RESUMEN
BACKGROUND: Use of statin has been associated with reduced risk of cardiovascular diseases events and mortality. However, in patients with end-stage renal disease (ESRD), the protective effects of statin are controversial. To evaluate the impact of chronic statin use on clinical outcomes of patients with acute myocardial infarction (AMI) with ESRD. METHODS: We enrolled 8056 patients with ESRD who were initially diagnosed and admitted for first AMI from Taiwan's National Health Insurance Research Database. Of which, 2134 patients underwent statin therapy. We randomly selected and use age, sex, hypertension, diabetes mellitus (DM), peripheral vascular diseases (PVD), heart failure (HF), cerebrovascular accidents (CVA), chronic obstructive pulmonary disease, matched with the study group as controls (non-stain user). We compared the effects of statin use in term of all-cause death among patients with AMI with ESRD. RESULTS: Statin use resulted in a significantly higher survival rate in patients ith AMI with ESRD compared with non-statin users. After adjusted the comorbidities the male patients and patients with DM, PVD, HF and CVA had lower long-term survival rate (all p<0.001). Patients who underwent percutaneous coronary intervention (p<0.001), ACE inhibitors/angiotensin II receptor blockers (p<0.001), ß receptor blockers (p<0.001) and statin therapy (p=0.007) had better long-term survival rate. Patients with AMI with ESRD on statin therapy exhibited a significantly lower risk of mortality compared with non-statin users (p<0.0001). CONCLUSION: Among patients with ESRD with AMI, statin therapy was associated with reduced all-cause mortality.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Fallo Renal Crónico , Infarto del Miocardio , Fármacos Cardiovasculares/uso terapéutico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Estudios de Casos y Controles , Causas de Muerte , Comorbilidad , Femenino , Humanos , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Mortalidad , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/mortalidad , Sustancias Protectoras/uso terapéutico , Factores Sexuales , Tasa de Supervivencia , Taiwán/epidemiología , TiempoRESUMEN
Peroxisome proliferator-activated receptor δ (PPARδ), the predominant PPAR subtype in the heart, is known to regulate cardiac function. PPARδ activation may inhibit cardiac hypertrophy in H9c2 cells while the potential mechanism has not been elucidated. Then, H9c2 cells incubated with high glucose to induce hypertrophy were used to investigate using GW0742 to activate PPARδ. The fluorescence assays were applied to determine the changes in cell size, cellular calcium levels, and free radicals. Western blot analyses for hypertrophic signals and assays of messenger RNA (mRNA) levels for hypertrophic biomarkers were performed. In H9c2 cells, GW0742 inhibited cardiac hypertrophy. In addition, increases in cellular calcium and hypertrophic signals, including calcineurin and nuclear factor of activated T-cells, were reduced by GW0742. This reduction was parallel to the decrease in the mRNA levels of biomarkers, such as brain/B-type natriuretic peptides and ß-myosin heavy chain. These effects of GW0742 were dose-dependently inhibited by GSK0660 indicating an activation of PPARδ by GW0742 to alleviate cardiac hypertrophy. Moreover, free radicals produced by hyperglycemia were also markedly inhibited by GW0742 and were later reversed by GSK0660. GW0742 promoted the expression of thioredoxin, an antioxidant enzyme. Direct inhibition of reactive oxygen species by GW0742 was also identified in the oxidant potassium bromate stimulated H9c2 cells. Taken together, these findings suggest that PPARδ agonists can inhibit free radicals, resulting in lower cellular calcium for reduction of hypertrophic signaling to alleviate cardiac hypertrophy in H9c2 cells. Therefore, PPARδ activation can be used to develop agent(s) for treating cardiac hypertrophy.
Asunto(s)
Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Hiperglucemia/tratamiento farmacológico , Tiazoles/uso terapéutico , Animales , Western Blotting , Calcio/metabolismo , Línea Celular , Radicales Libres/metabolismo , Hiperglucemia/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Sulfonas/farmacología , Tiofenos/farmacologíaRESUMEN
Erythropoietin (EPO) is known to stimulate erythropoiesis after binding with its specific receptor. In clinics, EPO is widely used in hemodialyzed patients with diabetes. However, changes in the expression of the erythropoietin receptor (EPOR) under diabetic conditions are still unclear. Therefore, we investigated EPOR expression both in vivo and in vitro. Streptozotocin-induced type 1-like diabetic rats (STZ rats) were used to evaluate the blood glucose-lowering effects of EPO. The expression and activity of the transducer and activator of transcription 3 (STAT3), the potential signaling molecule, was investigated in cultured rat skeletal myoblast (L6) cells incubated in high-glucose (HG) medium to mimic the in vivo changes. The EPO-induced reduction in hyperglycemia was more pronounced in diabetic rats. The increased EPOR expression in the soleus muscle of diabetic rats was reversed by the reduction in hyperglycemia. Glucose uptake was also increased in high-glucose (HG)-treated L6 cells. Western blotting results indicated that the EPO-induced hyperglycemic activity was enhanced mainly through an increase in EPOR expression. Increased EPOR expression was associated with the enhanced nuclear expression of STAT3 in HG-exposed L6 cells. In addition, treatment with siRNA specific to STAT3 reversed the increased expression of EPOR observed in these cells. Treatment with Stattic at a dose sufficient to inhibit STAT3 reduced the expression level of EPOR in STZ rats. In conclusion, the increased expression of EPOR by hyperglycemia is mainly associated with an augmented expression of nuclear STAT3, which was identified both in vivo and in vitro in the present study.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Eritropoyetina/uso terapéutico , Hiperglucemia/prevención & control , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Células Cultivadas , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/fisiopatología , Eritropoyesis/efectos de los fármacos , Hiperglucemia/etiología , Masculino , Ratas , Ratas Wistar , Receptores de Eritropoyetina/genética , Receptores de Eritropoyetina/metabolismo , EstreptozocinaRESUMEN
Morin is a flavonoid contained in guava that is known to reduce hyperglycemia in diabetes. Insulin secretion has been demonstrated to increase following the administration of morin. The present study is designed to investigate the potential mechanism(s) of morin-induced insulin secretion in the MIN6 cell line. First, we identified that morin induced a dose-dependent increase in insulin secretion and intracellular calcium content in MIN6 cells. Morin potentiated glucose-stimulated insulin secretion (GSIS). Additionally, we used siRNA for the ablation of imidazoline receptor protein (NISCH) expression in MIN6 cells. Interestingly, the effects of increased insulin secretion by morin and canavanine were markedly reduced in Si-NISCH cells. Moreover, we used KU14R to block imidazoline I3 receptor (I-3R) that is known to enhance insulin release from the pancreatic ß-cells. Without influence on the basal insulin secretion, KU14R dose-dependently inhibited the increased insulin secretion induced by morin or efaroxan in MIN6 cells. Additionally, effects of increased insulin secretion by morin or efaroxan were reduced by diazoxide at the dose sufficient to open KATP channels and attenuated by nifedipine at the dose used to inhibit L-type calcium channels. Otherwise, phospholipase C (PLC) is introduced to couple with imidazoline receptor (I-R). The PLC inhibitor dose-dependently inhibited the effects of morin in MIN6 cells. Similar blockade was also observed in protein kinase C (PKC) inhibitor-treated cells. Taken together, we found that morin increases insulin secretion via the activation of I-R in pancreatic cells. Therefore, morin would be useful to develop in the research and treatment of diabetic disorders.
Asunto(s)
Flavonoides/farmacología , Receptores de Imidazolina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Insulina/metabolismo , Animales , Técnicas de Cultivo de Célula , Línea Celular , Relación Dosis-Respuesta a Droga , Silenciador del Gen , Glucosa/farmacología , Receptores de Imidazolina/genética , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , RatonesRESUMEN
Diosmin is one of the flavonoids contained in citrus and has been demonstrated to improve glucose metabolism in diabetic disorders. However, the mechanism(s) of diosmin in glucose regulation remain obscure. Therefore, we investigated the potential mechanism(s) for the antihyperglycaemic action of diosmin in streptozotocin-induced diabetic rats (STZ-diabetic rats). Diosmin lowered hyperglycaemia in a dose-dependent manner in STZ-diabetic rats. This action was inhibited by naloxone at a dose sufficient to block opioid receptors. Additionally, we determined the changes in plasma ß-endorphin-like immunoreactivity (BER) using enzyme-linked immunosorbent assay (ELISA). Diosmin also increased BER dose-dependently in the same manner. Repeated treatment of STZ-diabetic rats with diosmin for 1 week resulted in an increase in the expression of the glucose transporter subtype 4 (GLUT 4) in the soleus muscle and a reduction in the expression of phosphoenolpyruvate carboxykinase (PEPCK) in the liver. These effects were also inhibited by naloxone at a dose sufficient to block opioid receptors. Bilateral adrenalectomy in STZ-diabetic rats eliminated the actions of diosmin, including both the reduction in hyperglycemia and the elevation of plasma BER. In conclusion, our results suggest that diosmin may act on the adrenal glands to enhance the secretion of ß-endorphin, which can stimulate the opioid receptors to attenuate hepatic gluconeogenesis and increase glucose uptake in soleus muscle, resulting in reduced hyperglycemia in STZ-diabetic rats.
Asunto(s)
Citrus , Diabetes Mellitus Tipo 1/sangre , Diosmina/uso terapéutico , Flavonoides/uso terapéutico , Hipoglucemiantes/uso terapéutico , betaendorfina/sangre , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diosmina/farmacología , Relación Dosis-Respuesta a Droga , Flavonoides/farmacología , Hiperglucemia/sangre , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes/farmacología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Depression is a common mental disorder that has been linked to a decrease in the expression of serotonin and/or the serotonin transporter in the brain. Antidepressants that target the monoaminergic system are widely used in the clinical setting. Peroxisome proliferator-activated receptor δ (PPAR δ) overexpression or activation is thought to improve depression-like behaviours in rodents. The present study was designed to characterize the changes in PPARδ expression in the hippocampus in rats with stress-induced depression. We used an unpredictable chronic mild stress (CMS) model in rats to study the role of PPARδ in the hippocampus. Behaviour was evaluated via a forced swim test (FST), a tail suspension test (TST), and a sucrose preference test (SPT). Then, the changes in PPARδ expression and other signals were determined using Western blots. We found that PPARδ expression in the hippocampus was markedly reduced in rats with depression. Moreover, the expression of the serotonin transporter was also significantly decreased. Treatment with a PPARδ agonist enhanced the expression of PPARδ and the serotonin transporter in the hippocampus of rats with stress-induced depression. Additionally, treatment with a PPARδ agonist increased the expression of the serotonin transporter in cultured hippocampal (H19-7) cells, and this action was ablated in the absence of PPARδ, which was attenuated with shRNA. Taken together, we found that PPARδ plays an important role in the regulation of serotonin transporter expression and that chronic stress may lower PPARδ expression in the brain via apoptosis and may attenuate serotonin transporter expression, thus inducing depression in rats.
Asunto(s)
Depresión/metabolismo , Depresión/psicología , Regulación de la Expresión Génica , PPAR delta/metabolismo , Estrés Psicológico/complicaciones , Animales , Apoptosis/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Línea Celular , Depresión/complicaciones , Depresión/patología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , PPAR delta/agonistas , Ratas , Ratas Sprague-Dawley , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismoRESUMEN
Cryptotanshinone is an active principal ingredient isolated from Salvia miltiorrhiza (Danshen), a medicinal plant used in China to treat cardiac disorders. The objective of this study was to investigate the effect of cryptotanshinone on myocardial fibrosis in diabetic rats. In streptozotocin-induced type 1 diabetic model hyperglycemic rats (STZ-treated rats), fasting blood glucose levels and heart weight/body weight ratio were markedly increased but both were not modified by cryptotanshinone. Additionally, cardiac performance in catheterized STZ-treated rats was improved. The histological results from Masson staining showed that cryptotanshinone attenuated cardiac fibrosis in STZ-treated rats. Moreover, both the mRNA and protein levels of the signal transducer and activator of transcription 3 (STAT3), matrix metalloproteinase-9, and connective tissue growth factor were reduced by cryptotanshinone in high glucose-cultured cardiomyocytes, similar to the reductions observed in the hearts of STZ-treated rats. In conclusion, while STAT3 regulates matrix metalloproteinase-9 and connective tissue growth factor expression in diabetic rats with cardiac fibrosis, cryptotanshinone inhibited fibrosis to improve cardiac function by suppressing the STAT3 pathway. Cryptotanshinone is suitable as an alternative remedy for therapy of cardiac fibrosis. Copyright © 2017 John Wiley & Sons, Ltd.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Fenantrenos/uso terapéutico , Factor de Transcripción STAT3/metabolismo , Estreptozocina/efectos adversos , Animales , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacología , Masculino , Fenantrenos/administración & dosificación , Fenantrenos/farmacología , RatasRESUMEN
Ginsenoside Rh2 (Rh2) is an active principal ingredient contained in ginseng (Panax ginseng Meyer), a medicinal herb used to enhance health worldwide. The present study is designed to investigate the effect of Rh2 on myocardial fibrosis in diabetic rats. In a streptozotocin-induced model of type-1 diabetic rats (STZ-diabetic rats), the increased fasting blood glucose levels and heart weight/body weight (HW/BW) ratio were substantially alleviated by Rh2. Moreover, Rh2 improved cardiac performance in STZ-diabetic rats. Histological results from Masson staining showed that Rh2 attenuated cardiac fibrosis in STZ-diabetic rats. The effects of Rh2 were reversed by GSK0660 at a dose sufficient to inhibit peroxisome proliferator-activated receptor δ (PPARδ) in STZ-diabetic rats. The role of PPARδ was subsequently investigated in vitro. Rh2 restored the decreased PPARδ expression level in high glucose-cultured cardiomyocytes. Moreover, increased protein levels of fibrotic signals, including signal transducer and activator of transcription 3 (STAT3), connective tissue growth factor (CCN2) and fibronectin, were reduced by Rh2 in high glucose-cultured cardiomyocytes. These effects of Rh2 were reversed by GSK0660 or siRNA specific for PPARδ Taken together, PPARδ activation may inhibit STAT3 activation to reduce CCN2 and fibronectin expression in diabetic rats with cardiac fibrosis. Moreover, Rh2 improves cardiac function and fibrosis by increasing PPARδ signaling. Therefore, Rh2 is suitable to develop as an alternative remedy for cardiac fibrosis.
Asunto(s)
Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Medicamentos Herbarios Chinos/farmacología , Ginsenósidos/farmacología , PPAR delta/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Biomarcadores , Glucemia , Cardiomiopatías/etiología , Cardiomiopatías/fisiopatología , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Expresión Génica , Pruebas de Función Cardíaca , Masculino , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , ARN Interferente Pequeño/genética , RatasRESUMEN
BACKGROUND: Despite the known risk of diabetes-induced cardiac fibrosis, less is known about whether diabetes causes an altered cardiac phenotype independent of coronary atherosclerosis. Peroxisome proliferator-activated receptor δ (PPARδ), a versatile regulator of metabolic homeostasis, may be a potential therapeutic target. Herein we investigated the effectiveness of telmisartan, a unique angiotensin receptor blocker that increases PPARδ expression, in improving left ventricular remodeling in diabetic humans and rats. METHODS: In this longitudinal, prospective study, we enrolled 15 diabetic patients receiving telmisartan (20 mg/day) for 12 weeks. After treatment, strain was measured and compared with the baseline value. Using streptozotocin to induce type 1 diabetes rat model, we measured PPARδ expression and downstream targets. RESULTS: After treatment with telmisartan, both longitudinal and circumferential strains improved in diabetic patients. Compared with that of controls, the diabetic rat heart developed significant fibrosis, which markedly decreased after treatment with telmisartan (30 mg/kg/day, orally) for 7 days. After incubation with 30 mM glucose, rat cardiomyocytes showed a significant down-regulation of PPARδ. Interestingly, the increased expression of fibrosis-associated proteins, including signal transducer and activator of transcription 3 (STAT3) was attenuated by the co-incubation of GW0742, a PPARδ agonist. By knockdown or inhibition of STAT3, the hyperglycemia related high expression of fibrosis associated targets was reversed. Independent from the hyperglycemic incubation, STAT3 over-expression led to similar results. Conversely, in the presence of GSK0660, a PPARδ inhibitor, the protective effects of telmisartan were diminished. CONCLUSION: Telmisartan improved the hyperglycemia-induced cardiac fibrosis through the PPARδ/STAT3 pathway. Graphical abstract Summary of the mechanism of telmisartan's effect on the suppression of hyperglycemia-induced cardiac fibrosis through PPARδ instead of the AMPK pathway. PPARδ peroxisome proliferator-activated receptor δ, STAT3 signal transducer and activator of transcription 3, CTGF connective tissue growth factor, MMP9 matrix metallopeptidase 9.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Bencimidazoles/uso terapéutico , Benzoatos/uso terapéutico , Cardiomiopatías Diabéticas/tratamiento farmacológico , Miocardio/metabolismo , PPAR gamma/efectos de los fármacos , Investigación Biomédica Traslacional , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Animales , Bencimidazoles/efectos adversos , Benzoatos/efectos adversos , Línea Celular , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 1/fisiopatología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/fisiopatología , Femenino , Fibrosis , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Miocardio/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , PPAR gamma/metabolismo , Estudios Prospectivos , Ratas Sprague-Dawley , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Estreptozocina , Telmisartán , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
BACKGROUND: As cancer therapies have improved, patient life spans have been extended but quality of life has been threatened by chemotherapy induced cardiotoxicity. Most cardiac complications remain unobserved until specific symptoms develop. Speckle-tracking echocardiography is a sensitive imaging modality in detecting early occult myocardial dysfunction. METHODS: A total number of 35 patients newly diagnosed with breast cancer and preparing for epirubicin therapy were prospectively recruited. Echocardiography, including speckle-tracking echocardiography, was performed sequentially at baseline (T1), after the first cycle (T2) and after the third cycle (T3) of epirubicin. At each visit, the severity of dyspnea was evaluated by the assessment scale. RESULTS: Compared with the baseline, right ventricular longitudinal strain (RVLS_FW) at T2 significantly declined (-22.49 ± 4.97 vs. -18.48 ± 4.46, p = 0.001), which was also positively associated with the development of dyspnea (R2 = 0.8, p = 0.01). At T3, both the left ventricular global longitudinal strain and RVLS_FW were significantly impaired (-21.4 ± 4.12 vs. -16.94 ± 6.81%; -22.49 ± 4.97 vs. -16.86 ± 7.27%, p = 0.01; 0.001, respectively). Also, the accumulating dose of epirubicin positively correlated with the development of dyspnea (R2 = 0.38, p = 0.04) and the decline of RVLS_FW (R2 = 0.53, p = 0.02). Notably, compared with the other echocardiographic parameters only RVLS_FW at the early stage (T2) significantly correlated with the development of dyspnea (odds ratio: 1.84, 95% confidence interval: 1.22-2.78, p = 0.04). CONCLUSIONS: RVLS_FW sensitively predicts dyspnea development in breast cancer patients receiving epirubicin therapy. However, larger scale studies are required to validate its role in long-term patient survival.
RESUMEN
The aim of the present study was to identify the effect of canavanine on the imidazoline receptor because canavanine is a guanidinium derivative that has a similar structure to imidazoline receptor ligands. Transfected Chinese hamster ovary-K1 cells expressing imidazoline receptors (nischarin (NISCH)-CHO-K1 cells) were used to elucidate the direct effects of canavanine on imidazoline receptors. In addition, the imidazoline I3 receptor has been implicated in stimulation of insulin secretion from pancreatic ß-cells. Wistar rats were used to investigate the effects of canavanine (0.1, 1 and 2.5 mg/kg, i.v.) on insulin secretion. In addition the a specific I3 receptor antagonist KU14R (4 or 8 mg/kg, i.v.) was used to block I3 receptors. Canavanine decreased blood glucose by increasing plasma insulin in rats. In addition, canavanine increased calcium influx into NISCH-CHO-K1 cells in a manner similar to agmatine, the endogenous ligand of imidazoline receptors. Moreover, KU12R dose-dependently attenuated canavanine-induced insulin secretion in HIT-T15 pancreatic ß-cells and in the plasma of rats. The data suggest that canavanine is an agonist of I3 receptors both in vivo and in vitro. Thus, canavanine would be a useful tool in imidazoline receptor research.
Asunto(s)
Canavanina/farmacología , Receptores de Imidazolina/metabolismo , Insulina/metabolismo , Animales , Glucemia/metabolismo , Células CHO , Calcio/metabolismo , Cricetinae , Cricetulus , Secreción de Insulina , Masculino , Ratas , Ratas WistarRESUMEN
Canavanine is a guanidinium derivative that contains the basic structure of the ligand(s) of imidazoline receptor (I-R). Canavanine has been reported to activate the imidazoline I-3 receptor (I-3R) both in vivo and in vitro. Additionally, the activation of the imidazoline I-2B receptor (I-2BR) by guanidinium derivatives may increase glucose uptake. Therefore, the effect of canavanine on the I-2BR was investigated in the present study. Glucose uptake into cultured C2 C12 cells was determined using the radio-ligated tracer 2-[(14) C]-deoxy-glucose. The changes in 5' AMP-activated protein kinase (AMPK) expression were also identified using Western blotting analysis. The canavanine-induced glucose uptake was inhibited in a dose-dependent manner by BU224 (0.01-1 µmol/L), which is a specific I-2BR antagonist, in the C2 C12 cells. Additionally, the canavanine-stimulated AMPK phosphorylation and glucose transporter (GLUT4) expression were also sensitive to BU224 inhibition in the C2 C12 cells. Moreover, both canavanine-stimulated glucose uptake and AMPK phosphorylation were attenuated by high concentrations of amiloride (1-2 µmol/L), which is another established I-2BR inhibitor, in a dose-dependent manner in C2 C12 cells. Additionally, compound C abolished the canavanine-induced glucose uptake and AMPK phosphorylation at a concentration (0.1 µmol/L) sufficient to inhibit AMPK. In conclusion, these data demonstrated that canavanine has an ability to activate I-2BR through the AMPK pathway to increase glucose uptake, which indicates I-2BR as a new target for diabetic therapy.
Asunto(s)
Canavanina/farmacología , Glucosa/metabolismo , Receptores de Imidazolina/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Línea Celular , Regulación de la Expresión Génica/efectos de los fármacos , Transportador de Glucosa de Tipo 4/metabolismo , Ratones , Fosforilación/efectos de los fármacosRESUMEN
OBJECTIVES: To study the role of tumor necrosis factor-α in bladder dysfunction associated with obesity. METHODS: Male 8-week-old C57BL/6J mice were divided into three groups: (i) control mice; (ii) vehicle-treated high-fat diet-fed mice; and (iii) etanercept-treated high-fat diet-fed mice. High-fat diet feeding lasted for 12 weeks, vehicle or etanercept (0.8 mg/kg/day, a tumor necrosis factor-α antagonist) treatment was given during the last 4 weeks. At the end of the treatment period, serum tumor necrosis factor-α, total cholesterol, triglyceride and blood glucose were measured. Bladder strip contractile responses to 1 µmol/L acetylcholine or 50 mmol/L KCl were studied in an organ bath. Bladder protein kinase Cζ, nuclear factor-κB and intercellular adhesion molecule-1 expressions were analyzed using western blots. RESULTS: Serum levels of tumor necrosis factor-α total cholesterol, triglyceride and glucose were significantly elevated in high-fat diet-fed mice; and the levels were not ameliorated by etanercept treatment. High-fat diet-fed mouse bladder showed reduced contractile responses to acetylcholine and KCl stimulation accompanied by high expression levels of phospho-protein kinase Cζ, nuclear nuclear factor-κB and intercellular adhesion molecule-1. Etanercept restored normal bladder contractile responses, as well as protein kinase Cζ nuclear factor-κB and intercellular adhesion molecule-1 expressions. CONCLUSIONS: A high-fat diet induces bodyweight gain, hyperlipidemia and hyperglycemia in mice. Elevated serum tumor necrosis factor-α level associated with increased protein kinase Cζ phosphorylation, nuclear factor-κB nuclear migration, intercellular adhesion molecule-1 expression and impaired muscle contractility are shown in the high-fat diet-fed mouse bladder. Tumor necrosis factor-α antagonist treatment restores normal bladder contractility, and protein kinase Cζ nuclear factor-κB and intercellular adhesion molecule-1 levels.
Asunto(s)
Contracción Muscular , Obesidad/complicaciones , Factor de Necrosis Tumoral alfa/sangre , Enfermedades de la Vejiga Urinaria/etiología , Vejiga Urinaria/metabolismo , Animales , Peso Corporal , Dieta Alta en Grasa/efectos adversos , Evaluación Preclínica de Medicamentos , Etanercept , Inmunoglobulina G/farmacología , Inmunoglobulina G/uso terapéutico , Técnicas In Vitro , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Obesidad/sangre , Fosforilación/efectos de los fármacos , Proteína Quinasa C/metabolismo , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Vejiga Urinaria/efectos de los fármacos , Enfermedades de la Vejiga Urinaria/sangre , Enfermedades de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
The phenolic aldehyde syringaldehyde (SA) has been shown to have an antihyperglycemic effect in diabetic rats due to increased glucose utilization and insulin sensitivity. To understand the direct effect of SA on the GLP-1 receptor, STZ-induced diabetic rats were used. The levels of pro-inflammatory cytokines, liver enzymes, and renal function were measured using specific ELISA kits. The mechanisms of SA effects were investigated using CHO-K1 cells, pancreatic Min-6 cells, and cardiomyocyte H9c2 cells. The results indicated that the antihyperglycemic effect of SA in diabetic rats was abolished by blocking the GLP-1 receptor with an antagonist. SA has a direct effect on the GLP-1 receptor when using CHO-K1 cells transfected with the exogenous GLP-1 receptor gene. In addition, SA stimulated insulin production in Min-6 cells by activating GLP-1 receptors. SA caused a dose-dependent rise in GLP-1 receptor mRNA levels in cardiac H9c2 cells. These in vitro results support the notion that SA has a direct effect on the GLP-1 receptor. Otherwise, SA inhibited the increase of pro-inflammatory cytokines, including interleukins and tumor TNF-α, in type 1 diabetic rats in a dose-dependent manner. Moreover, as with liraglutide, SA reduced plasma lipid profiles, including total cholesterol and triglyceride, in mixed diet-induced type 2 diabetic rats. Intriguingly, chronic treatment with SA (as with liraglutide) reversed the functions of both the liver and the kidney in these diabetic rats. SA displayed less efficiency in reducing body weight and food consumption compared to liraglutide. In conclusion, SA effectively activates GLP-1 receptors, resulting in a reduction in diabetic-related complications in rats. Therefore, it is beneficial to develop SA as a chemical agonist for clinical applications in the future.
RESUMEN
Introduction: Impairments in wound healing commonly occur among patients with diabetes. Herbal medicines have a long history of usage in wound care management. Super green (SG) is a newly discovered natural product obtained from Musa paradisiaca. This study aimed to investigate the efficacy of the topical application of SG in healing surgical wounds in diabetic rats. Material and methods: Wistar rats received a one-time intraperitoneal injection of streptozotocin to induce type 1 diabetes. Full-thickness excisional skin wounds were created on the backs of the rats. The relevant groups were topically treated with the indicated concentrations of SG or vehicle dressing throughout the study duration. Histological analysis was performed and the mRNA levels of proinflammatory cytokines were measured to evaluate the improvement of wound closure. Results: The wound area ratio of the SG (1/6000 dilution)-treated group was greatly reduced compared to that of the vehicle-treated group. The histological analysis showed fewer inflammatory cells, accelerated re-epithelialization, and increased collagen deposition in SG 1/6000-treated wounds. The gene expression levels of tumor necrosis factor-α, interleukin-1ß, and interleukin-6 were decreased and the levels of type I and type III collagen were increased after SG treatment. Conclusions: These results show that the most therapeutically efficacious concentration of SG (1/6000 dilution) can enhance wound repair in diabetic rats. SG has the potential to be a new treatment strategy for diabetic wounds.
RESUMEN
The role of imidazoline receptors in the regulation of vascular function remains unclear. In this study, we evaluated the effect of agmatine, an imidazoline receptor agonist, on systolic blood pressure (SBP) in spontaneously hypertensive rats (SHRs) and investigated the expressions of imidazoline receptors by Western blot. The isometric tension of aortic rings isolated from male SHRs was also estimated. Agmatine decreased SBP in a dose-dependent manner in SHRs but not in the normal group [Wistar-Kyoto (WKY) rats]. This reduction in SBP in SHRs was abolished by BU224, a selective antagonist of imidazoline I(2) -receptors. Higher expression of imidazoline receptors in SHR was observed. Moreover, agmatine-induced relaxation in isolated aortic rings precontracted with phenylephrine or KCl. This relaxation was also abolished by BU224 but was not modified by efaroxan, an imidazoline I(1) -receptor antagonist. Agmatine-induced relaxation was also attenuated by PNU 37883, a selective blocker of vascular ATP-sensitive potassium (K(ATP) ) channels. Additionally, vasodilatation by agmatine was reduced by an inhibitor of protein kinase A (PKA). We suggest that agmatine can lower blood pressure in SHRs through activation of the peripheral imidazoline I(2) -receptor, which is expressed more highly in SHRs.
Asunto(s)
Agmatina/farmacología , Antihipertensivos/farmacología , Aorta Torácica/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Receptores de Imidazolina/agonistas , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatología , Benzofuranos/farmacología , Western Blotting , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Humanos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Imidazoles/farmacología , Receptores de Imidazolina/metabolismo , Canales KATP/antagonistas & inhibidores , Canales KATP/metabolismo , Masculino , Bloqueadores de los Canales de Potasio/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Regulación hacia ArribaRESUMEN
BACKGROUND: The underlying mechanism of exercise on the development of diabetes-associated neuropathic pain is not well understood. We investigated in rats whether exercise regulates the functional recovery and heat shock protein 72 (Hsp72), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 expression in streptozotocin (STZ)-induced diabetes. METHODS: Male Wistar rats were divided into 4 groups: normal sedentary rats, normal rats with exercise, sedentary STZ-diabetic (SS) rats, and STZ-diabetic rats with exercise. Diabetes was induced with STZ (65 mg/kg IV). The trained rats ran daily on a treadmill 30 to 60 min/d with an intensity of 20 to 25 m/min. We monitored thermal withdrawal latency and mechanical withdrawal threshold as well as Hsp72, TNF-α, and IL-6 expression in the spinal cord and peripheral nerves. RESULTS: Two weeks after STZ injection, sedentary rats exhibited a marked and sustained hypersensitivity to von Frey tactile and heat stimuli. In contrast, diabetic rats undergoing exercise demonstrated delayed progress of tactile and thermal hypersensitivity. Exercise significantly suppressed diabetes-induced blood glucose levels and body weight loss, although they were not restored to control levels. Compared with normal sedentary rats, SS rats displayed significantly higher TNF-α and IL-6 levels in the spinal cord and peripheral nerves. The STZ-diabetic rats with exercise group showed greater Hsp72 expression and similar TNF-α or IL-6 level compared with the SS group in the spinal cord and peripheral nerves on day 14 after STZ treatment. CONCLUSIONS: These results suggest that progressive exercise training markedly decreases diabetes-associated neuropathic pain, including thermal hyperalgesia and mechanical allodynia. In rats, this protective effect is related to the increase of Hsp72, but not TNF-α and IL-6, expression in the spinal cord and peripheral nerves of STZ-induced diabetes.
Asunto(s)
Neuropatías Diabéticas/complicaciones , Proteínas del Choque Térmico HSP72/biosíntesis , Hiperalgesia/complicaciones , Condicionamiento Físico Animal/fisiología , Animales , Glucemia/metabolismo , Citocinas/biosíntesis , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 1/complicaciones , Calor , Interleucina-6/biosíntesis , Masculino , Nervios Periféricos/metabolismo , Estimulación Física , Ratas , Ratas Wistar , Médula Espinal/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Pérdida de Peso/fisiologíaRESUMEN
Silymarin is an herbal product showing potential as protection against hepatic disorders. In an attempt to develop the agent for the treatment of hepatic fibrosis, we screened the effects of silymarin on a rat model of hepatic fibrosis induced by carbon tetrachloride (CCl4). Intraperitoneal administration of CCl4 to rats for 8 weeks not only increased the plasma levels of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) but also induced a marked increase in the formation of hepatic fibrosis. Moreover, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were also reduced in the liver of rats treated with CCl4. Oral administration of silymarin (200 mg/kg, three times daily), in parallel, decreased the plasma levels of GOT and GPT. Furthermore, in addition to the improvement of hepatic fibrosis, the hepatic levels of hydroxyproline and connective tissue growth factor (CTGF) were both markedly decreased by silymarin. Silymarin also elevated the activities of SOD and GPx in liver isolated from CCl4-treated rats. The results suggest that oral administration of silymarin protects against CCl4-induced hepatic fibrosis in rats, likely due to the decrease in fibrotic parameters such as CTGF.
Asunto(s)
Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Silimarina/uso terapéutico , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Tetracloruro de Carbono , Glutatión Peroxidasa/metabolismo , Hidroxiprolina/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/metabolismo , Cirrosis Hepática/prevención & control , Masculino , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismoRESUMEN
Rhodiola rosea (Rhodiola) is grown at high altitudes and northern latitudes. It is mainly used clinically as an adaptogen, but antihypertensive effects have been reported for the extract. These have not been well investigated, so in the present study, we evaluated the effect of Rhodiola-water extract on blood pressure in spontaneously hypertensive rats (SHRs) and investigated the potential mechanism(s) for this action. In conscious male SHRs, systolic blood pressure (SBP) and heart rate were recorded using the tail-cuff method. Plasma ß-endorphin was measured by enzyme-linked immunosorbent assay. Rhodiola-water extract decreased SBP in SHRs in a dose-dependent manner, and this action was more significant than that in normal group named Wistar-Kyoto (WKY) rats. This reduction of SBP in SHRs was inhibited by pretreatment with the selective opioid µ-receptor antagonist, cyprodime, but not by naloxonazine, an antagonist specific to opioid µ1-receptor. Also, the SBP-lowering action of Rhodiola-water extract was attenuated in adrenalectomized SHRs. Moreover, Rhodiola-water extract dose-dependently increased ß-endorphin release in SHRs, and the elevation of ß-endorphin in SHRs was higher than that in WKY. Thus, we suggest that Rhodiola-water extract can induce release of ß-endorphin to lower SBP in SHRs.
Asunto(s)
Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Extractos Vegetales/farmacología , Rhodiola/química , betaendorfina/sangre , Animales , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Morfinanos/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
Andrographolide (ADG) is contained in bitter plants, and its effects are widely thought to be associated with taste receptors. The current study used animal studies and cell lines to investigate the role of ADG in diabetic models. The Takeda G-protein-coupled receptor (TGR5) was directly influenced by ADG, and this boosted GLP-1 synthesis in CHO-K1 cells transfected with the TGR5 gene. However, this was not seen in TGR5-mutant cells. The human intestinal L-cell line NCI-H716 showed an increase in GLP-1 production in response to ADG. In NCI-H716 cells, the TGR5 inhibitor triamterene reduced the effects of ADG, including the rise in TGR5 mRNA levels that ADG caused. Additionally, as with the antihyperglycemic impact in type-1 diabetic rats, the increase in plasma-active GLP-1 level caused by ADG was enhanced by a DPP-4 inhibitor. The recovery of the hypoglycemic effect in diabetic rats and the increase in plasma GLP-1 caused by ADG were both suppressed by TGR5 blockers. As a result, after activating TGR5, ADG may boost GLP-1 synthesis in diabetic rats, enhancing glucose homeostasis. In Min-6 cells, a pancreatic cell line grown in culture, ADG-induced insulin secretion was also examined. Blocking GLP-1 receptors had little impact, suggesting that ADG directly affects TGR5 activity in Min-6 cells. A TGR5 mRNA level experiment in Min-6 cells further confirmed that TGR5 is activated by ADG. The current study revealed a novel finding suggesting that ADG may activate TGR5 in diabetic rats in a way that results in enhanced insulin and GLP-1 production, which may be helpful for future research and therapies.