine hydrate and acetylacetone resulted in the formation of the cyclic pyrazole products 9 and 13. Sonication of naphthalen-2-yl acetate (1) with 2-chloropyridine, 2-chloropyrimidine and 2-(chloromethyl) oxirane gave naphthalen-2-yl 2-(pyridin-2-yl) acetate (10), naphthalen-2-yl 2-(pyrimidin-2-yl) acetate (11) and naphthalen-2-yl-3-(oxiran-2-yl) propanoate (12) respectively. Cyclocondensation reaction of 2-iminothiazolidin-4-one (14) with thioglycolic acid, thiolactic acid and thiomalic acid gave 1,6-dithia-4,9-diazaspiro [4.4]nonane-3,8-dione derivatives (15-17). The compounds were testedin vivofor the anticonvulsant activity by delaying strychnine-induced seizures. The diazaspirononane (17) and 1-(2-naphthyl)-2-bromoethanone (2) showed a high significant delay in the onset of convulsion and prolongation of survival time compared to phenobarbital. The molecular modelling study of anticonvulsant activity of synthesized compounds showed a CNS depressant activity via modulation of benzodiazepine allosteric site in GABA-A receptors.


Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/uso terapêutico , Naftalenos/química , Naftalenos/uso terapêutico , Receptores de GABA-A/metabolismo , Convulsões/tratamento farmacológico , Acetatos/síntese química , Acetatos/química , Acetatos/farmacologia , Acetatos/uso terapêutico , Regulação Alostérica/efeitos dos fármacos , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Naftalenos/síntese química , Naftalenos/farmacologia , Convulsões/induzido quimicamente , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , Estricnina
12.
Can J Physiol Pharmacol ; 95(4): 340-348, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28060522

RESUMO

There is evidence for a relationship between inflammation and seizures because epilepsy can be caused by or result in inflammation. This study aimed to investigate the effect of aspirin and (or) omega-3 polyunsaturated fatty acids (PUFAs) on seizure activity and neurodegeneration in pentylenetetrazole (PTZ)-kindled rats focusing on their effect on corticohippocampal production of lipoxin A4 (LXA4) and expression of formyl peptide receptor-like 1 (FPRL1) receptors. Male rats were injected with PTZ (35 mg/kg, i.p.) 3 times per week for a total of 15 doses. Rats were treated daily with aspirin (20 mg/kg, i.p.), omega-3 PUFAs (85 mg/kg, p.o.), or a combination of them for 35 days. Both LXA4 level and expression of FPRL1 receptor in the cortices and hippocampi of rats' brains were greater in PTZ-kindled rats compared to a saline control group. Cotreatment with aspirin and (or) omega-3 PUFAs reduced convulsive behaviour; reduced levels of LXA4, interleukin-1ß, and nuclear factor-κB; and showed a lower percentage of corticohippocampal degenerative cells compared to PTZ-kindled rats. The combination of the 2 therapeutic agents did not provide significant improvement in comparison with the monotherapies. These findings suggest the use of aspirin or omega-3 PUFAs may delay the development of seizures and provide neuroprotection in a clinical setting.


Assuntos
Aspirina/uso terapêutico , Epilepsia/prevenção & controle , Ácidos Graxos Ômega-3/uso terapêutico , Lipoxinas/metabolismo , Degeneração Neural/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Receptores de Lipoxinas/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Regulação para Baixo , Quimioterapia Combinada , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Interleucina-1beta/metabolismo , Masculino , NF-kappa B/metabolismo , Pentilenotetrazol/toxicidade , Ratos , Receptores de Formil Peptídeo/metabolismo
13.
Life Sci ; 171: 51-59, 2017 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-28062278

RESUMO

AIM: Oral mucositis is a common adverse effect of Methotrexate (MTX) that may limit its clinical use. Oxidative stress and apoptosis have been proposed to mediate MTX toxicity. The current study was conducted to assess the conceivable protective effect of α-lipoic acid (LA) against MTX induced toxicity on both buccal and lingual mucosae. MAIN METHODS: Thirty male Wistar rats were allocated into three groups; control, MTX-treated group subjected to single intraperitoneal injection of MTX (20mg/kg, i.p.) and LA- treated group treated with daily intraperitoneal injection of LA (10mg/kg, i.p.) for 5weeks before MTX injection (20mg/kg, i.p.). Rats were then sacrificed under anesthesia then their buccal and lingual mucosae were dissected out and processed for biochemical and histopathological studies. Biomarkers of oxidative stress and integrity of nuclear DNA (nDNA) were estimated. Immunostaining was used to determine Bax and PCNA localization. KEY FINDINGS: MTX-treated rats showed increased levels of MDA and fragmentation of DNA in addition to reduction of GSH levels and activities of catalase and SOD. Histological examination of MTX-treated rats demonstrated degenerative changes that involved the surface epithelium and lamina propria of their buccal and lingual mucosae. Immunohistochemical results of MTX-treated rats revealed strongly positive Bax and weakly positive PCNA staining reactivity of the nuclei of the basal and parabasal cells of the surface epithelium. However, LA significantly attenuated MTX-evoked alterations in the previous-stated parameters highlighting its antioxidant and anti-apoptotic potential. SIGNIFICANCE: LA may be suggested to be a prospective candidate to ameliorate MTX-induced oral mucositis.


Assuntos
Metotrexato/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Estomatite/prevenção & controle , Ácido Tióctico/farmacologia , Animais , Biomarcadores/metabolismo , DNA/efeitos dos fármacos , Diarreia/induzido quimicamente , Imuno-Histoquímica , Masculino , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/patologia , Ratos , Ratos Wistar , Estomatite/induzido quimicamente , Estomatite/patologia
14.
J Mol Endocrinol ; 53(1): 105-15, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24994913

RESUMO

Glucagon-like peptide 1 receptor (GLP1R) agonists, such as exendin-4, potentiate glucose-stimulated insulin secretion and are currently used in the management of type 2 diabetes. Interestingly, GLP1R agonists also have the ability to augment ß-cell mass. In this report, we provide evidence that in the presence of glucose, exendin-4 stimulates rodent islet cell DNA replication via the activation of ribosomal protein S6 kinase 1 (S6K1) and that this is mediated by the protein kinase B (PKB)-dependent activation of mTOR complex 1 (mTORC1). We show that activation of this pathway is caused by the autocrine or paracrine activation of the IGF1 receptor (IGF1R), as siRNA-mediated knockdown of the IGF1R effectively blocked exendin-4-stimulated PKB and mTORC1 activation. In contrast, pharmacological inactivation of the epidermal growth factor receptor has no discernible effect on exendin-4-stimulated PKB or mTORC1 activation. Therefore, we conclude that GLP1R agonists stimulate ß-cell proliferation via the PKB-dependent stimulation of mTORC1/S6K1 whose activation is mediated through the autocrine/paracrine activation of the IGF1R. This work provides a better understanding of the molecular basis of GLP1 agonist-induced ß-cell proliferation which could potentially be exploited in the identification of novel drug targets that increase ß-cell mass.


Assuntos
Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Complexos Multiproteicos/metabolismo , Peptídeos/farmacologia , Receptor IGF Tipo 1/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Peçonhas/farmacologia , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Exenatida , Técnicas de Silenciamento de Genes , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/citologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Receptores de Glucagon/agonistas , Transdução de Sinais/efeitos dos fármacos
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