RESUMEN
PURPOSE: The study aimed to investigate the potential nephroprotective effects of vitamin D3 in metabolic syndrome (MetS) and the molecular basis of the underlying mechanisms of its action. METHODS: MetS was induced in adult male Wistar rat s by adding fructose (10%) to every day drinking water and salt (3%) to the diet. Six weeks after fructose/salt consumption, fasting serum lipid profile and uric acid levels were determined, an oral glucose tolerance test (OGTT) was performed and kidney function was checked. MetS rats were then treated orally with vitamin D3 (10 µg/kg/day) for 6 weeks. At the end of the study period (12 weeks), the OGTT test was reperformed, anthropometrical parameters were measured, urine, blood and tissue samples were collected and the animals were euthanised. RESULTS: The incidence of MetS was confirmed 6 weeks after fructose/salt consumption, when the rats exhibited significant weight gain, dyslipidemia, hyperuricemia, insulin resistance, hyperinsulinemia and impaired glucose tolerance. After 12 weeks, MetS rats displayed markedly declined renal function alongside with extravagant renal histopathological damages and interstitial fibrosis. Furthermore, significantly enhanced renal oxidative stress and inflammation were manifested. Vitamin D3 supplementation in MetS rats significantly reversed all the above-mentioned deleterious effects. CONCLUSION: The study has indeed provided mounting evidence of the promising therapeutic potential of vitamin D3 against development and progression of MetS-induced nephropathy. A new insight has been introduced into the crucial role of dipeptidyl peptidase-4 inhibition and sirtuin-1/5'adenosine monophosphate-activated protein kinase activation in the renoprotective effects of vitamin D3.
Asunto(s)
Resistencia a la Insulina , Síndrome Metabólico , Animales , Glucemia , Colecalciferol , Suplementos Dietéticos , Fructosa , Masculino , Síndrome Metabólico/tratamiento farmacológico , Ratas , Ratas WistarRESUMEN
The current study aimed to investigate the molecular mechanisms of metformin and vitamin D3-induced nephroprotection in a metabolic syndrome (MetS) rat model, evaluating the capacity of vitamin D3 to potentiate metformin action. MetS was induced by 10% fructose in drinking water and 3% salt in the diet. After 6 weeks, serum lipid profile and uric acid were measured, an oral glucose tolerance test (OGTT) was performed, and kidney function was investigated. In conjunction with the same concentrations of fructose and salt feeding, MetS rats with significant weight gain, dyslipidemia, hyperuricemia, and dysglycemia were treated orally with metformin (200 mg/kg), vitamin D3 (10 µg/kg), or both daily for 6 weeks. At the end of the study period, anthropometrical parameters were recorded, OGTT was reperformed, urine and blood samples were collected, and tissue samples were harvested at sacrifice. MetS rats showed dramatically declined renal function, enhanced intrarenal oxidative stress and inflammation, and extravagant renal histopathological damage with interstitial fibrosis. Metformin and vitamin D3 significantly reversed all the aforementioned deleterious effects in MetS rats. The study has verified the nephroprotective effects of metformin and vitamin D3 in MetS, accentuating the critical role of AMP-activated protein kinase/sirtuin-1 activation and dipeptidyl peptidase-4 inhibition. Given the synergistic effects of the combination, vitamin D3 is worth being investigated as an additional therapeutic agent for preventing MetS-induced nephropathy.
Asunto(s)
Metformina , Proteínas Quinasas Activadas por AMP , Animales , Colecalciferol , Inhibidores de la Dipeptidil-Peptidasa IV , Masculino , Síndrome Metabólico , RatasRESUMEN
New series of phthalimide-sulfonylurea hybrids were prepared and examined for their in vivo anti-hyperglycemic activities in STZ-induced hyperglycemic rats using glibenclamide as a reference drug. Compounds 6c, 6d, 6g, 6h, 6j and 6k induced significant reduction in the blood glucose levels of diabetic rats ranging from 24.43 to 21.43%. Moreover, molecular docking and pharmacophore approaches were carried out to examine binding modes and fit values of the prepared compounds against PPARγ and SUR, respectively. Compounds 6c, 6d, 6j and 6m exhibited the highest binding free energies against PPARγ. Compounds 6c, 6j, 6k, 6l, and 6n showed the highest fit values against the generated pharmacophore model. Also, QSAR technique was carried out to estimate the proposed PPARγ binding affinities and insulin-secreting abilities. The synthesized compounds showed promising estimated activities. In-silico ADMET studies were performed to investigate pharmacokinetics of the synthesized compounds. They showed considerable human intestinal absorption with low BBB penetration.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Diseño de Fármacos , Hipoglucemiantes/farmacología , PPAR gamma/agonistas , Ftalimidas/farmacología , Compuestos de Sulfonilurea/farmacología , Receptores de Sulfonilureas/agonistas , Animales , Diabetes Mellitus Experimental/inducido químicamente , Relación Dosis-Respuesta a Droga , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Masculino , Modelos Moleculares , Estructura Molecular , Ftalimidas/química , Ratas , Ratas Wistar , Estreptozocina/administración & dosificación , Relación Estructura-Actividad , Compuestos de Sulfonilurea/químicaRESUMEN
The current study was conducted to evaluate the effect of 6-gingerol (6G) on cardiac complications in streptozotocin (STZ)-induced diabetic (DM) rats. STZ-induced DM rats (single 50 mg/kg i.p. injection, 15 days prior to drug treatment) or time-matched controls were treated with 6G (75 mg/day route orally). After a further 8 weeks, blood was collected for biochemical analysis and 8-isoprostenol was measured in urine. Cardiac hemodynamics and ECG was assessed. 6G significantly attenuated the increased level of blood glucose in diabetic rats and improved cardiac hemodynamics in including RR interval, max dP/dt, min dP/dt and Tau. In addition, 6G alleviated the elevated ST segment, T amplitude and R amplitude with no significant effect on disturbed levels of adiponectin, TGF-ß or 8-isoprostenol induced by diabetes. The results showed that treatment with 6G has an ameliorative effect on cardiac dysfunction induced by diabetes. Which may be not related to its potential antioxidant effect.
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Cardiotónicos/administración & dosificación , Catecoles/administración & dosificación , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/fisiopatología , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/fisiopatología , Alcoholes Grasos/administración & dosificación , Animales , Diabetes Mellitus Experimental/diagnóstico , Cardiomiopatías Diabéticas/diagnóstico , Relación Dosis-Respuesta a Droga , Hipoglucemiantes/administración & dosificación , Masculino , Ratas , Ratas Wistar , Resultado del TratamientoRESUMEN
Diabetes mellitus is possibly the world's largest growing metabolic disorder. Effective treatment of diabetes is increasingly dependent on active constituents of medicinal plants capable of controlling hyperglycemia as well as its secondary complications. Viscum schimperi Engl. is a plant growing in Saudi Arabia and known for its antidiabetic activity. The potential antidiabetic activity of its methanol extract as well as its chloroform, n-butanol, and the remaining water fractions was evaluated in streptozotocin-induced diabetic rats at two dose levels. The antidiabetic activity was assessed through the determination of fasting blood glucose level, insulin levels, area under the curve (AUC) in oral glucose tolerance test, glucose absorption in isolated rat gut assay, and glucose uptake by psoas muscle. Moreover, large-scale untargeted metabolite profiling of methanol extract was performed via UPLC-PDA and qTOF-MS (ultra-performance liquid chromatography photodiode array detection and quadrupole time-of-flight mass spectrometry) respectively, to explore its chemical composition and standardization of its extract. Multivariate statistical analysis including principal component analysis and orthogonal projection to latent structures discriminant analysis was used to determine bioactives in its fractions. In conclusion, oleanane triterpenes and O-caffeoyl quinic acid conjugates were the major compounds that might account for antihyperglycemic effect of the plant.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , 1-Butanol , Animales , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/farmacología , Masculino , Metanol , Extractos Vegetales/farmacología , Plantas Medicinales , Ratas , Arabia Saudita , Estreptozocina , Viscaceae , ViscumRESUMEN
Red onion scales (ROS) contain large amounts of flavonoids that are responsible for the reported antioxidant activity, immune enhancement, and anticancer property. Atypical prostatic hyperplasia (APH) was induced in adult castrated Wistar rats by both s.c. injection of testosterone (0.5 mg/rat/day) and by smearing citral on shaved skin once every 3 days for 30 days. Saw palmetto (100 mg/kg) as a positive control and ROS suspension at doses of 75, 150, and 300 mg/kg/day were given orally every day for 30 days. All medications were started 7 days after castration and along with testosterone and citral. The HPLC profile of ROS methanolic extract displayed two major peaks identified as quercetin and quercetin-4'-ß-O-D-glucoside. Histopathological examination of APH-induced prostatic rats revealed evidence of hyperplasia and inflammation with cellular proliferation and reduced apoptosis Immunohistochemistry showed increased tissue expressions of IL-6, IL-8, TNF-α, IGF-1, and clusterin, while TGF-ß1 was decreased, which correlates with the presence of inflammation. Both saw palmetto and RO scale treatment have ameliorated these changes. These ameliorative effects were more evident in RO scale groups and were dose dependent. In conclusion, methanolic extract of ROS showed a protective effect against APH induced rats that may be attributed to potential anti-inflammatory and immunomodulatory effects.
Asunto(s)
Factores Inmunológicos/uso terapéutico , Cebollas/química , Extractos Vegetales/uso terapéutico , Hiperplasia Prostática/tratamiento farmacológico , Animales , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Masculino , Ratas , Ratas Wistar , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The main objective of this study was to determine if the telmisartan-ameliorative effects of metabolic syndrome (MetS)-evoked nephropathy are attributed to the Hippo pathway. A secondary objective was to investigate the potential of vitamin D3 to enhance telmisartan-favourable effects. A diet composed of 24% fat and 3% salt, along with drinking water containing 10% fructose, was administered for 12 weeks to induce MetS. MetS-rats were given telmisartan (5 mg/kg/day), vitamin D3 (10 µg/kg/day) or both by gavage, starting in the sixth week of experimental diet administration. Assessments performed at closure included renal function, histological examination, catalase, malondialdehyde (MDA), nuclear factor kappa-B (NF-κB), interleukin-6 (IL-6), peroxisome proliferator-activated receptor-γ (PPAR-γ), phosphatase and tensin homolog (PTEN), and transforming growth factor-ß (TGF-ß). Matrix metalloproteinase-9 (MMP-9) immunostaining was conducted. The expression of the Hippo pathway components, as well as that of angiotensin II type 1 and type 2 (AT1 and AT2), receptors was evaluated. Telmisartan attenuated MetS-evoked nephropathy, as demonstrated by improvement of renal function and histological features, enhancement of catalase, reduction of MDA, inflammation (NF-κB, IL-6), and renal fibrosis (increased PPAR-γ and PTEN and reduced MMP-9 and TGF-ß). Telmisartan downregulated AT1-receptor, upregulated AT2-receptor and restored the Hippo pathway. Vitamin D3 replicated most of the telmisartan-elicited effects and enhanced the antifibrotic actions of telmisartan. The alleviative effects of telmisartan on MetS-evoked nephropathy may be related to the restoration of the Hippo pathway. The combination of vitamin D3 and telmisartan exerted more favourable effects on metabolic and nephropathic biomarkers compared with either one administered alone.
Asunto(s)
Vía de Señalización Hippo , Enfermedades Renales , Riñón , Síndrome Metabólico , Telmisartán , Animales , Telmisartán/farmacología , Telmisartán/uso terapéutico , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/metabolismo , Síndrome Metabólico/complicaciones , Síndrome Metabólico/patología , Masculino , Ratas , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , FN-kappa B/metabolismo , Colecalciferol/farmacología , Colecalciferol/uso terapéutico , Ratas Wistar , Metaloproteinasa 9 de la Matriz/metabolismo , Fosfohidrolasa PTEN/metabolismo , PPAR gamma/metabolismo , Estrés Oxidativo/efectos de los fármacos , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/metabolismo , Malondialdehído/metabolismo , Interleucina-6/metabolismo , Bencimidazoles/farmacología , Bencimidazoles/uso terapéuticoRESUMEN
The current study was conducted to investigate the nephroprotective effects of vildagliptin-metformin combination in an experimental model of fructose/salt-induced metabolic syndrome (MetS). A major aim was to evaluate the potential capacity of vitamin D3 to potentiate the pleiotropic nephroprotective effects of vildagliptin-metformin combination. MetS was induced in adult male Wistar rats by adding fructose (10%) to everyday drinking water and salt (3%) to the diet for 6 weeks. Along with the same concentrations of fructose/salt feeding, MetS rats were then treated orally with either vildagliptin (10 mg/kg/day)-metformin (200 mg/kg/day) combination, vitamin D3 (10 µg/kg/day), or the triple therapy for a further 6 weeks. The incidence of MetS was confirmed 6 weeks after fructose/salt consumption, when the rats exhibited significant weight gain, dyslipidemia, hyperuricemia, insulin resistance, hyperinsulinemia, and impaired glucose tolerance. At the end of the 12-week experimental period, MetS rats displayed significantly deteriorated renal function, enhanced intrarenal oxidative stress and inflammation together with exaggerated renal histopathological damages and interstitial fibrosis. The study has corroborated antioxidant, anti-inflammatory, and antifibrotic effects of vildagliptin-metformin combination, vitamin D3, and the triple collaborative therapy, conferring renoprotection in the setting of MetS. Due attention has been paid to the crucial role of dipeptidyl peptidase-4 inhibition and sirtuin-1/5' adenosine monophosphate-activated protein kinase activation as novel therapeutic targets to optimize renoprotection. The apparent potentiating effect, evoked upon coadministration of vitamin D3 with vildagliptin-metformin combination, may provide a cornerstone for further clinical investigations.
Asunto(s)
Adamantano , Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Síndrome Metabólico , Metformina , Adamantano/farmacología , Adamantano/uso terapéutico , Animales , Colecalciferol/farmacología , Colecalciferol/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Quimioterapia Combinada , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Masculino , Síndrome Metabólico/tratamiento farmacológico , Metformina/farmacología , Metformina/uso terapéutico , Nitrilos/farmacología , Pirrolidinas/farmacología , Pirrolidinas/uso terapéutico , Ratas , Ratas Wistar , Vildagliptina/farmacología , Vildagliptina/uso terapéuticoRESUMEN
Insulin resistance (IR) seemingly plays a role in chronic kidney disease (CKD). The present study has elucidated the crucial interplay of oxidative stress, inflammatory, apoptotic and profibrotic signaling pathways, linking IR to CKD. The study aimed at investigating the pleiotropic nephroprotective effects of either vildagliptin or vitamin D3 in a fructose/salt-induced IR rat model, highlighting the potential molecular mechanisms underlying their action. Another interesting target was to evaluate the potential capacity of vitamin D3 to potentiate the nephroprotective effects of vildagliptin. Indeed, a state of impaired fasting glucose, IR and compensatory hyperinsulinemia, constellating with significant weight gain, atherogenic dyslipidemia and hyperuricemia was established 6 weeks after fructose/salt consumption. IR rats were then treated orally with vildagliptin (10 mg/kg/day), vitamin D3 (10 µg/kg/day) or their combination for a further 6 weeks. By the end of the 12th week, untreated IR rats displayed significantly declined renal function with parallel interwined renal oxidative stress, inflammatory, apoptotic and profibrotic changes, renal histopathological damages and markedly enhanced collagen fiber deposition. Vildagliptin and vitamin D3 reversed hyperuricemia and exerted a plethora of renal anti-oxidant, anti-inflammatory, anti-apoptotic and anti-fibrotic effects. Our study has introduced a new insight into the role of dipeptidyl peptidase-4 inhibition and silent information regulator 1/5'adenosine monophosphate-activated protein kinase activation in the nephroprotective effects of either agent, elucidating their possible crosstalk with renin angiotensin aldosterone system downregulation. Considering the superadditive renoprotective effects evoked by the combination, vitamin D3 is worth being further investigated as an additional therapeutic agent for preventing IR-induced nephropathy.
Asunto(s)
Colecalciferol/farmacología , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Riñón/efectos de los fármacos , Riñón/metabolismo , Vildagliptina/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Glucemia/efectos de los fármacos , Creatinina/sangre , Inhibidores de la Dipeptidil-Peptidasa IV/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Hiperuricemia/tratamiento farmacológico , Riñón/patología , Corteza Renal/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , NADP/metabolismo , Estrés Oxidativo , Ratas , Ratas Wistar , Receptor de Angiotensina Tipo 1/metabolismo , Sirtuina 1 , Cloruro de Sodio/farmacología , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Urea/sangre , Ácido Úrico/sangre , Ácido Úrico/metabolismoRESUMEN
The present study was planned to assess the possible protective effect of geraniol on cardiovascular complications in an animal model with diabetes. Diabetes was induced in rats by a single streptozotocin injection. In the treated group, geraniol (150mgkg-1day-1) was administered orally starting from the 15th day after induction of diabetes, and ending after 7 weeks; diabetic control rats were given vehicle for the same period. At the end of the study, cardiac contractility was assessed by using a Millar microtip catheter in anesthetised rats, and cardiac conductivity determined by a surface ECG. Serum levels of glucose, cholesterol, triglyceride and adiponectin as well as urine 8-isoprostane were determined. In addition, cardiac superoxide dismutase (SOD) and catalase activity were measured. Geraniol administration significantly alleviated the attenuated cardiac systolic function associated with diabetes as indicated by inhibiting the decrease in the rate of rise (dP/dtmax) in ventricular pressure and the increase in systolic duration observed in diabetic rats. In addition, geraniol alleviated impaired diastolic function as shown by inhibiting the decrease in the rate of fall (dP/dtmin) in ventricular pressure and increased isovolumic relaxation constant (Tau) observed in diabetic rats. ECG recordings showed that geraniol prevented any increase in QTc and T-peak-T-end intervals, and markers of LV ischemia and arrhythmogenesis, seen in diabetic animals. Geraniol suppressed the exaggerated oxidative stress as evidenced by preventing the increase in 8-isoprotane. In diabetic heart tissue, geraniol prevented the inhibition in catalase activity but did not affect the heart SOD. Geraniol partially reduced hyperglycemia, prevented the hypercholesterolemia, but did not affect the serum level of adiponectin in diabetic animals. Results obtained in this study suggest that geraniol provides a potent protective effect against cardiac dysfunction induced by diabetes. This ameliorative effect could be attributed to its suppression of oxidative stress.
Asunto(s)
Complicaciones de la Diabetes/tratamiento farmacológico , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Terpenos/uso terapéutico , Monoterpenos Acíclicos , Adiponectina/sangre , Animales , Glucemia/metabolismo , Colesterol/sangre , Complicaciones de la Diabetes/patología , Complicaciones de la Diabetes/fisiopatología , Dinoprost/análogos & derivados , Dinoprost/farmacología , Electrocardiografía , Hemodinámica/efectos de los fármacos , Masculino , Isquemia Miocárdica/patología , Isquemia Miocárdica/fisiopatología , Ratas Wistar , Terpenos/farmacologíaRESUMEN
BACKGROUND: The study aims to analyse the action of zingerone in diabetes-related cardiac arrhythmias. METHODS: Diabetes was induced by streptozocin while treatment groups received 20 mg/kg zingerone daily. Following extra seven weeks, electrocardiography, extraction of blood, urine and heart for biochemical analysis, histopathology and immunofluorescence were undertaken. RESULTS: The suppression of QT and QTc prolongation in diabetic rats was indicative of prolonged cardiac repolarisation that was greatly reduced by zingerone treatment. In addition, the reduction in PR interval attested that zingerone improved AV delay in diabetic rats. The fibrogenic transforming growth factor ß1 upregulation in diabetic hearts was suppressed by zingerone. The marked glycogen deposition and muscle degeneration seen in diabetic heart sections were also alleviated by zingerone. Furthermore, zingerone prevented the decrease in of the serum anti-inflammatory cytokine adiponectin in diabetics. The heightened levels of oxidative stress markers 8-isoprostane and uric acid in diabetic rats were suppressed. In the diabetic heart, the reduced catalase activity was improved and the excessive expression of angiotensin receptor 1 was inhibited by zingerone. CONCLUSION: Cardiac delayed repolarisation and AV conduction in rats with diabetes were halted by zingerone. It appears that inhibition of cardiac fibrosis and associated inflammation-oxidative stress signalling underpins the zingerone effect.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Guayacol/análogos & derivados , Sistema de Conducción Cardíaco/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Inflamación/complicaciones , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/complicaciones , Electrocardiografía , Fibrosis , Guayacol/farmacología , Ventrículos Cardíacos/fisiopatología , Lípidos/sangre , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Aumento de PesoRESUMEN
AIM: The aim of the present study is to investigate the effect and possible mechanism of action of geraniol on the impaired vascular reactivity of aortic rings isolated from diabetes or metabolic syndrome (MS) -induced rats. METHODS: Male Wistar rats were divided into control, type 1 diabetes and metabolic syndrome (MS) groups. Diabetes was induced by a single intraperitoneal injection of streptozotocin (50mg/kg) and left for 10weeks to develop vascular complications. MS was induced by adding 10% fructose and 3% salt to water and diet for 12weeks. The present study investigated the effect of in vitro incubation with geraniol (10-300µM) on the vasoconstrictor response to phenylephrine (PE) and the vasodilator response to acetylcholine (ACh) as well as its effect on aortae incubated with methylglyoxal (MG) as an advanced glycation end product (AGE). To investigate the mechanism of action of geraniol, different blockers are used, including Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME, 100µM), tetraethylammonium chloride (TEA, 10mM), and indomethacin (INDO, 5µM). Moreover, the effect of calcium chloride (CaCl2) on aortic rings precontracted with PE or potassium chloride (KCl) was examined. RESULTS: Thirty minutes incubation with geraniol alleviated the exaggerated vasoconstriction in aortae isolated from diabetic or MS animals or in vitro exposed to MG in a concentration-dependent manner. In addition, geraniol improved the vasodilatation response of diabetic or MS aortae or aortae exposed to MG. In search for the mechanism; geraniol produced concentration-dependent relaxation of both PE and KCl-precontracted aorta. Geraniol relaxation was not affected by L-NAME, INDO or TEA. However, geraniol significantly inhibited voltage dependent and receptor mediated Ca(2+)-induced contraction activated by KCl or PE respectively. CONCLUSION: In conclusion, geraniol ameliorates impaired vascular reactivity in experimentally induced diabetes and MS. The effect may be partially attributed to an endothelium-independent pathway involving blockage of both voltage dependent and receptor operated calcium channel.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Síndrome Metabólico/tratamiento farmacológico , Terpenos/farmacología , Vasodilatación , Monoterpenos Acíclicos , Animales , Aorta/efectos de los fármacos , Canales de Calcio , Endotelio Vascular , Técnicas In Vitro , Masculino , Ratas , Ratas Wistar , VasodilatadoresRESUMEN
The aim of the present study was to investigate the effect and possible mechanism of action of zingerone, the main constituent of ginger, on vascular reactivity in isolated aorta from diabetic rats. The results show that incubation of aortae with zingerone alleviates the exaggerated vasoconstriction of diabetic aortae to phenylephrine, as well as the impaired relaxatory response to acetylcholine in a concentration-dependent manner. Furthermore, Zingerone directly relax phenylephrine-precontracted aortae. The vasorelaxatory response is significantly attenuated by the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester hydrochloride and the guanylate cyclase inhibitor methylene blue but no effect of either the potassium channels blocker tetraethylammonium chloride, or the cyclooxygenase inhibitor indomethacin was observed. Zingerone had no effect on advanced glycation end product formation as well. In conclusion, zingerone ameliorates enhanced vascular contraction in diabetic aortae which may be mediated by its vasodilator effect through NO- and guanylate cyclase stimulation.
Asunto(s)
Aorta/efectos de los fármacos , Aorta/fisiopatología , Diabetes Mellitus Experimental/fisiopatología , Guayacol/análogos & derivados , Vasoconstricción/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Aorta/metabolismo , Diabetes Mellitus Experimental/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Guayacol/farmacología , Masculino , Fenilefrina/farmacología , Ratas , Ratas Wistar , Vasodilatación/efectos de los fármacosRESUMEN
The aim of the current study was to evaluate the possible protective effect of allopurinol (Allo) on experimentally induced insulin resistance (IR) and vascular complications. Rats were divided into four groups: control, IR, allopurinol-treated IR (IR-Allo), and allopurinol-treated control (Allo). IR was induced by adding fructose and high fat, high salt diet for 12 weeks. The results showed that Allo has alleviated the increased level of TNF-α and the systolic, diastolic, mean, and notch pressure observed in IR with no change in pulse pressure. In addition, Allo decreased the heart rate in the treated group compared to IR rats. On the other hand, it has no effect on increased levels of insulin, glucose, fructosamine, or body weight gain compared to IR group, while it increased significantly the insulin level and body weight without hyperglycemia in the control group. Moreover, Allo treatment ameliorated increased level of 4HNE, Ang II, and Ang R1. In conclusion, the results of the current study show that Allo has a protective effect on vascular complications of IR which may be attributed to the effect of Allo on decreasing the TNF-α, 4HNE, Ang II, and Ang R1 as well as increasing the level of insulin secretion.
Asunto(s)
Alopurinol/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Resistencia a la Insulina , Aldehídos/metabolismo , Animales , Presión Sanguínea , Peso Corporal/efectos de los fármacos , Dieta Alta en Grasa , Inhibidores Enzimáticos/uso terapéutico , Fructosa/uso terapéutico , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Receptor de Angiotensina Tipo 2/metabolismo , Cloruro de Sodio Dietético , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The aim of the present study is to investigate the effect and potential mechanism of action of 6-gingerol on alterations of vascular reactivity in the isolated aorta from diabetic rats. Male Wistar rats were divided into two experimental groups, control and diabetics. Diabetes was induced by a single intraperitoneal injection of streptozotocin (50 mg kg(-1)), and the rats were left for 10 weeks to develop vascular complications. The effect of in vitro incubation with 6-gingerol (0.3-3 µM) on the vasoconstrictor response of the isolated diabetic aortae to phenylephrine and the vasodilator response to acetylcholine was examined. Effect of 6-gingerol was also examined on aortae incubated with methylglyoxal as an advanced glycation end product (AGE). To investigate the mechanism of action of 6-gingerol, the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester hydrochloride (100 µM), guanylate cyclase inhibitor methylene blue (5 µM), calcium-activated potassium channel blocker tetraethylammonium chloride (10 mM), and cyclooxygenase inhibitor indomethacin (5 µM) were added 30 minutes before assessing the direct vasorelaxant effect of 6-gingerol. Moreover, in vitro effects of 6-gingerol on NO release and the effect of 6-gingerol on AGE production were examined. Results showed that incubation of aortae with 6-gingerol (0.3-10 µM) alleviated the exaggerated vasoconstriction of diabetic aortae to phenylephrine in a concentration-dependent manner with no significant effect on the impaired relaxatory response to acetylcholine. Similar results were seen in the aortae exposed to methylglyoxal. In addition, 6-gingerol induced a direct vasodilation effect that was significantly inhibited by Nω-nitro-l-arginine methyl ester hydrochloride and methylene blue. Furthermore, 6-gingerol stimulated aortic NO generation but had no effect on AGE formation. In conclusion, 6-gingerol ameliorates enhanced vascular contraction in diabetic aortae, which may be partially attributed to its ability to increase the production of NO and stimulation of cyclic guanosine monophosphate.
Asunto(s)
Aorta/efectos de los fármacos , Catecoles/farmacología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Alcoholes Grasos/farmacología , Óxido Nítrico/biosíntesis , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Animales , Aorta/fisiología , Aorta/fisiopatología , Diabetes Mellitus Experimental/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
The antihyperglycaemic and hypolipidaemic effects of the methanolic extract of Caralluma tuberculata were investigated in streptozotocin (STZ)-induced diabetic rats. The antihyperglycaemic activity was assessed by the reduction in fasting blood glucose (54% at 4th week) and the peak of blood glucose at 120?min of an oral glucose tolerance test in diabetic rats. Further, the tested extract also increased plasma insulin by 206.8%. The hypolipidaemic action of the extract was evident by the significant decrease in the levels of total cholesterol, triglycerides and LDL-cholesterol by 41.5%, 36.7% and 49.1%, respectively, compared to diabetic rat values. Interestingly, the extract increased the cardio-protective lipid HDL-cholesterol by 147.97% as compared to diabetic rat value. The present data suggests that the methanolic extract of C. tuberculata has both antihyperglycaemic and hypolipidaemic effects in STZ-induced diabetic rats that may need further studies to be used in the management of diabetes and associated hyperlipedaemia.
Asunto(s)
Apocynaceae/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacología , Fitoterapia/métodos , Extractos Vegetales/farmacología , Análisis de Varianza , Animales , Glucemia/análisis , Colesterol/sangre , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/análisis , Hipolipemiantes/análisis , Insulina/sangre , Metanol , Extractos Vegetales/análisis , Ratas , Triglicéridos/sangreRESUMEN
BACKGROUND: Atypical prostatic hyperplasia (APH) is a pseudoneoplastic lesion that can mimic prostate adenocarcinoma because of its cytologic and architectural features. Suspension of date palm pollen (DPP) is an herbal mixture that is widely used in folk medicine for male infertility. The aim of the present study was to evaluate the effect of DPP suspension and extract on APH-induced rats. METHODS: APH was induced in adult castrated Wistar rats by both s.c. injection of testosterone (0.5 mg/rat/day) and smearing citral on shaved skin once every 3 days for 30 days. Saw palmetto (100mg/kg), DPP suspension (250, 500 and 1000 mg/kg), and lyophilized DPP extract (150,300 and 600 mg/kg) were given orally daily for 30 days. All medications were started 7 days after castration and along with testosterone and citral. RESULTS: The histopathological feature in APH-induced prostate rats showed evidence of hyperplasia and inflammation. Immunohistochemical examination revealed that the expressions of IL-6, IL-8, TNF-α, IGF-1 and clusterin were increased, while the expression of TGF-ß1 was decreased that correlates with presence of inflammation. Moreover, histopathological examination revealed increased cellular proliferation and reduced apoptosis in ventral prostate. Both saw palmetto and DPP treatment has ameliorated these histopathological and immunohistochemical changes in APH-induced rats. These improvements were not associated with reduction in the prostatic weight that may be attributed to the persistence of edema. CONCLUSION: DPP may have a potential protective effect in APH-induced Wistar rats through modulation of cytokine expression and/or upregulation of their autocrine/paracrine receptors.
RESUMEN
Retama raetam (RR) fruits are used in Saudi traditional medicine for the treatment of diabetes. Current study aimed at evaluating the potential and mechanisms of the antidiabetic activity of the RR methanolic extract in streptozotocin-induced diabetic rats. Oral LD(50) of the extract was found to be 1995 mg/kg. The extract was administered once orally to STZ-diabetic rats at three dose levels; 100, 250 or 500 mg/kg/day for 4 consecutive weeks. RR extract at 250 or 500 mg/kg significantly lowered blood glucose levels at the 3rd and 1st week of treatment, respectively. Meanwhile, oral glucose tolerance test indicated that the same two doses significantly lowered glucose levels at 30 and 60 min after glucose challenge. Administration of RR extract at 500 mg/kg/day for 4 consecutive weeks significantly increased serum insulin level. In vitro studies indicated that the extract significantly inhibits glucose absorption by rat isolated intestine. The extract neither altered glucose uptake by rat isolated psoas muscle nor the activity of hepatic microsomal glucose-6-phosphatase. In conclusion, the methanolic extract of RR improves STZ-induced diabetes in rats. This can be attributed, at least partly, to stimulating pancreatic insulin release and reducing intestinal glucose absorption.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Genista/química , Hipoglucemiantes/farmacología , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/sangre , Frutas/química , Genista/toxicidad , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Glucosa-6-Fosfatasa/metabolismo , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/toxicidad , Insulina/sangre , Absorción Intestinal , Dosificación Letal Mediana , Masculino , Metanol , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Fitoterapia , Músculos Psoas/efectos de los fármacos , Músculos Psoas/metabolismo , Ratas , Ratas Sprague-Dawley , SolventesRESUMEN
Marrubium vulgare and Withania somnifera are used in folk medicine of several countries. Many researches showed that they are used for the treatment of variety of diseases due to their antioxidant effects. The present aim of this study was to evaluate the antihepatotoxic and antioxidant activities of the both extracts against carbon tetrachloride (CCl4)-induced hepatic damage in rats. Both extracts were given orally in a dose of 500 mg/kg/day for 4 weeks along with CCl4 started at the 7th week of induction of hepatotoxicity. The antihepatotoxic activity was assessed by measuring aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), reduced glutathione (GSH), tissue content and malondialdehyde (MDA) as well as histopathological examination. Both extracts showed a significant antihepatotoxic effect by reducing significantly the levels of AST, ALT and LDH. However, ALP levels were decreased non-significantly. Regarding the antioxidant activity, they exhibited significant effects by increasing the GPx, GR and GST activities with increased GSH tissue contents and decreased production of MDA level. Furthermore, both extracts alleviated histopathological changes in rats' liver treated with CCl4. M. vulgare and W. somnifera protect the rats' liver against CCl4-induced hepatotoxicity. This effect may be attributed, at least in part, to the antioxidant activities of these extracts.