Oxidative stress plays an important role in cancer development and treatment. Recent data implicate the tumor suppressor BRCA1 in regulating oxidative stress, but the molecular mechanism and the ...impact in BRCA1-associated tumorigenesis remain unclear. Here, we show that BRCA1 regulates Nrf2-dependent antioxidant signaling by physically interacting with Nrf2 and promoting its stability and activation. BRCA1-deficient mouse primary mammary epithelial cells show low expression of Nrf2-regulated antioxidant enzymes and accumulate reactive oxygen species (ROS) that impair survival in vivo. Increased Nrf2 activation rescues survival and ROS levels in BRCA1-null cells. Interestingly, 53BP1 inactivation, which has been shown to alleviate several defects associated with BRCA1 loss, rescues survival of BRCA1-null cells without restoring ROS levels. We demonstrate that estrogen treatment partially restores Nrf2 levels in the absence of BRCA1. Our data suggest that Nrf2-regulated antioxidant response plays a crucial role in controlling survival downstream of BRCA1 loss. The ability of estrogen to induce Nrf2 posits an involvement of an estrogen-Nrf2 connection in BRCA1 tumor suppression. Lastly, BRCA1-mutated tumors retain a defective antioxidant response that increases the sensitivity to oxidative stress. In conclusion, the role of BRCA1 in regulating Nrf2 activity suggests important implications for both the etiology and treatment of BRCA1-related cancers.
Mutations in the tumor suppressor BRCA1 predispose women to breast and ovarian cancers. The mechanism underlying the tissue-specific nature of BRCA1's tumor suppression is obscure. We previously ...showed that the antioxidant pathway regulated by the transcription factor NRF2 is defective in BRCA1-deficient cells. Reactivation of NRF2 through silencing of its negative regulator KEAP1 permitted the survival of BRCA1-null cells. Here we show that estrogen (E2) increases the expression of NRF2-dependent antioxidant genes in various E2-responsive cell types. Like NRF2 accumulation triggered by oxidative stress, E2-induced NRF2 accumulation depends on phosphatidylinositol 3-kinase–AKT activation. Pretreatment of mammary epithelial cells (MECs) with the phosphatidylinositol 3-kinase inhibitor BKM120 abolishes the capacity of E2 to increase NRF2 protein and transcriptional activity. In vivo the survival defect of BRCA1-deficient MECs is rescued by the rise in E2 levels associated with pregnancy. Furthermore, exogenous E2 administration stimulates the growth of BRCA1-deficient mammary tumors in the fat pads of male mice. Our work elucidates the basis of the tissue specificity of BRCA1-related tumor predisposition, and explains why oophorectomy significantly reduces breast cancer risk and recurrence in women carrying BRCA1 mutations.
Introduction: To assist save endangered species from extinction and to aid in their care, it is crucial to sustaining their reproductive capacity. The fetus's life and growth processes begin at ...conception and proceed in accordance with a biological clock's timing. With today's understanding through cryobiology, observing scientific ethics problems and interfering with the clock's operation by stopping its biological time is possible. Practically, it is accomplished by storing the cell at -196 °C, or the temperature of liquid nitrogen, where all metabolic activity ceases. Since 200 years ago, germ cell preservation has been a common practice. Since then, there have been many improvements, particularly for at-risk women. Since then, significant progress has been achieved, and several freezing techniques are being used to preserve ovarian tissue, follicles, and oocytes in women who are at risk of infertility. Different approaches have different levels of success. Among preservation techniques, vitrification performs better and is used more frequently. The cellular configuration of the mammalian oocyte is intricate. This cell's constituent parts are particularly sensitive to osmosis and variations in temperature. For instance, the alterations to the cell membrane that occur during maturation, in vitro fertilization, and the differential between the permeability of water and cryoprotectants can all be mentioned. Oocyte freezing results in a variety of impairments, including a reduction in the quality and viability of cells after thawing. Recent studies are looking for ways to enhance freezing procedures and raise the caliber of frozen oocytes. The favorable or negative effects of freezing on the oocyte and its potential, or embryo development, are the subject of this review article.
Pressurized metered dose inhalers are commonly used in patients with asthma. However, the need to coordinate inhalation with inhaler actuation means that they are not suitable for use per se. Valved ...holding chamber devices were developed to overcome some of the problems of pressurized metered dose inhalers. Several types of holding chambers of different sizes are available in Iran. This study was designed to compare the effects of 2 commonly used valved holding chambers (Asthm Yar and Dam Yar) in Iran on bioavailability of salbutamol spray and also spirometric parameters in asthmatic patients.
This was a comparative experimental crossover study. Patients with mild to moderate asthma were entered in this study. Lung function was assessed using a portable spirometer (Spirolab, Progetti, Italy). Spirometric parameters of forced expiratory flow (FEF)(50%), FEF(25-75%), peak expiratory flow (PEF), forced expiratory volume in the first second of expiration (FEV(1)), forced vital capacity (FVC), and FEV(1)/FVC were measured. Urinary concentration of salbutamol as an index of pulmonary bioavailability was assayed with high-performance liquid chromatography.
Forty patients (25 women and 15 men) with the mean age of 43.10 ± 12.99 years were studied. Mean ± SD changes of spirometric parameters before and after using Asthm Yar were not significantly different from those of Dam Yar. The relative bioavailability after inhalation with Asthm Yar was significantly higher than after inhalation with Dam Yar (P = 0.002).
Although the results indicate that relative bioavailability to the lung after inhalation with Asthm Yar was significantly higher than after inhalation with Dam Yar, its clinical importance should be tested.
Purpose Pressurized metered dose inhalers are commonly used in patients with asthma. However, the need to coordinate inhalation with inhaler actuation means that they are not suitable for use per se. ...Valved holding chamber devices were developed to overcome some of the problems of pressurized metered dose inhalers. Several types of holding chambers of different sizes are available in Iran. This study was designed to compare the effects of 2 commonly used valved holding chambers (Asthm Yar and Dam Yar) in Iran on bioavailability of salbutamol spray and also spirometric parameters in asthmatic patients. Methods This was a comparative experimental crossover study. Patients with mild to moderate asthma were entered in this study. Lung function was assessed using a portable spirometer (Spirolab, Progetti, Italy). Spirometric parameters of forced expiratory flow (FEF).sub.50% , FEF.sub.25-75% , peak expiratory flow (PEF), forced expiratory volume in the first second of expiration (FEV.sub.1 ), forced vital capacity (FVC), and FEV.sub.1 /FVC were measured. Urinary concentration of salbutamol as an index of pulmonary bioavailability was assayed with high-performance liquid chromatography. Results Forty patients (25 women and 15 men) with the mean age of 43.10 + - 12.99 years were studied. Mean + - SD changes of spirometric parameters before and after using Asthm Yar were not significantly different from those of Dam Yar. The relative bioavailability after inhalation with Asthm Yar was significantly higher than after inhalation with Dam Yar (P = 0.002). Conclusions Although the results indicate that relative bioavailability to the lung after inhalation with Asthm Yar was significantly higher than after inhalation with Dam Yar, its clinical importance should be tested.
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