| Summary: |
Rational: Liver malfunction are one of the main problems associated with several pathological conditions including obesity.
Additionally, many forms of liver toxicity are also associated with drugs used in the treatment of a wide range of chronic diseases. Unfortunately, the clinical the use of many pharmacological agents including some anti-inflammatory, anti-depressant, anti-retroviral, anti-cholesterolemic and anti-neoplasic is limited by a dose-related liver toxicity. It has been described that obesity and drug-induced liver disease that cause hepatocyte dysfunction are associated with increased levels of oxidative damage and apoptosis, involving mitochondria in the process. In fact, a considerable amount of work has established mitochondrial defects associated with these conditions at the level of the phosforylative system and
calcium accumulation. Many preventive and therapeutic strategies have been explored against that dysfunction, including antioxidants and exercise. It is expected that the benefits of exercise in these patients may include the protection of the liver tissue and mitochondria against the deleterious effects induced by these conditions(1-5). However, the mechanisms related to this protection targeting mitochondria remain elusive. It is known that pathological conditions leading to liver dysfunction
compromise several components of the mitochondrial phosphorylating system(6, 7). In addition, one important physiological event in cell death is the mitochondrial permeability transition pore (mtPTP). The liver mtPTP is augmented in mitochondria from rats with some types of liver injury(6, 7)
Aim: to analyze the effects of life-span voluntary physical activity against liver mitochondrial dysfunction characterizing pathological conditions leading to liver injury such as obesity and in vivo and in vitro treatments with some types of anti-cancer, anti-retroviral, anti-depressant and anti-inflammatory drugs affecting liver tissue and mitochondri  |
Summary
Rational: Liver malfunction are one of the main problems associated with several pathological conditions including obesity.
Additionally, many forms of liver toxicity are also associated with drugs used in the treatment of a wide range of chronic diseases. Unfortunately, the clinical the use of many pharmacological agents including some anti-inflammatory, anti-depressant, anti-retroviral, anti-cholesterolemic and anti-neoplasic is limited by a dose-related liver toxicity. It has been described that obesity and drug-induced liver disease that cause hepatocyte dysfunction are associated with increased levels of oxidative damage and apoptosis, involving mitochondria in the process. In fact, a considerable amount of work has established mitochondrial defects associated with these conditions at the level of the phosforylative system and
calcium accumulation. Many preventive and therapeutic strategies have been explored against that dysfunction, including antioxidants and exercise. It is expected that the benefits of exercise in these patients may include the protection of the liver tissue and mitochondria against the deleterious effects induced by these conditions(1-5). However, the mechanisms related to this protection targeting mitochondria remain elusive. It is known that pathological conditions leading to liver dysfunction
compromise several components of the mitochondrial phosphorylating system(6, 7). In addition, one important physiological event in cell death is the mitochondrial permeability transition pore (mtPTP). The liver mtPTP is augmented in mitochondria from rats with some types of liver injury(6, 7)
Aim: to analyze the effects of life-span voluntary physical activity against liver mitochondrial dysfunction characterizing pathological conditions leading to liver injury such as obesity and in vivo and in vitro treatments with some types of anti-cancer, anti-retroviral, anti-depressant and anti-inflammatory drugs affecting liver tissue and mitochondrial structure and function, thereby limiting their clinical use by a dose-related toxicity
Experimental setup justification: Several exercise models have been used with excellent positive outcomes on peripheral tissue. The explored exercise models include endurance training and life-span voluntary running on free wheels, which have demonstrated promising results in tissue protection against deleterious conditions. The last regimen will therefore be considered in this project as well as in vivo models of hepatic injury resulting from the conditions of obesity and from the treatment with drugs that induce liver tissue and mitochondrial injury and also in vitro mitochondrial toxicity with pharmacological agents
Repercussions of the work and hypothesis: With the present project, an important contribution to understand the mitochondrial mechanisms associated with the possible role of exercise in the prevention of liver toxicity characterizing obesity, anti-inflammatory, anti-depressive or anti-cancer therapies by will be provided. Depending on the data obtained, a conclusion may be reached that an active life-style reduced hepatic damage, mitochondrial dysfunction, and apoptotic cell death and thus should likely be advised in patients with liver injury or patients clinically assigned to consume pharmacological drugs, which the main side-effect is the hepatotoxicity
Experimental Approach: For in vivo studies, sets of rats will be assigned into the following groups: Sedentary, sedentary diseased (Zucker fatty or wild type treated with drug-induced liver injury), 32wks free wheel life-long |