RESUMEN
Epilepsy is a neurological disorder characterized by recurrent spontaneous seizures alongside other neurological comorbidities. Cognitive impairment is the most frequent comorbidity secondary to progressive neurologic changes in epilepsy. Sigma 1 receptors (σ1 receptors) are involved in the neuroprotection and pathophysiology of both conditions and targeting these receptors may have the potential to modulate both seizures and comorbidities. The current research demonstrated the effect of clemastine (10 mg/kg, P.O.), a non-selective σ1 receptor agonist, on pentylenetetrazol (PTZ) (35 mg/kg, i.p., every 48 h for 14 doses)-kindling rats by acting on σ1 receptors through its anti-inflammatory/antioxidant capacity. Clemastine and phenytoin (30 mg/kg, P.O.) or their combination were given once daily. Clemastine treatment showed a significant effect on neurochemical, behavioural, and histopathological analyses through modulation of σ1 receptors. It protected the kindling animals from seizures and attenuated their cognitive impairment in the Morris water maze test by reversing the PTZ hippocampal neuroinflammation/oxidative stress state through a significant increase in inositol-requiring enzyme 1 (IRE1), x-box binding protein 1 (XBP1), along with a reduction of total reactive oxygen species (TROS) and amyloid beta protein (Aß). The involvement of σ1 receptors in the protective effects of clemastine was confirmed by their abrogation when utilizing NE-100, a selective σ1 receptor antagonist. In light of our findings, modulating σ1 receptors emerges as a compelling therapeutic strategy for epilepsy and its associated cognitive impairments. The significant neuroprotective effects observed with clemastine underscore the potential of σ1 receptor-targeted treatments to address both the primary symptoms and comorbidities of neurological disorders.
RESUMEN
PURPOSE: Hypertensive emergency, a sudden and severe increase in blood pressure, necessitates immediate intervention to avoid end-organ damage. Cilostazol, a selective phosphodiesterase-III inhibitor, has vasodilator effect. Here, we investigated the effect of two commonly used statins, atorvastatin or rosuvastatin, on cilostazol antihypertensive activity in acute model of hypertension. METHODS: Hypertensive emergency was induced via angiotensin II intravenous infusion (120 ng.kg-1.min-1). Rats were subjected to real-time arterial hemodynamics and electrocardiogram recording while investigated drugs were injected slowly at cumulative doses 0.5, 1, and 2 mg.kg-1, individually or in combination, followed by baroreflex sensitivity (BRS) analysis and serum electrolytes (Na+ and K+) and vasomodulators (norepinephrine (NE), and nitric oxide (NO)) assessment. RESULTS: Cilostazol reduced systolic blood pressure (SBP), while co-injection with rosuvastatin augmented cilostazol SBP-reduction up to 30 mmHg. Compared to atorvastatin, rosuvastatin boosted the cilostazol-associated reduction in peripheral resistance, as evidenced by further decrease in diastolic, pulse, and dicrotic-notch pressures. Rosuvastatin co-injection prevented cilostazol-induced changes of ejection and non-ejection durations. Additionally, rosuvastatin coadministration produced better restoration of BRS, with an observed augmented increase in BRS indexes from spectral analysis. Greater reduction in sympathetic/parasympathetic ratio and serum NE upon rosuvastatin coadministration indicates further shift in sympathovagal balance towards parasympathetic dominance. Additionally, rosuvastatin coinjection caused a greater decrease in serum sodium, while more increase in NO indicating augmented reduction of extracellular volume and endothelial dysfunction. CONCLUSION: Rosuvastatin boosted cilostazol's antihypertensive actions through effects on peripheral resistance, BRS, sympathovagal balance, endothelial dysfunction, and electrolytes balance, while atorvastatin did not demonstrate a comparable impact.
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Antihipertensivos , Hipertensión , Ratas , Animales , Cilostazol/farmacología , Atorvastatina , Antihipertensivos/uso terapéutico , Rosuvastatina Cálcica/uso terapéutico , Hipertensión/tratamiento farmacológico , Electrólitos/uso terapéuticoRESUMEN
INTRODUCTION: Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD). Agomelatine, a melatonin receptor agonist, has a potent anti-inflammatory activity. The current study aimed to determine the ameliorative anti-inflammatory effect of agomelatine against DN. METHODS: We used 10 % fructose with streptozotocin (STZ) to induce DN in male Wistar rats. Diabetic rats were treated with agomelatine in presence or absence of melatonin receptor antagonist (luzindole) or Sirtuin1 (SIRT1) inhibitor (EX527). SIRT1 expression was measured by qRT-PCR and immunohistochemical analysis. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), 5'adenosine monophosphate-activated protein kinase (AMPK), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) were measured using ELISA. Histological assessment was performed using hematoxylin and eosin-stained renal sections. RESULTS: Fructose and STZ treatment induced diabetes, insulin resistance, and renal damage accompanied by reduced SIRT1 expression, increased NFκB activation, and decreased AMPK phosphorylation in the kidney. Agomelatine treatment improved kidney histology and function and upregulated SIRT1 expression (2-fold). Inhibition of melatonin receptors and SIRT1 activity increased NFκB phosphorylation (2.13 and 1.98-folds, respectively), reduced AMPK activation (0.51 and 0.53-folds, respectively), increased inflammatory markers ICAM-1 (2.16 and 2.23-folds, respectively), VCAM-1 (2.19 and 2.26-folds, respectively), and MCP-1(2.84 and 3.12-folds, respectively), and inhibited the ameliorative effect of agomelatine on kidney structure and function. CONCLUSION: Our findings reveal the ameliorative anti-inflammatory activity of agomelatine against STZ-induced DN and this effect is SIRT1- and melatonin receptor-dependent. Therefore, agomelatine may be beneficial to prevent the development of ESRD from diabetes mellitus.
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Diabetes Mellitus Experimental , Nefropatías Diabéticas , Fallo Renal Crónico , Melatonina , Ratas , Masculino , Animales , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Receptores de Melatonina/uso terapéutico , Sirtuina 1/metabolismo , Estreptozocina , Molécula 1 de Adhesión Intercelular , Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Mellitus Experimental/metabolismo , Melatonina/uso terapéutico , Melatonina/farmacología , Molécula 1 de Adhesión Celular Vascular , Ratas Wistar , Transducción de Señal , FN-kappa B/metabolismo , Antiinflamatorios/farmacologíaRESUMEN
AIMS: The nephrotoxicity of cyclosporine A (CsA) limits its use as an immunosuppressant. Wnt/ß-catenin signaling is involved in the pathogenesis of both acute and chronic kidney disease, and it is inhibited by peroxisome proliferator-activated receptor gamma (PPARγ). We aimed to evaluate if geraniol, which can modulate both PPARγ and Wnt signaling, could protect against CsA-induced nephrotoxicity. MATERIALS AND METHODS: Rats (6 groups) received the vehicle or a combination of CsA (30 mg/kg) with the vehicle, geraniol (50, 100, or 200 mg/kg), or the PPARγ agonist pioglitazone for 4 weeks. Blood pressure (BP), markers of renal injury (serum urea, serum creatinine, blood urea nitrogen, and urinary NAG), oxidative stress (glutathione peroxidase), inflammation (ICAM-1, IL-18, and NF-κB), apoptosis (caspase-3), extracellular matrix remodeling [matrix metalloproteinase-9 (MMP-9)], and fibrosis (TGF-ß1, Smad3, and Smad7) were assessed. Renal histological analysis, Wnt signaling components (Wnt-4/ß-catenin and E-cadherin), and PPARγ expression were evaluated. KEY FINDINGS: CsA group had renal injury, as well as increased BP, renal oxidative stress, inflammation, and fibrosis. The latter changes were associated with altered renal architecture, active Wnt signaling (higher Wnt-4 and ß-catenin expression and E-cadherin down-regulation), and lower PPARγ levels. Geraniol protected against kidney damage and the associated biochemical and histomorphological changes in a dose-dependent manner. The latter effects were comparable or superior to those of pioglitazone. SIGNIFICANCE: The down-regulation of Wnt/ß-catenin and the increase in PPARγ by geraniol suggest that both pathways are involved in its renoprotective potential. The study highlights geraniol as a valuable protective asset against chemically induced nephrotoxicity.
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Lesión Renal Aguda/tratamiento farmacológico , Monoterpenos Acíclicos/farmacología , Lesión Renal Aguda/metabolismo , Monoterpenos Acíclicos/metabolismo , Animales , Apoptosis/efectos de los fármacos , Ciclosporina/efectos adversos , Inflamación , Riñón/metabolismo , Enfermedades Renales/patología , Masculino , FN-kappa B/metabolismo , PPAR gamma/metabolismo , Ratas , Ratas Wistar , Vía de Señalización Wnt/efectos de los fármacos , Vía de Señalización Wnt/fisiología , beta Catenina/metabolismoRESUMEN
AIMS: This study was designated to investigate the means through which quercetin confers its cardioprotective action against remote cardiomyopathy elicited by renal ischemia/reperfusion (I/R). Potential involvement of hydrogen sulfide (H2S) and its related mechanisms were accentuated herein. MAIN METHODS: In anesthetized male Wistar rats, renal I/R was induced by bilateral renal pedicles occlusion for 30 min (ischemia) followed by 24 h reperfusion. Quercetin (50 mg/kg, gavage) was administered at 5 h post reperfusion initiation and 2 h before euthanasia. Cystathionine ß-synthase (CBS) inhibitor, amino-oxyacetic acid (AOAA; 10 mg/kg, i.p) was given 30 min prior to each quercetin dose. KEY FINDINGS: Quercetin reversed renal I/R induced derangements; as quercetin administration improved renal function and reversed I/R induced histopathological changes in both myocardium and kidney. Further, quercetin enhanced renal CBS content/activity, while mitigated myocardial cystathionine ɤ-lyase (CSE) content/activity as well as myocardial H2S. On the other hand, quercetin augmented myocardial nitric oxide (NO), nuclear factor erythroid 2-related factor 2 (Nrf2) and its nuclear trasnslocation, glutamate cysteine ligase (GCL), reduced glutathione (GSH) and peroxiredoxin-2 (Prx2), while further reduced lipid peroxidation measured as malondialdehyde (MDA) as well as nuclear factor-kappa B (NF-κB), caspase-3 content and activity, and Rho-kinase activity. SIGNIFICANCE: Cardioprotective effects of quercetin may be mediated through regulation of Rho-kinase pathway and H2S production.
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Sulfuro de Hidrógeno/metabolismo , Riñón/metabolismo , Infarto del Miocardio/metabolismo , Quercetina/uso terapéutico , Daño por Reperfusión/metabolismo , Quinasas Asociadas a rho/metabolismo , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Riñón/patología , Masculino , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Quercetina/farmacología , Ratas , Ratas Wistar , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/patologíaRESUMEN
The incidence of chronic kidney disease is escalating; cardiorenal syndrome (CRS) type 4 is gaining a major health concern causing significant morbidity and mortality, putting major burdens on the healthcare system. This study was designed to compare the cardioprotective effects of carvedilol versus atenolol against CRS type 4 induced by subtotal 5/6 nephrectomy in rats and to explore the underlying mechanisms. Immediately after surgery, carvedilol (20 mg/kg/day) or atenolol (20 mg/kg/day) was added to drinking water for 10 weeks. Carvedilol was more effective than atenolol in improving kidney functions, decreasing elevated blood pressures, attenuating cardiac hypertrophy, reducing serum brain natriuretic peptide, and diminished cardiac fibrous tissue deposition. However, carvedilol was equivalent to atenolol in modulating ß1-adrenergic receptors (ß1ARs) and cardiac diacylglycerol (DAG) signaling, but carvedilol was superior in modulating ß-arrestin2, phosphatidyl inositol 4,5 bisphosphates (PIP2), and caspase 3 levels. Carvedilol has superior cardioprotective effects than atenolol in a rat model of CRS type 4. These protective effects are mediated through modulating cardiac ß1ARs/ß-arrestin2/PIP2/DAG as well as abating cardiac apoptotic signaling pathways (caspase3/pS473 protein kinase B (Akt)).
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Atenolol/uso terapéutico , Síndrome Cardiorrenal/tratamiento farmacológico , Cardiomegalia/tratamiento farmacológico , Cardiotónicos/uso terapéutico , Carvedilol/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Atenolol/farmacología , Presión Sanguínea/efectos de los fármacos , Síndrome Cardiorrenal/metabolismo , Síndrome Cardiorrenal/fisiopatología , Síndrome Cardiorrenal/cirugía , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatología , Cardiomegalia/cirugía , Cardiotónicos/farmacología , Carvedilol/farmacología , Diacilglicerol Quinasa/metabolismo , Modelos Animales de Enfermedad , Riñón/efectos de los fármacos , Riñón/fisiología , Masculino , Miocardio/metabolismo , Nefrectomía , Fosfatidilinositol 4,5-Difosfato/metabolismo , Ratas Wistar , Receptores Adrenérgicos beta 1/metabolismo , Arrestina beta 2/metabolismoRESUMEN
The phosphodiesterase-3 inhibitor, cilostazol has been recently shown to protect against chemically induced colitis in animal models. However, whether cyclic adenosine monophosphate (cAMP) contributes to the anti-inflammatory activity of cilostazol in colitis is still unknown. In the current study, we investigated the role of cAMP/silent information regulator-1 (SIRT-1) pathway in the protective effect of cilostazol using rat model of acetic acid-induced colitis. Upregulation of SIRT1 activity and expression has been recently shown to protect against chemically induced colitis. Our results demonstrated that cilostazol alleviated the histopathological changes associated with acetic acid-induced colitis. Interestingly, pre-administration of cilostazol increased cAMP concentration and SIRT1 expression in colonic mucosa to levels similar to that observed in control animals without induction of colitis. In addition, cilostazol inhibited the SIRT1 targets; NF-κB, Akt and MAPK inflammatory pathways as demonstrated by suppression of acetic acid-induced upregulation of NF-κB activity, p-AKT levels and the expression of p38 MAPK. NF-κB activity and the levels of p-AKT, tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß) were similar in rats pretreated with cilostazol prior to induction of colitis and the control rats without colitis. Furthermore, cilostazol reduced acetic acid-induced oxidative stress and apoptosis. In conclusion, the protective effect of cilostazol against acetic acid-induced colitis may be attributed to activation of SIRT1 expression by cAMP. SIRT1 is suggested to contribute to cilostazol-induced suppression of NF-κB, Akt and MAPK inflammatory pathways, oxidative stress and apoptosis.
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Antiinflamatorios/farmacología , Cilostazol/farmacología , Colitis/prevención & control , Colon/efectos de los fármacos , AMP Cíclico/metabolismo , Sirtuina 1/metabolismo , Ácido Acético , Animales , Colitis/inducido químicamente , Colitis/enzimología , Colitis/patología , Colon/enzimología , Colon/patología , Citoprotección , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Masculino , FN-kappa B/genética , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Wistar , Transducción de Señal , Sirtuina 1/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Excess dietary sugar is associated with deleterious metabolic effects, liver injury, and coenzyme-Q10 (CoQ10) deficiency. This study investigates the ability of CoQ10 to protect against fructose-induced hepatic damage. METHODS: Rats were fed tap water or 30% fructose for 12 weeks with or without CoQ10 (10 mg/kg, po). An additional group of rats were allowed to feed on either water or 30% fructose for 12 weeks, followed by four weeks of treatment with either the vehicle or CoQ10. RESULTS: Fructose-fed rats showed lower CoQ10 levels, increased systolic pressure, increased body weight, higher liquid consumption, decreased food intake and hyperglycemia. Fructose-fed rats also showed deteriorated serum and liver lipid profiles, impaired liver function tests and oxidative status, and lower expression of adiponectin receptor 1 and 2 along with higher GLUT-2 levels. Furthermore, following fructose treatment, tyrosine kinase-PI3K pathway was inhibited. Additionally, there was an increase in the levels of apoptotic markers and serum visfatin and a decrease in the levels of adiponectin and soluble receptor of the advanced glycated end product. Consequently, several histopathological changes were detected in the liver. Concurrent or three months post-exposure administration of CoQ10 in fructose rats significantly reversed or attenuated all the measured parameters and hepato-cytoarchitecture alterations. CONCLUSION: This study suggests CoQ10 supplement as a possible prophylaxis or treatment candidate for fructose-induced liver injury.
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Hígado Graso/metabolismo , Hígado Graso/prevención & control , Fructosa/toxicidad , Hígado/enzimología , Ubiquinona/análogos & derivados , Animales , Hígado Graso/inducido químicamente , Hígado/efectos de los fármacos , Masculino , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Sustancias Protectoras/administración & dosificación , Ratas , Ratas Wistar , Ubiquinona/administración & dosificación , Ubiquinona/metabolismoRESUMEN
BACKGROUND: Upregulation of the sodium glucose co-transporter (SGLT2) is implicated in acute renal injury (ARI) progression and is regulated by extracellular signal-regulated kinase (ERK), hypoxia-inducible factor 1 alpha (HIF1α) or prostaglandin E2 (PGE2). This study aimed to assess the possible protective effect of nebivolol on renal ischemia/reperfusion (IR) and glycerol-induced ARI targeting SGLT2 via modulating the ERK-HIF1α pathway. METHODS: Rats were divided into control, sham, IR or nebivolol-treated group, in which rats were treated with nebivolol (10 mg/kg) for 3 days prior to the induction of IR. The rats were subjected to renal ischemia by bilateral clamping of the pedicles for 45 min, followed by 24 h reperfusion. Another group of rats received the vehicle or nebivolol (10 mg/kg) for 3 days followed by injection of 50% glycerol (8 ml/kg, IM) or saline. Kidney function tests, systolic blood pressure (SBP), oxidative stress markers [malondialdehyde (MDA) and NADPH oxidase] and kidney levels of nitric oxide (NO), inducible nitric oxide synthase (iNOS), HIF1α, ERK phosphorylation and PGE2 were determined. Additionally, renal sections were used for histological grading of renal injury and immunological expression of SGLT2. RESULTS: ARI rats showed significantly increased SBP, poor kidney function tests, increased oxidative stress, iNOS, NO, HIF1α levels, decreased PGE2 and ERK phosphorylation and upregulation of SGLT2 expression. Nebivolol treatment protected against the kidney damage both on the biochemical and histological levels. CONCLUSION: Nebivolol has a direct renoprotective effect, at least in part, by down-regulating SGLT2 possibly via modulating HIF1α, ERK activity and PGE2 production.
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Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/prevención & control , Modelos Animales de Enfermedad , Nebivolol/uso terapéutico , Daño por Reperfusión/metabolismo , Transportador 2 de Sodio-Glucosa/biosíntesis , Lesión Renal Aguda/patología , Animales , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Glicerol/toxicidad , Masculino , Nebivolol/farmacología , Ratas , Daño por Reperfusión/patologíaRESUMEN
Insulin resistance and chronic alcoholism are risk factors for renal dysfunction. This study investigated the therapeutic effects of two imidazoline-1 receptor (I1R) agonists on renal dysfunction in rats after chronic, sequential fructose and ethanol administration. Daily drinking water was supplemented with fructose (10%, w/v) for 12 weeks and then with ethanol (20%, v/v) for another 8 weeks. Rats were treated with rilmenidine and clonidine in the last two weeks of the study. Blood glucose and serum insulin (sIns) levels, lipid profiles, kidney function and renal histopathology were evaluated at the end of the experiment. Additionally, renal gene expression of nischarin, phosphatidylcholine-specific phospholipase C (PC-PLC) and prostaglandin E2 (PGE2) were measured. Renal levels of superoxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS) and total NO (tNO) were detected, and we determined the relative renal gene expression levels of alpha smooth muscle actin (α-SMA), hydroxyproline, interleukin 10 (IL-10), tumour necrosis factor alpha (TNF-α) and caspase-3. The results showed significant deterioration of blood glucose, sIns, lipid profiles, kidney function and renal histopathology in fructose/ethanol-fed rats. Additionally, markers of inflammation, fibrosis, apoptosis and oxidative stress were upregulated. The administration of rilmenidine or clonidine significantly improved blood glucose and sIns levels and reduced renal dysfunction. Our work showed that chronic, sequential fructose and ethanol administration induced fasting hyperglycaemia and renal impairment, and these effects were ameliorated by I1R agonists.
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Etanol/efectos adversos , Fructosa/efectos adversos , Receptores de Imidazolina/agonistas , Riñón/efectos de los fármacos , Riñón/fisiopatología , Animales , Dinoprostona/metabolismo , Relación Dosis-Respuesta a Droga , Etanol/administración & dosificación , Fructosa/administración & dosificación , Regulación de la Expresión Génica/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Malondialdehído/metabolismo , Óxido Nítrico/metabolismo , Ratas , Factores de TiempoRESUMEN
Sodium-glucose cotransporter-2 (SGLT2) is known to be involved in the progression of acute renal injury (ARI) and is regulated by different mediators in the kidneys including extracellular signal-regulated kinase (ERK), hypoxia-inducible factor 1 alpha (HIF1α) and prostaglandin E2 (PGE2). In the present study, we investigated the possible protective effect of doxazosin on renal ischaemia/reperfusion (IR) and glycerol-induced ARI by determining its effect on SGLT2 via modifying ERK-HIF1α pathway and/or PGE2. Rats were divided into control, sham or IR where the rats received the vehicle, doxazosin (8 mg/kg) or the SGLT2 inhibitor, dapagliflozin (10 mg/kg) for 3 days followed by 45 minutes bilateral renal ischaemia then 24 hours reperfusion. Another group of rats received the vehicle, doxazosin or dapagliflozin for three days followed by injection of 50% glycerol (8 mL/kg, IM) or saline. Kidney function tests, systolic blood pressure (SBP), oxidative stress markers (malondialdehyde [MDA] and NADPH oxidase), nitric oxide (NO), inducible nitric oxide synthase (iNOS), HIF1α, ERK phosphorylation and PGE2 levels were determined. Additionally, renal sections were used for immunological expression of SGLT2. ARI rats showed significantly increased SBP; worsened kidney function tests; increased oxidative stress, iNOS, NO, HIF1α levels; and decreased PGE2 and ERK phosphorylation along with up-regulated SGLT2. Doxazosin treatment protected against the kidney damage and attenuated the associated biochemical changes. Doxazosin has a direct renoprotective effect possibly by down-regulating SGLT2.
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Lesión Renal Aguda/tratamiento farmacológico , Doxazosina/farmacología , Riñón/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Transportador 2 de Sodio-Glucosa/metabolismo , Lesión Renal Aguda/metabolismo , Animales , Compuestos de Bencidrilo/farmacología , Presión Sanguínea/efectos de los fármacos , Dinoprostona/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Glucósidos/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Riñón/irrigación sanguínea , Riñón/patología , Masculino , Óxido Nítrico Sintasa de Tipo II/metabolismo , Distribución Aleatoria , Ratas , Daño por Reperfusión/metabolismoRESUMEN
Peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, pioglitazone, is used clinically to improve the glycemic state in patients with type-2 diabetes mellitus. Independent of its blood glucose-lowering properties, pioglitazone ameliorates different cardiovascular disorders. The aim of the present study was to investigate the effect of pioglitazone on cardiovascular complications of N-nitro-L-arginine methyl ester (L-NAME)-induced hypertension and to determine the role of oxidative and endoplasmic reticulum (ER) stress in its activity. Nitric oxide (NO) deficiency induced by chronic L-NAME administration was associated with high blood pressure (BP) and cardiac hypertrophy. L-NAME induced oxidative stress as indicated by reduced glutathione (GSH) levels, superoxide dismutase (SOD) and catalase activities as well as increased malondialdehyde (MDA) levels. Furthermore, L-NAME increased the expression of ER stress markers, activating transcription factor-4 (ATF-4) and C/EPBα-homologous protein-10 (CHOP-10) in both heart and aorta of hypertensive rats. Activation of PPAR-γ by pioglitazone reduced BP, restored the blunted NO levels, increased endothelial NO synthase (eNOS) expression, and restored the antioxidant status of L-NAME-induced hypertensive rats. Moreover, the antihypertensive activity of pioglitazone was associated with a reduction in ER stress and this effect was PPAR-γ dependent. Interestingly, the effect of ER stress inhibitor, 4-phenylbutyric acid (4-PBA) and antioxidant, N-acetylcysteine (NAC), on BP, NO availability, oxidative stress and ER stress mimics the activity of pioglitazone. Taken together, our data suggests that PPAR-γ is a potential target to inhibit vascular complications and cardiac damage associated with NO-deficient HTN and puts more emphasis on the importance of ER stress in regulating PPAR-γ activity.
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Hipertensión/tratamiento farmacológico , PPAR gamma/metabolismo , Pioglitazona/farmacología , Animales , Antioxidantes/farmacología , Aorta/metabolismo , Presión Sanguínea/efectos de los fármacos , Catalasa/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Glutatión/metabolismo , Corazón/fisiología , Hipertensión/metabolismo , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , PPAR gamma/agonistas , Pioglitazona/metabolismo , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismoRESUMEN
Stress induced gastric ulcer is a serious health problem in diabetic patients. Some studies reported that hesperidin (HDN), a citrus bioflavonoid, can bind to and stimulate peroxisome proliferator-activator receptor-gamma (PPAR-γ) which may mediate its antidiabetic, anti-inflammatory and anti-oxidant effects. This work aims to study the possible protective effect of HDN against stress induced gastric ulcer in diabetic rats as well as the possible involvement of PPARγ in this effect. Type 2 diabetes was induced using streptozotocin and nicotinamide. Diabetic rats received either HDN (100 mg/kg/day, orally) & omeprazole (20 mg/kg/day, orally) or HDN (100 mg/kg/day, orally) + GW9662, PPARγ antagonist, (1 mg/kg/day, i.p.) for 8 weeks then acute gastric injury was induced by cold restraint stress technique. Glycemic controls and gastroprotective effects were evaluated by measuring serum levels of glucose and insulin, gastric free and total acidity and gastric ulcer indices. Histopathological examination of gastric mucosa was also performed. To determine the underlying mechanism of action, gastric mucosal expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), hemeoxygenase-1 (HO-1), cluster of differentiation 45 (CD45), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NFκB) and inducible nitric oxide synthase (iNOS), gastric contents of reduced glutathione (GSH), malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α) and nitric oxide (NO); as well as superoxide dismutase (SOD) and catalase activities were measured. HDN significantly improved glycemic level; it also reduced gastric acidity and gastric ulcer index and histopathological changes comparable to that produced by omeprazole. Moreover, HDN reduced lipid peroxidation and inflammatory markers levels and enhanced antioxidant capacity. The use of GW9662 significantly abrogated the gastric protective effect of HDN as well as reduced the antioxidant and anti-inflammatory effects. Our work showed, for the first time that, HDN has promising protective effect against stress induced gastric ulcer in diabetic rats through activation of PPARγ.
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Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Hesperidina/uso terapéutico , PPAR gamma/metabolismo , Sustancias Protectoras/uso terapéutico , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/metabolismo , Estrés Fisiológico , Animales , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Diabetes Mellitus Experimental/sangre , Progresión de la Enfermedad , Hesperidina/farmacología , Concentración de Iones de Hidrógeno , Insulina/sangre , Antígenos Comunes de Leucocito/metabolismo , Masculino , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Omeprazol/farmacología , Omeprazol/uso terapéutico , Oxidantes/metabolismo , Sustancias Protectoras/farmacología , Ratas Wistar , Estómago/efectos de los fármacos , Estómago/patología , Úlcera Gástrica/sangre , Úlcera Gástrica/patología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Chronic alcoholism is a risk factor for kidney injury. Clonidine is an α2-adrenergic receptor/imidazoline-1 receptor agonist that can reduce blood pressure and maintain renal functions. This study aims to investigate the possible ameliorative effects of clonidine on ethanol induced kidney injury and its mechanism of action. Kidney injury was induced in rats by adding ethanol to drinking water for eight weeks. Clonidine effects on kidney functions and histopathology were measured. Moreover, phentolamine (α-adrenergic receptor antagonist), efaroxan (imidazoline-1 receptor antagonist) and rilmenidine (imidazoline-1 receptor agonist) were used to clarify the role of imidazoline-1 receptor in mediating renal ameliorative effects. Also, the effect of clonidine on liver functions and metabolic changes, in addition to renal oxidative stress, inflammatory and apoptotic pathways were measured. Results showed that, clonidine improved renal functions and reduced ethanol induced renal inflammation and fibrosis. On the other hand, efaroxan, only, blocked clonidine effects on kidney functions. Rilmenidine decreased kidney injury like clonidine. Both clonidine and rilmenidine increased renal nischarin gene expression. Furthermore, clonidine improved liver functions, increased serum insulin and decreased serum advanced glycation end products (metabolic markers). Also, clonidine reduced renal oxidative stress as reflected by decreased myeloperoxidase, malondialdehyde, inducible nitric oxide synthase and total nitric oxide levels and increased superoxide dismutase level. Moreover, clonidine reduced renal tumor necrosis factor-α (inflammatory marker) and caspase-3 (apoptotic marker) levels, while increased renal prostaglandine E2 and interleukin-10 levels (anti-inflammatory markers). In conclusion, clonidine can reduce ethanol induced kidney injury, at least in part, by stimulating imidazoline-1 receptor signaling.
Asunto(s)
Clonidina/farmacología , Etanol/efectos adversos , Receptores de Imidazolina/metabolismo , Riñón/efectos de los fármacos , Riñón/lesiones , Animales , Apoptosis/efectos de los fármacos , Clonidina/uso terapéutico , Citoprotección/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Hígado/efectos de los fármacos , Hígado/fisiopatología , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
Hepatic fibrosis is a potential health problem that may end with life-threatening cirrhosis and primary liver cancer. Recent studies point out to the protective effects of silent information regulator1 (SIRT1), against different models of organs fibrosis. This work aimed to investigate the possible protective effect of sildenafil (SIRT1 activator) against hepatic fibrosis induced by bile duct ligation (BDL). Firstly, three different doses of sildenafil (5, 10, 20mg/kg/day) were investigated; to detect the most protective one against BDL induced liver dysfunction and hepatic fibrosis. The most protective dose is then used; to study its effect on BDL induced SIRT1 downregulation, imbalance of oxidant/antioxidant status, increased inflammatory cytokines and fibrosis. Sildenafil (20mg/kg/day) was the most protective one, it caused upregulation of SIRT1, reduction of hepatic malondialdehyde (MDA) content, increase in expression of nuclear factor erythroid 2-related factor 2 (Nrf2), hemeoxygenease (HO)-1, reduced glutathione (GSH) content and superoxide dismutase (SOD) activity. Hepatic content of tumor necrosis factor-α (TNF-α) and nuclear factor κB (NFκB) expression & content displayed significant reductions with sildenafil treatment, Furthermore, sildenafil caused marked reductions of transforming growth factor (TGF)-ß content, expression of plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), α-smooth muscle actin (α-SMA), fibronectin, collagen I (α1) and hydroxyproline content. However, sildenafil protective effects were significantly reduced by co-administration of EX527 (SIRT1 inhibitor). Our work showed, for the first time that, sildenafil has promising protective effects against BDL induced liver dysfunction and hepatic fibrosis. These effects may be, in part, mediated by up regulation of SIRT1.
Asunto(s)
Colestasis/tratamiento farmacológico , Cirrosis Hepática Biliar/prevención & control , Hígado/efectos de los fármacos , Sustancias Protectoras/farmacología , Citrato de Sildenafil/farmacología , Sirtuina 1/metabolismo , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Biomarcadores/metabolismo , Carbazoles/farmacología , Colestasis/complicaciones , Colestasis/enzimología , Colestasis/patología , Citoprotección , Modelos Animales de Enfermedad , Inhibidores de Histona Desacetilasas/farmacología , Mediadores de Inflamación/metabolismo , Ligadura , Hígado/enzimología , Hígado/patología , Cirrosis Hepática Biliar/enzimología , Cirrosis Hepática Biliar/etiología , Cirrosis Hepática Biliar/patología , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Sirtuina 1/antagonistas & inhibidores , Regulación hacia ArribaRESUMEN
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
Nonalcoholic fatty liver disease (NAFLD) is an accumulation of excessive amounts of fats in the liver that is not caused by alcohol consumption. It is considered as the most common liver disease in Western societies. The aim of this study is to investigate the possible protective effects of nicorandil and pioglitazone, the benefits of their combination and the possible mechanism underlie these effects in NAFLD. Rats were fed a high-fat diet (HFD) for eight weeks to induce NAFLD. In the next eight weeks, rats were fed the HFD along with pioglitazone (4 mg/kg) or nicorandil in two dose levels (3 or 15 mg/kg), alone or in combination. Chronic HFD administration resulted in significant elevations in serum levels of liver enzymes, total cholesterol, triglycerides, glucose, insulin and HOMA-IR index as compared with the control group. This was coupled with significant increments in liver triglycerides, MDA content and TNF-α as well as a significant reduction in liver GSH content. In comparison with the control group; liver expression of NF-κB was significantly elevated while liver eNOS expression and nitric oxide content were significantly decreased in HFD group. Treatment with pioglitazone or nicorandil either alone or in combination successfully ameliorated the deleterious effects of HFD on the all previous parameters. In conclusion, this investigation indicates a novel role of nicorandil in rats with NAFLD. This effect is mediated through, nitric oxide donor, antioxidant and anti-inflammatory properties, leading to improvement of insulin resistance. It is worth mentioning that the combinations were more effective than the individual drugs.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Nicorandil/farmacología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Biomarcadores/sangre , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Colesterol/sangre , Citoprotección/efectos de los fármacos , Interacciones Farmacológicas , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Homeostasis/efectos de los fármacos , Insulina/sangre , Resistencia a la Insulina , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Hígado/patología , Masculino , FN-kappa B/genética , Nicorandil/uso terapéutico , Óxido Nítrico Sintasa de Tipo III/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Estrés Oxidativo/efectos de los fármacos , Pioglitazona , Ratas , Ratas Wistar , Tiazolidinedionas/farmacología , Triglicéridos/sangre , Triglicéridos/metabolismo , 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.
Asunto(s)
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.