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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.
Nutr Cancer ; : 1-12, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33570439

RESUMO

INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Medemia argun (MA) fruits have been found to possess proanthocyanidins (PACs), having antioxidant activity. Methods: Intraperitoneal (IP) diethyl nitrosamine (DENA; 200 mg/kg, once) and carbon tetra chloride (CCl4, 3 ml/kg/week, subcutaneously, for 6 weeks) induced HCC in rats. Animals groups: Group I; received vehicle (control). Group II; received MA seed extract, 100 mg/kg (twice/week) for 12 weeks, IP. Group III; received carcinogenic agents only. Group IV; received MA for two weeks before administration of DENA/CCl4 till the end of the experiment. The total period of the experiment was three months. Results: DENA and CCl4 induced HCC, elevated serum alpha-fetoprotein (AFP), liver size, weight, tissue lymphocytic infiltration, nuclear/cytoplasmic ratio, collagen fiber and polysaccharide deposition, cellular proliferation, excessive pro-apoptotic caspase-3 accumulation, disrupted apoptosis. MA prior to DENA/CCl4, significantly protected liver against cancer progression, indicated by serum enzymes, antioxidant markers(glutathione, nitric oxide, and depressed malondialdehyde contents) in the MA-pretreated group, compared to the HCC one, without apparent useful action on superoxide dismutase activity, enhanced apoptosis in liver, through increased casapase-3 expression. The HCC group showed decreased antioxidant defense and BAX/Bcl-2 ratio. Conclusions: This study assumes that MA has a chemo-preventive effect against hepatocarcinogenesis.

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.
Life Sci ; 253: 117725, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32348835

RESUMO

AIMS: Non-alcoholic fatty liver disease (NAFLD) is a common liver disease. This study aimed to evaluate the role of exenatide compared with metformin in halting the progression of fatty liver stimulated by a high-fat diet (HiFD) in rats. MAIN METHODS: Thirty male Wistar rats were allocated into 6 groups, 5 rats per each group. Group I: maintained on normal diet (normal group) for fourteen weeks. The other five groups were kept on HiFD throughout the experiment, HiFD was administered beside pharmacological treatments/or vehicle. Group II: (NAFLD control group), group III: received metformin (60 mg/kg/day, P.O.), group IV-VI: received exenatide (10, 20, and 40 µg/kg/day, S.C.) respectively for 7 weeks. At the end of the therapeutic period, fasting blood glucose was determined, and body weight was registered. Rats were sacrificed, and blood samples were taken to measure serum insulin, lipids, and liver enzymes. The liver index and homeostasis model of insulin resistance (HOMA-IR) index were calculated. Further, livers were dissected for histopathological examination and Western blot analysis. KEY FINDINGS: NAFLD control group showed hyperglycemia, hyperinsulinemia, increased liver enzymes, hypertriglyceridemia, elevated hepatic lipid peroxides, and inflammatory mediators (interlukin 6, nuclear factor-κB, tumor necrosis factor-α and Toll-like receptor4) in addition to hepatic fatty degeneration. In a dose-dependent manner, exenatide significantly improved most of the above mentioned markers in comparsion with NAFLD at P≤0.05. SIGNIFICANCE: The current results suggest that exenatide is equivalent to metformin in controlling insulin resistance, body weight gain, improving liver function, suppressing inflammation, and attenuating NAFLD progression in male rats.


Assuntos
Exenatida/farmacologia , Hipoglicemiantes/farmacologia , Inflamação/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Progressão da Doença , Relação Dose-Resposta a Droga , Exenatida/administração & dosagem , Hipoglicemiantes/administração & dosagem , Inflamação/patologia , Resistência à Insulina , Masculino , Metformina/farmacologia , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
5.
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
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.
Anat Histol Embryol ; 47(6): 544-550, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30058209

RESUMO

Progesterone receptors (PR) are necessary to mediate the biological effects of progesterone and are integral to the regulation of a number of different aspects of reproduction in mammals including ovulation of the oocyte, implantation of the conceptus and maintenance of pregnancy. This study investigated the expression and localization of progesterone receptors in the uterine wall of both pregnant and cyclic (nonpregnant) camels. Uterine tissue samples were collected from healthy animals and processed for routine histological and immunohistochemical staining techniques to reveal nuclear PR. Demonstration of PR was performed by indirect immunohistochemical techniques using monoclonal antibodies raised against human PR. Immunolocalization of PR was more intense in all four endometrial zones (I-IV) as well as the myometrium of non pregnant (cyclic) animals (animals with newly formed corpus luteum). In contrast, PR immunostaining in both the endometrium and the myometrium was greatly reduced in pregnancy, particularly in the latest stage examined (approximately 366 days of gestation). In conclusion, a better understanding of the expression of steroid hormones and their receptors, including progesterone and the PR is critical to improving the reproductive health and pregnancy in the domesticated dromedary camel.


Assuntos
Endométrio/metabolismo , Ciclo Estral/metabolismo , Imunofluorescência/veterinária , Miométrio/metabolismo , Receptores de Progesterona/análise , Útero/metabolismo , Animais , Camelus , Corpo Lúteo/metabolismo , Feminino , Gravidez , Progesterona/metabolismo
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.
Cancer Chemother Pharmacol ; 80(4): 745-753, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28785995

RESUMO

PURPOSE: Doxorubicin (DOX) is a highly active antineoplastic agent; however, its clinical use is limited due to associated cardiotoxicity. This study was performed to evaluate the beneficial effects of allicin, a dietary garlic active constituent against DOX-induced cardiotoxicity. METHODS: Forty male Swiss albino mice were divided into five groups, which received normal saline, oral allicin (20 mg kg-1 once daily), intraperitoneal DOX (on the 7, 9 and 11th day of the experiment), or DOX plus once daily allicin at 10 or 20 mg kg-1. Sera were collected for evaluation of cardiac injury markers and proinflammatory cytokines. Additionally, heart tissue spacemen were harvested for determination of oxidative stress markers, as well as for histopathological examination and immunohistochemical analysis. RESULTS: DOX administration induced significant (p < 0.05) reductions in cardiac tissue level of reduced glutathione and activities of antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase). Moreover, it induced significant (p < 0.05) elevations in cardiac tissue concentrations of nitric oxide and malondialdehyde as well as serum levels of cardiac injury biomarkers (lactate dehydrogenase, creatine kinase, and creatine kinase-MB) and proinflammatory cytokines (interleukin-1ß, and tumor necrosis factor-alpha). The histopathological examination showed necrotic and degenerative changes in the cardiac tissue, while immunohistochemical analysis revealed marked myocardial expression of activated caspase-3 and cyclooxygenase-2, following DOX adminstration. Allicin pretreatment significantly improved (p < 0.05) all examined parameters, and restored the cardiac architecture. CONCLUSION: The current study demonstrated that allicin effectively mitigates cardiac oxidative damage, apoptosis and inflammation, induced by acute DOX intoxication. Therefore, allicin could be a promising cytoprotective agent against DOX cardiotoxicity.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Antioxidantes/farmacologia , Cardiotoxicidade/prevenção & controle , Doxorrubicina/toxicidade , Ácidos Sulfínicos/farmacologia , Animais , Antioxidantes/administração & dosagem , Apoptose/efeitos dos fármacos , Biomarcadores/sangue , Cardiotoxicidade/etiologia , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Masculino , Malondialdeído/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácidos Sulfínicos/administração & dosagem
10.
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
11.
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
12.
Naunyn Schmiedebergs Arch Pharmacol ; 390(5): 483-492, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28124089

RESUMO

Celecoxib, a selective cyclooxygenase-2 inhibitor, produces thrombotic events in patients predisposed to cardiovascular risk factors. One theory reported an increase in endothelial expression of tissue factor (TF) as a predisposing factor. This work explored the effect of evening primrose oil (EPO), a source of prostaglandin E1, and forskolin (a cyclic adenosine monophosphate stimulator) against the prothrombotic effect of celecoxib in mice. Lipopolysaccharide mouse model of endotoxemia was used to induce an upregulation of TF activity. Male mice received celecoxib (25 mg/kg), celecoxib plus EPO, or celecoxib plus forskolin for 4 weeks and then subjected to a prothrombotic challenge in the form of an intraperitoneal injection of lipopolysaccharide. Results showed an increase in plasma TF activity, endothelial TF expression, and thrombin-antithrombin (TAT) but lower antithrombin III (ATIII) level in mice that received celecoxib in comparison to those that received the vehicle. Adding EPO or forskolin to celecoxib regimen significantly decreased the prothrombotic effect of celecoxib. A positive correlation (r = 0.8501) was found between TF activity and TAT. Co-administration of EPO or forskolin decreased the activity of TF and mitigated the prothrombotic effect of celecoxib. Therefore, these combinations may have the utility to abrogate the prothrombotic adverse effect of celecoxib in clinical setting.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Celecoxib , Colforsina/farmacologia , Inibidores de Ciclo-Oxigenase 2 , Endotoxemia/induzido quimicamente , Fibrinolíticos/farmacologia , Ácidos Linoleicos/farmacologia , Lipopolissacarídeos , Óleos Vegetais/farmacologia , Tromboplastina/metabolismo , Trombose/prevenção & controle , Ácido gama-Linolênico/farmacologia , Animais , Antitrombina III/metabolismo , Modelos Animais de Doenças , Endotoxemia/sangue , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Peptídeo Hidrolases/sangue , Trombose/sangue , Trombose/induzido quimicamente , Regulação para Cima
13.
Toxicol Rep ; 3: 685-695, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28959593

RESUMO

Environmental xenoestrogen contaminant bisphenol A (BPA), widely used as a monomer in the manufacture of epoxy, polycarbonate plastics and polystyrene resins. However, exposure to BPA has raised concerns, and the negative impacts of its exposure on reproduction have been controversial. The purpose of this work was directed to assess the potential adverse effects of BPA on dam rats and their first generation females in a comparative toxicological study. Fifteen pregnant female rats were classified into three equal groups; first group was orally administered corn oil and served as control (group1), second and third groups were orally administered BPA at dose levels of 50 and 200 mg/kg b.wt respectively (groups 2 & 3). The administration was carried out daily from zero day through the gestation period (21 days) until the last day of the lactation period (21days) and was extended after weaning for three months, in which female off springs of first generation (F1) of the three groups of dams were classified into; F1control group (group 4), F1 group treated with low dose of BPA (group 5) and F1 group treated with high dose of BPA (group 6) which continued in daily oral administration of BPA at the same previously mentioned doses for three months. The results elucidated a clear marked DNA fragmentation in the ovary of both dam and F1 female groups especially at higher examined concentration. Also, the data demonstrated a significant increase in the serum levels of GGT, ALP, glucose, total cholesterol, triglycerides, LDH and also in the serum level of estrogen hormone. Meanwhile, our study recorded a significant decrease in total protein, catalase, GST, HDL and FSH hormone in both treated dam and F1 female groups which was more significantly decreased in F1 female rats. Moreover, our experiment illustrated up-regulation in the immunoexpression of ERß in ovary, uterus and liver of dam and F1 female groups. The histopathological investigation showed degeneration in the epithelial lining of ovarian follicles, submucosal leukocytic infiltration and increase in vaculation of hepatic cells with proliferation of kupffer cells. The lesions were more sever in groups 3 & 6 of both dam and their F1 females. Our data speculated that long- term exposure to BPA at 50 and 200 mg/kg.b.wt. depicted total genomic damage, significant alterations in liver enzymes, lipid profile, antioxidant enzymes and reproductive hormones with up-regulation in the expression of ERß which were more significantly perturbed in group 3 and group 6 of both dam and F1 female rats.

14.
Eur Rev Med Pharmacol Sci ; 13(2): 81-93, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19499842

RESUMO

In renal ischemia reperfusion (V/R), opening of adenosine-triphosphate (ATP)-sensitive potassium (K(ATP)) channels results in massive influx of neutrophils in both renal and lung tissues. Our study was focused on the role of ATP-dependent potassium channel modulators, glimepiride and glibenclamide on I/R induced renal injury in rats. Additionally we evaluated their effects on normal heart and on ischemic reperfused heart subjected to ischemic preconditioning protection afforded by diazoxide. To test this hypothesis, we used renal I/R and cardiac I/R experiment. Renal ischemia reperfusion induced marked renal dysfunction associated with significant increase in arterial pressure, TNF-alpha levels, superoxide anion production, and myeloperoxidase activity. Treatment with glibenclamide or glimepiride, demonstrated a significant improvement in the reperfusion-induced injury in both kidney and lung. Glimepiride has no effect on superoxide anion production. However glibenclamide induced a significant improvement in these measurements as compared to glimepiride group. Before coronary artery ligation, neither diazoxide nor glimepiride pretreatment influenced significantly the electrocardiographic parameters in comparison with control group. Conversely, glibenclamide supplementation induced a significant elevation in these parameters. After left coronary artery ligation, reperfusion of the ischemic hearts caused a significant elevation in the measured electrocardiographic parameters. These elevations were significantly ameliorated by the pretreatment with diazoxide. In conclusion, the administration of glibenclamide significantly abolished the protective effects of diazoxide, while the pretreatment with glimepiride didn't abolish it. So, glimepiride offers some promise for therapy of renal I/R with minimizing the undesirable cardiac side effects.


Assuntos
Glibureto/farmacologia , Canais KATP/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Compostos de Sulfonilureia/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Diazóxido/farmacologia , Modelos Animais de Doenças , Eletrocardiografia , Glibureto/efeitos adversos , Precondicionamento Isquêmico Miocárdico/métodos , Rim/efeitos dos fármacos , Rim/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Bloqueadores dos Canais de Potássio/efeitos adversos , Ratos , Traumatismo por Reperfusão/fisiopatologia , Traumatismo por Reperfusão/prevenção & controle , Compostos de Sulfonilureia/efeitos adversos , Superóxidos/metabolismo , Vasodilatadores/farmacologia
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