ABSTRACT
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
Diethylcarbamazine (DEC) is an antifilarial drug with potent anti-inflammatory properties as a result of its interference with the metabolism of arachidonic acid. The aim of the present study was to evaluate the anti-inflammatory activity of DEC in a mouse model of acute inflammation (carrageenan-induced pleurisy). The injection of carrageenan into the pleural cavity induced the accumulation of fluid containing a large number of polymorphonuclear cells (PMNs) as well as infiltration of PMNs in lung tissues and increased production of nitrite and tumor necrosis factor-α and increased expression of interleukin-1ß, cyclooxygenase (COX-2), and inducible nitric oxide synthase. Carrageenan also induced the expression of nuclear factor-κB. The oral administration of DEC (50 mg/Kg) three days prior to the carrageenan challenge led to a significant reduction in all inflammation markers. The present findings demonstrate that DEC is a potential drug for the treatment of acute lung inflammation.
Subject(s)
Carrageenan/adverse effects , Diethylcarbamazine/chemistry , Gene Expression Regulation/drug effects , Lung Injury/chemically induced , Lung Injury/drug therapy , Administration, Oral , Animals , Anti-Inflammatory Agents/chemistry , Cyclooxygenase 2/metabolism , Inflammation , Interleukin-1beta/metabolism , Leukocytes/drug effects , Lipoxygenase Inhibitors/chemistry , Lung/metabolism , Male , Mice , Nitric Oxide Synthase Type II/metabolism , Pleurisy/chemically induced , Random AllocationABSTRACT
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
Some pharmacological studies showed that diethylcarbamazine (DEC) interferes with the arachidonic acid metabolism, acting as an anti-inflammatory drug. The chronic alcohol consumption activates the hepatic inflammatory response associated to T-cell activation and overproduction of pro-inflammatory cytokines. The present work analyzed the anti-inflammatory effect of DEC on hepatic cells of alcoholic mice. Thirty-two male C57BL/6 mice were equally divided in the following groups: (a) control group (C), which received only water, (b) DEC-treated group, which received 50 mg/kg for 12 day (DEC50), (c) the alcoholic group (EtOH), submitted to only alcohol and (d) the alcohol-DEC treated group (EtOH50), submitted to alcohol plus DEC treatment after the induction of chronic alcoholism for 5 weeks. Biochemical analyses were performed and liver fragments were processed for light microscopy, transmission electron microscopy, immunohistochemical and western blot. The level of AST increased significantly in alcoholic group whereas a significant reduction of serum AST was detected in the EtOH50 group. Histological and ultrastructural analysis of alcoholic group showed evident hepatocellular damage, which was strikingly reduced in the alcoholic DEC-treated group. Immunohistochemistry results revealed highly expression of inflammatory markers as MDA, NF-κB, TNF-α, IL-6, VCAM and ICAM by the hepatic cells of the EtOH group; however no immunoreactivity for any of these cytokines was detected after DEC treatment. Western blot analyses showed increased MCP-1 and iNOS expression in EtOH group, which was significantly inhibited by DEC treatment. According to the present results, DEC can be a potential drug for the treatment of chronic inflammation induced by chronic alcoholism.
Subject(s)
Diethylcarbamazine/therapeutic use , Ethanol/administration & dosage , Hepatitis, Alcoholic/drug therapy , Hepatitis, Alcoholic/metabolism , Inflammation Mediators/antagonists & inhibitors , Animals , Diethylcarbamazine/pharmacology , Ethanol/adverse effects , Hepatitis, Alcoholic/pathology , Inflammation Mediators/metabolism , Male , Mice , Mice, Inbred C57BL , Treatment OutcomeABSTRACT
Vardenafil citrate is a potent vasodilator used in the treatment of patients with erectile dysfunction. Its mechanism of action is based on the selective inhibition of phosphodiesterase-5 (PDE5), specific to guanosine 3',5'-cyclic monophosphate (cGMP). Recently, chronic treatment with Vardenafil has been successfully used in cases of pulmonary hypertension and, despite being used in high doses for long periods, little is known about its effects on other systems. In the present study, female mice were treated daily with 5 mg/kg Vardenafil for 4 weeks, after which the ovaries were collected for morphological analyses and sera were collected for biochemical assays. This study found that treatment with Vardenafil decreased HDL serum levels and the number of antral follicles as well as induced lesser lipid content in luteal cells, suggesting that high levels of cGMP may affect follicle development.