RESUMO
OBJECTIVE: Vitamin D status is primarily dependent upon sun exposure and dietary sources, however genetic, cultural, and environmental factors can have a modulating role in the measured amount. One under-reported factor is the effect of regular living quarters on the degree of sun exposure. Herein, we assess vitamin D status in the blood of Rhesus monkeys (Macaca mulatta) housed in high amounts of sunlight (corn-cribs), medium sunlight (corrals with shaded areas), and minimal sunlight (quarantine cages). METHODS: Fifty-five male Rhesus monkeys, aged 1 to 31 years were housed in varying amounts of sun exposure at the Caribbean Primate Research Center. Serum was collected and analyzed for 25 OH Vitamin D which is the preferred metabolite for determination of Vitamin D using High Performance Liquid Chromatography (HPLC). RESULTS: 25 OH Vitamin D levels in blood were significantly greater in corn-cribhoused monkeys than in corral or quarantine-housed animals (p > 0.01 and p > 0.001 respectively). Significant differences of serum levels were not found when ages of animals housed in the same environment were compared. CONCLUSION: Monkeys housed in a tropical environment with the greatest amount of exposure to sunlight maintain the highest serum levels of 25 OH vitamin D independent of age. These findings emphasize the importance of documenting the environment in which subjects typically spend their time when Vitamin D results are interpreted.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Abrigo para Animais , Luz Solar , Vitamina D/análogos & derivados , Animais , Região do Caribe , Macaca mulatta , Masculino , Vitamina D/sangueRESUMO
Changes in mitochondrial DNA (mtDNA) integrity have been reported in many cancers; however, the contribution of mtDNA integrity to tumorigenesis is not well understood. We used a transgenic mouse model that is haploinsufficient for the apurinic/apyrimidinic endonuclease 1 (Apex1+/-) gene, which encodes the base excision repair (BER) enzyme APE1, to determine its role in protecting mtDNA from the effects of azoxymethane (AOM), a carcinogen used to induce colorectal cancer. Repair kinetics of AOM-induced mtDNA damage was evaluated using qPCR after a single AOM dose and a significant induction in mtDNA lesions in colonic crypts from both wild-type (WT) and Apex1+/-animals were observed. However, Apex1+/- mice had slower repair kinetics in addition to decreased mtDNA abundance. Tumors were also induced using multiple AOM doses, and both WT and Apex1+/-animals exhibited significant loss in mtDNA abundance. Surprisingly, no major differences in mtDNA lesions were observed in tumors from WT and Apex1+/- animals, whereas a significant increase in nuclear DNA lesions was detected in tumors from Apex1+/- mice. Finally, tumors from Apex1+/- mice displayed an increased proliferative index and histologic abnormalities. Taken together, these results demonstrate that APE1 is important for preventing changes in mtDNA integrity during AOM-induced colorectal cancer.Implications: AOM, a colorectal cancer carcinogen, generates damage to the mitochondrial genome, and the BER enzyme APE1 is required to maintain its integrity. Mol Cancer Res; 15(7); 831-41. ©2017 AACR.
Assuntos
Neoplasias Colorretais/genética , Dano ao DNA/efeitos dos fármacos , DNA Mitocondrial/efeitos dos fármacos , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Animais , Azoximetano/toxicidade , Carcinógenos/toxicidade , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/patologia , Reparo do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Genoma Mitocondrial , Humanos , Camundongos , Camundongos TransgênicosRESUMO
Plasmodium parasites are exposed to endogenous and exogenous oxidative stress during their complex life cycle. To minimize oxidative damage, the parasites use glutathione (GSH) and thioredoxin (Trx) as primary antioxidants. We previously showed that disruption of the Plasmodium berghei gamma-glutamylcysteine synthetase (pbggcs-ko) or the glutathione reductase (pbgr-ko) genes resulted in a significant reduction of GSH in intraerythrocytic stages, and a defect in growth in the pbggcs-ko parasites. In this report, time course experiments of parasite intraerythrocytic development and morphological studies showed a growth delay during the ring to schizont progression. Morphological analysis shows a significant reduction in size (diameter) of trophozoites and schizonts with increased number of cytoplasmic vacuoles in the pbggcs-ko parasites in comparison to the wild type (WT). Furthermore, the pbggcs-ko mutants exhibited an impaired response to oxidative stress and increased levels of nuclear DNA (nDNA) damage. Reduced GSH levels did not result in mitochondrial DNA (mtDNA) damage or protein carbonylations in neither pbggcs-ko nor pbgr-ko parasites. In addition, the pbggcs-ko mutant parasites showed an increase in mRNA expression of genes involved in oxidative stress detoxification and DNA synthesis, suggesting a potential compensatory mechanism to allow for parasite proliferation. These results reveal that low GSH levels affect parasite development through the impairment of oxidative stress reduction systems and damage to the nDNA. Our studies provide new insights into the role of the GSH antioxidant system in the intraerythrocytic development of Plasmodium parasites, with potential translation into novel pharmacological interventions.
Assuntos
Glutamato-Cisteína Ligase/genética , Glutationa Redutase/genética , Glutationa/metabolismo , Malária/parasitologia , Plasmodium berghei/genética , Animais , Antioxidantes/metabolismo , Núcleo Celular/genética , Dano ao DNA/genética , DNA Mitocondrial/genética , Técnicas de Inativação de Genes , Glutationa/deficiência , Estágios do Ciclo de Vida/genética , Malária/tratamento farmacológico , Malária/genética , Estresse Oxidativo/genética , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium berghei/patogenicidade , Tiorredoxinas/genética , Tiorredoxinas/metabolismoRESUMO
Mitochondria-generated reactive oxygen species (ROS) play a crucial role in the pathogenesis of aging and age-associated diseases. In this study, we evaluated the effects of XJB-5-131 (XJB), a mitochondria-targeted ROS and electron scavenger, on cardiac resistance to ischemia-reperfusion (IR)-induced oxidative stress in aged rats. Male adult (5-month old, n=17) and aged (29-month old, n=19) Fischer Brown Norway (F344/BN) rats were randomly assigned to the following groups: adult (A), adult+XJB (AX), aged (O), and aged+XJB (OX). XJB was administered 3 times per week (3mg/kg body weight, IP) for four weeks. At the end of the treatment period, cardiac function was continuously monitored in excised hearts using the Langendorff technique for 30 min, followed by 20 min of global ischemia, and 60-min reperfusion. XJB improved post-ischemic recovery of aged hearts, as evidenced by greater left ventricular developed-pressures and rate-pressure products than the untreated, aged-matched group. The state 3 respiration rates at complexes I, II and IV of mitochondria isolated from XJB-treated aged hearts were 57% (P<0.05), 25% (P<0.05) and 28% (P<0.05), respectively, higher than controls. Ca(2+)-induced swelling, an indicator of permeability transition pore opening, was reduced in the mitochondria of XJB-treated aged rats. In addition, XJB significantly attenuated the H2O2-induced depolarization of the mitochondrial inner membrane as well as the total and mitochondrial ROS levels in cultured cardiomyocytes. This study underlines the importance of mitochondrial ROS in aging-induced cardiac dysfunction and suggests that targeting mitochondrial ROS may be an effective therapeutic approach to protect the aged heart against IR injury.