ABSTRACT
Cardiovascular diseases are the major causes of preventable health loss from disease in the world and lead to functional disturbances including hematological parameters. The inflammatory and hypoxemic nature of cardiovascular diseases causes a stimulus in the bone marrow and, depending on the intensity of this stimulus, there is a release of immature cells or increase of other cells in the bloodstream. Therefore, their presence in the circulation is an important variable used to diagnose, stratify and predict diseases. In the last five decades, with the advent of automated counting of immature cells in the peripheral blood, the hemogram was transformed into a clinical tool of great importance in hospital surveillance for demonstrating this daily variability in the hematopoietic response according to the existing injury in the patient. Studies have shown that the presence of nucleated red blood cells and increases in mean platelet volume, immature granulocytes and neutrophil to lymphocyte ratio in the systemic circulation are independent prognostic biomarkers. This review article has as main objective to demonstrate the association of these hematological parameters to cardiovascular diseases, emphasizing their importance in clinical decision making.
Subject(s)
Biomarkers/blood , Blood Cell Count/methods , Cardiovascular Diseases/blood , Humans , PrognosisABSTRACT
Non-alcoholic fatty liver disease (NAFLD) defines a wide spectrum of liver diseases that extends from simple steatosis to non-alcoholic steatohepatitis. Although the pathogenesis of NAFLD remains undefined, it is recognized that insulin resistance is present in almost all patients who develop this disease. Thiazolidinediones (TZDs) act as an insulin sensitizer and have been used in the treatment of patients with type 2 diabetes and other insulin-resistant conditions, including NAFLD. Hence, therapy of NAFLD with insulin-sensitizing drugs should ideally improve the key hepatic histological changes, while also reducing cardiometabolic and cancer risks. Controversially, TZDs are associated with the development of cardiovascular events and liver problems. Therefore, there is a need for the development of new therapeutic strategies to improve liver function in patients with chronic liver diseases. The aim of the present study was to assess the therapeutic effects of LPSF/GQ-02 on the liver of LDLR-/- mice after a high-fat diet. Eighty male mice were divided into 4 groups and two different experiments: 1-received a standard diet; 2-fed with a high-fat diet (HFD); 3-HFD+pioglitazone; 4-HFD+LPSF/GQ-02. The experiments were conducted for 10 or 12 weeks and in the last two or four weeks respectively, the drugs were administered daily by gavage. The results obtained with an NAFLD murine model indicated that LPSF/GQ-02 was effective in improving the hepatic architecture, decreasing fat accumulation, reducing the amount of collagen, decreasing inflammation by reducing IL-6, iNOS, COX-2 and F4 / 80, and increasing the protein expression of IκBα, cytoplasmic NFκB-65, eNOS and IRS-1 in mice LDLR -/-. These results suggest a direct action by LPSF/GQ-02 on the factors that affect inflammation, insulin resistance and fat accumulation in the liver of these animals. Further studies are being conducted in our laboratory to investigate the possible mechanism of action of LPSF/GQ-02 on hepatic lipid metabolism.
Subject(s)
Non-alcoholic Fatty Liver Disease/drug therapy , Thiazolidinediones/therapeutic use , Animals , Cyclooxygenase 2/metabolism , Diet, High-Fat , Disease Models, Animal , Epidermal Growth Factor/metabolism , I-kappa B Proteins/metabolism , Inflammation , Interleukin-6/metabolism , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , NF-KappaB Inhibitor alpha , Nitric Oxide Synthase Type II/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Pioglitazone , Receptors, LDL/deficiency , Receptors, LDL/genetics , Triglycerides/analysis , Triglycerides/bloodABSTRACT
BACKGROUND: Atherosclerotic cardiovascular disease is a chronic inflammatory condition. Thiazolidinediones (TZDs) are used to enhance sensitivity to insulin and have demonstrated a protective effect over a variety of cardiovascular markers and risk factors. Controversially, the TZDs are associated with the development of heart failure. Thus, lines of research have invested in the search for new molecules in order to obtain more selective and less harmful treatment alternatives for the pathogenesis of atherosclerosis and its risk factors. METHODS: Animals were fed a diet rich in fat for 10 weeks. In the last 2 weeks, animals received either pioglitazone, LPSF/GQ-02, or LPSF/GQ-16 daily through gavage. At the end of the treatment, blood was collected for biochemical analysis and the aortas were dissected for subsequent analyses. RESULTS: No changes in the blood lipid profile were found following the use of the drugs in comparison to the control. However, the new thiazolidine derivatives were more efficient in improving insulin resistance in comparison to pioglitazone and the control group. Morphometric analyses revealed that neither pioglitazone nor LPSF/GQ16 led to satisfactory effects over atherosclerosis. However, LPSF/GQ-02 led to a reduction in area of the atherosclerotic lesions. Ultrastructural analyses revealed extensive degeneration of the endothelium and an increase in apoptotic cells in the subendothelial space following the use of pioglitazone and LPSF/GQ-16. However, LPSF/GQ-02 caused minimal cell alterations in the aortic endothelium. Regarding markers, endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase 9 (MMP-9), LPSF/GQ-16, and pioglitazone exerted similar effects, increasing the expression of MMP-9, and had no effect on the expression of eNOS compared with the control group. On the other hand, LPSF/GQ-02 was effective in reducing the expression of MMP-9 and increased eNOS significantly. CONCLUSIONS: The results suggest that the new thiazolidine derivative LPSF/GQ-02 is a promising candidate for the treatment of atherosclerosis.
Subject(s)
Aorta/drug effects , Aortic Diseases/drug therapy , Atherosclerosis/drug therapy , Cardiovascular Agents/pharmacology , Receptors, LDL/deficiency , Thiazolidinediones/pharmacology , Thiazolidines/pharmacology , Animals , Aorta/metabolism , Aorta/ultrastructure , Aortic Diseases/genetics , Aortic Diseases/pathology , Apoptosis/drug effects , Atherosclerosis/blood , Atherosclerosis/genetics , Atherosclerosis/pathology , Blood Glucose/drug effects , Blood Glucose/metabolism , Blotting, Western , Cardiovascular Agents/toxicity , Disease Models, Animal , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Immunohistochemistry , Insulin/blood , Insulin Resistance , Lipids/blood , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Electron, Transmission , Nitric Oxide Synthase Type III/metabolism , Pioglitazone , Plaque, Atherosclerotic , Receptors, LDL/genetics , Thiazolidinediones/toxicity , Thiazolidines/toxicity , Time FactorsABSTRACT
AIMS: The present study investigated the effect of a maternal diet rich in omega-6 (E6D) or omega-9 (E9D) on atherogenesis in the offspring of mice. MAIN METHODS: LDL receptor-deficient mice were fed a diet rich in either omega-6 (E6D) or omega-9 (E9D) for 45 days prior to mating and until the birth of the offspring, evaluating the effect on the offspring aorta in comparison to a standard diet (STD), by immunohistochemical analysis, morphometric analysis and electron microscopy. KEY FINDINGS: Hypercholesterolemic female mice fed E6D generated offspring with high levels of total cholesterol, triglycerides (TG) and CC-chemokine ligand 2/monocyte chemoattractant protein 1 (CCL2/ MCP-1) as well as a reduction in high-density lipoprotein. The ascending aorta of these animals exhibited an increase in arterial wall thickness as well as increased expression of CCL2/MCP-1 and vascular cell adhesion molecule 1. The ultrastructural analysis revealed severe alterations in endothelial cells. The offspring from mothers fed E9D exhibited a reduction in TG and an increase in low-density lipoprotein. The ultrastructural analysis revealed a well-preserved aortic endothelium in these animals. SIGNIFICANCE: The results suggest that hypercholesterolemic mothers feed a diet rich in omega-6 predispose their offspring to endothelial dysfunction.
