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1.
Arch Med Sci ; 19(5): 1508-1519, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37732053

RESUMO

Introduction: Obesity is one of the most burdensome health problems and is closely linked to leptin resistance. The study examined whether an alternate-day high-fat diet (ADF) and/or GLP-1 agonist (exenatide) modulate brain leptin resistance caused by a high-fat diet (HFD). Material and methods: Sixty adult male mice were divided into 6 groups: (i) normal palatable diet (NPD), (ii) exenatide control (NPD received exenatide) (iii) HFD, (iv) ADF treated, (v) exenatide treated, (vi) ADF and exenatide treated. All animal groups were fed a HFD for 8 weeks, before they received treatment (ADF and/or exenatide) for 8 additional weeks. Body weight was assessed at the start and at the end of the experiment. Lipid profile, brain leptin and its receptor expression with the leptin-sensitive pathway, JAK2/STAT3/SOCS3/PTP1B, fasting blood glucose (FBG), serum insulin, liver metabolic handling via its regulators IRS1/PI3K/GLUT4 for hyperinsulinemia/obesity-induced PDK3/NAFLD2 modification, and liver enzymes were determined at the end of the experiment. Results: ADF and exenatide reduced body weight and FBG in HFD-obese mice (p < 0.05). The combined ADF and exenatide regimen enhanced the brain anorexic leptin/JAK2/STAT3 and attenuated the SOCS3/PTP1B pathway (p < 0.05). The ADF/exenatide anorexigenic brain effect also modulated liver glucose via IRS1/PI3K/GLUT4 expression (p < 0.05), attenuating NAFLD2 and PDK3 expression (p < 0.05). Liver enzymes and the histopathological profile confirmed the improvement. Conclusions: In HFD caloric consumption, a combination of ADF and GLP-1 agonist enhances the brain leptin anorexigenic effect with the improvement of the metabolic sequelae of hyperinsulinemia, hyperlipidemia and liver steatosis.

2.
Arch Med Sci ; 17(6): 1783-1796, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34900060

RESUMO

INTRODUCTION: Ischemic preconditioning (Ipre) provides protection against renal ischemia-reperfusion (I/R) injury with its associated remote organ damage. This study examined the enhancing protective effect of Ipre with levosimendan or cilostazol in I/R-induced kidney and lung injury in a rat model. MATERIAL AND METHODS: Rats were divided into: sham-operated, I/R control, Ipre control, I/R + cilostazol or levosimendan and Ipre + cilostazol or levosimendan. Drugs were given 30 min before left renal I/R or 4 cycles of Ipre just before renal ischemia. RESULTS: The Ipre combined with the implemented drugs enhanced physiological antioxidant defense genes including renal nuclear factor erythroid 2-related factor 2 (Nrf2) and its dependent genes heme oxygenase-1 (HO-1) and NADPH-quinone oxidoreductase-1 (NQO-1) and improved malondialdehyde and superoxide dismutase renal tissue levels. The combined effect improved I/R consequences for blood urea, creatinine, and creatinine clearance and improved blood oxygenation and metabolic acidosis. Moreover, the combination improved the renal soluble intercellular adhesion molecule (ICAM), tumor necrosis factor α (TNF-α) and interlukin-6 (IL-6) with histopathological improvement of tubular necrosis with a decrease in the apoptotic marker caspase-3 and an increase in the anti-apoptotic Bcl-2 expression. CONCLUSIONS: Cilostazol or levosimendan potentiates the renoprotective effect of Ipre against renal I/R injury, associated with upregulation of antioxidant genes Nrf2, HO-1, and NOQ-1 expression.

3.
Molecules ; 26(22)2021 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-34833950

RESUMO

Nifuroxazide is an antidiarrheal medication that has promising anticancer activity against diverse types of tumors. The present study tested the anticancer activity of nifuroxazide against Ehrlich's mammary carcinoma grown in vivo. Furthermore, we investigated the effect of nifuroxazide on IL-6/jak2/STAT3 signaling and the possible impact on tumor angiogenesis. The biological study was supported by molecular docking and bioinformatic predictions for the possible effect of nifuroxazide on this signaling pathway. Female albino mice were injected with Ehrlich carcinoma cells to produce Ehrlich's solid tumors (ESTs). The experimental groups were as follows: EST control, EST + nifuroxazide (5 mg/kg), and EST + nifuroxazide (10 mg/kg). Nifuroxazide was found to reduce tumor masses (730.83 ± 73.19 and 381.42 ± 109.69 mg vs. 1099.5 ± 310.83) and lessen tumor pathologies. Furthermore, nifuroxazide downregulated IL-6, TNF-α, NFk-ß, angiostatin, and Jak2 proteins, and it also reduced tumoral VEGF, as indicated by ELISA and immunohistochemical analysis. Furthermore, nifuroxazide dose-dependently downregulated STAT3 phosphorylation (60% and 30% reductions, respectively). Collectively, the current experiment shed light on the antitumor activity of nifuroxazide against mammary solid carcinoma grown in vivo. The antitumor activity was at least partly mediated by inhibition of IL-6/Jak2/STAT3 signaling that affected angiogenesis (low VEGF and high angiostatin) in the EST. Therefore, nifuroxazide might be a promising antitumor medication if appropriate human studies will be conducted.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Ehrlich/tratamento farmacológico , Hidroxibenzoatos/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Nitrofuranos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Carcinoma de Ehrlich/metabolismo , Feminino , Interleucina-6/metabolismo , Janus Quinase 2/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Neovascularização Patológica/metabolismo , Fator de Transcrição STAT3/metabolismo
4.
Mol Biol Rep ; 48(9): 6457-6470, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34431038

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is a consequence of diabetes mellitus (DM) and is associated with early changes in renal angiotensin II (ANG II). These changes were evaluated using ANG II blocker valsartan early from week two of diabetes (experiment I, renoprotective) and late from week nine of diabetes (experiment II, renotherapeutic) to the end of both experiments at week twelve. METHODS AND RESULTS: In both experiments, adult male Wister rats were divided into (i) vehicle group; (ii) valsartan received oral 30 mg/Kg/day; (iii) diabetic received single 50 mg/Kg intraperitoneal streptozotocin injection; (iv) renoprotection, diabetic rats received valsartan treated in experiments I and II. DM effects on urine albumin excretion, blood pressure, and renal ANG II were measured. Urinary nephrin, kidney injury molecule-1 (KIM-1), renal angiopoietin-like protein 2 (ANGPTL2), and toll-like receptor 4 (TLR 4) mRNA expression were tested. DM-initiated fibrotic markers integrin, α-smooth muscle actin expression, and collagen IV and apoptotic protein caspase 3 were tested. DM induced early changes starting from week four in the tested variables. At week twelve, in both experiments, valsartan intervention showed a significant reduction in ANG II, ANGPTL2, TLR 4 and integrin expression and improvement in albuminuria, blood pressure, urinary biomarkers, fibrotic and apoptotic markers. CONCLUSIONS: Changes leading to DN starts early in the disease course and ANG II reduction decreased the expression of ANGPTL2 and integrin which preserve the glomerular barrier. Blocking ANG II was able to decrease TLR 4 and inflammatory cytokines leading to decreasing DN.


Assuntos
Proteína 2 Semelhante a Angiopoietina/genética , Antagonistas de Receptores de Angiotensina/administração & dosagem , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/genética , Expressão Gênica/efeitos dos fármacos , NF-kappa B/genética , Substâncias Protetoras/administração & dosagem , Receptor 4 Toll-Like/genética , Valsartana/administração & dosagem , Angiotensina II/metabolismo , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/metabolismo , Rim/metabolismo , Masculino , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real/métodos , Receptor Tipo 2 de Angiotensina/metabolismo , Estreptozocina/administração & dosagem , Estreptozocina/efeitos adversos , Resultado do Tratamento
5.
Life Sci ; 235: 116824, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476305

RESUMO

AIMS: Leflunomide is a disease modifying anti-rheumatic drug (DMARD) beneficial in refractory cases of rheumatoid arthritis. Since leflunomide approval, hepatotoxicity and instructions of liver function monitoring have been recommended. The current work aimed to explore the possible role of inflammation in leflunomide-induced hepatotoxicity with a focus on the TLR4-mediated stimulation of PI3K/mTOR/NFκB pathway. MAIN METHODS: Forty-eight male albino mice were allocated into four different groups (n; 12 mice/group). Group (i): normal mice, Group (ii-iv) mice received escalating dosed/s of leflunomide (2.5, 5 or 10 mg/kg, p.o.) every 48 h for eight weeks. At the end of the study, mice were sacrificed, and blood samples were collected for determination of liver enzymes. Liver samples were collected; (1) formalin-fixed for histologic examination, (2) frozen for PI3K and mTOR genes PCR assays. KEY FINDINGS: Results indicated a significant elevation of liver enzymes in leflunomide-treated mice (10 mg/kg); AST and ALT activities were 218.17 ±â€¯6.83 U/L and 99.83 ±â€¯9.82 U/L versus 130.5 ±â€¯12.79 U/L and 44.72 ±â€¯3.58 U/L in the vehicle group. Additionally, histopathological examination revealed higher necro-inflammatory scores in leflunomide-treated mice. Immunohistochemistry indicated dose-dependent increased staining of TLR4 and caspase 3. Furthermore, leflunomide-treated mice (5 or 10 mg/kg) showed greater staining for NFκB compared to vehicle control. RT-PCR results revealed upregulations in genes expressing PI3K and mTOR by leflunomide. SIGNIFICANCE: The current study highlights the possible role of TLR4-PI3K/mTOR/NFκB in the pathogenesis of leflunomide-induced hepatic injury. A better understanding of mechanisms of leflunomide-induced hepatotoxicity may be of translational implication for the predictive, preventive and therapeutic purposes.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Leflunomida/efeitos adversos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Caspase 3/metabolismo , Relação Dose-Resposta a Droga , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
6.
Can J Physiol Pharmacol ; 97(7): 661-674, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31157553

RESUMO

Diabetes increases the sensitivity of myocardium to ischemic damage and impairs response of the myocardium to cardioprotective interventions. The present study aimed to elucidate the potential cardioprotective effect provided by ranolazine during myocardial infarction in nondiabetic and diabetic male rats. As AMP-activated protein kinase (AMPK) has been shown to be involved in the cellular response to ischemic injury, in this context, the present animal study evaluated the modulating role of ranolazine in the AMPK expression in isoprenaline-induced myocardial ischemic rat model. Male rats were divided into 2 experiments: experiment I and II (nondiabetic and diabetic rats) and assigned to normal control, saline control for isoprenaline, isoprenaline control, and ranolazine-treated groups. Ranolazine administration revealed effectiveness in attenuating the severity of isoprenaline-induced myocardial injury in both nondiabetic and diabetic rats as revealed by ECG signs, histopathological score, and apoptotic markers via abrogating the increments in the inflammatory and oxidative stress markers and modulating AMPK expression. Therefore, the current cardioprotective effect of ranolazine was, at least in part, mediated through inhibition of apoptosis and modulation of AMPK expression, encouraging considering the utility of ranolazine in protection from acute myocardial infarction.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Diabetes Mellitus Experimental/complicações , Isoproterenol/efeitos adversos , Infarto do Miocárdio/patologia , Ranolazina/farmacologia , Doença Aguda , Animais , Glicemia/metabolismo , Eletrocardiografia , Hemoglobinas Glicadas/metabolismo , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
7.
Can J Physiol Pharmacol ; 97(8): 708-720, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30970225

RESUMO

This study examined the effect of the aromatase inhibitor letrozole (0.5 mg/kg) alone or in combination with the angiotensin-receptor blocker valsartan (30 mg/kg) against streptozocin-induced diabetic nephropathy (DN) in hypogonadal (HG) rats for 12 weeks. First, we tested the HG effect on hormone levels, inflammatory cytokines, and oxidative stress in nondiabetic (ND) and diabetic (D) rats. HG was induced with the luteinizing hormone-releasing hormone antagonist cetrorelix (0.71 mg/kg). Diabetes enhanced hormonal hypogonadism and increased inflammation and oxidative stress. Next, experiments examined the effect of early letrozole and valsartan intervention on DN in HG rats. HG-ND and HG-D rats were treated with letrozole alone or in combination with valsartan. HG-D rats developed proteinuria and had increased blood urea nitrogen and creatinine, and histopathological evidence of renal injury, including glomerular hypertrophy and mesangial expansion. Valsartan alone or in combination with letrozole reduced proteinuria, improved renal functions, and reduced diabetes-induced renal angiotensin II. Both agents ameliorated nuclear factor kappa light chain enhancer of activated B cells, interleukin 1ß, interleukin 6, and tumor necrosis factor alpha levels. The combination decreased superoxide dismutase, malondialdehyde, and glutathione peroxidase levels, and prevented glomerular hypertrophy. In HG-D rats, valsartan reduced renal collagen IV and transforming growth factor-beta 1, especially when the testosterone level was corrected by letrozole. Thus, normalizing testosterone and inhibiting renal angiotensin II have a renoprotective effect against DN in HG male rats.


Assuntos
Angiotensinas/antagonistas & inibidores , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/tratamento farmacológico , Hipogonadismo/complicações , Angiotensina II/sangue , Animais , Colágeno Tipo IV/sangue , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Hemoglobinas Glicadas/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Letrozol/farmacologia , Letrozol/uso terapêutico , Hormônio Luteinizante/sangue , Masculino , NF-kappa B/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Testosterona/sangue , Fator de Crescimento Transformador beta1/sangue , Valsartana/farmacologia , Valsartana/uso terapêutico
8.
Life Sci ; 205: 113-124, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29763613

RESUMO

AIMS: Painful diabetic neuropathy (PDN) is one of the most frequent complications of diabetes and the current therapies have limited efficacy. This study aimed to study the neuroprotective effect of duloxetine, a serotonin noradrenaline reuptake inhibitor (SNRI), in a mouse model of diabetic neuropathy. MAIN METHODS: Nine weeks after developing of PDN, mice were treated with either saline or duloxetine (15 or 30 mg/kg) for four weeks. The effect of duloxetine was assessed in terms of pain responses, histopathology of sciatic nerve and spinal cord, sciatic nerve growth factor (NGF) gene expression and on the spinal expression of astrocytes (glial fibrillary acidic protein, GFAP) and microglia (CD11b). KEY FINDINGS: The present results highlighted that duloxetine (30 mg/kg) increased the withdrawal threshold in von-Frey test. In addition, both doses of duloxetine prolonged the licking time and latency to jump in the hot-plate test. Moreover, duloxetine administration downregulated the spinal expression of both CD11b and GFAP associated with enhancement in sciatic mRNA expression of NGF. SIGNIFICANCE: The current results highlighted that duloxetine provided peripheral and central neuroprotective effects in neuropathic pain is, at least in part, related to its downregulation in spinal astrocytes and microglia. Further, this neuroprotective effect was accompanied by upregulation of sciatic expression of NGF.


Assuntos
Antidepressivos/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Cloridrato de Duloxetina/uso terapêutico , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Animais , Astrócitos/metabolismo , Antígeno CD11b/biossíntese , Antígeno CD11b/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/biossíntese , Masculino , Camundongos , Neuralgia/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Nervo Isquiático/patologia , Síndrome da Serotonina/metabolismo , Medula Espinal/metabolismo , Coluna Vertebral/citologia
9.
Eur J Pharmacol ; 832: 81-89, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-29787773

RESUMO

Obesity constitutes a major worldwide problem in which hyperlipidemia and insulin resistance represents adverse metabolic consequences of it. The present study was conducted to elucidate the role of raspberry ketones (RKs) in controlling body weight gain, hyperlipidemia and insulin resistance in male obese rats through affecting the expression of various adipocytokines. As Aquaporin-7 is co-related with the expression of various adipocytokines and has recently emerged as a modulator of adipocyte metabolism, the present study evaluated the effect of RKs on adipose tissue expression of aquaporin-7(AQP7) in high-fat (HF) diet-fed rats. Groups of male rats were assigned to normal, HF diet-fed control rats and RKs-treated (250 and 500 mg/kg) groups. RKs administration effectively abrogated hyperlipidemia and oxidative burden and enhanced insulin sensitivity. In addition, treatment with RKs ameliorated adipose tissue and liver indices and the reduced adipocyte diameters. Moreover, administration of the low dose of RKs ameliorated the expression of apelin and its receptor, and visfatin with upregulating adiponectin expression compared to HF diet control rats. However, both doses effectively downregulated leptin expression. It was obvious that both RKs doses revealed effectiveness in upregulating the AQP7 expression. The present data suggest the promising therapeutic role of RKs in HF diet-induced obesity that is likely attributable, at least in part, to upregulation of AQP7 expression.


Assuntos
Adipocinas/genética , Tecido Adiposo/efeitos dos fármacos , Aquaporinas/genética , Butanonas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperlipidemias/tratamento farmacológico , Resistência à Insulina , Tecido Adiposo/metabolismo , Animais , Butanonas/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Hiperlipidemias/complicações , Hiperlipidemias/genética , Hiperlipidemias/patologia , Masculino , Obesidade/induzido quimicamente , Obesidade/complicações , Ratos , Ratos Wistar
10.
J Cardiovasc Pharmacol Ther ; 23(5): 456-471, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29685053

RESUMO

Hyperlipidemia and hypercoagulability states are linked with the increased risks of myocardial infarction (MI). Levosimendan has vasorelaxant and anti-aggregatory properties. The present study evaluated the anti-aggregatory and cardioprotective effects of levosimendan versus cilostazol in high-fat diet (HFD)-fed rats subjected to isoproterenol-induced MI. Rats were assigned to normal, HFD, HFD + isoproterenol, HFD + isoproterenol + cilostazol, and HFD + isoproterenol + levosimendan. The present study investigated the anti-aggregatory effect of both levosimendan and cilostazol and revealed that both drugs attenuated the severity of platelet aggregation. Moreover, both levosimendan and cilostazol revealed effectiveness in attenuating the severity of HFD/isoproterenol-induced myocardial injury as revealed by electrocardiogram signs, apoptotic markers, and histopathological score via counteracting the oxidative stress burden, increments in the expression of inflammatory mediators, and modulating nuclear factor kappa-B (NF-κB) and phosphatidylinositide 3-kinases (PI3K)/protein kinase B (Akt)/ mechanistic target of rapamycin (mTOR) pathway. It was obvious that levosimendan offered more cardioprotective properties than cilostazol. The study showed the relations between hyperlipedemia, hyperaggregability state, and myocardial injury with the modulation of NF-κB and PI3K/Akt/mTOR pathway.


Assuntos
Apoptose/efeitos dos fármacos , Cilostazol/farmacologia , Dieta Hiperlipídica , Isoproterenol , Infarto do Miocárdio/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Simendana/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Modelos Animais de Doenças , Frequência Cardíaca/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Lipídeos/sangue , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/patologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Ratos , Transdução de Sinais/efeitos dos fármacos
11.
Pharmacol Rep ; 70(3): 509-518, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29660654

RESUMO

BACKGROUND: In liver fibrosis, a major morbid and mortal disease, oxidative stress motivation of hepatic stellate cells (HSCs)-into myofibroblasts terminated in collagen deposition remain the key pathophysiological deal. Serotonin (5-HT) through its HSCs-expressed receptors, especially 5-HT2A and 7, shows crucial events in fibrogenesis of chronic liver diseases. Molecular hepatic oxidative stress-fibrotic roles of 5-HT2A and 7 receptors antagonists (ketanserin and SB-269970 respectively) are still a challenging issue. METHODS: Seven groups of adult male Wistar rats (n=10) were used. A carbon tetrachloride (CCl4) solution was injected intraperitoneally twice weekly for 6 weeks. On the 7th week, rats developed liver fibrosis were treated either by ketanserin (1mg/kg/day, ip) or SB-269970 (2mg/kg/day, ip) for 14days. Survival rates, and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in addition to hepatic malondialdehyde (MDA) and reduced glutathione (GSH) levels, superoxide dismutase (SOD) and catalase (CAT) activities, and transforming growth factor-beta1 (TGF-ß1) and procollagen type I N-terminal propeptide (PINP) levels, beside the hepatic histopathological fibrotic changes, were evaluated. RESULTS: In CCl4-challenged rats, each therapeutic approach showed significant reductions in elevated serum ALT, and AST levels, hepatic MDA, TGF-ß1, and PINP levels, and histopathological hepatic fibrotic scores as well as significant elevations in survival rates, reduced hepatic GSH levels, and SOD, and CAT activities. Remarkably, significant ameliorative measurements were observed in SB-269970 treated group. CONCLUSION: Blockade of 5-HT2A and 7 receptors each alone could be a future reliable therapeutic approach in liver fibrosis through a reduction in oxidative stress/TGF-ß1-induced HSCs activation pathway.


Assuntos
Tetracloreto de Carbono/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Ketanserina/farmacologia , Cirrose Hepática/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Sulfonamidas/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Células Estreladas do Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Masculino , Malondialdeído/metabolismo , Fitoterapia/métodos , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Taxa de Sobrevida
12.
Eur J Pharmacol ; 814: 114-123, 2017 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-28821451

RESUMO

The neurotransmitter 5-hydroxytryptamine (5-HT) is involved in regulation of local tissue inflammation and repair through a set of receptors (5-HT1-7 receptors), which are expressed in the lung. Considering the protective importance of 5-HT receptor antagonists against development of pulmonary fibrosis, we evaluated whether 5-HT7 receptor antagonist (SB-269970) modulates lung inflammatory and fibrogenic processes in comparison with 5-HT2A/B receptor antagonist (terguride), in bleomycin (BLM)-induced idiopathic pulmonary fibrosis (IPF) model. IPF model induced by a single dose of intra-tracheal BLM instillation (5mg/kg), and rats were treated with intraperitoneal injection of SB-269970 (1mg/kg day) or terguride (1.2mg/kg/d). The experiment was carried out on two separate sets of rats that were killed at day 7th and day 21st to evaluate the endpoint of the IPF inflammatory and fibrogenic phases, respectively. During the inflammatory phase 5-HT2A/B and 5-HT7 receptor antagonists attenuated the BLM-induced increase in the lung fluid content, the inflammatory cytokines levels and oxidative stress burden. In the fibrogenic phase, both SB-269970 and terguride reduced the serotonin concentrations in lung homogenates and significantly protected against IPF fibrogenic phase by attenuating collagen deposition and mRNA expression of both transforming growth factor-ß1 (TGF- ß1), and procollagen type Ӏ (PINP). 5-hydroxytryptamine 5-HT7 receptor antagonist showed more benefits than 5-HT2A/B receptor antagonist on the deleterious effects accompanied BLM instillation. The present study showed involvement of 5-HT7 receptor in the pathophysiology of BLM-induced IPF in rats and identified it as a potential therapeutic target in lung fibrotic disorders.


Assuntos
Bleomicina/efeitos adversos , Regulação para Baixo/efeitos dos fármacos , Lisurida/análogos & derivados , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Receptores de Serotonina/metabolismo , Sulfonamidas/farmacologia , Animais , Colágeno/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Lisurida/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Fenóis/uso terapêutico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos , Sulfonamidas/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Água/metabolismo
13.
Int Immunopharmacol ; 44: 72-86, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28088698

RESUMO

Diabetes has been listed as a risk factor for various types of cancer. Cancer cell development can be promoted by increased levels of IGF-1 and hyperinsulinemia that are associated with diabetes type II. Metformin is an anti-diabetic agent and its potential antitumor impact has become the objective of numerous studies. In this vein, we hypothesize that using metformin in diabetes type II mice may synergistic with carboplatin for reducing the risk of cancer. Therefore, the study aimed to evaluate the in vivo antitumor activity of metformin against solid EAC tumor growth in female diabetic mice and its potential pro-apoptotic and anti-proliferative effects with clarification of its inconclusive biological mechanisms. Mice were assigned into nine groups; normal control, diabetic control, diabetic plus EAC control, EAC control, and treated groups received carboplatin and/or metformin (100, 200mg/kg). Metformin administration especially with high dose potentiated the antitumor activity of carboplatin displayed by increased pro-apoptotic activators "caspase-3 and bax" and reduced anti-apoptotic protein bcl-2. This was confirmed by the histopathological scores. Moreover, the combination therapy was effective in attenuating the expression of the pro-angiogenic mediator "VEGF" and the microvessel density as revealed by the CD34. Additionally, this combination down-regulated the high levels of the mutagenic element "IGF-1" and its receptor expression, and attenuated the intensity of inflammatory mediators. In conclusion, it was found that metformin therapy could enhance apoptotic marker, and suppress the neovascularization and proliferation process. This clarified the ability of metformin to support carboplatin activity in reducing tumor progression in type II diabetes.


Assuntos
Antineoplásicos/uso terapêutico , Carboplatina/uso terapêutico , Carcinoma de Ehrlich/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Fator de Crescimento Insulin-Like I/metabolismo , Metformina/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Carcinoma de Ehrlich/complicações , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Sinergismo Farmacológico , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Camundongos Endogâmicos , Neovascularização Patológica/complicações , Receptor IGF Tipo 1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Biomed Pharmacother ; 82: 106-16, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27470345

RESUMO

Colon cancer is the third leading cause of cancer mortality worldwide, which results from interactions of different factors. It is frequently a pathological consequence of persistent inflammation. Diabetes affects several cancers and is positively correlated with the incidence of colon cancer. This study aimed to study the effect of exenatide in ameliorating inflammation, angiogenesis and cell proliferation in 1,2-dimethyl hydrazine (DMH) induced colorectal carcinoma in diabetic mice. Mice were randomly allocated into six groups, 8 mice each. Group 1: vehicle control group. Group 2: diabetic control group. Group 3: DMH control group: diabetic mice treated with DMH (20mg/kg/week,s.c.) for 15 week. Group 4: DMH-cisplatin group: mice received cisplatin (4mg/kg/week, i.p.). Groups 5 & 6: DMH-exenatide (10 and 20µg/kg) group: mice received exenatide (10 or 20µg/kg/day,s.c.), respectively. The present results highlighted an increase in angiogenic markers and cell proliferation in the DMH-diabetic group in comparison with the control group with greater expression of endothelial marker (CD34) and Ki-67 in colon tissue. Monotherapy with cisplatin or exenatide (10 and 20µg/kg) downregulated these markers to different extents. The current results provided evidence that exenatide represents a promising chemopreventive effect against DMH-induced colon carcinogenesis in diabetic mice, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms.


Assuntos
Neoplasias do Colo/irrigação sanguínea , Neoplasias do Colo/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Peptídeos/uso terapêutico , Peçonhas/uso terapêutico , 1,2-Dimetilidrazina , Animais , Antígenos CD34/metabolismo , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/sangue , Neoplasias do Colo/induzido quimicamente , Ciclo-Oxigenase 2/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Exenatida , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interleucina-6/sangue , Antígeno Ki-67/metabolismo , Masculino , Camundongos , Neovascularização Patológica/patologia , Peptídeos/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sobrevida , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Peçonhas/farmacologia
15.
Int Immunopharmacol ; 24(1): 80-7, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25488045

RESUMO

Methotrexate (MTX) is a cornerstone disease modifying anti-rheumatic drug. One of its major drawbacks is hepatotoxicity, resulting in poor compliance of therapy. Coenzyme Q10 (CoQ10) is an antioxidant and anti-inflammatory compound, possessing both anti-arthritic and hepatoprotective potential. The present study was carried out to evaluate the effect of CoQ10 (10mg/kg) alone and in combination with MTX (2mg/kg) on the progression of adjuvant-induced arthritis in rats, and to elucidate the potential properties of CoQ10 in ameliorating MTX-induced liver damage in rats. Rats were assigned to; normal, arthritic, MTX treated, CoQ10 treated or a combination of MTX and CoQ10. CoQ10 administration potentiated the antiarthritic effect of MTX. Moreover, the combination therapy was effective in attenuating the severity of MTX-induced liver damage displayed by the improvement in hepatospecific serum markers and confirmed by the histo-pathological evaluation. Additionally, it attenuated the hepatic oxidative stress and the intensity of inflammatory mediators associated with MTX administration as evident by the regulation of oxidant/anti-oxidant balance and the inhibitory effects on TNF-α and IL-6 levels. These results revealed that CoQ10 can serve as a useful adjuvant and promote the safe use of MTX in the management of arthritis, not only by potentiating the antiarthritic effect of MTX, but also by alleviating MTX-induced hepatocellular injury.


Assuntos
Antioxidantes/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Experimental/tratamento farmacológico , Fígado/efeitos dos fármacos , Metotrexato/administração & dosagem , Membrana Sinovial/efeitos dos fármacos , Ubiquinona/análogos & derivados , Animais , Células Cultivadas , Sinergismo Farmacológico , Quimioterapia Combinada , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Membrana Sinovial/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Ubiquinona/administração & dosagem
16.
Pharmacology ; 94(1-2): 41-50, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25171542

RESUMO

AIM: The identification and application of stem cells to treat central nervous system disorders represent a dramatic evolution and expansion into the realms of neurorestoration and neuroregeneration. The aim of this study was to assess the possible ameliorative effect of mesenchymal stem cells (MSCs) in comparison to gabapentin on pentylenetetrazole (PTZ)-induced epileptogenesis and its consequences. METHODS: Thirty-two rats were divided into 4 equal groups; group I: saline-injected group, group II: PTZ group, which received 13 intraperitoneal (i.p.) injections of PTZ (30 mg/kg) 3 times/week, groups III and IV: groups received PTZ and were treated with i.p. gabapentin (200 mg/kg) 60 min before each PTZ injection (group III) or a single intravenous injection of 10(6) MSCs/rat at day 22 (group IV). RESULTS: Treatment with either gabapentin or MSCs demonstrated a significant improvement in the PTZ-induced epileptogenesis and its severe consequences, i.e. oxidative stress damage, motor and cognitive impairments. Moreover, they enhanced the GABA neurotransmitter levels. Meanwhile, MSC administration to chronic epileptic rats afforded more ameliorative effects on PTZ-induced epileptogenesis and its severe consequences in comparison to gabapentin. CONCLUSION: These data indicate that MSCs were superior to gabapentin in ameliorating PTZ-induced epileptogenesis and verified the potential use of MSCs in seizure control, motor and cognitive impairments, oxidative stress, and the impairing GABA level in experimentally induced epilepsy.


Assuntos
Aminas/farmacologia , Ácidos Cicloexanocarboxílicos/farmacologia , Epilepsia/prevenção & controle , Transplante de Células-Tronco Mesenquimais/métodos , Convulsões/prevenção & controle , Ácido gama-Aminobutírico/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Gabapentina , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Pentilenotetrazol , Ratos , Ratos Wistar , Cordão Umbilical/citologia , Ácido gama-Aminobutírico/metabolismo
17.
J Pharm Sci ; 103(2): 602-12, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24395640

RESUMO

The present study aimed to develop optimized quercetin (QT)-loaded self-nanoemulsifying drug delivery system (SNEDDS) that offers protective effect against liver damage. Solubility study of QT in different oils, surfactants, and cosurfactants was performed. Ternary phase mixtures of the selected components were constructed to select a suitable range for each component. Experimental mixture design was utilized to optimize SNEDDSs that possess smaller globule size with enhanced emulsification and dissolution rates. QT SNEDDS was compared with QT suspension control and silymarin. In vivo evaluation and histopatholgical study of the selected QT SNEDDSs were achieved after administration of paracetamol over dosage to albino rats. Two optimized formulations were selected; one based on Sefsol and the other based on linoleic acid as an oily phase, Tween(®) 80 and polyethylene glycol 400 as surfactant and cosurfactant, respectively. Both Sefsol and linoleic-acid-optimized SNEDDS formulation showed no symptoms associated with toxicity and offered protective effect against paracetamol-induced hepatotoxicity by scavenging free radicals, attenuating lipid peroxidation, and enhancing the activity of antioxidants. The histopatholgical observations revealed that the inflammatory infiltrations induced by paracetamol were significantly ameliorated.


Assuntos
Acetaminofen/toxicidade , Analgésicos não Narcóticos/toxicidade , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Substâncias Protetoras , Quercetina/farmacologia , Animais , Antioxidantes/administração & dosagem , Antioxidantes/metabolismo , Química Farmacêutica , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Emulsões , Peroxidação de Lipídeos/efeitos dos fármacos , Testes de Função Hepática , Nanopartículas , Tamanho da Partícula , Polietilenoglicóis , Polissorbatos , Quercetina/administração & dosagem , Ratos , Silimarina/farmacologia , Solubilidade , Espectrofotometria Ultravioleta , Tensoativos
18.
Pharmacol Rep ; 64(5): 1223-33, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23238478

RESUMO

BACKGROUND: Diabetic nephropathy is a serious diabetic complication that leads to end stage renal disease. Cell therapies with human embryonic and specific adult stem cells have emerged as an alternative management for various diseases. METHODS: To test this hypothesis, the present study was conducted to compare effect of MNCs treatment (iv injection once in the tail vein for diabetic rats in a dose of 150 x 10(6) MNCs cells/rat) versus pioglitazone (10 mg/kg, for eight weeks) on improving the renal structure and function changes and reducing laminin deposition associated with STZ-induced diabetic nephropathy in rats. RESULTS: Treatment with pioglitazone orMNCs, demonstrated a significant improvement in the STZ-induced renal functional and structural changes in comparison with diabetic control group. Additionally, our histopathological and immunohistochemical studies confirm these results. Meanwhile, MNCs treated group exhibited more improvement in all studied parameters as compared to pioglitazone treated group. CONCLUSION: These data indicate that MNCs treatment was superior to pioglitazone in controlling hyperglycemia, improving the renal structure and function changes and reducing renal laminin expression associated with STZ-induced diabetic nephropathy in rats.


Assuntos
Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Leucócitos Mononucleares/fisiologia , Tiazolidinedionas/uso terapêutico , Animais , Glicemia/análise , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Laminina/metabolismo , Masculino , Pioglitazona , Ratos , Estreptozocina
19.
Eur Rev Med Pharmacol Sci ; 16(5): 600-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22774400

RESUMO

OBJECTIVES: Diabetes mellitus (DM) causes organ dysfunction and increases the sensitivity of organs to damages.To test this hypothesis, we used renal ischemia/reperfusion (I/R) experiment to evaluate the renoprotective activity of telmisartan versus pioglitazone on I/R induced renal damage in diabetic rats. MATERIALS AND METHODS: Renal I/R was performed in both normal and diabetic rats. The protocol comprised ischemia for 45 minutes followed by the reperfusion for 24 hours and a treatment period of two weeks before induction of ischemia. RESULTS: Renal I/R in both control and diabetic rats induced marked renal dysfunction associated with a significant increase in the arterial pressure, tumor necrosis factor alpha (TNF-alpha) levels, and the malondialdehyde formation (MDA). The activities of the anti-oxidant enzymes such as reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were found to be decreased significantly compared to control rats. Diabetic animals that underwent renal I/R exhibited a significant increase in all the studied parameters with a reduction in the anti-oxidant enzymes as compared to non-diabetic rats. Histo-pathological studies confirm these results. Treatment with pioglitazone or telmisartan demonstrated a significant improvement in the reperfusion-induced renal injury in comparison with diabetic I/R group, without difference between the two treated groups. Therefore, the treatment with pioglitazone or telmisartan have the same corrective effect. CONCLUSIONS: Type 2 diabetes had exaggerated renal I/R injury in STZ-NAD induced diabetes. Telmisartan treatment is equieffective as pioglitazone in attenuating acute I/R-induced renal injury in diabetic rats by a modification in the oxidative stress and the inflammation.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Hipoglicemiantes/farmacologia , Rim/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Tiazolidinedionas/farmacologia , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Catalase/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/fisiopatologia , Glutationa/metabolismo , Mediadores da Inflamação/sangue , Rim/irrigação sanguínea , Rim/metabolismo , Rim/fisiopatologia , Peroxidação de Lipídeos/efeitos dos fármacos , Peróxidos Lipídicos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pioglitazona , Ratos , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/fisiopatologia , Superóxido Dismutase/metabolismo , Telmisartan , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangue
20.
Eur J Pharmacol ; 689(1-3): 186-93, 2012 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-22659583

RESUMO

Idiopathic pulmonary fibrosis is the most prevalent chronic fibrosing lung disease. Peroxisome proliferator-activated receptors-gamma agonists provide potential therapy for fibrotic diseases of the lung. Peroxisome proliferator-activated receptors-alpha agonists may be helpful in the treatment of lung inflammatory diseases, however their therapeutic potential on the "fibro-proliferative" process and extracellular matrix accumulation in idiopathic pulmonary fibrosis has been less well studied. So, the present study was conducted to evaluate the anti-fibrotic effects of fenofibrate (peroxisome proliferator-activated receptors-alpha agonist) alone and in combination with rosiglitazone (peroxisome proliferator-activated receptors-gamma agonist) on lung injury induced by bleomycin administration. Oral administration of either rosiglitazone (5 mg/kg/d) or fenofibrate (100 mg/kg/d) for 14 days, attenuated the severity of bleomycin-induced lung injury and fibrosis through decreasing lung water contents, lung fibrotic grading, lung hydroxyproline contents and lung transforming growth factor-beta1 levels; with no significant difference between them. Combined low doses of rosiglitazone (1 mg/kg/d) and fenofibrate (30 mg/kg/d) provided more benefits than full separate doses of each on the deleterious effects accompanied bleomycin administration. These findings suggested the potential use of peroxisome proliferator-activated receptors-alpha ligands as anti-fibrotic agents in lung fibrosis. Additionally, the concurrent administration of fenofibrate and rosiglitazone in low doses has synergistic effect and enhanced the beneficial effects afforded by either fenofibrate or rosiglitazone.


Assuntos
Antifibrinolíticos/administração & dosagem , Bleomicina/toxicidade , Fenofibrato/administração & dosagem , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Tiazolidinedionas/administração & dosagem , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Quimioterapia Combinada , Masculino , Fibrose Pulmonar/patologia , Ratos , Rosiglitazona , Resultado do Tratamento
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