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- Soy consumption during menopause. [Journal Article]
- Facts Views Vis Obgyn 2012; 4(1):30-7.
In developed countries, the life expectancy of women is currently extending more than 30 years beyond the age of menopause. The menopausal transition is often associated with complaints. The conflicting results on the effectivity of phytoestrogens to alleviate menopausal symptoms. This discrepancy in treatment effect may be due to the large interindividual variation in isoflavone bioavailability in general and equol production in particular. Equol, a microbial metabolite of daidzein, has been hypothesized as a clue to the effectiveness of soy and its isoflavones, but only about 30-50% of the population harbor an intestinal microbial ecosystem supporting the conversion of daidzein into equol. There is much concern on breast cancer, since this incidence of this disease increases with age. There is indication that soy phytoestrogens may decrease this breast cancer incidence. In order to evaluate the estrogenic potential of these exposure levels, we studied the isoflavone-derived E2α- and E2β-equivalents (i.e. 17β-estradiol (E2)-equivalents towards ERα and ERβ, respectively) in human breast tissue. Total isoflavones showed a breast adipose/glandular tissue distribution of 40/60 and their derived E2β-equivalents exceeded on average 21 ± 4 and 40 ± 10 times the endogenous E2 concentrations in corresponding adipose and glandular biopsies, respectively, whereas the E2α/E2 ratios were 0.4 ± 0.1 and 0.8 ± 0.2 in adipose and glandular breast tissue, respectively. These calculations suggest that, at least in this case, soy consumption could elicit partial ERβ agonistic effects in human breast tissue. We are currently characterizing the differential activation of estrogen-responsive genes between dietary isoflavones, the chemopreventive selective ER modulators tamoxifen and raloxifene and exogenous estrogens in a controlled dietary intervention trial that integrates data on the exposure to estrogenically active compounds, expression of isoflavone and estrogen target genes, and epigenetic events. During the menopause, there is a close relation between the drop in serum estrogen and negative metabolic changes such as the increase in bone resorption and negative change in the serum lipid profile. Randomized controlled trials measuring bone turnover markers in menopausal women revealed that soy isoflavone supplements significantly but moderately decrease the bone resorption marker urinary deoxypyridinoline without significant effects on the bone formation markers serum bone alkaline phosphatase and osteocalcin.
- Epithelial-to-mesenchymal transition and estrogen receptor α mediated epithelial dedifferentiation mark the development of benign prostatic hyperplasia. [JOURNAL ARTICLE]
- Prostate 2014 Apr 22.
Epithelial-to-mesenchymal transition (EMT) has been reported involved in the pathogenesis of fibrotic disorders and associated with stemness characteristics. Recent studies demonstrated that human benign prostatic hyperplasia (BPH) development involves accumulation of mesenchymal-like cells derived from the prostatic epithelium. However, the inductive factors of EMT in the adult prostate and the cause-and-effect relationship between EMT and stemness characteristics are not yet resolved.EMT expression patterns were immunohistochemically identified in the human epithelia of normal/BPH prostate tissue and in a rat BPH model induced by estrogen/androgen (E2/T, ratio 1:100) alone or in the presence of the ER antagonist raloxifene. Gene expression profiles were analyzed in micro-dissected prostatic epithelia of rat stimulated by E2/T for 3 days.Two main morphological features both accompanied with EMT were observed in the epithelia of human BPH. Luminal cells undergoing EMT dedifferentiated from a cytokeratin (CK) CK18(+) /CK8(+) /CK19(+) to a CK18(-) /CK8(+) /CK19(-) phenotype and CK14 expression increased in basal epithelial cells. ERα expression was closely related to these dedifferentiated cells and the expression of EMT markers. A similar pattern of EMT events was observed in the E2/T induced rat model of BPH in comparison to the prostates of untreated rats, which could be prevented by raloxifene.Epithelial and mesenchymal phenotype switching is an important mechanism in the etiology of BPH. ERα mediated enhanced estrogenic effect is a crucial inductive factor of epithelial dedifferentiation giving rise to activation of an EMT program in prostate epithelium. Prostate © 2014 Wiley Periodicals, Inc.
- Whole body vibration during fracture healing intensifies the effects of estradiol and raloxifene in estrogen-deficient rats. [JOURNAL ARTICLE]
- Bone 2014 Apr 13.
Current osteoporosis therapies aim to delay bone destruction and have additional anabolic effects. While they have demonstrated some positive effects on bone healing, more progress is needed in this area. This study used the well-known osteoporotic agents estrogen (E) and raloxifene (R) in conjunction with biomechanical whole body vibration (WBV) at a frequency of 70Hz twice daily for six weeks to stimulate bone healing. Eighty-four 3-month old female Sprague-Dawley rats (12 per group) were bilaterally ovariectomized to develop osteopenia within eight weeks. Osteotomy of the metaphyseal tibiae was performed and fracture healing was then studied using mechanical tests, histomorphometry, computed tomography (μCT), and gene analysis. We found that E and R improved the structure of osteopenic bones as did WBV alone, although significant levels for WBV were seldom reached. Combination treatments significantly enhanced stiffness (R+WBV; p<0.05), endosteal bone (R+WBV; p<0.01), and trabecular density (E+WBV; p<0.05, R+WBV; p<0.05). In addition, the expression of osteoclast-specific Trap was significantly reduced after treatment with E, R, or their combination with WBV (p<0.01). The effects were additive and not inhibitory, leading us to conclude that the combined applications of WBV with E or R may improve the healing of osteopenic bones. The therapies studied are all currently approved for human use, suggesting ready applicability to clinical practice. To better understand the effects of WBV on osteopenic bones, the ideal vibration regime will require further study.
- Raloxifene activates G protein-coupled estrogen receptor 1/Akt signaling to protect dopamine neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice. [JOURNAL ARTICLE]
- Neurobiol Aging 2014 Mar 20.
Raloxifene, used in the clinic, is reported to protect brain dopaminergic neurons in mice. Raloxifene was shown to mediate an effect through the G protein-coupled estrogen receptor 1 (GPER1). We investigated if raloxifene neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated male mice is mediated through GPER1 by using its antagonist G15. Striatal concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid to dopamine ratio as well as dopamine transporter and vesicular monoamine transporter 2 showed that raloxifene neuroprotection of dopaminergic neurons was blocked by G15. Protection by raloxifene was accompanied by activation of striatal Akt signaling (but not ERK1/2 signaling) and increased Bcl-2 and brain-derived neurotrophic factor levels; these effects were abolished by coadministration with G15. The effect of raloxifene was not mediated through increased levels of 17β-estradiol. MPTP mice had decreased plasma testosterone, dihydrotestosterone, and 3β-diol levels; this was prevented in raloxifene-treated MPTP mice. Our results suggest that raloxifene acted through GPER1 to mediate Akt activation, increase Bcl-2 and brain-derived neurotrophic factor levels, and protection of dopaminergic neurons and plasma androgens.
- Formulation, development and optimization of raloxifene-loaded chitosan nanoparticles for treatment of osteoporosis. [JOURNAL ARTICLE]
- Drug Deliv 2014 Apr 14.
Abstract Context: Osteoporosis (OP) is a disease of skeletal system and is associated with fragility fracture at the hip, spine and wrist. Various drugs have been used to treat OP. One of them is raloxifene hydrochloride (RLX), a second-generation selective estrogen receptor modulator (SERM) approved by the USFDA. RLX possesses only 2% absolute bioavailability (BA) by oral route due to its extensive first-pass metabolism. Objective: The purpose of the current research work was to develop and evaluate RLX-loaded chitosan nanoparticles (CS-NPs) for treatment of OP with enhanced BA. Materials and methods: The RLX-loaded CS-NPs were prepared by gelation of CS with tripolyphosphate (TPP) by ionic cross-linking. Formulation was optimized and in vitro drug release and in vivo study were performed. Results and discussions: CS-NPs were formed by the ionic gelation method. The particle size, entrapment efficiency and loading efficiency varied from 216.65 to 1890 nm, 32.84 to 97.78% and 23.89 to 62.46%, respectively. Release kinetics showed diffusion-controlled and Fickian release pattern. In vivo study indicated higher plasma drug concentration with NPs administered intranasally as compared to drug suspension administered through oral route (p < 0.05). A significantly higher drug concentration in plasma was achieved in 10 min after nasal administration with respect to oral administration. Conclusion: The results suggest that RLX-loaded CS-NPs have better BA and would be a promising approach for intranasal (i.n.) delivery of RLX for the treatment of OP.
- Effects of sequential osteoporosis treatments on trabecular bone in adult rats with low bone mass. [JOURNAL ARTICLE]
- Osteoporos Int 2014 Apr 11.
We used an osteopenic adult ovariectomized (OVX) rat model to evaluate various sequential treatments for osteoporosis, using FDA-approved agents with complementary tissue-level mechanisms of action. Sequential treatment for 3 months each with alendronate (Aln), followed by PTH, followed by resumption of Aln, created the highest trabecular bone mass, best microarchitecture, and highest bone strength.Individual agents used to treat human osteoporosis reduce fracture risk by ∼50-60 %. As agents that act with complementary mechanisms are available, sequential therapies that mix antiresorptive and anabolic agents could improve fracture risk reduction, when compared with monotherapies.We evaluated bone mass, bone microarchitecture, and bone strength in adult OVX, osteopenic rats, during different sequences of vehicle (Veh), parathyroid hormone (PTH), Aln, or raloxifene (Ral) in three 90- day treatment periods, over 9 months. Differences among groups were evaluated. The interrelationships of bone mass and microarchitecture endpoints and their relationship to bone strength were studied.Estrogen deficiency caused bone loss. OVX rats treated with Aln monotherapy had significantly better bone mass, microarchitecture, and bone strength than untreated OVX rats. Rats treated with an Aln drug holiday had bone mass and microarchitecture similar to the Aln monotherapy group but with significantly lower bone strength. PTH-treated rats had markedly higher bone endpoints, but all were lost after PTH withdrawal without follow-up treatment. Rats treated with PTH followed by Aln had better bone endpoints than those treated with Aln monotherapy, PTH monotherapy, or an Aln holiday. Rats treated initially with Aln or Ral, then switched to PTH, also had better bone endpoints, than monotherapy treatment. Rats treated with Aln, then PTH, and returned to Aln had the highest values for all endpoints.Our data indicate that antiresorptive therapy can be coupled with an anabolic agent, to produce and maintain better bone mass, microarchitecture, and strength than can be achieved with any monotherapy.
- Raloxifene Suppresses Experimental Autoimmune Encephalomyelitis and NF-κB-Dependent CCL20 Expression in Reactive Astrocytes. [Journal Article]
- PLoS One 2014; 9(4):e94320.
Recent clinical data have led to the consideration of sexual steroids as new potential therapeutic tools for multiple sclerosis. Selective estrogen receptor modulators can exhibit neuroprotective effects like estrogen, with fewer systemic estrogen side effects than estrogen, offering a more promising therapeutic modality for multiple sclerosis. The important role of astrocytes in a proinflammatory effect mediated by CCL20 signaling on inflammatory cells has been documented. Their potential contribution to selective estrogen receptor modulator-mediated protection is still unknown. Using a mouse model of chronic neuroinflammation, we report that raloxifene, a selective estrogen receptor modulator, alleviated experimental autoimmune encephalomyelitis-an animal model of multiple sclerosis-and decreased astrocytic production of CCL20. Enzyme-linked immunosorbent assay, immunohistochemistry imaging and transwell migration assays revealed that reactive astrocytes express CCL20, which promotes Th17 cell migration. In cultured rodent astrocytes, raloxifene inhibited IL-1β-induced CCL20 expression and chemotaxis ability for Th17 migration, whereas the estrogen receptor antagonist ICI 182,780 blocked this effect. Western blotting further indicated that raloxifene suppresses IL-1β-induced NF-κB activation (phosphorylation of p65) and translocation but does not affect phosphorylation of IκB. In conclusion, these data demonstrate that raloxifene provides robust neuroprotection against experimental autoimmune encephalomyelitis, partially via an inhibitory action on CCL20 expression and NF-κB pathways in reactive astrocytes. Our results contribute to a better understanding of the critical roles of raloxifene in treating experimental autoimmune encephalomyelitis and uncover reactive astrocytes as a new target for the inhibitory action of estrogen receptors on chemokine CCL20 expression.
- Poly (ε-caprolactone) nanocapsules for oral delivery of raloxifene: process optimization by hybrid design approach, in vitro and in vivo evaluation. [JOURNAL ARTICLE]
- J Microencapsul 2014 Apr 3.
Abstract Raloxifene HCl (RLX), a selective oestrogen receptor modulator, has low oral bioavailability (<2%) in humans due to its poor aqueous solubility and extensive first-pass metabolism in gut. In this study, we optimised the method of preparation for poly (ε-caprolactone) (PCL) based nanocapsules of RLX by double emulsion method (w/o/w). A hybrid design approach, Plackett-Burman design followed by rotatable central composite design, was used to arrive at the optimised formulation. The optimised formulation was subjected to in vitro and in vivo evaluation. RLX loaded nanocapsules were spherical in shape with particle size less than 200 nm and high encapsulation efficiency (>80%). RLX-loaded nanocapsules showed 2.1-fold increase in oral bioavailability compared to free RLX. IV pharmacokinetic studies indicated that RLX loaded into nanocapsule had significantly low clearance in comparison with free RLX. Designed nanocapsules showed promise as delivery systems to enhance oral bioavailability and in reducing clearance of raloxifene.
- Stable Reporter Gene Assay Based on Gal4-Vitamin D Receptor β Fusion Proteins in Medaka (Oryzias latipes), and Its Transactivational Properties. [Journal Article]
- Zoolog Sci 2014 Apr; 31(4):195-201.
The transactivational property of natural and synthetic chemicals via medaka vitamin D receptor β subtype (VDRβ) was investigated after the development of a stable cell line expressing a Gal4-VDRβ fusion protein for reporter gene assay. Members of vitamin D class, including 1α, 25- dihydroxyvitamin D3 (1,25VD3) were specifically detected as agonists in our system. Although other steroids and chemicals used in the present estimation induced no agonistic response, 10 compounds displayed antagonistic or synergistic activity. Spironolactone, which is an antagonist of corticoid receptors in mammals, competitively inhibited the transactivity of 1,25VD3 by over 80% in a dosedependent manner. Mifepristone and cyproterone acetate were also detected as antagonists, but they significantly acted only at 10µ. Pregnenolone and raloxifene dose-dependently enhanced the activity of 1,25VD3 at EC50 to the maximum level. Diethylstilbestrol, 17α-ethynylestradiol, genistein, and stanozolol were also synergists, but their potency was low. Interestingly, dibutyltin dichloride, which is used as a stabilizer in the production of polyvinyl chloride plastics, produced greater response than maximum effect of 1,25VD3 although the concentration-response curve was not typically sigmoidal. In the present study, we successfully developed a stable reporter gene assay, which allows assessment of the vitamin D-like chemicals toward the medaka VDRβ.
- A novel role for raloxifene nanomicelles in management of castrate resistant prostate cancer. [Journal Article]
- Biomed Res Int 2014.:323594.
Of patients with castrate resistant prostate cancer (CRPC), less than 25-33% survive more than five years. Recent studies have implicated estrogen, acting either alone or synergistically with androgens in the development of castrate resistant prostate cancer. Several in vitro and in vivo studies, as well as a limited number of clinical trials, have highlighted the potential of selective estrogen receptor modulators, such as raloxifene (Ral) for the treatment of castrate resistant prostate cancer. However, the poor oral bioavailability and metabolism of selective estrogen receptor modulators limit their efficiency in clinical application. To overcome these limitations, we have used styrene co-maleic acid (SMA) micelle to encapsulate raloxifene. Compared to free drug, SMA-Ral micelles had 132 and 140% higher cytotoxicity against PC3 and DU 145 prostate cell lines, respectively. SMA-Ral effectively inhibits cell cycle progression, increases apoptosis, and alters the integrity of tumor spheroid models. In addition, the micellar system induced changes in expression and localization of estrogen receptors, epidermal growth factor receptor (EGFR), and downstream effectors associated with cell proliferation and survival. Finally, SMA-Ral treatment decreased migration and invasion of castrate resistant prostate cancer cell lines. In conclusion, SMA-Ral micelles can potentially benefit new strategies for clinical management of castrate resistant prostate cancer.