RESUMO
A major contributor to dementia seen in aging is Alzheimer's disease (AD). Amyloid beta (Aß), a main component of senile plaques (SPs) in AD, induces neuronal death through damage to cellular organelles and structures, caused by oxidation of important molecules such as proteins by reactive oxygen species (ROS). Hyperphosphorylation and accumulation of the protein tau in the microtubules within the brain also promote ROS production. Methionine, a residue of proteins, is particularly sensitive to oxidation by ROS. One of the enzyme systems that reverses the oxidative damage in mammalian cells is the enzyme system known as Methionine Sulfoxide Reductases (MSRs). The components of the MSR system, namely MSRA and MSRB, reduce oxidized forms of methionine (Met-(o)) in proteins back to methionine (Met). Furthermore, the MSRs scavenge ROS by allowing methionine residues in proteins to utilize their antioxidant properties. This review aims to improve the understanding of the role of the MSR system of enzymes in reducing cellular oxidative damage and AD pathogenesis, which may contribute to effective therapeutic approaches for AD by targeting the MSR system.
RESUMO
Unlike the mammalian brain, Drosophila melanogaster can tolerate several hours of hypoxia without any tissue injury by entering a protective coma known as spreading depression. However, when oxygen is reintroduced, there is an increased production of reactive oxygen species (ROS) that causes oxidative damage. Methionine sulfoxide reductase (MSR) acts to restore functionality to oxidized methionine residues. In the present study, we have characterized in vivo effects of MSR deficiency on hypoxia tolerance throughout the lifespan of Drosophila. Flies subjected to sudden hypoxia that lacked MSR activity exhibited a longer recovery time and a reduced ability to survive hypoxic/re-oxygenation stress as they approached senescence. However, when hypoxia was induced slowly, MSR deficient flies recovered significantly quicker throughout their entire adult lifespan. In addition, the wildtype and MSR deficient flies had nearly 100% survival rates throughout their lifespan. Neuroprotective signaling mediated by decreased apoptotic pathway activation, as well as gene reprogramming and metabolic downregulation are possible reasons for why MSR deficient flies have faster recovery time and a higher survival rate upon slow induction of spreading depression. Our data are the first to suggest important roles of MSR and longevity pathways in hypoxia tolerance exhibited by Drosophila.
RESUMO
BACKGROUND: Actinic keratoses (AKs) are a precancerous condition of the skin that have the potential to become squamous cell cancer (SCC). Sulindac is a Food and Drug Administration (FDA)-approved nonsteroidal anti-inflammatory drug (NSAID) that has been shown to have clinically significant anticancer effects. Malignant cells may have a different response to oxidative stress than normal cells. OBJECTIVE: To establish a role of increased reactive oxygen species (ROS) in the mechanism of cancer killing by sulindac in the presence of an oxidizing agent. To assess the tolerability and efficacy of the combination of gels containing sulindac and hydrogen peroxide in the treatment of patients with AKs. METHODS: Cell culture studies were performed using a skin SCC cell line and normal human epidermal keratinocytes. After treatment with sulindac and an oxidizing agent, cell viability, and intracellular ROS levels were measured. An open-label clinical trial was performed using sulindac and hydrogen peroxide gels daily for 3 weeks on AKs involving the upper extremities. RESULTS: In SCC cells, a combination of sulindac and an oxidizing agent lead to 400 to 500% increases in intracellular ROS, which resulted in significant cell death. In sharp contrast, normal keratinocytes did not show increases in ROS levels and were not killed. A clinical trial using the combination of sulindac and hydrogen peroxide therapy in 5 patients with AKs revealed that 60% of the treated AKs responded and 50% showed no residual AK on histopathology specimens after skin biopsy. LIMITATIONS: The small number of patients and the lack of a placebo group. CONCLUSION: Increased levels of ROS appear to be important in the selective killing of cancer cells in the presence of sulindac and oxidizing agents. Further studies are necessary to define the role of the combination of sulindac and oxidizing agent therapy in patients with AKs and skin cancer.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antineoplásicos/uso terapêutico , Peróxido de Hidrogênio/uso terapêutico , Ceratose Actínica/tratamento farmacológico , Oxidantes/uso terapêutico , Sulindaco/uso terapêutico , Administração Tópica , Anti-Inflamatórios não Esteroides/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma de Células Escamosas , Linhagem Celular Tumoral , Quimioterapia Combinada , Géis , Humanos , Peróxido de Hidrogênio/administração & dosagem , Oxidantes/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio , Neoplasias Cutâneas , Sulindaco/administração & dosagemRESUMO
The deleterious alteration of protein structure and function due to the oxidation of methionine residues has been studied extensively in age-associated neurodegenerative disorders such as Alzheimer's and Parkinson's Disease. Methionine sulfoxide reductases (MSR) have three well-characterized biological functions. The most commonly studied function is the reduction of oxidized methionine residues back into functional methionine thus, often restoring biological function to proteins. Previous studies have successfully overexpressed and silenced MSR activity in numerous model organisms correlating its activity to longevity and oxidative stress. In the present study, we have characterized in vivo effects of MSR deficiency in Drosophila. Interestingly, we found no significant phenotype in animals lacking either methionine sulfoxide reductase A (MSRA) or methionine sulfoxide reductase B (MSRB). However, Drosophila lacking any known MSR activity exhibited a prolonged larval third instar development and a shortened lifespan. These data suggest an essential role of MSR in key biological processes.
RESUMO
BACKGROUND: Sulindac is an FDA-approved non-steroidal anti-inflammatory drug (NSAID) that affects prostaglandin production by inhibiting cyclooxygenases (COX) 1 and 2. Sulindac has also been of interest for more than decade as a chemopreventive for adenomatous colorectal polyps and colon cancer. PRINCIPAL FINDINGS: Pretreatment of human colon and lung cancer cells with sulindac enhances killing by an oxidizing agent such as tert-butyl hydroperoxide (TBHP) or hydrogen peroxide. This effect does not involve cyclooxygenase (COX) inhibition. However, under the conditions used, there is a significant increase in reactive oxygen species (ROS) within the cancer cells and a loss of mitochondrial membrane potential, suggesting that cell death is due to apoptosis, which was confirmed by Tunel assay. In contrast, this enhanced killing was not observed with normal lung or colon cells. SIGNIFICANCE: These results indicate that normal and cancer cells handle oxidative stress in different ways and sulindac can enhance this difference. The combination of sulindac and an oxidizing agent could have therapeutic value.