Copper induces damage, oxidative stress and cell death in endothelium of chronic intoxicated Wistar rats / El cobre induce daño, estrés oxidativo y muerte celular en el endotelio de ratas Wistar intoxicadas

SUMMARY: Reactive Oxygen Species (ROS) are part of the functional balance of various systems, they can generate cellular damage by oxidative stress associated with disease processes such as atherosclerosis, cardiovascular disease, diabetes, and aging. Some studies report that copper induces damage to the endothelium, which could be associated with cardiovascular pathologies. This study was an experimental comparative, prospective, longitudinal, and controlled clinical trial in a murine animal model. Twenty-four male Wistar rats were included, the distribution of the groups was time-depending chronic exposition to copper, and a control group. Results show gradual alterations in the groups treated with copper: areas with loss of the endothelium, signs of disorganization of smooth muscle fibers in the tunica media, as well as areas with the fragmentation of the elastic sheets. A significant statistical difference was observed in the active- Caspase-3 analysis expression in the aortic endothelium and endothelium of the capillaries and arterioles of the lung between the control group vs 300 ppm of copper. Expression of eNOS was detected in the endothelium of the aorta and vessels of the lung. Our study shows histological changes in the walls of the great vessels of intoxicated rats with copper, and the increment of inflammatory cells in the alveoli of the study model, mainly at a high dose of copper exposition. These results will be useful to understand more about the mediators involved in the effect of copper over endothelium and cardiovascular diseases in chronic intoxication in humans.

RESUMEN: Las Especies Reactivas de Oxígeno (ROS) son parte del equilibrio funcional de varios sistemas, pueden generar daño celular por estrés oxidativo asociado a procesos patológicos como aterosclerosis, enfermedades cardiovasculares, diabetes y envejecimiento. Algunos estudios informan que el cobre induce daños en el endotelio, lo que podría estar asociado a patologías cardiovasculares. Este estudio fue un ensayo clínico experimental comparativo, prospectivo, longitudinal y controlado en un modelo animal murino. Se incluyeron veinticuatro ratas Wistar macho, la distribución de los grupos fue la exposición crónica al cobre en función del tiempo y un grupo de control. Los resultados muestran alteraciones graduales en los grupos tratados con cobre: áreas con pérdida del endotelio, signos de desorganización de las fibras musculares lisas en la túnica media, así como áreas con la fragmentación de las láminas elásticas. Se observó una diferencia estadística significativa en la expresión del análisis de caspasa-3 activa en el endotelio aórtico y el endotelio de los capilares y arteriolas del pulmón entre el grupo de control frente a 300 ppm de cobre. Se detectó expresión de eNOS en el endotelio de la aorta y los vasos del pulmón. Nuestro estudio muestra cambios histológicos en las paredes de los grandes vasos de ratas intoxicadas con cobre, y el incremento de células inflamatorias en los alvéolos del modelo de estudio, principalmente a una alta dosis de exposición de cobre. Estos resultados serán útiles para comprender más sobre los mediadores involucrados en el efecto del cobre sobre el endotelio y las enfermedades cardiovasculares en la intoxicación crónica en humanos.

Aspirin with or without statin in the treatment of endotheliitis, thrombosis, and ischemia in coronavirus disease

Abstract INTRODUCTION: In the genesis of coronavirus disease (COVID-19), there is a process of endotheliitis associated with thrombotic changes, no studies have reported the use of acetylsalicylic acid (ASA) as a possible therapeutic approach. Statins could potentiate the ASA therapy. METHODS: This is a series of 14 cases with a laboratory-confirmed diagnosis of COVID-19. All patients underwent the ASA therapy. Those who had risk factors for vascular disease also underwent the high-potency statin therapy. When symptoms were totally or practically resolved, patients were discharged and advised to continue medications for a complementary time, according to the clinical evolution of each patient. RESULTS: The mean age of monitored patients was 48.6 years. A total of 78.6% patients presented with at least one comorbidity, which could have contributed as a risk factor for a poor prognosis in the evolution of COVID-19. Four patients had secondary bacterial infections; three patients needed hospitalization. None of the cases progress to stage III, and all patients had remission of symptoms, with 100% survival. CONCLUSIONS: the process of endothelial dysfunction in COVID-19 involves disseminated thrombosis, initially microvascular and later expansion into larger vessels. ASA could act as a secondary prophylaxis and prevent thrombosis from developing and reaching stage III of the disease. As this was a case series, we cannot provide definitive conclusions; however, this study allows us to formulate hypotheses and support clinical trials to evaluate benefits of the ASA therapy in the treatment of COVID-19.

Dual effect of atorvastatin on endothelium; reduction In LDL And TXA2 levels but unaltered HCY levels In obese hyperlipidemic rats

Objective: The objective of the study was to observe the effect of lipid lowering therapy on homocysteine and TXA[2] concentration in obese hyperlipidemic Sprague Dawley rats

Design: Randomized Control Trial [RCT]

Place and Duration of study: The study was conducted in Department of Physiology and Centre for Research in Experimental and Applied Medicine [CREAM], Army Medical College, Rawalpindi; and National Institute of Health [NIH] Islamabad over a period of 12 months

Methodology: Ninety healthy Sprague Dawley rats divided into three equal groups. Group I [n=30] were healthy controls, group II [n=30] were made obese and group III [n=30] were obese treated [atorvastatin 10 mg/kg/day orally by gavage method for three weeks]. Body weight was recorded thrice weekly, lipid profile was measured by colorimetric method on microlab and homocysteine and TXA2 were measured by Enzyme Linked Immunosorbant Assay

Results: Serum low density lipoproteins and TXA2 decreased after three weeks of atorvastatin administration, elevated HCY concentration in obese hyperlipidemic rats however was not significantly affected

Conclusion: Atorvastatin apart from lowering lipid levels in the body also reduces TXA[2] concentration which is a vasoprotective. Elevated HCY concentration which is deleterious to the endothelium however is not affected

Vosodilator effect of pelargonium odoratissimum on isolated rat aorta

The vasodilator effect of Pelargonium odoratissimum was investigated using isolated rat aortic rings. Eethanolic extract has shown a profound relaxing effect on noradrenaline-precontracted aortic rings. There was a difference in the effect in the absence or presence of endothelium. Relaxing effect of the ethanolic extract was obviously more potent in the presence of endothelium. These data clearly indicate that relaxing effect of Pelargonium odoratissimum is partially endothelium-dependent

Insulin in the critically ill with focus on cytokines, reactive oxygen species, HLA-DR expression.

Insulin is essential for glucose homeostasis. Insulin/glucose-insulin-potassium (GIK) regimen suppresses the production of tumor necrosis factor-alpha (TNF-alpha), interleukins-6 (IL-6), macrophage migration inhibitory factor (MIF) and other pro-inflammatory cytokines and reactive oxygen species (ROS), enhances the synthesis of endothelial nitric oxide (eNO), and anti-inflammatory cytokines interleukins-4 (IL-4) and interleukin-10 (IL-10). In subjects who are critically ill, monocyte HLA-DR expression was significantly decreased with a concomitant increase in plasma IL-10 and IL-4 concentrations. Large increases in the plasma concentrations of TNF-alpha, IL-6, sustained increase in the expression of leukocyte CD11b/CD18, and ROS generation following surgery and infections were found to be associated with increased mortality. By virtue of its actions on pro- and anti-inflammatory cytokines and ROS, insulin may have the ability to alter HLA-DR expression in the critically ill and thus bring about its beneficial actions in sepsis/septic shock, myocardial recovery following acute myocardial infarction, improve prognosis of those who are critically ill, and suppress inflammation.

Green tea polyphenols inhibit oxidized LDL-induced NF-KB activation in human umbilical vein endothelial cells.

AIM: To examine the anti-inflammatory effects of green tea polyphenols on oxLDL-mediated TNFalpha expression and NF-KB activation in the human umbilical vein endothelial cells (HUVECs). METHODS: We postulate that green tea polyphenols regulate TNF-alpha gene expression by modulating NF-KB activation through their inhibition effect on IKB Kinase (IKK) activity and as scavenger of free radicals. Pretreatment of green tea polyphenols reduced oxLDL-induced production of proinflammatory cytokine TNF-alpha and NF-KB activation in dose dependent manner (p < 0.05). Post hoc comparison test with Mann Whitney between various dosage of green tea polyphenols in inhibition of NF-KB activation showed significant result (p < 0.05). RESULTS: In TNF-alpha expression, there was also declined TNF-alpha productions (p 0.09; 0.2 vs 0.4mg/ml: ns). The effect of green tea polyphenols on TNF-alpha expression were determined by Mann-Whitney test. There is significant difference between the first dose (0.1mg/ml) vs 0.2mg/ml polyphenols (p=0.009); between 0.1 vs 0.4 mg/ml polyphenols (p=0.009). There was no difference when the dose was increased from 0.2 mg/ml to 0,4 mg/ml polyphenols (0.141). In this study, green tea polyphenols showed significant effects on the inhibition of TNF-alpha through NF-KB activation pathway in HUVECs with oxidized LDL. CONCLUSION: Green tea polyphenol can be used to prevent the development of atherosclerosis.

Nanoparticles-A Thoracic Toxicology Perspective

A substantial literature demonstrates that the main ultrafine particles found in ambient urban air are combustion-derived nanoparticles (CDNP) which originate from a number of sources and pose a hazard to the lungs. For CDNP, three properties appear important-surface area, organics and metals. All of these can generate free radicals and so induce oxidative stress and inflammation. Inflammation is a process involved in the diseases exhibited by the individuals susceptible to the effects of PM- development and exacerbations of airways disease and cardiovascular disease. It is therefore possible to implicate CDNP in the common adverse effects of increased PM. The adverse effects of increases in PM on the cardiovascular system are well-documented in the epidemiological literature and, as argued above, these effects are likely to be driven by the combustion-derived NP. The epidemiological findings can be explained in a number of hypotheses regarding the action of NP:-1) Inflammation in the lungs caused by NP causes atheromatous plaque development and destabilization; 2) The inflammation in the lungs causes alteration in the clotting status or fibrinolytic balance favouring thrombogenesis; 3) The NP themselves or metals/organics released by the particles enter the circulation and have direct effects on the endothelium, plaques, the clotting system or the autonomic nervous system/ heart rhythm. Environmental nanoparticles are accidentally produced but they provide a toxicological model for a new class of purposely 'engineered' NP arising from the nanotechnology industry, whose effects are much less understood. Bridging our toxicological knowledge between the environmental nanoparticles and the new engineered nanoparticles is a considerable challenge.

Insulin therapy--role beyond glucose control.

Larger studies had shown improved patient outcome and lower probability of coronary artery disease in insulin treated groups. The classical lipid abnormalities associated with type 2 diabetes are low HDL-cholesterol concentration and high triglyceride concentration. Insulin usage leads to a decrease in triglyceride concentration, primarily by its effect on the enzyme adipose tissue lipoprotein lipase. Insulin suppresses the enzyme, thereby controlling lipolysis in uncontrolled diabetes. Insulins therapy also improves the endothelial dysfunction especially in people with evident macrovascular complications. Though insulin is noted to increase adrenergic tone and may cause elevation of blood pressure, still patients with insulinoma do not have high blood pressure. Some studies suggest weight gain with insulin therapy, others contradict it. One study suggests that insulin does not affect treatment satisfaction. Insulin is known to improve the glycaemic scenario and also the insulin secretory pattern by reducing the glucotoxicity.

Endothelial cell injury in newborn rat liver by antenatal chloroqine exposure

To see the effect of chloroquine on endothelial cells in developing liver of albino rats. Design: Case control prospective study. Place and Duration of Study: Anatomy Department of Post Graduate Medical Institute, Lahore from September to December 2000. Subjects and Twenty-four pregnant female albino rats were divided in 4 groups. The gestation period in rats ranges from 20-22 days, which was divided into three trimesters of seven days each. Oral dose of chloroquine 700 mg/kg body weight in first, second and third weeks of pregnancy was administered. Hepatic tissue of newborn rats were analyzed histologically. Chloroquine induced considerable endothelial cell injury in newborn rat liver. Central venular endothelial cells[CVECs] and sinusoidal endothelial cells[SECs] were specially involved. Livers from animals exposed to chloroquine during the third trimester showed many areas of intrahepatic hemorrhage due to complete destruction of endothelial lining of central veins. Chloroquine is toxic to endothelial cells of liver and should be avoided during pregnancy

Estudo morfométrico do efeito do Tenoxicam e do seu diluente no endotélio venoso, em coelhos / Morphometric study on the effect of tenoxicam and its diluent in the venous endothelium, in rabbits

Com o objetivo de avaliar pela morfometria o efeito do tenoxicam e do seu diluente no endotélio venoso, foram utilizados 48 coelhos (Oryctolagus cuniculus), brancos, da linhagem Nova Zelândia, machos, com idade acima de 10 semanas, com peso variando entre 2.350 e 3.500 gramas, divididos em dois grupos, denominados Experimento e Controle, que foram observados nos tempos de 6, 12 e 24 horas. Administrou-se nas venae auriculares dextra e sinistra, diluente ou tenoxicam/diluente no Grupo Experimento e cloreto de sódio a 0,9 por cento no Grupo Controle. Näo se constatou diferença estatisticamente significante entre o peso dos animais do Grupo Experimento e do Grupo Controle, antes da realizaçäo do procedimento. Pode-se observar que após a administraçäo do tenoxicam com o seu diluente ou do diluente isolado, os diâmetros dos núcleos das células endoteliais apresentaram significativamente menor dimensäo, quando comparados aos do grupo Controle, em que foi injetado cloreto de sódio a 0,9 por cento. Os resultados encontrados permitem concluir que o tenoxicam com o seu diluente comercial ou o diluente isolado reduzem o diâmetro dos núcleos das células endoteliais das venae em que foram injetados os fármacos.

Fructose, 1,6-diphosphate mitigates CCl4 suppressed nitric oxide synthase activity in rats.

Effect of fructose 1,6-diphosphate (FDP) and carbon tetrachloride (CCl4) were studied individually and in combination on rat endothelial (ET) and smooth muscle cell (SMC) nitric oxide synthase (NOS) activities in vivo, inhibition of ET and SMC NOS activity in CCl4 treated rats was reversed in FDP + CCl4 treated animals. Cellular based NOS activity was significantly increased in FDP treated group of rats when compared to non treated controls. The results suggest a significant increase in NOS in rats treated with a combination of FDP + CCl4 thus overcoming the suppression of NOS exposed to CCl4 alone.

Dose-dependent effect of resveratrol on proliferation and apoptosis in endothelial and tumor cell cultures

Experimental data suggest that Resveratrol, a compound found in grapes and other fruits may influence cell proliferation and apoptosis. The aim of our experiments was to study the effect of Resveratrol on tumor cell cultures and an endothelial cell culture in order to examine the effect of various doses of this compound on active cell death and cell proliferation. Human tumor (HT-29, SW-620, HT-1080) and endothelial (HUV-EC-C) cells were treated with various doses of (0.1 to 100.0 microg/ml) Resveratrol in vitro. Cell number, apoptotic and mitotic index was measured 24, 48 and 72 h after treatment. Low doses (0.1-1.0 microg/ml) of Resveratrol enhance cell proliferation, higher doses (10.0-100.0 microg/ml) induce apoptosis and decrease mitotic activity, which is reflected in changes of cell number. Resveratrol influences dose dependently the proliferative and apoptotic activity of human tumor and endothelial cells. The possible role of formaldehyde in the mechanism of action of Resveratrol is discussed.

Enfermedades cardiovasculares en la postmenopausia / Cardiovascular diseases in postmenopause

Las enfermedades cardiovasculares son la causa de muerte mas frecuente en la posmenopausia. El incremento de la longevidad proyectada para los próximos cincuenta años para la población general con la mayor longevidad de las mujeres comparada con la de los varones, prevee un gran número de individuos que van a entrar en menopausia y sufriran sus complicaciones. Este periódo biológico de las mujeres se prolongará durante unos treinta años aproximadamente. La transición de la premenopausia a la posmenopausia ha sido definida tradicionalmente como una etapa de declincaión. Sin embargo, con los avances de la medicina en general y de la medicina cardiovascular en particular, el comienzo de la posmenopausia representa hoy una gran oportunidad para la prevención. Estos cambios biológicos se reconocen como los marcadores iniciales de los nuevos eventos que van a ocurrir. Si se establece una comunicación abierta y bilateral entre el médico y la paciente, se llegará a una adecuada educación y prevención de las dos complicaciones mas teminads durante la posmenopausia como son las complicaciones cardiovasculares y la osteoporosis. El objeto del presente trabajo es discutir los mecanismos envueltos en la fisiopatología de las manifestaciones cardiovasculares y su prevención.

Evaluación de estudios clínicos de recuperación de la función endotelial con fármacos hipotensores

El endotelio cumple un papel crucial en el mantenimiento de la integridad del sistema cardiovascular, a través de sus funciones vasodilatadoras, antitrombóticas y antiaterogénicas. La disfunción endotelial ha sido implicada en la génesis de importantes enfermedades como la hipertensión arterial, la aterosclerosis, la enfermedad arterial coronaria, la insuficiencia cardiaca crónica, la diabetes mellitus, etc. Varios métodos clínicos han sido descritos para valorar la función endotelial; entre los mejor estandarizados están el de la respuesta vasomotora coronaria a la infusión de acetilcolina o bradicinina en arterias de conducción evaluada por pletismografía, y la vasodilatación dependiente de flujo (VDF) en arterias de conducción del antebrazo, valorada por el cambio en el diámetro de la arteria braquial de frente a la hiperemia reactiva, determinado por eco-doppler. En el presente artículo revisamos los diferentes estudios dirigidos a investigar el efecto de diferentes drogas hipotensoras en la recuperación de la función endotelial en pacientes con hipertensión esencial, enfermedad arterial coronaria e insuficiencia cardíaca crónica. Los inhibidores de la enzima convertidora de la angiotensina (ECA-I) son los fármacos que con más consistencia ejercen un efecto beneficioso en la recuperación de la función vasodilatadora dependiente de endotelio. Existen diferencias en la capacidad de mejorar la función endotelial entre los diferentes componentes

Farmacología del endotelio

La farmacología del endotelio a través del conocimiento de éste y de su biología molecular, ha expandido el uso y la combinación de fármacos en procura de una mejor función endotelial (y por ende del nuevo concepto de manejo integral tanto a nivel de prevención primaria como secundaria y terciaria). Ya se sabía que la aspirina disminuye la agregación plaquetaria. Los nitratos se convierten prácticamente en terapia celular. Los IECA (inhibidores de la enzima convertidora de angiotensina) ya no solo se usan para hipertensión arterial e insuficiencia cardíaca. Tienen utilidad también en pacientes con enfermedad coronaria, en post-infarto y post-angioplastia. Su gran ventaja no está solo en bloquear la enzima convertidora de angiotensina (kininasa II), sino que potencia bradiquinina, lo cual se traduce en restauración en la producción de óxido nítrico, prostaciclina y factor hiperpolarizante derivado del endotelio. Los inhibidores de la HMGCoA reductasa además de mejorar el pronóstico específico de la hipercolesterolemia, disminuyen eventos cardiovasculares e incluso, estabilizan la placa evitando los eventos isquémicos agudos; algunos parecen tener propiedades antiplaquetarias intrínsecas y pueden prevenir el reinfarto. La simvastatina tiene un efectivo beneficio adicional en enfermos diabéticos; los antioxidantes prometen cada vez más ser útiles en procesos en donde la peroxidación lipídica o el estrés oxidativo se convierten en mediadores de procesos patológicos. Igualmente los calcioantagonistas previenen y protegen contra la acción deletérea del aumento del calcio en las células del músculo liso vascular y en el mismo miocardio, y de alguna manera influencian, retardando o modulando el proceso aterogénico. Ultimamente, los inhibidores del receptor de angiotensina tipo I, además de bloquear el efecto deletéreo de la angiotensina, regulan el proceso de apoptosis endotelial y liberan óxido nítrico, aunque en menor escala que los IECA. Hoy día se ha expandido la aplicación de muchos fármacos hacia una meta final común: el endotelio

Efeito dos ácidos graxos omega-3 sobre o relaxamento-dependente do endotélio em coelhos hipercolesterolêmicos / Effects of omega-3 fatty acids on endothelium-dependent relaxation in hypercholesterolemic rabbits

OBJETIVO: Estudar o efeito dos acidos graxos omega-3 sobre o relaxamento-dependente do endotelio, o colesterol plasmatico, as LDL, VLDL, HDL, triglicérides e a peroxidaçäo dipídica das partículas de LDL-nativas, oxidadas e da parede arterial....

Nicotine and endothelial permeability

The effect of nicotine was studied on the permeability of the coronary endothelium of Sprague Dawley rats. Nicotine was administered in drinking water from 4 to 6 week in a dose of 5mg/kg body weight/day. Endothelial permeability was studied by intramuscular injection of Evans blue dye and was found to be increased in nicotine treated animals. The mode of penetration was seen to be through the endothelial cells to begin with and later the intercellular gaps were also involved