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Ospemifene for the treatment of dyspareunia associated with vulvar and vaginal atrophy: potential benefits in bone and breast. - International journal of women's health
Ospemifene is a selective estrogen receptor modulator (SERM), or estrogen receptor agonist/antagonist, that was recently approved by the US Food and Drug Administration for the treatment of dyspareunia associated with vulvar and vaginal atrophy, a chronic condition that affects up to 60% of postmenopausal women. Ospemifene is the first and only nonestrogen compound approved for this indication. Compared with other approved SERMs, such as tamoxifen, toremifene, bazedoxifene, and raloxifene, the estrogen-like effects of ospemifene in the vaginal epithelium are unique. This review first discusses the rationale for developing ospemifene, including its mechanism of action, and then focuses on the clinical development of ospemifene for the treatment of dyspareunia associated with vulvar and vaginal atrophy. Included are discussions of the effects of ospemifene on the endometrium, serum lipids, coagulation markers, bone, and breast cancer. In conclusion, ospemifene is a SERM with a unique estrogen agonist/antagonist tissue profile that was recently approved in the US for the treatment of dyspareunia associated with vulvar and vaginal atrophy in postmenopausal women. Ospemifene warrants further clinical investigation for the treatment and prevention of osteoporosis and breast cancer.
Nitrogen monoxide inhibits haem synthesis in mouse reticulocytes. - The Biochemical journal
AI (anaemia of inflammation) often manifests in patients with chronic immune activation due to cancer, chronic infections, autoimmune disorders, rheumatoid arthritis and other diseases. The pathogenesis of AI is complex and involves cytokine-mediated inhibition of erythropoiesis, insufficient erythropoietin production and diminished sensitivity of erythroid progenitors to this hormone, and retention of iron in haemoglobin-processing macrophages. NO (nitric oxide) is a gaseous molecule produced by activated macrophages that has been identified as having numerous effects on iron metabolism. In the present study, we explore the possibility that NO affects iron metabolism in reticulocytes and our results suggest that NO may also contribute to AI. We treated reticulocytes with the NO donor SNP (sodium nitroprusside). The results indicate that NO inhibits haem synthesis dramatically and rapidly at the level of erythroid-specific 5-aminolaevulinic acid synthase 2, which catalyses the first step of haem synthesis in erythroid cells. We also show that NO leads to the inhibition of iron uptake via the Tf (transferrin)-Tf receptor pathway. In addition, NO also causes an increase in eIF2Î± (eukaryotic initiation factor 2Î±) phosphorylation levels and decreases globin translation. The profound impairment of haem synthesis, iron uptake and globin translation in reticulocytes by NO raises the possibility that this gas may also contribute to AI.
Ospemifene, vulvovaginal atrophy, and breast cancer. - Maturitas
The incidence and severity of vulvovaginal atrophy (VVA) in postmenopausal breast cancer patients has a significant impact on quality of life. While the etiology of VVA is primarily related to low estrogen levels seen in menopause, women with breast cancer have an added risk of VVA induced by a combination of chemotherapy, hormonal therapy, and menopause. Ospemifene is a new, non-hormonal selective estrogen receptor modulator (SERM) triphenylethylene derivative that is effective in treating VVA in postmenopausal women. Although other SERMs have antagonistic effects on the vagina, ospemifene exerts an estrogen-like effect on the vaginal epithelium. This review will focus on data demonstrating the antiestrogenic activity of ospemifene in several unique breast cancer animal models, and the implications for utilizing ospemifene in patients with breast cancer suffering from VVA. Additional research addressing the expanded use of ospemifene in breast cancer patients is also warranted.Published by Elsevier Ireland Ltd.
Absolute lymphocyte count in the emergency department predicts a low CD4 count in admitted HIV-positive patients. - Academic emergency medicine : official journal of the Society for Academic Emergency Medicine
This study sought to determine if the automated absolute lymphocyte count (ALC) predicts a "low" (<200 Ã— 10(6) cells/Î¼L) CD4 count in patients with known human immunodeficiency virus (HIV+) who are admitted to the hospital from the emergency department (ED).This retrospective cohort study over an 8-year period was performed in a single, urban academic tertiary care hospital with over 85,000 annual ED visits. Included were patients who were known to be HIV+ and admitted from the ED, who had an ALC measured in the ED and a CD4 count measured within 24 hours of admission. Back-translated means and confidence intervals (CIs) were used to describe CD4 and ALC levels. The primary outcome was to determine the utility of an ALC threshold for predicting a CD4 count of <200 Ã— 10(6) cells/Î¼L by assessing the strength of association between log-transformed ALC and CD4 counts using a Pearson correlation coefficient. In addition, area under the receiver operator curve (AUC) and a decision plot analysis were used to calculate the sensitivity, specificity, and the positive and negative likelihood ratios to identify prespecified optimal clinical thresholds of a likelihood ratio of <0.1 and >10.â€‚ A total of 866 patients (mean age 42 years, 40% female) met inclusion criteria. The transformed means (95% CIs) for CD4 and ALC were 34 (31-38) and 654 (618-691), respectively. There was a significant relationship between the two measures, r = 0.74 (95% CI = 0.71 to 0.77, p < 0.01). The AUC was 0.92 (95% CI = 0.90 to 0.94, p < 0.001). An ALC of <1700 Ã— 10(6) cells/Î¼L had a sensitivity of 95% (95% CI = 93% to 96%), specificity of 52% (95% CI = 43% to 62%), and negative likelihood ratio of 0.09 (95% CI = 0.05 to 0.2) for a CD4 count of <200 Ã— 10(6) cells/Î¼L. An ALC of <950 Ã— 10(6) cells/Î¼L has a sensitivity of 76% (95% CI = 73% to 79%), specificity of 93% (95% CI = 87% to 96%), and positive likelihood ratio of 10.1 (95% CI = 8.2 to 14) for a CD4 count of <200 Ã— 10(6) cells/Î¼L.â€‚ Absolute lymphocyte count was predictive of a CD4 count of <200 Ã— 10(6) cells/Î¼L in HIV+ patients who present to the ED, necessitating hospital admission. A CD4 count of <200 Ã— 10(6) cells/Î¼L is very likely if the ED ALC is <950 Ã— 10(6) cells/Î¼L and less likely if the ALC is >1,700 Ã— 10(6) cells/Î¼L. Depending on pretest probability, clinical use of this relationship may help emergency physicians predict the likelihood of susceptibility to opportunistic infections and may help identify patients who should receive definitive CD4 testing.Â© 2011 by the Society for Academic Emergency Medicine.
Lysosomal proteolysis is the primary degradation pathway for cytosolic ferritin and cytosolic ferritin degradation is necessary for iron exit. - Antioxidants & redox signaling
Cytosolic ferritins sequester and store iron, consequently protecting cells against iron-mediated free radical damage. However, the mechanisms of iron exit from the ferritin cage and reutilization are largely unknown. In a previous study, we found that mitochondrial ferritin (MtFt) expression led to a decrease in cytosolic ferritin. Here we showed that treatment with inhibitors of lysosomal proteases largely blocked cytosolic ferritin loss in both MtFt-expressing and wild-type cells. Moreover, cytosolic ferritin in cells treated with inhibitors of lysosomal proteases was found to store more iron than did cytosolic ferritins in untreated cells. The prevention of cytosolic ferritin degradation in MtFt-expressing cells significantly blocked iron mobilization from the protein cage induced by MtFt expression. These studies also showed that blockage of cytosolic ferritin loss by leupeptin resulted in decreased cytosolic ferritin synthesis and prolonged cytosolic ferritin stability, potentially resulting in diminished iron availability. Lastly, we found that proteasomes were responsible for cytosolic ferritin degradation in cells pretreated with ferric ammonium citrate. Thus, the current studies suggest that cytosolic ferritin degradation precedes the release of iron in MtFt-expressing cells; that MtFt-induced cytosolic ferritin decrease is partially preventable by lysosomal protease inhibitors; and that both lysosomal and proteasomal pathways may be involved in cytosolic ferritin degradation.
Both Nramp1 and DMT1 are necessary for efficient macrophage iron recycling. - Experimental hematology
Divalent metal transporter 1 (DMT1) and natural resistance-associated macrophage protein 1 (Nramp1) are iron transporters that localize, respectively, to the early and late endosomal compartments. DMT1 is ubiquitously expressed, while Nramp1 is found only within macrophages and neutrophils. Our previous studies have identified a role for Nramp1 during macrophage erythrophagocytosis; however, little is known about the function of DMT1 during this process.Wild-type RAW264.7 macrophages (RAW), and those stably transfected with Nramp1 (RAW/Nramp1) were treated with either DMT1-small interfering RNA, or with ebselen, a selective inhibitor of DMT1.Although macrophages lacking either functional DMT1 or Nramp1 experienced a moderate reduction in iron recycling efficiency, the ability of macrophages lacking both functional DMT1 and Nramp1 to recycle hemoglobin-derived iron was severely compromised. Compared to macrophages singly deficient in either DMT1 or Nramp1 transport ability, macrophages where DMT1 and Nramp1 were both compromised exhibited an abrogated increase in labile iron pool content, released less iron, and experienced diminished upregulation of ferroportin and heme-oxygenase 1 levels following erythrophagocytosis.These results suggest that although the loss of either Nramp1 or DMT1 transport ability results in minor impairment after erythrophagocytosis, the simultaneous loss of both Nramp1 and DMT1 iron transport activity is detrimental to the iron recycling capacity of the macrophage.2010 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
Hepcidin, the hormone of iron metabolism, is bound specifically to alpha-2-macroglobulin in blood. - Blood
Hepcidin is a major regulator of iron metabolism. Hepcidin-based therapeutics/diagnostics could play roles in hematology in the future, and thus, hepcidin transport is crucial to understand. In this study, we identify alpha2-macroglobulin (alpha2-M) as the specific hepcidin-binding molecule in blood. Interaction of 125I-hepcidin with alpha2-M was identified using fractionation of plasma proteins followed by native gradient polyacrylamide gel electrophoresis and mass spectrometry. Hepcidin binding to nonactivated alpha2-M displays high affinity (Kd 177 +/- 27 nM), whereas hepcidin binding to albumin was nonspecific and displayed nonsaturable kinetics. Surprisingly, the interaction of hepcidin with activated alpha2-M exhibited a classical sigmoidal binding curve demonstrating cooperative binding of 4 high-affinity (Kd 0.3 microM) hepcidin-binding sites. This property probably enables efficient sequestration of hepcidin and its subsequent release or inactivation that may be important for its effector functions. Because alpha2-M rapidly targets ligands to cells via receptor-mediated endocytosis, the binding of hepcidin to alpha2-M may influence its functions. In fact, the alpha2-M-hepcidin complex decreased ferroportin expression in J774 cells more effectively than hepcidin alone. The demonstration that alpha2-M is the hepcidin transporter could lead to better understanding of hepcidin physiology, methods for its sensitive measurement and the development of novel drugs for the treatment of iron-related diseases.
Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo. - Proceedings of the National Academy of Sciences of the United States of America
Natural resistance-associated macrophage protein 1 (Nramp1) is a divalent metal transporter expressed exclusively in phagocytic cells. We hypothesized that macrophage Nramp1 may participate in the recycling of iron acquired from phagocytosed senescent erythrocytes. To evaluate the role of Nramp1 in vivo, the iron parameters of WT and KO mice were analyzed after acute and chronic induction of hemolytic anemia. We found that untreated KO mice exhibited greater serum transferrin saturation and splenic iron content with higher duodenal ferroportin (Fpn) and divalent metal transporter 1 (DMT1) expression. Furthermore, hepatocyte iron content and hepcidin mRNA levels were dramatically lower in KO mice, indicating that hepcidin levels can be regulated by low-hepatocyte iron stores despite increased transferrin saturation. After acute treatment with the hemolytic agent phenylhydrazine (Phz), KO mice experienced a significant decrease in transferrin saturation and hematocrit, whereas WT mice were relatively unaffected. After a month-long Phz regimen, KO mice retained markedly increased quantities of iron within the liver and spleen and exhibited more pronounced splenomegaly and reticulocytosis than WT mice. After injection of (59)Fe-labeled heat-damaged reticulocytes, KO animals accumulated erythrophagocytosed (59)Fe within their liver and spleen, whereas WT animals efficiently recycled phagocytosed (59)Fe to the marrow and erythrocytes. These data imply that without Nramp1, iron accumulates within the liver and spleen during erythrophagocytosis and hemolytic anemia, supporting our hypothesis that Nramp1 promotes efficient hemoglobin iron recycling in macrophages. Our observations suggest that mutations in Nramp1 could result in a novel form of human hereditary iron overload.
Overexpression of mitochondrial ferritin sensitizes cells to oxidative stress via an iron-mediated mechanism. - Antioxidants & redox signaling
Mitochondrial ferritin (MtFt) is a newly identified H-ferritin-like protein expressed only in mitochondria. Previous studies have shown that its overexpression markedly affects intracellular iron homeostasis and rescues defects caused by frataxin deficiency. To assess how MtFt exerts its function under oxidative stress conditions, MtFt overexpressing cells were treated with tert-butyl-hydroperoxide (tBHP), and the effects of MtFt expression on cell survival and iron homeostasis were examined. We found that MtFt expression was associated with decreased mitochondrial metabolic activity and reduced glutathione levels as well as a concomitant increase in reactive oxygen species levels and apoptosis. Moreover, mechanistic studies demonstrated that tBHP treatment led to a prolonged decrease in cytosolic ferritins levels in MtFt-expressing cells, while ferritin levels recovered to basal levels in control counterparts. tBHP treatment also resulted in elevated transferrin receptors, followed by more iron acquisition in MtFt expressing cells. The high molecular weight desferrioxamine, targeting to lysosomes, as well as the hydrophobic iron chelator salicylaldehyde isonicotinoyl hydrazone significantly attenuated tBHP-induced cell damage. In conclusion, the current study indicates that both the newly acquired iron from the extracellular environment and internal iron redistribution from ferritin degradation may be responsible for the increased sensitivity to oxidative stress in MtFt-expressing cells.
Nramp1 equips macrophages for efficient iron recycling. - Experimental hematology
Natural resistance-associated macrophage protein 1 (Nramp1) is a divalent metal transporter expressed exclusively in phagocytic cells, such as macrophages and neutrophils. As macrophages are responsible for the engulfment and clearance of senescent red blood cells (RBC), we hypothesize that Nramp1 may participate in the recycling of iron acquired through phagocytosis.To test this hypothesis, we examined the contribution of Nramp1 expression to iron metabolism in macrophages loaded with iron via either hemin or opsonized RBC.Western blot analysis indicated that Nramp1 protein levels increased with hemin, opsonized erythrocytes, or erythropoietin treatment. The pool of chelatable iron was also found to transiently increase following iron-loading with hemin or opsonized RBCs, with a greater increase observed in macrophages expressing Nramp1. Overexpression of Nramp1 was also found to result in a greater cellular release of (59)Fe following phagocytosis of (59)Fe-labeled reticulocytes. Expression of Nramp1 was associated with a twofold increase in heme oxygenase-1 (HO-1) levels in macrophages undergoing erythrophagocytosis. Nramp1-expressing macrophages were also found to phagocytose nearly twice as many RBC than their Nramp1-deficient counterparts.The rapid and strong induction of Nramp1 during erythrophagocytosis, combined with its positive effects on (59)Fe-release, HO-1 induction and phagocytic ability, suggest that Nramp1 has a role in the recycling of hemoglobin-derived iron by macrophages.
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