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BACKGROUND: Multiple murine models of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) have been established by using obesogenic diets and/or chemical induction. MS-NASH mouse (formally FATZO) is a spontaneously developed dysmetabolic strain that can progress from hepatosteatosis to moderate fibrosis when fed a western diet supplemented with 5% fructose (WDF). This study aimed to use carbon tetrachloride (CCl4) to accelerate and aggravate progression of NAFLD/NASH in MS-NASH mouse. METHODS: Male MS-NASH mice at 8 weeks of age were fed WDF for the entire study. Starting at 16 weeks of age, CCl4 was intraperitoneally administered twice weekly at a dose of 0.2 mL/kg for 3 weeks or 0.08 mL/kg for 8 weeks. Obeticholic acid (OCA, 30 mg/kg, QD) was administered in both MS-NASH and C57Bl/6 mice fed WDF and treated with CCl4 (0.08 mL/kg). RESULTS: WDF enhanced obesity and hepatosteatosis, as well as induced moderate fibrosis in MS-NASH mice similar to previous reports. Administration of CCl4 accelerated liver fibrosis with increased bridging and liver hydroxyproline contents, but had no significant impact on liver steatosis and lipid contents. High dose CCl4 caused high mortality and dramatic elevation of ALT and ASL, while low dose CCl4 resulted in a moderate elevation of ALT and AST with low mortality. Compared to C57BI/6 mice with WDF and CCl4 (0.08 mL/kg), MS-NASH mice had more prominent hepatosteatosis and fibrosis. OCA treatment significantly lowered liver triglycerides, steatosis and fibrosis in both MS-NASH and C57Bl/6 mice fed WDF with CCl4 treatment. CONCLUSIONS: CCl4 reduced induction time and exacerbated liver fibrosis in MS-NASH mice on WDF, proving a superior NASH model with more prominent liver pathology, which has been used favorably in pharmaceutical industry for testing novel NASH therapeutics.
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Enfermedad del Hígado Graso no Alcohólico , Animales , Tetracloruro de Carbono , Dieta Alta en Grasa/efectos adversos , Dieta Occidental , Modelos Animales de Enfermedad , Fructosa , Hígado , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológicoRESUMEN
BACKGROUND: High serum levels of cholesterol, in particular low-density lipoprotein cholesterol, are considered a significant risk factor for development of cardiovascular disease. Therefore, rigorous treatment regimens with statins and other pharmaceuticals have been used extensively to reduce elevated cholesterol levels. Literature data have not clearly concluded whether long-chain omega-3 fatty acids reduce, increase or leave circulating cholesterol unaffected. In the present study a novel krill-oil derived preparation of omega-3 rich phospholipids, mainly phosphatidylcholine, was administered orally at increasing doses for 12 weeks to dyslipidemic non-human primates, and cholesterols and several other risk factors for cardiovascular disease were measured before, during and after treatment. METHODS: Six dyslipidemic non-human primates suffering from naturally occurring diabetes type-2 were included, three in a vehicle control group and three being treated with the omega-3 rich phospholipid preparation. The control and test items were given daily by gavage and the doses of the test item were 50, 150 and 450 mg phospholipids/kg/day. Each dose level was given for 4 weeks. Plasma concentrations of the omega-3 fatty acids were measured in connection with change in dose and the omega-3 index in erythrocytes was determined bi-weekly. Blood lipids, apolipoproteins and diabetes, inflammatory and safety biomarkers were determined either weekly, biweekly or every 4 weeks. For the blood lipids and apolipoproteins, control-adjusted mean values are presented while absolute values are presented for the other parameters. Due to the low number of animals in each group, no statistical analyses were done. RESULTS: The only detectable effects measured during dosing with the lowest dose were an increase in HDL-cholesterol and apolipoprotein A1. The intermediate and high doses decreased total cholesterol, LDL-cholesterol, apolipoprotein B100 and triglycerides and increased HDL-cholesterol and apolipoprotein A1. No effects were seen on the diabetes and inflammatory markers and on safety biomarkers. CONCLUSIONS: The results indicate that the omega-3 rich phospholipid preparation had a positive impact on cardiovascular disease risk factors by reducing total cholesterol, LDL-cholesterol and triglycerides and increasing HDL-cholesterol. These findings justify further investigations of this preparation in animal models of dyslipidemia and, provided the current findings are confirmed, in human trials.
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Enfermedades Cardiovasculares/etiología , Diabetes Mellitus Tipo 2/complicaciones , Dislipidemias/complicaciones , Euphausiacea/química , Ácidos Grasos Omega-3/farmacología , Macaca fascicularis , Animales , Colesterol/sangre , Femenino , Masculino , Fosfolípidos/química , Fosfolípidos/farmacología , Factores de RiesgoRESUMEN
BACKGROUND: A commonly used measure to reflect the intake of the long-chain omega-3 fatty acids EPA and DHA is the omega-3 index, defined as the sum of EPA + DHA as % of total fatty acids in erythrocyte membrane. When the omega-3 index changes it follows that the relative fractions of other fatty acids in the membrane are also changed. In the present study, increasing doses of a preparation of omega-3 rich phospholipids extracted from krill oil were administered orally to non-human primates for 12 weeks and the time course of EPA, DHA and 22 other fatty acids in erythrocytes was determined bi-weekly during treatment and for 8 weeks after cessation of treatment. Plasma concentrations of six endocannabinoid-type mediators being downstream metabolites of some fatty acids analyzed in erythrocytes were also determined. METHODS: Six diabetic, dyslipidemic non-human primates were included, three in a vehicle control group and three being treated with the omega-3 rich phospholipid preparation. The vehicle control and test items were given daily by gavage and the test item doses were 50, 150 and 450 mg phospholipids/kg/day. Each dose level was given for four weeks. Blood was sampled at baseline and thereafter bi-weekly. Fatty acids were determined in erythrocytes by methylation followed by gas-chromatography. Endocannabinoids and endocannabinoid-like mediators were analyzed in plasma by liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry. RESULTS: The treatment resulted in a dose-related increase in the fraction of EPA and DHA in erythrocyte membranes and a dose-related decrease of other poly-unsaturated fatty acids, in particular omega-6 polyunsaturated fatty acids. Erythrocyte concentrations of saturated fatty acids remained unchanged throughout the experiment. Plasma concentrations of endocannabinoids and endocannabinoid-like mediators changed accordingly as those being downstream arachidonic acid decreased, downstream of the saturated palmitic and oleic acids remained unchanged while a downstream EPA metabolite increased. CONCLUSION: Increasing the omega-3 index by administering an omega-3 rich phospholipid extracted from krill oil did not alter the ratio of unsaturated vs. saturated fatty acids in the erythrocyte membranes but only the relative concentrations of unsaturated fatty acids, in particular unsaturated omega-6 fatty acids. Concentrations of saturated fatty acids remained unchanged.
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Diabetes Mellitus Tipo 2/metabolismo , Grasas de la Dieta/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Membrana Eritrocítica/metabolismo , Euphausiacea/química , Administración Oral , Animales , Glucemia/metabolismo , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/patología , Grasas de la Dieta/administración & dosificación , Endocannabinoides/metabolismo , Membrana Eritrocítica/química , Membrana Eritrocítica/efectos de los fármacos , Ácidos Grasos/metabolismo , Ácidos Grasos Omega-6/metabolismo , Femenino , Hemoglobina Glucada/metabolismo , Insulina/sangre , Macaca fascicularis , Masculino , Triglicéridos/sangreRESUMEN
BACKGROUND: Diabetes is one of the major risk factors for cardiomyopathy and heart failure with reduced ejection fraction (EF) and highly associated with left ventricular (LV) dysfunction in human. This study aimed 1) to noninvasively assess cardiac function using echocardiography; 2) to test the hypothesis that like diabetic human, cardiac function may also be compromised; in spontaneously developed obese, dysmetabolic and diabetic nonhuman primates (NHPs). METHODS: Cardiovascular functions were measured by noninvasive echocardiography in 28 control, 20 dysmetabolic/pre-diabetic and 41 diabetic cynomolgus monkeys based on fasting blood glucose and other metabolic status. RESULTS: The LV end-systolic volume (ESV) was higher while end-diastolic volume (EDV, 12 ± 5.7 mL) and EF (63 ± 12.8 %) significantly lower in the diabetic compared to control (14 ± 7 mL and 68 ± 9.8 %) group, respectively. The E/A ratio of LV trans-mitral peak flow rate during early (E) over late (A) diastole was significantly lower in the diabetic (1.19 ± 0.45) than control (1.44 ± 0.48) group. E-wave deceleration time (E DT) was prolonged in the diabetic (89 ± 41 ms) compared to control (78 ± 26 ms) group. Left atrial (LA) maximal dimension (LADmax) was significantly greater in the diabetic (1.3 ± 0.17 cm) than control (1.1 ± 0.16 cm) group. Biochemical tests showed that total cholesterol and LDL were significant higher in the diabetic (167 ± 63 and 69 ± 37 mg/dL) than both pre-diabetic (113 ± 37 and 41 ± 23 mg/dL) and control (120 ± 28 and 41 ± 17 mg/dL) groups, respectively. Multivariable logistic regression analysis demonstrated that LV systolic (reduced EF) and diastolic (abnormal E/A ratio) dysfunctions are significantly correlated with aging and hyperglycemia. Histopathology examination of the necropsy heart revealed inflammatory infiltration, cardiomyocyte hypertrophy and fragmentation, indicating the myocardial ischemia and remodeling which is consistent with the LV dysfunction phenotype. CONCLUSIONS: Using noninvasive echocardiography, the present study demonstrated for the first time that dysmetabolic and diabetic NHPs are associated with LV systolic (increased ESV, decreased EF, etc.) and diastolic (decreased EDV and E/A ratio, prolonged E DT, etc.) dysfunctions, accompanied by LA hypertrophic remodeling (increased LADmax), the phenotypes similarly to those found in diabetic patients. Thus, spontaneously developed dysmetabolic and diabetic NHPs is a highly translatable model to human diseases not only in the pathogenic mechanisms but also can be used for testing novel therapies for cardiometabolic disorders.
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Diabetes Mellitus/fisiopatología , Angiopatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Hiperglucemia/fisiopatología , Disfunción Ventricular Izquierda/fisiopatología , Envejecimiento/patología , Animales , Angiopatías Diabéticas/complicaciones , Angiopatías Diabéticas/diagnóstico por imagen , Femenino , Hiperglucemia/complicaciones , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Macaca fascicularis , Masculino , Miocardio/patología , Ultrasonografía , Disfunción Ventricular Izquierda/complicaciones , Disfunción Ventricular Izquierda/diagnóstico por imagenRESUMEN
BACKGROUND: The α2-adrenoceptor agonist xylazine as an anesthetic has been widely used either alone or in combination with other anesthetics, such as ketamine, in veterinary clinic and research. In the last decade xylazine has been used in drug abusers in certain geographic area. This study investigated the effects of xylazine on blood glucose level and insulin secretion in normoglycemic and insulin-dependent diabetic monkeys. METHODS: Both adult cynomolgus (n = 10) and rhesus (n = 8) monkeys with either sex were used in the study. Xylazine (1-2 mg/kg) was administrated intramuscularly. Blood glucose, insulin, glucagon and glucagon-like peptide 1 in overnight-fasted monkeys were measured immediately before and after xylazine administration. The hyperinsulinemic-euglycemic clamp method was used in the study for assessing the potential mechanism of xylazine-induced hyperglycemia. RESULTS: Xylazine administration increased the blood glucose levels from 58 ± 3 to 108 ± 12 mg/dL in normoglycemic (n = 5, p < 0.01) and from 158 ± 9 to 221 ± 13 mg/dL in insulin-dependent diabetic (n = 5, p < 0.01) monkeys and was not accompanied by any significant changes in blood insulin, glucagon, and glucagon-like peptide-1. Xylazine-induced hyperglycemia occurred within 10 min and reached the peak at 35 min after injection. Xylazine-induced hyperglycemia declined slowly in diabetic animals. The α2-adrenoceptor antagonist yohimbine was administrated to bring down the elevated glucose level to the pre-xylazine one in 4 out of 5 diabetic animals. To assess the potential mechanism, the hyperinsulinemic-euglycemic clamp was used to maintain a nearly saturated and constant insulin level for minimizing endogenous insulin glucoregulation. Xylazine administration decreased glucose infusion rate, from 14.3 ± 1.4 to 8.3 ± 0.8 mg/min/kg (n = 6, p < 0.01) in normoglycemic rhesus monkeys, which indicates that the glucose metabolic rate (M rate) was decreased by xylazine. In addition, after clamping blood glucose level in a range of 55 to 75 mg/dL for 40 min with constant glucose infusion, xylazine administration still increased blood glucose concentration. CONCLUSIONS: We conclude that xylazine administration induces hyperglycemia in normoglycemic and insulin-dependent diabetic monkeys potentially via stimulation of α2-adrenoceptors and then reducing tissue sensitivity to insulin and glucose uptake.
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Inadequate ß-cell mass is essential for the pathogenesis of type 2 diabetes (T2D). Previous report showed that an immunomodulator FTY720, a sphingosine 1-phosphate (S1P) receptor modulator, sustainably normalized hyperglycemia by stimulating ß-cell in vivo regeneration in db/db mice. We further examined the effects of FTY720 on glucose homeostasis and diabetic complications in a translational nonhuman primate (NHP) model of spontaneously developed diabetes. The male diabetic cynomolgus macaques of 18-19 year old were randomly divided into Vehicle (Purified water, n = 5) and FTY720 (5 mg/kg, n = 7) groups with oral gavage once daily for 10 weeks followed by 10 weeks drug free period. Compared with the Vehicle group, FTY720 effectively lowered HbA1c, blood concentrations of fasting glucose (FBG) and insulin, hence, decreased homeostatic model assessment of insulin resistance (HOMA-IR); ameliorated glucose intolerance and restored glucose-stimulated insulin release, indicating rejuvenation of ß-cell function in diabetic NHPs. Importantly, after withdrawal of FTY720, FBG, and HbA1c remained at low level in the drug free period. Echocardiography revealed that FTY720 significantly reduced proteinuria and improved cardiac left ventricular systolic function measured by increased ejection fraction and fractional shortening in the diabetic NHPs. Finally, flow cytometry analysis (FACS) detected that FTY720 significantly reduced CD4 + and CD8 + T lymphocytes as well as increased DC cells in the circulation. Immunomodulator FTY720 improves glucose homeostasis via rejuvenation of ß-cell function, which can be mediated by suppression of cytotoxic CD8 + T lymphocytes to ß-cells, thus, may be a novel immunotherapy to reverse T2D progression and ameliorate the diabetic complications.
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Complicaciones de la Diabetes , Diabetes Mellitus Tipo 2 , Animales , Complicaciones de la Diabetes/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Clorhidrato de Fingolimod/farmacología , Glucosa , Hemoglobina Glucada , Homeostasis , Factores Inmunológicos , Insulina , Masculino , Primates , RejuvenecimientoRESUMEN
BACKGROUND: Glucagon-like peptide-1 (GLP-1) is a hormone predominately synthesized and secreted by intestinal L-cells. GLP-1 modulates multiple cellular functions and its receptor agonists are now used clinically for diabetic treatment. Interestingly, preclinical and clinical evidence suggests that GLP-1 agonists produce beneficial effects on dysfunctional hearts via acting on myocardial GLP-1 receptors. As the effects of GLP-1 on myocyte electrophysiology are largely unknown, this study was to assess if GLP-1 could affect the cardiac voltage-gated L-type Ca2+ current (I(Ca)). METHODS: The whole-cell patch clamp method was used to record I(Ca) and action potentials in enzymatically isolated cardiomyocytes from adult canine left ventricles. RESULTS: Extracellular perfusion of GLP-1 (7-36 amide) at 5 nM increased I(Ca) by 23 ± 8% (p < 0.05, n = 7). Simultaneous bath perfusion of 5 nM GLP-1 plus 100 nM Exendin (9-39), a GLP-1 receptor antagonist, was unable to block the GLP-1-induced increase in I(Ca); however, the increase in I(Ca) was abolished if Exendin (9-39) was pre-applied 5 min prior to GLP-1 administration. Intracellular dialysis with a protein kinase A inhibitor also blocked the GLP-1-enhanced I(Ca). In addition, GLP-1 at 5 nM prolonged the durations of the action potentials by 128 ± 36 ms (p < 0.01) and 199 ± 76 ms (p < 0.05) at 50% and 90% repolarization (n = 6), respectively. CONCLUSIONS: Our data demonstrate that GLP-1 enhances I(Ca) in canine cardiomyocytes. The enhancement of I(Ca) is likely via the cAMP-dependent protein kinase A mechanism and may contribute, at least partially, to the prolongation of the action potential duration.
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Canales de Calcio Tipo L/metabolismo , Señalización del Calcio , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Miocitos Cardíacos/enzimología , Fragmentos de Péptidos/metabolismo , Potenciales de Acción , Animales , Canales de Calcio Tipo L/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Perros , Activación Enzimática , Receptor del Péptido 1 Similar al Glucagón , Técnicas In Vitro , Miocitos Cardíacos/efectos de los fármacos , Técnicas de Placa-Clamp , Fragmentos de Péptidos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Glucagón/antagonistas & inhibidores , Receptores de Glucagón/metabolismo , Factores de TiempoRESUMEN
Meal ingestion elicits a variety of neuronal, physiological and hormonal responses that differ in healthy, obese or diabetic individuals. The mixed meal tolerance test (MMTT) is a well-established method to evaluate pancreatic ß-cell reserve and glucose homeostasis in both preclinical and clinical research in response to calorically defined meal. Nonhuman primates (NHPs) are highly valuable for diabetic research as they can naturally develop type 2 diabetes mellitus (T2DM) in a way similar to the onset and progression of human T2DM. The purpose of this study was to investigate the reproducibility and effects of a MMTT containing acetaminophen on plasma glucose, insulin, C-peptide, incretin hormones, lipids, acetaminophen appearance (a surrogate marker for gastric emptying) in 16 conscious obese cynomolgus monkeys (Macaca fascicularis). Plasma insulin, C-peptide, TG, aGLP-1, tGIP, PYY and acetaminophen significantly increased after meal/acetaminophen administration. A subsequent study in 6 animals showed that the changes of plasma glucose, insulin, C-peptide, lipids and acetaminophen were reproducible. There were no significant differences in responses to the MMTT among the obese NHPs with (n = 11) or without (n = 5) hyperglycemia. Our results demonstrate that mixed meal administration induces significant secretion of several incretins which are critical for maintaining glucose homeostasis. In addition, the responses to the MMTTs are reproducible in NHPs, which is important when the MMTT is used for evaluating post-meal glucose homeostasis in research.
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Alimentación Animal , Glucemia/metabolismo , Vaciamiento Gástrico , Prueba de Tolerancia a la Glucosa , Células Secretoras de Insulina/metabolismo , Lípidos/química , Acetaminofén , Animales , Péptido C/sangre , Diabetes Mellitus Tipo 2/embriología , Polipéptido Inhibidor Gástrico/sangre , Hormonas Gastrointestinales , Glucosa , Homeostasis , Incretinas/farmacología , Insulina/metabolismo , Macaca fascicularis , Masculino , Reproducibilidad de los ResultadosRESUMEN
Coded-aperture imagers typically have a smaller field-of-view (FOV) than in un-collimated gamma imaging systems. However, sources out of the fully coded field-of-view (FCFOV) can cause pseudo hotspots on the wrong side of an image reconstructed using the cross-correlation method. In this work, we propose a neural network method to identify and localize the sources within the partially coded field-of-view (PCFOV). The model was trained using Monte Carlo simulation data and evaluated with both simulation and experimental data. The results showed that the proposed model can identify and localize sources with good classification accuracy, low positioning error, and strong robustness to the statistical noise.
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BACKGROUND: Cardiorenal complications are common in patients with dysmetabolism and diabetes. The present study aimed to examine if a nonhuman primate (NHP) model with spontaneously developed metabolic disorder and diabetes develops similar complications to humans, such as proteinuria and cardiac dysfunction at resting condition or diminished cardiac functional reserve following dobutamine stress echocardiography (DSE). METHODS AND RESULTS: A total of 66 dysmetabolic and diabetic cynomolgus (Macaca fascicularis) NHPs were enrolled to select 19 NHPs (MetS) with marked metabolic disorders and diabetes (fasting blood glucose: 178⯱â¯18 vs. 61⯱â¯3â¯mg/dL) accompanied by proteinuria (ACR: 134⯱â¯34 vs. 1.5⯱â¯0.4â¯mg/mmol) compared to 8 normal NHPs (CTRL). Under resting condition, MetS NHPs showed mild left ventricular (LV) diastolic dysfunction (E/A: 1⯱â¯0.06 vs. 1.5⯱â¯0.13), but with preserved ejection fraction (EF: 65⯱â¯2 vs. 71⯱â¯3%) compared to CTRL. DSE with an intravenous infusion of dobutamine at ascending doses (5, 10, 20, 30 and 40⯵g/kg/min, 7â¯min for each dose) resulted in a dose-dependent increase in cardiac function, however, with a significantly diminished magnitude at the highest dose of dobutamine infusion (40⯵g/kg/min) in both diastole (E/A: -12⯱â¯3 vs. -38⯱â¯5%) and systole (EF: 25⯱â¯3 vs. 33⯱â¯5%) as well as ~42% reduced cardiac output reserve (COR: 63⯱â¯8 vs. 105⯱â¯18%, pâ¯<â¯0.02) in the MetS compared to CTRL NHPs. CONCLUSION: These data demonstrate that MetS NHPs with cardiorenal complications: proteinuria, LV diastolic dysfunction and preserved LV systolic function under resting conditions displayed compromised cardiac functional reserve under dobutamine stress. Based on these phenotypes, this NHP model of diabetes with cardiorenal complications can be used as a highly translational model mimic human disease for pharmaceutical research.
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Proteinuria , Disfunción Ventricular Izquierda , Animales , Gasto Cardíaco , Diabetes Mellitus , Dobutamina/farmacología , Macaca fascicularis , Proteinuria/complicaciones , Volumen Sistólico , Disfunción Ventricular Izquierda/complicacionesRESUMEN
The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels modulate and regulate cardiac rhythm and rate. It has been suggested that, unlike the HCN1 and HCN2 channels, the slower HCN4 channel may not exhibit voltage-dependent hysteresis. We studied the electrophysiological properties of human HCN4 (hHCN4) channels and its modulation by cAMP to determine whether hHCN4 exhibits hysteresis, by using single-cell patch-clamp in HEK293 cells stably transfected with hHCN4. Quantitative real-time RT-PCR was also used to determine levels of expression of HCNs in human cardiac tissue. Voltage-clamp analysis revealed that hHCN4 current (I(h)) activation shifted in the depolarizing direction with more hyperpolarized holding potentials. Triangular ramp and action potential clamp protocols also revealed hHCN4 hysteresis. cAMP enhanced I(h) and shifted activation in the depolarizing direction, thus modifying the intrinsic hHCN4 hysteresis behavior. Quantitative PCR analysis of human sinoatrial node (SAN) tissue showed that HCN4 accounts for 75% of the HCNs in human SAN while HCN1 (21%), HCN2 (3%), and HCN3 (0.7%) constitute the remainder. Our data suggest that HCN4 is the predominant HCN subtype in the human SAN and that I(h) exhibits voltage-dependent hysteresis behavior that can be modified by cAMP. Therefore, hHCN4 hysteresis potentially plays a crucial role in human SAN pacemaking activity.
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Relojes Biológicos/fisiología , Canales Catiónicos Regulados por Nucleótidos Cíclicos/fisiología , Proteínas Musculares/fisiología , Nodo Sinoatrial/fisiología , AMP Cíclico/fisiología , Fenómenos Electrofisiológicos , Células HEK293 , Humanos , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Técnicas de Placa-Clamp , Canales de Potasio , TransfecciónRESUMEN
Starting in the 1970s the hypothesis that the low mortality from coronary heart disease among the Greenland Eskimos was due to their high consumption of n-3 fish oil fatty acids, initiated many studies to find if the n-3 polyunsaturated fatty acids in fish oils (PUFAs) could prevent cardiac atherosclerosis. To date this possibility has not achieved clinical recognition. The recent literature shows an increase of intervention studies to learn if the fish oil fatty acids can reduce mortality from sudden cardiac death, and the mechanism(s) of such a protective effect. Indeed the most definite beneficial cardiac action of these n-3 PUFAs seems now to be their ability in the short term to prevent sudden cardiac death. It is apparent that over long periods of time the n-3 fish oil fatty acids also prevent atherosclerosis. Definition of the fatty acids to which I will be referring in the text: n-6 (omega-6) polyunsaturated fatty acids; linoleic acid (18:2n-6, LA); arachidonic acid (C20:4n-6, AA). n-3 (omega-3) fatty acids; alpha-linolenic acid (18:3n-3, ALA); eicosapentaenoic acid (20:5n-3, EPA); docosahexaenoic acid (C22:6n-3, DHA). The bold, underlined abbreviation will appear in the text to identify the fatty acid being discussed.
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Fármacos Cardiovasculares/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Ácidos Grasos Omega-3/uso terapéutico , Aceites de Pescado/uso terapéutico , Animales , Aterosclerosis/prevención & control , Canales de Calcio Tipo L/efectos de los fármacos , Células Cultivadas , Muerte Súbita Cardíaca/prevención & control , Perros , Electrofisiología , Humanos , Miocitos Cardíacos/efectos de los fármacos , RatasRESUMEN
OBJECTIVE: To determine the prevalence and evaluate the risk factors of canine echinococcosis based on a field survey of dog infections with Echinococcus granulosus and E. multilocularis in Chalong, Kalong, Dade and Chazha Townships in a district of Ganzi County, Sichuan Province, China. METHOD: Questionnaire associated with the acquisition of canine echinococcosis was administered to dog owners. Stray dogs were examined post-mortem and rectal faeces at necropsy were collected to validate a copro-antigen ELISA. Owned dogs were screened for Echinococcus spp. infection in faeces using the genus specific copro-ELISA and the effectiveness of dog treatment was assessed. Chi-square and one-way ANOVA were used for statistical analysis. RESULTS: The prevalence of Echinococcus spp. infection at necropsy in stray dogs was 60.9% (14/23) in 2000; E. multilocularis infection accounted for 34.8% (8/23) and E. granulosus for 26.1% (6/23). The specificity of the copro-ELISA was 80.0% and the sensitivity was 92.3%, compared with the results at necropsy. Fifty percent of owned dogs (290/580) tested was copro-antigen positive at the beginning of the project in 2000, which decreased to 17% (99/580) in the same cohort of owned dogs after praziquantel treatment (5 mg/ kg) at 6-monthly period from 2003 to 2005. Analysis for risk factors associated with copro-antigen positive dogs showed that the never tethered dogs had a higher rate (40.4%, 65/161) than dogs tethered during the day (32.3%, 109/337), or tethered at night [29.2% (21/72)], or those always tethered [20%(2/10)](P<0.01). Dogs that their owners lacked hydatid transmission knowledge [38.1% (121/318)] and did not have de-worming practice [47.7% (92/193)] had significantly higher copro-antigen positive rate than those dogs that their owners knew relevant knowledge [28.6% (75/262)] and were dewormed regularly [20.4% (79/387)](P<0.05 and P<0.01). There was no correlation between the prevalence and dog sex or age or the varieties of livestock that the owner raised. CONCLUSION: Local dogs show high prevalence with both E. granulosus and E. multilocularis. The copro-ELISA can be used to detect infection of Echinococcus in dogs. Allowing dogs to roam, lack of the basic knowledge of hydatid disease transmission and no de-worming practice for dogs are significant factors for the transmission of canine echinococcosis.
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Enfermedades de los Perros/epidemiología , Enfermedades de los Perros/parasitología , Equinococosis/veterinaria , Animales , China/epidemiología , Perros , Equinococosis/epidemiología , Echinococcus granulosus , Análisis Factorial , Heces/parasitología , Prevalencia , Medición de Riesgo , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
The three major enzyme systems, cyclo-oxygenase, lipoxygenase, and cytochrome P450 (P450/CYP), metabolize arachidonic acid (AA) to biologically active compounds. P450 and its associated monooxygenase activities have been identified in mammalian cardiac tissue, including humans. The four regioisomeric eicosanoids, 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) of AA metabolites derived by P450 epoxygenases have shown to possess potent biological effects in numerous tissues. In the coronary circulation the EETs are leading candidates for endothelial-derived hyperpolarizing factors that hyperpolarize vascular smooth muscle cells by opening Ca2+-activated K+ channels. Recently, the effects of the CYP pathways and their metabolites on cardiac ischemia-reperfusion injury have been evaluated in animal models. Some of these AA metabolites are cardioprotective and some are detrimental. However, EETs appear to be cardioprotective in CYP2J2 transgenic mice and in a canine ischemic model. Multiple effects of EETs on cardiac ion channels have been observed, such as activation of ATP-sensitive K+ channels and L-type Ca2+ channels in cardiomyocytes and inhibition of cardiac Na+ channels and L-type Ca2+ channels reconstructed in planar lipid bilayers. This brief review summarizes EET-induced modulation of cardiac ion channels.
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Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Canales de Calcio Tipo L/fisiología , AMP Cíclico/fisiología , Corazón/efectos de los fármacos , Miocardio/metabolismo , Canales de Potasio/fisiología , Ácido 8,11,14-Eicosatrienoico/farmacología , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Animales , Canales de Calcio Tipo L/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/metabolismo , Compuestos Epoxi/farmacología , Isoproterenol/farmacología , Canales de Potasio/efectos de los fármacos , Canales de Sodio/efectos de los fármacos , Canales de Sodio/fisiologíaRESUMEN
Recently an immunological test for Echinococcus spp. antigens in dog faeces has been developed. The antigens appear to be carbohydrates, which survive proteolytic digestion and environmental degradation. For ELISA a capture antibody is used to capture the antigens, followed by a detection antibody. This paper describes a modification of the test whereby capture and detection antibodies are generated exclusively to the carbohydrate portion of the parasite tegument. Faecal extracts were heated to 70 degrees C overnight and the addition of foetal calf serum to the extracts was not necessary. The use of this modification as a surveillance tool in an extensive field trial of hydatid control in Western Sichuan is described. From 2003 onwards all dogs received a treatment with praziquantel pills in the spring and the autumn of each year. On each of six occasions 580 faecal samples were collected from 29 villages and analysed. Prevalence of Echinococcus spp. coproantigen-positive samples was 50% in year 2000, and decreased from 35% to 17% through 2003-2005. This coproantigen technique is now being used as part of the Chinese National Hydatid Disease Control Program, initially in 10 counties in Sichuan Province.
Asunto(s)
Enfermedades de los Perros/epidemiología , Equinococosis/veterinaria , Echinococcus/inmunología , Ensayo de Inmunoadsorción Enzimática/veterinaria , Heces/parasitología , Animales , Enfermedades de los Perros/parasitología , Perros , Equinococosis/epidemiología , Endopeptidasa K , Tibet/epidemiologíaRESUMEN
BACKGROUND: Overgrazing was assumed to increase the population density of small mammals that are the intermediate hosts of Echinococcus multilocularis, the pathogen of alveolar echinococcosis in the Qinghai Tibet Plateau. This research tested the hypothesis that overgrazing might promote Echinococcus multilocularis transmission through increasing populations of small mammal, intermediate hosts in Tibetan pastoral communities. METHODS: Grazing practices, small mammal indices and dog Echinococcus multilocularis infection data were collected to analyze the relation between overgrazing and Echinococcus multilocularis transmission using nonparametric tests and multiple stepwise logistic regression. RESULTS: In the investigated area, raising livestock was a key industry. The communal pastures existed and the available forage was deficient for grazing. Open (common) pastures were overgrazed and had higher burrow density of small mammals compared with neighboring fenced (private) pastures; this high overgrazing pressure on the open pastures measured by neighboring fenced area led to higher burrow density of small mammals in open pastures. The median burrow density of small mammals in open pastures was independently associated with nearby canine Echinococcus multilocularis infection (P = 0.003, OR = 1.048). CONCLUSION: Overgrazing may promote the transmission of Echinococcus multilocularis through increasing the population density of small mammals.
Asunto(s)
Enfermedades de los Perros/transmisión , Equinococosis/transmisión , Echinococcus multilocularis , Animales , Perros , Equinococosis/veterinaria , Humanos , Densidad de Población , TibetRESUMEN
Normal rhythm in a healthy human heart originates from the natural biological pacemaker, the sinoatrial (SA) node which locates in the right atrium. SA node dysfunction or atrial-ventricular (AV) conduction block causes improper heart rate (bradycardia). Such dysfunction, if severe enough, is currently treated by implanting an electronic pacemaker which has been well established technically, but there are some limitations and inadequacies. Recently, progress in developing engineered cardiac biopacemakers with use of genes or cells has been made in experimental animal models. The hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channel (pacemaker channel) modulates cardiac automaticity via the hyperpolarization-activated cation current (I(f)). HCN genes have been delivered to animal myocardium via viral vectors or HCN-transferred cells for recreating biological pacemakers. Approaches with non-HCN genes or transplantation of beating cells are also novel and have been investigated for generating cardiac biopacers. This article summarizes the progresses in research on recreation of cardiac biopacemakers. Genetically engineered biological pacemaker holds great promise to potentially cure severe bradycardia if critical issues, such as their stability and longevity, are properly solved.
Asunto(s)
Relojes Biológicos/fisiología , Bradicardia/terapia , Marcapaso Artificial , Ingeniería Genética , Corazón , Frecuencia Cardíaca , Ventrículos Cardíacos , Humanos , Canales Iónicos , Miocardio , Nodo SinoatrialRESUMEN
Timely knowing glucose level helps diabetic patients to manage the disease, including decisions about food, physical activity and medication. This study compared two continuous glucose monitoring systems in conscious and moving-free nonhuman primates (NHPs, Macaca fascicularis). Each normoglycemic or diabetic monkey was implanted with one Dexcom G4 Platinum subcutaneously or one HD-XG glucose sensor arterially for glucose monitoring. The glucose levels measured by both telemetry devices significantly correlated with the glucometer readings. The data of oral glucose tolerance test (oGTT) showed that the glucose levels measured by either Dexcom G4 Platinum or HD-XG transmitter were very similar to glucometer readings. However, compared to HD-XG transmitter or glucometer, Dexcom G4 Platinum detected a decreased glucose peak of ivGTT with approximately 10 min delay due to interstitial glucose far behind blood glucose change. Our data showed the advantages of the telemetry systems are: (1) consecutive data collection (day and night); (2) no bleeding; (3) no anesthesia (moving freely); (4) recording natural response without physical restriction and stress; (5) less labor intensity during ivGTT and other tests; (6) quick outcomes without lab tests. This article summarized and compared the differences of the general characteristics of two continuous glucose monitoring systems in diabetic research.
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Análisis Químico de la Sangre/métodos , Glucemia , Animales , Análisis Químico de la Sangre/instrumentación , Prueba de Tolerancia a la Glucosa/métodos , Hemoglobina Glucada , Insulina/sangre , Macaca fascicularis , TelemetríaRESUMEN
Control of hydatidosis is less effective without the support of dog-owners, and this support can only be obtained if the people have a clear understanding of the life-cycle of the hydatid parasite(s) and what risk factors contribute to human infections. Dissemination of this information is the biggest challenge for hydatid control. Participatory planning between dog-owners and community leaders should evaluate the possible control technologies, and should enable a choice of those aspects that suit the sociology and economic status of the particular community. Collection of baseline data is essential, as is on-going surveillance. Hydatid control should be mainly self-funded, which again requires the support of the dog-owner. A pilot hydatid control program for Tibetan herdsmen is described.
Asunto(s)
Control de Enfermedades Transmisibles/métodos , Enfermedades de los Perros/prevención & control , Equinococosis/prevención & control , Animales , China/epidemiología , Enfermedades de los Perros/parasitología , Enfermedades de los Perros/transmisión , Perros , Equinococosis/parasitología , Equinococosis/transmisión , Echinococcus granulosus , Echinococcus multilocularis , Educación en Salud/métodos , Planificación en Salud/métodos , Humanos , Nueva Zelanda/epidemiología , Tibet/epidemiologíaRESUMEN
Tumor necrosis factor-alpha (TNF-alpha) plays an important role in the pathogenesis of myocardial infarction. Stem cells are able to regenerate infarcted myocardium. This study investigated whether TNF-alpha was able to induce migration of embryonic stem cells (ESCs) in vitro. We used a Transwell assay in which neonatal rat cardiomyocytes, with or without transfection of TNF-alpha cDNA, were plated in the lower compartments and mouse ESCs tagged with green fluorescent protein were added to the upper compartments. TNF-alpha level was significantly increased in the medium of the lower compartments seeded with TNF-alpha-transfected cardiomyocytes. Compared with the controls, overexpression of TNF-alpha significantly enhanced migration of ESCs to the lower compartments. This enhancement was attenuated by preincubation of ESCs with the antibody against the type II TNF-alpha receptor (TNF-RII), but not by the antibody against the type I TNF-alpha receptor (TNF-RI). Western blot analysis showed that the phosphorylated protein levels of p38 and c-Jun amino-terminal kinase (JNK) were significantly increased in TNF-alpha-treated ESCs. Inhibition of the activity of p38 or JNK significantly attenuated TNF-alpha-induced ESC migration. Our data demonstrate that excessive TNF-alpha stimulates TNF-RII and enhances migration of ESCs in vitro. Activation of p38 and JNK is required for TNF-alpha-enhanced ESC migration.