RESUMEN
We aimed to investigate the acute and chronic effects of carvedilol on insulin resistance in high-fructose, high-fat diet (HFrHFD) - fed mice and the implication of the ß-arrestin2 pathway. The acute effect of carvedilol (10 mg/kg, i.p.) on glucose tolerance and hepatic lipid signaling in normal and insulin resistant mice was investigated. Then, the chronic effect of carvedilol on insulin resistance and dyslipidemia in HFrHFD-fed mice was examined. Changes in ß-arrestin2 and its downstream signals in liver, skeletal muscle, and adipose tissue were measured. This involved measuring phosphatidylinositol 4,5-bisphosphate (PIP2) and diacylglycerol (DAG) levels and protein kinase B (AKT) activity. Carvedilol acutely reduced fasting blood glucose levels in both normal and insulin resistant mice without significantly affecting the glucose tolerance. These acute effects were associated with increased hepatic PIP2 but decreased hepatic DAG levels. Chronic administration of carvedilol significantly ameliorated insulin resistance and dyslipidemia in HFrHFD-fed mice. These chronic effects were associated with increased ß-arrestin2, PIP2, and AKT activity levels but decreased DAG levels in the classical insulin target tissues. In conclusion, carvedilol acutely maintains glucose homeostasis and chronically ameliorates insulin resistance and dyslipidemia in HFrHFD-fed mice. The insulin sensitizing effects of carvedilol are highly correlated with the upregulation of ß-arrestin2 pathway.
Asunto(s)
Carvedilol/administración & dosificación , Carvedilol/farmacología , Dieta Alta en Grasa/efectos adversos , Carbohidratos de la Dieta/efectos adversos , Dislipidemias/tratamiento farmacológico , Dislipidemias/etiología , Fructosa/efectos adversos , Glucosa/metabolismo , Resistencia a la Insulina/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Arrestina beta 2/metabolismo , Animales , Carbohidratos de la Dieta/administración & dosificación , Diglicéridos/metabolismo , Dislipidemias/metabolismo , Fructosa/administración & dosificación , Homeostasis/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
AIMS: ß-Arrestin2 signaling has emerged as a promising therapeutic target for the management of insulin resistance and related complications. Moreover, recent studies have shown that certain G protein-coupled receptor (GPCR) ligands can modulate ß-arrestin2 signaling. The current study examined the effects of the ß-blocker propranolol and a low dose of the agonist isoproterenol (L-D-ISOPROT) on ß-arrestin2 signaling, insulin resistance, and cardiac remodeling in high-fructose, high-fat diet (HFrHFD)-fed mice. In addition, the effects of these agents were compared to those of the clinical antidiabetic agent, metformin. MATERIALS AND METHODS: Insulin resistance was induced by HFrHFD feeding for 16 weeks. Mice were then randomly allocated to groups receiving propranolol, L-D-ISOPROT, metformin, or vehicle (control) for 4 weeks starting on week 13 of HFrHFD feeding. Survival rate, body weight, visceral fat weight, blood glucose, serum insulin, insulin resistance index, hepatic ß-arrestin2 signaling, heart weight, left and right ventricular thicknesses, cardiac fibrosis severity, serum endothelin-1, cardiac cardiotrophin-1, and cardiac ß-arrestin2 signaling were then compared among groups. KEY FINDINGS: HFrHFD for 16 weeks significantly increased insulin resistance index, cardiac fibrosis area, and serum endothelin-1, and reduced hepatic ß-arrestin2 signaling, cardiac cardiotrophin-1, and cardiac ß-arrestin2 signaling without significant changes in survival rate, body weight, visceral fat weight, heart weight, or left and right ventricular thicknesses. All three drugs reduced insulin resistance and cardiac remodeling parameters and enhanced ß-arrestin2 signaling with variable efficacies. SIGNIFICANCE: Propranolol and L-D-ISOPROT, like metformin, can reduce insulin-resistance and cardiac remodeling in HFrHFD-fed mice, possibly by upregulating ß-arrestin2 signaling activity. Therefore, ß-arrestin2-signaling modulation might be a promising strategy for insulin-resistance treatment.
Asunto(s)
Resistencia a la Insulina/fisiología , Propranolol/farmacología , Arrestina beta 2/metabolismo , Animales , Glucemia/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Fructosa/farmacología , Glucosa/metabolismo , Corazón/efectos de los fármacos , Insulina/farmacología , Isoproterenol/metabolismo , Isoproterenol/farmacología , Masculino , Metformina/metabolismo , Metformina/farmacología , Ratones , Propranolol/metabolismo , Transducción de Señal/efectos de los fármacos , Remodelación Ventricular/fisiología , Arrestina beta 2/efectos de los fármacosRESUMEN
Aluminum is well recognized as a nephrotoxic agent. Its hazardous effects arise from the high risk of daily exposure. The consumption of fructose also represents a critical health issue that might negatively impact different organs, including the kidneys. To pursue our previous work, this study aimed to investigate the potential renoprotective effects of glycyrrhizic acid (GLYA) on aluminum-induced nephrotoxicity in insulin-resistant rats. Insulin resistance (IR) was induced by adding fructose (10%) in drinking water for 18 weeks. Male Wistar rats were divided into five groups: control (CTRL), aluminum chloride (ALM, 34 mg/kg/day), fructose (FRCT), aluminum plus fructose (AL/FR), and GLYA (rats received AL/FR and treated with 40 mg/kg GLYA daily). AL/FR resulted in abnormal renal function tests and renal tissue injury. This was associated with increased oxidative stress and inflammation in the renal tissue. Moreover, the expressions of the toll-like receptor 4 (TLR4) and its adaptor proteins were increased in AL/FR group. The administration of GLYA mollified AL/FR-induced renal injury, oxidative stress, activation of the TLR4 signaling pathway, and inflammation. In conclusion, we provide evidence for the promising renoprotective effect of GLYA against AL/FR-induced kidney damage in rats. The renoprotection is attributed to the suppression of oxidative stress and inhibition of the TLR4/NF-κB signaling pathway in the kidneys.
Asunto(s)
Cloruro de Aluminio/toxicidad , Ácido Glicirrínico/farmacología , Resistencia a la Insulina , Enfermedades Renales/prevención & control , Animales , Modelos Animales de Enfermedad , Fructosa/toxicidad , Inflamación/inducido químicamente , Inflamación/prevención & control , Enfermedades Renales/inducido químicamente , Masculino , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismoRESUMEN
Renal ischemia-reperfusion injury (R-IRI) is the main cause of acute renal failure. Carvedilol has been shown to protect against R-IRI. However, the underlying mechanisms are still not completely clarified. This study aimed to investigate the role of lipid signaling in mediating carvedilol protective effects against R-IRI in insulin-resistant mice by using two different lipid signaling modulators, quercetin and lithium chloride (LiCl). Mice were fed high-fructose, high-fat diet (HFrHFD) for 16 weeks to induce insulin resistance. At the end of feeding period, mice were randomly distributed into five groups; Sham, R-IRI, Carvedilol (20 mg/kg, i.p.), Carvedilol + Quercetin (10 mg/kg, i.p.), Carvedilol + LiCl (200 mg/kg, i.p.). R-IRI was performed by applying 30 min of unilateral renal ischemia followed by one hour of reperfusion. Quercetin and LiCl were administered 30 min before carvedilol administration and carvedilol was administered 30 min before ischemia. Changes in kidney function tests, histopathology, fibrosis area, lipid signaling, inflammatory, apoptosis and oxidative stress markers in the kidney were measured. Results showed that R-IRI decreased kidney function, impaired renal tissue integrity, modulated lipid signaling and increased renal inflammation, apoptosis and oxidative stress. Carvedilol treatment decreased the detrimental effects induced by R-IRI. In addition, pre-injection of both quercetin and LiCl potentiated the reno-protective effects of carvedilol against R-IRI independent of changes in lipid mediators like phosphatidyl inositol 4,5 bisphosphate (PIP2) and diacylglycerol (DAG). In conclusion, quercetin and LiCl potentiate the protective effects of carvedilol against R-IRI in HFrHFD-fed mice by reducing inflammation and oxidative stress independent of lipid signaling.
Asunto(s)
Carvedilol/farmacología , Dieta Alta en Grasa/efectos adversos , Fructosa/administración & dosificación , Riñón/efectos de los fármacos , Cloruro de Litio/farmacología , Quercetina/farmacología , Daño por Reperfusión/prevención & control , Animales , Apoptosis/efectos de los fármacos , Citoprotección/efectos de los fármacos , Sinergismo Farmacológico , Riñón/irrigación sanguínea , Riñón/metabolismo , Riñón/patología , Masculino , Malondialdehído/metabolismo , Ratones , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/inducido químicamente , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND AND AIMS: Diabetes Mellitus (DM) and depression occur comorbidly and share some pathophysiological mechanisms. The course of depression in patients with the two conditions is severe. Treatment of depression in diabetic patients requires special attention because most of psychopharmacological agents can worsen glycemic control. This article aims to review studies evaluating the antidepressant effect of anti-hyperglycemic agents from preclinical perspective. METHODS: A literature search was performed with PubMed and Google Scholar using relevant keywords (antidiabetic; diabetes; depression; antidepressant; animals) to extract relevant studies evaluating the antidepressant activity of anti-hyperglycemic agents in experimental models. RESULTS: Several studies have reported that some traditional anti-hyperglycemic agents reduce depression-like behavior in the absence or presence of diabetes. These drugs include insulin, glyburide, metformin, pioglitazone, vildagliptin, liraglutide, and exenatide. The antidepressant activity of anti-hyperglycemic agents may be mediated by reducing the blood glucose level, ameliorating the central oxidative stress and inflammation, and regulating the hypothalamic-pituitary-adrenal axis (HPAA). CONCLUSIONS: Drugs which have both antidiabetic and antidepressant activities can provide better treatment strategy for patients with diabetes-associated depression. However, further research studies are still required in human subjects.
Asunto(s)
Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Diabetes Mellitus Experimental/tratamiento farmacológico , Modelos Animales de Enfermedad , Hipoglucemiantes/farmacología , Animales , Depresión/etiología , Depresión/patología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patologíaRESUMEN
Metabolic Syndrome (MetS) increases the risk of developing type 2 diabetes mellitus and cardiovascular complications. The crosstalk between the hypothalamus and periphery is vital for regulating food intake and energy homeostasis. However, it is impaired during MetS. The present study aimed to compare the distinct central and peripheral metabolic derangements induced by a high-fructose drink or high-fat diet, as well as the possible intervention by fenofibrate. Rats were divided into five groups: standard chow diet (SCD) group, high-fructose group (FR), high-fat group (HF), FR plus fenofibrate group (FR-F), and HF plus fenofibrate group (HF-F). FR and HF groups showed hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hyperleptinemia, steatosis, and adipocyte hypertrophy. This was associated with elevated circulating levels of proinflammatory cytokines and free fatty acids (FFAs). The latter mediators are involved in the hypothalamic inflammation and dysregulation of signaling cascades that control food intake and glucose homeostasis. The effects were more pronounced in the HF group than FR group, which were matched with the observed higher levels of plasma FFAs and cytokines. Fenofibrate administration improved not only the peripheral metabolic disturbances, but also the central disturbances associated with insulin resistance induced by FR or HF diet. This study sheds light on the pivotal role of the hypothalamus in diet-induced MetS. Furthermore, the study suggests the utmost importance of developing a standardized model of metabolic syndrome in place of the great diversity between available models, which can induce different effects and negatively impact the validity of prospective studies.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Azúcares de la Dieta/efectos adversos , Fenofibrato/farmacología , Fructosa/efectos adversos , Hipolipemiantes/farmacología , Hipotálamo/efectos de los fármacos , Síndrome Metabólico/etiología , Hipernutrición/complicaciones , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/patología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Hipotálamo/metabolismo , Lípidos/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Hipernutrición/etiología , Ratas Sprague-DawleyRESUMEN
Insulin resistance is a worldwide health problem. This study investigated the acute effects of eicosapentanoic acid (EPA) on glucose homeostasis focusing on the role of free fatty acid receptor 1 (FFAR1) and the chronic effects of fish oil omega-3 fatty acids on insulin resistance. Insulin resistance was induced by feeding mice high-fructose, high-fat diet (HFrHFD) for 16 weeks. In the first part, the acute effects of EPA alone and in combination with GW1100 and DC260126 (FFAR1 blockers) on glucose homeostasis and hepatic phosphatidyl-inositol 4,5-bisphosphate (PIP2) and diacylglycerol (DAG) were investigated in standard chow diet (SCD)- and HFrHFD-fed mice. In the second part, mice were treated with fish oil omega-3 fatty acids for 4 weeks starting at the week 13 of feeding HFrHFD. Changes in the blood- and liver tissue-insulin resistance markers and FFAR1 downstream signals were recorded at the end of experiment. Results showed that EPA increased 0 and 30 min blood glucose levels after glucose load in SCD-fed mice but improved glucose tolerance in HFrHFD-fed mice. Moreover, FFAR1 blockers reduced EPA effects on glucose tolerance and hepatic PIP2 and DAG levels. On the other hand, chronic use of fish oil omega-3 fatty acids increased FBG levels and decreased serum insulin and triglycerides levels without improving the index of insulin resistance. Also, they increased hepatic ß-arrestin-2, PIP2, and pS473 Akt levels but decreased DAG levels. In conclusion, EPA acutely improved glucose homeostasis in HFrHFD-fed mice by modulating the activity of FFAR1. However, the chronic use of fish oil omega-3 fatty acids did not improve the insulin resistance.
Asunto(s)
Glucemia/efectos de los fármacos , Glucemia/metabolismo , Ácidos Grasos Omega-3/farmacología , Resistencia a la Insulina/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Animales , Benzoatos/farmacología , Dieta Alta en Grasa/efectos adversos , Ácido Eicosapentaenoico/farmacología , Fructosa/administración & dosificación , Fructosa/toxicidad , Masculino , Ratones , Pirimidinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidoresRESUMEN
BACKGROUND: Insulin resistance (IR) is a well-known risk factor for cardiovascular complications. This study aimed to investigate the effect of a dietary model of IR in mice on cardiac remodeling, cardiac ß-arrestin2 signaling, and the protective effects of carvedilol as a ß-arrestin-biased agonist. METHODS AND RESULTS: Insulin resistance was induced by feeding mice high-fructose/high-fat diet (HFrHFD) for 16 weeks. Carvedilol was adiministered for 4 weeks starting at week 13. At the end of the experiment, body weight, heart weight, left and right ventricular thickness, visceral fat weight, fasting blood glucose (FBG), serum insulin, IR index, and serum endothelin-1 were measured. In addition, cardiac tissue samples were histopathologically examined. Also, cardiac levels of cardiotrophin-1, ß-arrestin2, phosphatidylinositol 4,5 bisphosphate (PIP2), diacylglycerol (DAG), and phosphoserine 473 Akt (pS473 Akt) were measured. Results showed significant increases in the FBG, serum insulin, IR index, serum endothelin-1, cardiac DAG, cardiac fibrosis, and degenerated cardiac myofibrils in HFrHFD-fed mice associated with a significant reduction in cardiac levels of cardiotrophin-1, ß-arrestin2, PIP2, and pS473 Akt. On the other hand, carvedilol significantly reduced the heart weight, FBG, serum insulin, IR index, serum endothelin-1, cardiac DAG, left ventricular thickness, right ventricular fibrosis, and degeneration of cardiac myofibrils. In addition, carvedilol significantly increased cardiac levels of cardiotrophin-1, ß-arrestin2, PIP2, and pS473 Akt. CONCLUSION: Carvedilol enhances cardiac ß-arrestin2 signaling and reduces cardiac remodeling in HFrHFD-fed mice.
Asunto(s)
Cardiomegalia/prevención & control , Carvedilol/farmacología , Resistencia a la Insulina , Miocitos Cardíacos/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Derecha/efectos de los fármacos , Arrestina beta 2/agonistas , Animales , Cardiomegalia/etiología , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatología , Citocinas/metabolismo , Dieta Alta en Grasa , Azúcares de la Dieta , Modelos Animales de Enfermedad , Fibrosis , Fructosa , Masculino , Ratones , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fosfatidilinositol 4,5-Difosfato/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Remodelación Ventricular/efectos de los fármacos , Arrestina beta 2/metabolismoRESUMEN
Diabetes mellitus and depression are comorbid diseases affecting many patients all over the world. The current study was designed to compare the antidepressant effect of some antidiabetic drugs such as vildagliptin, pioglitazone, glyburide, and metformin on depression-related or unrelated to type 2 diabetes mellitus (T2DM). T2DM was induced by high-fat diet and streptozotocin, while diabetes-unrelated depression was induced by reserpine. Antidiabetic agents reduced diabetes-associated depression as indicated by the reduction in the immobility time in the forced swim test, elevation of cortical and hippocampal serotonin and brain-derived neurotrophic factor (BDNF), and the increase in serum ß-Amyloid 1-42 (Aß1-42) levels. Antidiabetic agents also reduced serum corticosterone levels suggesting their inhibitory effect on hypothalamus-pituitary-adrenal axis activity. The antidepressant activity of the tested compounds was associated with reduction of oxidative stress and inflammation in brain. Vildagliptin showed the highest, while glyburide showed the least antidiabetic and antidepressant activity. Antidepressant activities of pioglitazone and metformin were comparable. The difference in antioxidant and anti-inflammatory activities between groups showed the same pattern of the antidepressant effect suggesting that these two pathways may play role in ameliorating depression in diabetic rats. On the other hand, the administration of reserpine in small doses (0.2 mg/kg) induced depression associated with hyperglycemia in non-diabetic rats. Although all treatments improved glycemic parameters to similar levels, vildagliptin showed the greatest effect on Aß1-42, serotonin, norepinephrine, and BDNF levels. In conclusion, vildagliptin seems to be the leading drug among the tested antidiabetics and may be the most appropriate antidiabetic for managing diabetes-associated depression.
Asunto(s)
Antiinflamatorios/administración & dosificación , Antidepresivos/administración & dosificación , Antioxidantes/administración & dosificación , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Depresión/prevención & control , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Administración Oral , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Depresión/etiología , Depresión/metabolismo , Depresión/fisiopatología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Mediadores de Inflamación/metabolismo , Masculino , Norepinefrina/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Ratas Wistar , Reserpina , Serotonina/metabolismoRESUMEN
Aluminium is a ubiquitous element that occurs naturally in the soil making human exposure to it unavoidable. It is implicated in the aetiology of different neurodegenerative diseases and can induce liver injury. In addition, insulin resistance (IR) plays an essential role in the pathogenesis and the progression of liver disorders. The increased consumption of fructose contained in soft drinks and western pattern diet results in IR that along with the wide distribution of aluminium make the concurrent exposure conceivable and increase the risk of liver injury. Therefore, the present study explores the hepatotoxic effects of aluminium and fructose administered concurrently and evaluates the possible protection by monoammonium glycyrrhizinate (MAG). Liver injury was induced by the administration of aluminium chloride (34 mg/kg/d) plus 10% (w/v) fructose in drinking water. Male rats were treated with either MAG (40 mg/kg/d) or silymarin (SIL, 100 mg/kg/d). The concurrent administration of aluminium and fructose (FRUAL) induced liver injury manifested as a significant elevation of serum liver enzymes activities, bilirubin level, and prothrombin time, as well as reduction of albumin level. On the other hand, the administration of MAG improved the FRUAL-induced aberrations of liver function tests and hepatic cytoarchitecture. We assume that the MAG-induced suppression of oxidative stress, toll-like receptor 4 pathway activation, inflammation, and apoptosis might play a crucial role in the hepatoprotective effect of MAG in this model. Intriguingly, the hepatoprotective effect MAG against FRUAL-induced liver injury surpasses that of the gold standard SIL, suggesting MAG as a better alternative to SIL.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Ácido Glicirrínico/farmacología , Hígado/efectos de los fármacos , Sustancias Protectoras/farmacología , Silimarina/farmacología , Cloruro de Aluminio , Animales , Biomarcadores/sangre , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Modelos Animales de Enfermedad , Fructosa , Ácido Glicirrínico/análogos & derivados , Mediadores de Inflamación/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas Wistar , Transducción de Señal , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Triglicéridos/sangreRESUMEN
Hepatic ischemia/reperfusion injury (H-IRI) is associated with irreversible liver damage. The current study aimed to investigate the protective effect of carvedilol against H-IRI in high-fructose high-fat diet (HFrHFD)-fed mice and the role of G protein-coupled receptor kinase 2 and 5 (GRK2 and GRK5). Mice were fed HFrHFD for 16â¯weeks; then mice were subjected to 30â¯min of ischemia followed by 1â¯h of reperfusion at the end of feeding period. Carvedilol (20â¯mg/kg, i.p.) was administered 30â¯min before ischemia. To explore the role of GRK2 and GRK5 in mediating carvedilol effects, paroxetine (GRK2 inhibitor, 10â¯mg/kg, i.p.) and amlexanox (GRK5 inhibitor, 25â¯mg/kg, i.p.) were administered 30â¯min before carvedilol administration. Liver function, histopathology and hepatic oxidative stress, as well as inflammatory and apoptotic markers were measured at the end of the experiment. In addition, adrenergic receptor downstream signals were measured in the liver. Results showed increased markers of liver injury (ALT and AST) in mice subjected to H-IRI. Moreover, liver injury was associated with slight collagen deposits as revealed by histopathology and elevated hepatic levels of oxidative stress, inflammatory and apoptotic markers. On the other hand, carvedilol protected mice against H-IRI and improved all associated pathological changes. Furthermore, pre-injection of either GRK2 or GRK5 inhibitor did not change carvedilol effects on serum ALT level and liver collagen deposits, while increased its antioxidant, anti-inflammatory and anti-apoptotic effects. In conclusion, carvedilol protects against H-IRI in HFrHFD-fed mice. GRK2 and GRK5 may not play a potential role in mediating this effect.
Asunto(s)
Carvedilol/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Fructosa/toxicidad , Quinasa 2 del Receptor Acoplado a Proteína-G/fisiología , Quinasa 5 del Receptor Acoplado a Proteína-G/fisiología , Daño por Reperfusión/prevención & control , Animales , Carvedilol/farmacología , Fructosa/administración & dosificación , Quinasa 2 del Receptor Acoplado a Proteína-G/antagonistas & inhibidores , Quinasa 5 del Receptor Acoplado a Proteína-G/antagonistas & inhibidores , Hepatopatías/metabolismo , Hepatopatías/prevención & control , Masculino , Ratones , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Daño por Reperfusión/inducido químicamente , Daño por Reperfusión/metabolismo , Vasodilatadores/farmacología , Vasodilatadores/uso terapéuticoRESUMEN
Aluminum is implicated in the etiology of different neurodegenerative diseases, diabetes and cancer. The current study was conducted to evaluate the protective effects of glycyrrhizic acid (GAM) and silymarin (SLY) on AlCl3-induced neurotoxicity in insulin resistant rats. Insulin resistance (IR) was induced by fructose (10%) in drinking water for 18 weeks. Rats received AlCl3 (34 mg/kg/day) with or without fructose, GAM (40 mg/kg/day), or SLY (100 mg/kg/day). The administration of GAM or SLY suppressed AlCl3-induced memory deficit, oxidative stress, and neuroinflammation in brain tissue of IR rats. Both agents inhibited AlCl3-induced activation of TLR4 signaling pathway including the downstream activation of NF-κB. The results show that IR can partly exacerbate AlCl3-induced neurotoxicity, particularly memory deficit and neuroinflammation. In addition, GAM and SLY showed promising neuroprotective effect against AlCl3-induced brain damage in IR rats. The neuroprotection induced by these natural products might be mediated through their antioxidant and anti-inflammatory effects. The latter effect seems to be mediated via inhibition of TLR4 signaling pathway providing new insights on the mechanisms implicated in AlCl3-induced neurotoxicity and the neuroprotection afforded by GAM and SLY.
Asunto(s)
Aluminio/toxicidad , Encéfalo/efectos de los fármacos , Ácido Glicirrínico/farmacología , Resistencia a la Insulina , Fármacos Neuroprotectores/farmacología , Transducción de Señal/efectos de los fármacos , Silimarina/farmacología , Receptor Toll-Like 4/metabolismo , Acetilcolinesterasa/metabolismo , Cloruro de Aluminio/toxicidad , Animales , Glucemia/análisis , Química Encefálica/efectos de los fármacos , Fructosa/farmacología , Inflamación/tratamiento farmacológico , Insulina/sangre , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Neurotoxinas/toxicidad , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor Toll-Like 4/fisiología , Triglicéridos/sangre , Factor de Necrosis Tumoral alfa/análisisRESUMEN
Hepatocellular carcinoma (HCC) is a major global health problem. Therapeutic interventions of HCC are still limited because of its complicated molecular pathogenesis. Many reports showed that renin-angiotensin system (RAS) contributes to the development of different types of malignancies. Therefore, the present study aimed to examine the effect of RAS inhibition using perindopril (1â¯mg/kg), fosinopril (2â¯mg/kg), or losartan (10â¯mg/kg) on diethylnitrosamine-induced HCC compared to sorafenib (30â¯mg/kg). The administration of RAS inhibitors resulted in improved liver function and histologic picture with a reduction in AFP levels. These effects found to be mediated through inactivation of NFкB pathway by the inhibition of NFĸB p65 phosphorylation at the Ser536 residue and inhibition of the phosphorylation-induced degradation of NFĸBia. Consequently, expression levels of cyclin D1 mRNA were significantly lowered. In addition, NFкB-induced TNF-α and TGF-ß1 levels were reduced leading to lower levels of MMP-2 and VEGF. We concluded that RAS inhibition either through inhibiting the ACE or the blockade of AT1R has the same therapeutic benefit and that the tissue affinity of the ACEIs has no impact on its anti-tumor activity. These results suggest that ACEIs and ARBs can serve as promising candidates for further clinical trials in the management of HCC.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Dietilnitrosamina , Fosinopril/farmacología , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Losartán/farmacología , FN-kappa B/metabolismo , Perindopril/farmacología , Sistema Renina-Angiotensina/efectos de los fármacos , Animales , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Ciclina D1/genética , Ciclina D1/metabolismo , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Inhibidor NF-kappaB alfa/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacología , Compuestos de Fenilurea/farmacología , Fosforilación , Transducción de Señal/efectos de los fármacos , Sorafenib , Factores de Tiempo , Factor de Transcripción ReIA/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Therapeutic interventions for liver fibrosis are still limited due to the complicated molecular pathogenesis. Renin-angiotensin system (RAS) seems to contribute to the development of hepatic fibrosis. Therefore, we aimed to examine the effect of RAS inhibition on CCl4-induced liver fibrosis. Mice were treated with silymarin (30 mg·kg-1), perindopril (1 mg·kg-1), fosinopril (2 mg·kg-1), or losartan (10 mg·kg-1). The administration of RAS inhibitors improved liver histology and decreased protein expression of alpha smooth muscle actin (α-SMA) and hepatic content of hydroxyproline. These effects found to be mediated via inactivation of nuclear transcription factor kappa B (NFκB) pathway by the inhibition of NFκB p65 phosphorylation at the Ser536 residue and phosphorylation-induced degradation of nuclear factor kappa-B inhibitor alpha (NFκBia) subsequently inhibited NFκB-induced TNF-α and TGF-ß1, leading to lower levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF). We concluded that the tissue affinity of the angiotensin converting enzyme inhibitors (ACEIs) has no impact on its antifibrotic activity and that interfering the RAS either through the inhibition of ACE or the blockade of AT1R has the same therapeutic benefit. These results suggest RAS inhibitors as promising candidates for further clinical trials in the management of hepatic fibrosis.
Asunto(s)
Tetracloruro de Carbono/farmacología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/fisiopatología , FN-kappa B/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Actinas/metabolismo , Alanina Transaminasa/sangre , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Hidroxiprolina/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Masculino , Metaloproteinasa 2 de la Matriz/sangre , Ratones , Inhibidor Tisular de Metaloproteinasa-1/sangre , Factor de Crecimiento Transformador beta/sangre , Factor de Necrosis Tumoral alfa/sangre , alfa-Fetoproteínas/metabolismoRESUMEN
Doxorubicin (DOX) possesses a broad-spectrum antineoplastic activity; however, its clinical application is impeded by cardiotoxicity. This study aimed to investigate the protective effect of pentoxifylline (PXF), which possesses antioxidant and anti-inflammatory properties against cardiotoxicity induced by a single high dose (15 mg/kg, i.p.) or multiple low doses (2.5 mg/kg, i.p., three times per week for 2 weeks) of DOX. At the end of the experimental period, the serum creatine kinase (CK)-MB and lactate dehydrogenase (LDH) activities were measured. The hearts were then removed for evaluating TNF-α, NO, malondialdehyde (MDA), and reduced glutathione (GSH) levels, superoxide dismutase (SOD) and catalase (CAT) activities, and the expression of iNOS, NF-κB, Fas ligand (FasL), and caspase-3. The administration of DOX in both dose regimens caused increases in serum CK-MB and LDH activities, in cardiac TNF-α, NO and MDA levels, as well as in the cardiac expression of iNOS, NF-κB, FasL and caspase-3, whereas it significantly reduced the cardiac GSH level, as well as SOD and CAT activities (P < 0.05). Prophylactic treatment of rats with PXF diminished DOX-induced alterations in theses parameters. Our results warrant the clinical use of PXF as an adjuvant therapy to abrogate cardiotoxicity of DOX and extend its clinical applications.
RESUMEN
Spirulina is a blue-green alga used as a dietary supplement. It has been shown to possess anti-inflammatory, antioxidant, and hepatoprotective properties. This study was designed to evaluate the antitumor effect of spirulina (200 and 800 mg/kg) against a murine model of solid Ehrlich carcinoma compared to a standard chemotherapeutic drug, 5-fluorouracil (20 mg/kg). Untreated mice developed a palpable solid tumor after 13 days. Unlike fluorouracil, spirulina at the investigated two dose levels failed to exert any protective effect. In addition, spirulina did not potentiate the antitumor effect of fluorouracil when they were administered concurrently. Interestingly, their combined administration resulted in a dose-dependent increase in mortality. The present study demonstrates that spirulina lacks antitumor effect against this model of solid Ehrlich carcinoma and increased mortality when combined with fluorouracil. However, the implicated mechanism is still elusive.
RESUMEN
Acute kidney injury (AKI) is associated with high mortality resulting from extra-renal organ damage, particularly the heart. The present study aimed to investigate the protective effect of sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, against renal and remote cardiac damage induced by ischemia/reperfusion (IR), a leading cause of AKI. In this attempt, we compared the effects of sitagliptin to furosemide, a loop diuretic. Furosemide is commonly used clinically in AKI however, there is a lack of evidence regarding its beneficial effects in AKI. In addition, the combined administration of both drugs was also investigated. Ischemia was induced in anesthetized male Wistar rats by occluding both renal pedicles for 30min followed by reperfusion for 24h. Sitagliptin (5mg kg(-1)), furosemide (245mg kg(-1)) or their combination were administered orally at 5h post-IR and 2h before euthanasia. Administration of sitagliptin or furosemide ameliorated renal and cardiac deterioration induced by renal IR. This was manifested as significant reduction of serum creatinine, urea, cystatin c, creatine kinase-MB, cardiac troponin-I and lactate dehydrogenase (P<0.05). Drug treatment significantly inhibited IR-induced elevation of TNF-α, NF-κB and caspase-3 (P<0.05) in kidney and heart tissue. In addition, they significantly suppressed malondialdehyde, NO and iNOS content, whereas they increased glutathione and antioxidative enzymes activity (P<0.05) in both tissues. Interestingly, a superior protection was observed with the combination compared to the individual drugs. We assume that this combination represents a promising regimen for managing AKI, particularly with the poor clinical outcome obtained with furosemide alone.
Asunto(s)
Furosemida/farmacología , Daño por Reperfusión Miocárdica/prevención & control , Pirazinas/farmacología , Triazoles/farmacología , Animales , Biomarcadores/metabolismo , Caspasa 3/metabolismo , Furosemida/administración & dosificación , Riñón/patología , Masculino , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Miocardio/patología , FN-kappa B/metabolismo , Estrés Oxidativo , Pirazinas/administración & dosificación , Ratas , Ratas Wistar , Fosfato de Sitagliptina , Triazoles/administración & dosificación , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The metabolic syndrome (MS) is characterized by insulin resistance, dyslipidemia and hypertension. It is associated with increased risk of cardiovascular diseases and type-2 diabetes. Consumption of fructose is linked to increased prevalence of MS. Ursodeoxycholic acid (UDCA) is a steroid bile acid with antioxidant, anti-inflammatory activities and has been shown to improve insulin resistance. The current study aims to investigate the effect of UDCA (150 mg/kg) on MS induced in rats by fructose administration (10%) in drinking water for 12 weeks. The effects of UDCA were compared to fenofibrate (100 mg/kg), an agonist of PPAR-α receptors. Treatment with UDCA or fenofibrate started from the 6th week after fructose administration once daily. Fructose administration resulted in significant increase in body weight, elevations of blood glucose, serum insulin, cholesterol, triglycerides, advanced glycation end products (AGEs), uric acid levels, insulin resistance index and blood pressure compared to control rats. Moreover, fructose increased oxidative stress in aortic tissues indicated by significant increases of malondialdehyde (MDA), expression of iNOS and reduction of reduced glutathione (GSH) content. These disturbances were associated with decreased eNOS expression, increased infiltration of leukocytes and loss of aortic vascular elasticity. Treatment with UDCA successfully ameliorated the deleterious effects of fructose. The protective effect of UDCA could be attributed to its ability to decrease uric acid level, improve insulin resistance and diminish oxidative stress in vascular tissues. These results might support possible clinical application of UDCA in MS patients especially those present with liver diseases, taking into account its tolerability and safety. However, further investigations on human subjects are needed before the clinical application of UDCA for this indication.
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Fructosa/efectos adversos , Síndrome Metabólico/tratamiento farmacológico , Ácido Ursodesoxicólico/farmacología , Animales , Glucemia/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Colesterol/sangre , Fenofibrato/farmacología , Glutatión/metabolismo , Productos Finales de Glicación Avanzada/sangre , Insulina/sangre , Resistencia a la Insulina/fisiología , Masculino , Malondialdehído/metabolismo , Síndrome Metabólico/sangre , Síndrome Metabólico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Triglicéridos/sangre , Ácido Úrico/sangreRESUMEN
Hepatic fibrosis is a significant health problem that may progress to cirrhosis and cancer. It may be caused by viruses or chemicals such as dimethylnitrosamine, which is used as a preservative in processed meats and industrial products. The present study was designed to investigate the antifibrotic effect of hesperidin (100 or 200 mg/kg, a flavanone glycoside with potent anti-inflammatory and antioxidant activities) against liver fibrosis in rats compared to silymarin (100 mg/kg). Liver fibrosis was induced in rats using dimethylnitrosamine (10 mg/kg/day, i.p.) three times per week on alternating days for 4 weeks. After 28 days, tissue and blood samples were collected to assess the protective effect of hesperidin. Dimethylnitrosamine caused liver fibrosis as evidenced by the elevation in the levels of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total and direct bilirubin, as well as hepatic malondialdehyde content, gene expression of inducible nitric oxide synthase, α-smooth muscle actin and caspase-3. In addition, dimethylnitrosamine caused a reduction in serum total protein, albumin and hepatic glutathione content. Treatment with hesperidin (100 or 200 mg/kg) successfully ameliorated the deleterious effects of dimethylnitrosamine on all tested parameters. Our study indicates a novel protective effect of hesperidin against dimethylnitrosamine-induced liver fibrosis. Interestingly, the protection evoked by hesperidin (200 mg/kg) was superior to that of the standard silymarin.
Asunto(s)
Dimetilnitrosamina/toxicidad , Hesperidina/uso terapéutico , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/prevención & control , Animales , Cirrosis Hepática/metabolismo , Masculino , Distribución Aleatoria , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismoRESUMEN
We cultured isolated islets from human or porcine origin in the presence or absence of IL1 and TNFα and studied cytoprotective effects of two structurally different PBR ligands. Storage of pig or human islets in the presence of cytokines significantly lowered the fraction of vital beta-cells. Compared with cytokine incubations PK11195 alone or in combination with cytokines was effective to prevent cytokine induced cell death. The data indicate that cold storage in the presence of PK11195 may further protect beta-cells from cytokine induced cell death. This ligand may be helpful to preserve beta-cell survival before transplantation.