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K. Harper - One of the best experts on this subject based on the ideXlab platform.
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Effects of arzoxifene on bone, lipid markers, and safety parameters in postmenopausal women with low bone mass
Osteoporosis International, 2010Co-Authors: R. W. Downs, A. M. Moffett, A. Ghosh, S. A. Dowsett, K. HarperAbstract:In this Phase 2 study of postmenopausal women with low bone, arzoxifene (a Selective estrogen receptor Modulator (SERM)) significantly reduced bone turnover marker levels and increased bone mineral density (BMD) versus placebo. Arzoxifene generally had greater effects on bone turnover and BMD than raloxifene, a SERM in current clinical use. Arzoxifene’s safety profile appeared similar to raloxifene. Introduction This 6-month, Phase 2, double-blind, placebo- and raloxifene-controlled study was designed to assess the effects of arzoxifene on bone turnover and overall safety in postmenopausal women with low bone mass. Methods Postmenopausal women ( N = 219; mean age, 59 years) with a T-score between −1 and −2.5 were randomly assigned to daily arzoxifene 5, 10, 20, or 40 mg, raloxifene 60 mg, or placebo. All received daily calcium. Results All arzoxifene doses significantly reduced osteocalcin (primary endpoint), type 1 collagen C-telopeptide, bone specific alkaline phosphatase, and procollagen type I amino-terminal propeptide versus placebo, and increased lumbar spine BMD. Arzoxifene generally had greater effects on bone turnover and BMD than raloxifene. Arzoxifene decreased cholesterol, low-density lipoprotein cholesterol, and fibrinogen versus placebo. Endometrial thickness change with arzoxifene was not significantly different from placebo or raloxifene; no cases of endometrial hyperplasia or adenocarcinoma were observed. Adverse event reporting with arzoxifene was similar to that with raloxifene, as were hot flush and night sweat reporting. Conclusions Arzoxifene suppressed bone turnover and increased BMD. Within the limitations of this study, the endometrial safety profile of arzoxifene appeared similar to that of raloxifene. While no clear dose effect was evident, arzoxifene 20 and 40 mg/day appeared the optimal doses for reducing bone turnover.
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Effect of raloxifene on bone mineral density and biochemical markers of bone turnover in Japanese postmenopausal women with osteoporosis: results from a randomized placebo-controlled trial
Osteoporosis International, 2003Co-Authors: H. Morii, Y. Ohashi, Y. Taketani, M. Fukunaga, T. Nakamura, A. Itabashi, S. Sarkar, K. HarperAbstract:The safety and efficacy of raloxifene, a Selective estrogen receptor Modulator (SERM), has been studied extensively in large, global clinical trials. However, the effect of raloxifene on bone mineral density (BMD) and on biochemical markers of bone turnover in Japanese postmenopausal women with osteoporosis has not been rigorously evaluated. This study was designed to assess the safety and efficacy of raloxifene in Japanese postmenopausal women with osteoporosis following 1 year of therapy. Participants in this multicenter trial were randomly assigned to receive placebo, raloxifene 60 mg/day (RLX60), or raloxifene 120 mg/day (RLX120). Lumbar spine BMD was measured at baseline, 24, 40, and 52 weeks, and biochemical markers of bone turnover were assessed at baseline, 12, 24, and 52 weeks. Serum lipids were assessed at baseline, 12, 24, 40, and 52 weeks, and breast examinations and transvaginal ultrasound of the endometrium were performed at enrollment and 52 weeks. Compared with baseline, women taking RLX60 had significant increases in lumbar spine (L2-L4) BMD at 24 weeks (+3.3%, p
D. D. Thompson - One of the best experts on this subject based on the ideXlab platform.
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Lasofoxifene (CP-336,156), a novel Selective estrogen receptor Modulator, in preclinical studies
Journal of the American Aging Association, 2002Co-Authors: H. Z. Ke, T. A. Brown, D. D. ThompsonAbstract:Estrogen replacement therapy is reported to reduce the incidence of vertebral fractures in postmenopausal women, however, its compliance is limited because of side effects and safety concerns. Estrogen’s side effects on breast and uterine tissues leading to the potential increased risk of uterine and breast cancer limit widespread estrogen usage. Thus, there is a significant medical need for a therapy that protects against postmenopausal bone loss but is free of estrogen’s negative effects on reproductive tissues. Selective estrogen receptor Modulators (SERMs) have been investigated as an alternative to hormone replacement therapy. One such compound, raloxifene, has been approved for the prevention and treatment of osteoporosis. Lasofoxifene (LAS), a new, nonsteroidal, and potent SERM, is an estrogen antagonist or agonist depending on the target tissue. LAS Selectively binds with high affinity to human estrogen receptors. In ovariectomized (OVX) rat studies, LAS prevented the decrease in femoral bone mineral density, tibial and lumbar vertebral trabecular bone mass at an ED_100 of about 60 μg/kg/day. LAS inhibited the activation of trabecular and endocortical bone resorption and bone turnover in tibial metaphyses and diaphyses, and lumbar vertebral body in OVX rats. In addition, LAS decreased total serum cholesterol, inhibited body weight gain and increased soleus muscle weight in OVX rats. Similarly, LAS prevented bone loss induced by orchidectomy or aging in male rats by decreasing bone resorption and bone turnover while it had no effect in the prostate. Further, LAS decreased total serum cholesterol in intact aged male rats or in orchidectomized male rats. Synergestic skeletal effects were found with LAS in combination with bone anabolic agents such as prostaglandin E_2 (PGE_2), parathyroid hormone (PTH) or a growth hormone secretagoue (GHS) in OVX rats. In combination with estrogen, LAS inhibited the uterine stimulating effects of estrogen but did not block the bone protective effects of estrogen. In immature and aged female rats, LAS did not affect the uterine weight and uterine histology. In OVX adult female rats, LAS slightly but significantly increased uterine weight. These results demonstrated that LAS produced effects on the skeleton indistinguishable from estrogen in female and male rats. However, unlike estrogen, LAS had little effect on uterine weight and cellular proliferation of uterus in female rats. In preclinical anti-tumor studies, LAS inhibited human breast cancer growth in mice bearing MCF7 tumors, prevented NMU-induced mammary carcinomas and possessed chemotherapeutic effects in NMU-induced carcinomas in rats. Therefore, we conclude that LAS possesses the antiestrogenic effects in breast tissue and estrogenic effects in bone and serum cholesterol, but lacks estrogen’s side effects on uterine tissue. These data support the therapeutic potential of LAS for the prevention and treatment of postmenopausal bone loss and mammary carcinomas in humans.
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Droloxifene does not blunt bone anabolic effects of prostaglandin E2, but maintains prostaglandin E2-restored bone in aged, ovariectomized rats
Bone, 1999Co-Authors: H. Z. Ke, Christine M. Pirie, D. T. Crawford, H. A. Simmons, K. L. Chidsey-frink, W. S S Jee, H K Chen, H Qi, D. D. ThompsonAbstract:Droloxifene (DRO) is a Selective estrogen receptor Modulator that prevents bone loss by inhibition of bone turnover associated with estrogen deficiency in both growing and aged female rats. The purposes of this study were to test: (a) whether DRO can maintain prostaglandin E2(PGE2)-restored bone after discontinuation of PGE2in aged, ovariectomized (ovx) rats; (b) if an inhibition of bone turnover by DRO reduces bone anabolic effects of PGE2; and (c) whether bone mass restored by PGE2plus DRO can be maintained after discontinuation of both agents. Female rats at 12 months of age were sham-operated (sham) or ovx. Three months postsurgery, ovx rats were treated with either PGE2(3 mg/kg per day, subcutaneously [s.c.]) alone, or PGE2plus DRO (10 mg/kg per day, per os [p.o.]) for 2 months. Thereafter, the PGE2or PGE2plus DRO treatment was withdrawn and the rats were then treated with either vehicle or DRO for another 1.5 months. Using dual-energy X-ray absorptiometry (DXA), total lumbar vertebral bone mineral density (LV-BMD) was determined in vivo at months 0, 3, 5, and 6.5. At the end of the study, the rats were autopsied, and BMD of total femur, femoral shaft, distal femoral metaphysis, and proximal femur was determined ex vivo by DXA. Standard static and dynamic bone histomorphometric parameters were determined on the fourth lumbar vertebral body (L-4). At 3, 5, or 6.5 months postsurgery, LV-BMD decreased significantly (-15%, -19%, and -19%, respectively) in the vehicle-treated ovx rats compared with sham. Beginning at 3 months post-ovx, PGE2alone or in combination with DRO for 2 months completely restored LV-BMD back to the sham level. There was no difference in LV-BMD in PGE2alone or PGE2plus DRO. Upon cessation of PGE2treatment, a significant decrease in LV-BMD was observed in the PGE2-alone group (-12%). On the other hand, when DRO treatment was given after discontinuation of PGE2, the PGE2-restored LV-BMD was completely maintained. In the PGE2plus DRO group, no loss in LV-BMD was observed after cessation of either PGE2alone or both PGE2and DRO. However, treatment with DRO following 2 months of PGE2plus DRO further increased LV-BMD (+10%). At the end of the study, ex vivo femoral BMD data confirmed the observation in lumbar vertebrae. Histomorphometric results of L-4 indicated that loss in bone mass after cessation of PGE2in PGE2alone group was associated with increased bone turnover. Treatment with DRO in the maintenance phase inhibited bone turnover and prevented bone loss induced by withdrawal of PGE2. Trabecular bone mass was maintained in the PGE2plus DRO followed by vehicle group and further increased in the PGE2plus DRO followed by DRO groups. We found that: (a) DRO is efficacious in maintaining PGE2-restored bone after discontinuation of PGE2; (b) DRO did not blunt the anabolic effects of PGE2; (c) bone loss occurred after cessation of treatment in the PGE2-alone group, whereas it was maintained after cessation of treatment in PGE2plus DRO group; and (d) an additional anabolic effect was found in ovx rats treated with PGE2plus DRO followed by DRO. Copyright (C) 1999 Elsevier Science Inc.
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droloxifene does not blunt bone anabolic effects of prostaglandin e2 but maintains prostaglandin e2 restored bone in aged ovariectomized rats
Bone, 1999Co-Authors: H. Z. Ke, Christine M. Pirie, D. T. Crawford, H. A. Simmons, H K Chen, H Qi, K L Chidseyfrink, D. D. ThompsonAbstract:Abstract Droloxifene (DRO) is a Selective estrogen receptor Modulator that prevents bone loss by inhibition of bone turnover associated with estrogen deficiency in both growing and aged female rats. The purposes of this study were to test: (a) whether DRO can maintain prostaglandin E2 (PGE2)-restored bone after discontinuation of PGE2 in aged, ovariectomized (ovx) rats; (b) if an inhibition of bone turnover by DRO reduces bone anabolic effects of PGE2; and (c) whether bone mass restored by PGE2 plus DRO can be maintained after discontinuation of both agents. Female rats at 12 months of age were sham-operated (sham) or ovx. Three months postsurgery, ovx rats were treated with either PGE2 (3 mg/kg per day, subcutaneously [s.c.]) alone, or PGE2 plus DRO (10 mg/kg per day, per os [p.o.]) for 2 months. Thereafter, the PGE2 or PGE2 plus DRO treatment was withdrawn and the rats were then treated with either vehicle or DRO for another 1.5 months. Using dual-energy X-ray absorptiometry (DXA), total lumbar vertebral bone mineral density (LV-BMD) was determined in vivo at months 0, 3, 5, and 6.5. At the end of the study, the rats were autopsied, and BMD of total femur, femoral shaft, distal femoral metaphysis, and proximal femur was determined ex vivo by DXA. Standard static and dynamic bone histomorphometric parameters were determined on the fourth lumbar vertebral body (L-4). At 3, 5, or 6.5 months postsurgery, LV-BMD decreased significantly (−15%, −19%, and −19%, respectively) in the vehicle-treated ovx rats compared with sham. Beginning at 3 months post-ovx, PGE2 alone or in combination with DRO for 2 months completely restored LV-BMD back to the sham level. There was no difference in LV-BMD in PGE2 alone or PGE2 plus DRO. Upon cessation of PGE2 treatment, a significant decrease in LV-BMD was observed in the PGE2-alone group (−12%). On the other hand, when DRO treatment was given after discontinuation of PGE2, the PGE2-restored LV-BMD was completely maintained. In the PGE2 plus DRO group, no loss in LV-BMD was observed after cessation of either PGE2 alone or both PGE2 and DRO. However, treatment with DRO following 2 months of PGE2 plus DRO further increased LV-BMD (+10%). At the end of the study, ex vivo femoral BMD data confirmed the observation in lumbar vertebrae. Histomorphometric results of L-4 indicated that loss in bone mass after cessation of PGE2 in PGE2 alone group was associated with increased bone turnover. Treatment with DRO in the maintenance phase inhibited bone turnover and prevented bone loss induced by withdrawal of PGE2. Trabecular bone mass was maintained in the PGE2 plus DRO followed by vehicle group and further increased in the PGE2 plus DRO followed by DRO groups. We found that: (a) DRO is efficacious in maintaining PGE2-restored bone after discontinuation of PGE2; (b) DRO did not blunt the anabolic effects of PGE2; (c) bone loss occurred after cessation of treatment in the PGE2-alone group, whereas it was maintained after cessation of treatment in PGE2 plus DRO group; and (d) an additional anabolic effect was found in ovx rats treated with PGE2 plus DRO followed by DRO.
Wolfgang Wuttke - One of the best experts on this subject based on the ideXlab platform.
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effects of estradiol benzoate raloxifen and an ethanolic extract of cimicifuga racemosa in nonclassical estrogen regulated organs of ovariectomized rats
Planta Medica, 2009Co-Authors: Dana Seidlovawuttke, Hubertus Jarry, Wolfgang WuttkeAbstract:The special extract of Cimicifuga racemosa (CR) BNO 1055 was shown to have bone protective effects without exerting estrogenic effects in the uterus or mammary gland. Whether the effects of CR BNO 1055 would be exerted in other organs that also express estrogen receptors (ERs) but in which the effects of estrogens and of the Selective estrogen receptor Modulator raloxifen (Ral) were not thoroughly studied was therefore investigated in the present contribution. Rats were ovariectomized (ovx) and their food immediately substituted with estradiol benzoate (EB), Ral or 2 doses of CR BNO 1055 for 3 months. Expressions of estrogen receptor alpha (ERα), estrogen receptor beta (ERβ) and of insulin-like growth factor-1 (IGF-1 ) genes were determined in the vagina, liver, thyroid gland, lung, spleen, colon and kidney by means of quantitative RT-PCRs. Body weights in all treatment groups were significantly reduced and uterine weights in the EB treated animals were largely and in the Ral treated animals slightly but significantly increased. CR BNO 1055 was without effects in the uterus. We tested 3 genes: ERα gene expression was significantly reduced in the vagina, liver and kidney and remained unaffected in all other organs with the exception of the thyroid gland where ERα gene expression was stimulated by EB, Ral had - if any -similar effects in these organs. The CR extract BNO 1055 was devoid of any effect on ERα gene expression. ERβ gene expression was suppressed in the vagina and colon by EB and this effect was shared by Ral in the colon. In the thyroid, EB and Ral stimulated ERβ gene expression. Expression of IGF-1 gene was stimulated by EB and CR BNO 1055 in the vagina and kidney and inhibited by EB and Ral in the liver. No effects were observed by CR BNO 1055 in these organs. The effects of Ral, if occurring, were similar to those of EB while CR BNO 1055 was ineffective in all organs but the vagina. In the colon, reduced ERβ gene activity may augment ERα mediated effects. In all other organs the effects of ER await further investigation. The CR BNO 1055 did not show any activity pattern which would be similar to the pattern observed under EB or Ral. Therefore the observed effects of CR BNO 1055 in these organs are most likely not estrogenic in nature.
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evidence for Selective estrogen receptor Modulator activity in a black cohosh cimicifuga racemosa extract comparison with estradiol 17beta
European Journal of Endocrinology, 2003Co-Authors: Dana Seidlovawuttke, Barbara Spengler, Volker Christoffel, Tamara Becker, Oda Hesse, Hubertus Jarry, Wolfgang WuttkeAbstract:Objective: Some phytoestrogens are believed to have Selective estrogen receptor Modulator (SERM) activity with no action in the uterus but beneficial effects in the hypothalamo/pituitary unit and in the bone and are presently the focus of clinical interest. In the present experiments, the effects of the clinically used Cimicifuga racemosa (CR) extract BNO 1055 in the uterus, in the bone and on serum luteinizing hormone (LH) were compared with the effects of estradiol-17b (E2) under acute and chronic conditions in ovariectomized rats. Methods: Ovariectomized rats were treated either acutely (6 h) or chronically (3 months) with E2 or the CR extract. Gene expression of some estrogen-regulated genes in the metaphysis of the tibia and the uterus was determined. Furthermore, bone mineral density was measured by quantitative computer tomography. Results: When given acutely, both E2 and the CR extract inhibited LH secretion and slightly stimulated gene expression of IGF-I, collagen-1a1, osteoprotegerin and osteocalcin (all osteoblast products), and of tartrate-resistant acid phosphatase (TRAP, an osteoclast product) in the metaphysis of the femur. While E2 stimulated uterine weight and expression of progesterone receptor (PR), the complement protein (C3) and IGF-I genes, and inhibited gene expression of the estrogen receptor b (ERb) in the uterus, no such effect was observed under acute CR treatment. After chronic application with pelleted food over 3 months E2 had profound effects in the uterus on weight and gene expression (ERb, PR, C3 and IGF-I) which were not seen in the CR-treated animals. Within 3 months after ovariectomy, control rats had lost more than 50% of the metaphyseal bone mass of the tibia, an effect prevented by E2 and partially by CR supplementation. Conclusions: These data confirm the concept that the CR extract BNO 1055 contains as yet unidentified substances with SERM properties which act in the hypothalamo/pituitary unit and in the bone but not in the uterus.
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in vitro effects of the cimicifuga racemosa extract bno 1055
Maturitas, 2003Co-Authors: Hubertus Jarry, Maria Metten, Barbara Spengler, Volker Christoffel, Wolfgang WuttkeAbstract:Abstract Objectives: Extracts of Black cohosh ( Cimicifuga racemosa or CR) have been used for the treatment of climacteric complaints since decades. Efficacy, particularly concerning neurovegetative and psychic symptoms, has been proven in clinical trials. As active principle yet unknown substances with Selective estrogen receptor Modulator (SERM) activity are assumed. Recently, evidence arose that CR may also contain dopaminergic compounds, which may contribute to the therapeutic activity of the extract. Methods: Two subtypes of the estrogen receptor (ERα and ERβ) are known. To examine, whether active substances of CR extract BNO 1055 (which is contained in Klimadynon® and Menofem®) bind to either of the two estrogen receptors, subtype-specific estrogen receptor ligand-binding assays with recombinant ERα or ERβ were conducted. A ligand-binding assay with recombinant dopamine D 2 -receptor protein was employed to assess possible dopaminergic activity in the CR extract BNO 1055. Results: While a displacement of radiolabeled estradiol from binding sites of a cytosol preparation from procine and human endometrium by CR extract BNO 1055 was shown no such displacement was achieved when either ERα or ERβ protein was used as ligands for tracer. Dopaminergic activity in the CR extract BNO 1055 could be demonstrated with the D 2 -receptor assay. A countercurrent chromatography resulted in a separation of estrogenic and dopaminergic activity in two distinct fractions. Conclusions: It is suggested that not yet identified substances in the CR extract BNO 1055 bind to a yet unknown estrogen-binding site in the endometrium. Also, yet unknown dopaminergic compounds may contribute to the pharmacological profile of CR extract BNO 1055.
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In vitro effects of the Cimicifuga racemosa extract BNO 1055.
Maturitas, 2003Co-Authors: Hubertus Jarry, Maria Metten, Barbara Spengler, Volker Christoffel, Wolfgang WuttkeAbstract:Extracts of Black cohosh (Cimicifuga racemosa or CR) have been used for the treatment of climacteric complaints since decades. Efficacy, particularly concerning neurovegetative and psychic symptoms, has been proven in clinical trials. As active principle yet unknown substances with Selective estrogen receptor Modulator (SERM) activity are assumed. Recently, evidence arose that CR may also contain dopaminergic compounds, which may contribute to the therapeutic activity of the extract. Two subtypes of the estrogen receptor (ERalpha and ERbeta) are known. To examine, whether active substances of CR extract BNO 1055 (which is contained in Klimadynon and Menofem) bind to either of the two estrogen receptors, subtype-specific estrogen receptor ligand-binding assays with recombinant ERalpha or ERbeta were conducted. A ligand-binding assay with recombinant dopamine D(2)-receptor protein was employed to assess possible dopaminergic activity in the CR extract BNO 1055. While a displacement of radiolabeled estradiol from binding sites of a cytosol preparation from procine and human endometrium by CR extract BNO 1055 was shown no such displacement was achieved when either ERalpha or ERbeta protein was used as ligands for tracer. Dopaminergic activity in the CR extract BNO 1055 could be demonstrated with the D(2)-receptor assay. A countercurrent chromatography resulted in a separation of estrogenic and dopaminergic activity in two distinct fractions. It is suggested that not yet identified substances in the CR extract BNO 1055 bind to a yet unknown estrogen-binding site in the endometrium. Also, yet unknown dopaminergic compounds may contribute to the pharmacological profile of CR extract BNO 1055.
Kai Kaarniranta - One of the best experts on this subject based on the ideXlab platform.
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Influence of Selective estrogen receptor Modulators on interleukin-6 expression in human retinal pigment epithelial cells (ARPE-19)
European Journal of Pharmacology, 2010Co-Authors: Tuomas Paimela, Juha M. T. Hyttinen, Johanna Viiri, Tuomas Ryhänen, Matti K. Karvonen, Mikko Unkila, Hannu Uusitalo, Antero Salminen, Kai KaarnirantaAbstract:Since estrogen and Selective estrogen receptor Modulators can inhibit inflammatory responses, we studied the regulatory role of several Selective estrogen receptor Modulators on interleukin-6 (IL-6) expression in human retinal pigment epithelial cells (ARPE-19). ARPE-19 cells were exposed to lipopolysaccharide with simultaneous exposure to different Selective estrogen receptor Modulators with the secretion of IL-6 cytokine being analyzed by enzyme-linked immunosorbent assay (ELISA). We demonstrate that 17β-estradiol and HM-D, a novel Selective estrogen receptor Modulator compound, clearly reduced the IL-6 expression levels after lipopolysaccharide exposure in ARPE-19 cells. Molecular effects of Selective estrogen receptor Modulators and estrogen on the estrogen response element-mediated transcription were studied using MCF-7 and ARPE-19 cell lines carrying the estrogen response element-luciferase reporter gene. Estrogen and HM-D stimulated the activity of estrogen response element-reporter gene in MCF-7 cells but did not affect the activity in ARPE-19 cells. In addition, HM-D did not activate estrogen receptor α when studied by nuclear receptor peptide estrogen receptor α ELISA in ARPE-19 cells. These results indicate that estrogen and HM-D can suppress the lipopolysaccharide-induced inflammatory response but signalling is not mediated through estrogen response element transcription in human retinal pigment epithelial cells.
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Influence of Selective estrogen receptor Modulators on interleukin-6 expression in human retinal pigment epithelial cells (ARPE-19).
European journal of pharmacology, 2010Co-Authors: Tuomas Paimela, Juha M. T. Hyttinen, Johanna Viiri, Tuomas Ryhänen, Matti K. Karvonen, Mikko Unkila, Hannu Uusitalo, Antero Salminen, Kai KaarnirantaAbstract:Since estrogen and Selective estrogen receptor Modulators can inhibit inflammatory responses, we studied the regulatory role of several Selective estrogen receptor Modulators on interleukin-6 (IL-6) expression in human retinal pigment epithelial cells (ARPE-19). ARPE-19 cells were exposed to lipopolysaccharide with simultaneous exposure to different Selective estrogen receptor Modulators with the secretion of IL-6 cytokine being analyzed by enzyme-linked immunosorbent assay (ELISA). We demonstrate that 17beta-estradiol and HM-D, a novel Selective estrogen receptor Modulator compound, clearly reduced the IL-6 expression levels after lipopolysaccharide exposure in ARPE-19 cells. Molecular effects of Selective estrogen receptor Modulators and estrogen on the estrogen response element-mediated transcription were studied using MCF-7 and ARPE-19 cell lines carrying the estrogen response element-luciferase reporter gene. Estrogen and HM-D stimulated the activity of estrogen response element-reporter gene in MCF-7 cells but did not affect the activity in ARPE-19 cells. In addition, HM-D did not activate estrogen receptor alpha when studied by nuclear receptor peptide estrogen receptor alpha ELISA in ARPE-19 cells. These results indicate that estrogen and HM-D can suppress the lipopolysaccharide-induced inflammatory response but signalling is not mediated through estrogen response element transcription in human retinal pigment epithelial cells.
Riko Nagata - One of the best experts on this subject based on the ideXlab platform.
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human urat1 slc22a12 gene promoter is regulated by 27 hydroxycholesterol through estrogen response elements
bioRxiv, 2019Co-Authors: Masaya Matsubayashi, Yoshihiko M Sakaguchi, Yoshiki Sahara, Hitoki Nanaura, Arvand Ashari, Shinko Kobashigawa, Mari Nakanishi, Riko Nagata, Sotaro Kikuchi, Takeshi K MatsuiAbstract:Abstract Elevated levels of uric acid, a metabolite of purine in humans, is related to various diseases, such as gout, atherosclerosis and renal dysfunction. The excretion and reabsorption of uric acid to/from urine is tightly regulated by uric acid transporters. The amino acid sequences of uric acid reabsorption transporters, URAT1/SLC22A12, OAT4/SLC22A11, and OAT10/SLC22A13, share closer phylogenic relationship, whereas the gene promoter sequences are distant phylogenic relationship. Through the single-cell RNA-sequencing analysis of an adult human kidney, we found that only a small number of cells express these transporters, despite their role in the regulation of serum uric acid levels. Transcriptional motif analysis on these transporter genes, revealed that the URAT1/SLC22A12 gene promoter displayed the most conserved estrogen response elements (EREs) among the three transporters. The endogenous Selective estrogen receptor Modulator (SERM) 27-hydroxycholesterol (27HC) had positive effects on the transcriptional activity of URAT1/SLC22A12. We also found that 27HC increased the protein and gene expression of URAT1/SLC22A12 in mouse kidneys and human kidney organoids, respectively. These results strongly suggest the role of 27HC for URAT1/SLC22A12 expression in renal proximal tubules and upregulation of serum uric acid levels and also show the relationship between cholesterol metabolism and serum uric acid regulation. Significance Statement The elevated levels of serum uric acid cause various diseases, and the excretion/reabsorption of uric acid to/from urine is tightly regulated by the uric acid transporters. We found that despite the role in serum uric acid regulation, only a small number of cells express URAT1/SLC22A12. We also found that URAT1/SLC22A12 gene promoter region has effective estrogen response elements, and endogenous Selective estrogen receptor (ER) Modulator 27-hydroxycholesterol (27HC) increased URAT1/SLC22A12 expression in the mice kidneys and human kidney organoids. These suggest that 27HC increases URAT1/SLC22A12 expression and upregulate serum uric acid levels. Since 27HC connects cholesterol metabolism, our study indicates the important link between cholesterol metabolism and serum uric acid regulation, and also provides a novel therapeutic approach to hyperuricemia.
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Human URAT1/SLC22A12 gene promoter is regulated by 27-hydroxycholesterol through estrogen response elements
bioRxiv, 2019Co-Authors: Masaya Matsubayashi, Yoshihiko M Sakaguchi, Yoshiki Sahara, Hitoki Nanaura, Arvand Ashari, Shinko Kobashigawa, Mari Nakanishi, Sotaro Kikuchi, Riko NagataAbstract:Abstract Elevated levels of uric acid, a metabolite of purine in humans, is related to various diseases, such as gout, atherosclerosis and renal dysfunction. The excretion and reabsorption of uric acid to/from urine is tightly regulated by uric acid transporters. The amino acid sequences of uric acid reabsorption transporters, URAT1/SLC22A12, OAT4/SLC22A11, and OAT10/SLC22A13, share closer phylogenic relationship, whereas the gene promoter sequences are distant phylogenic relationship. Through the single-cell RNA-sequencing analysis of an adult human kidney, we found that only a small number of cells express these transporters, despite their role in the regulation of serum uric acid levels. Transcriptional motif analysis on these transporter genes, revealed that the URAT1/SLC22A12 gene promoter displayed the most conserved estrogen response elements (EREs) among the three transporters. The endogenous Selective estrogen receptor Modulator (SERM) 27-hydroxycholesterol (27HC) had positive effects on the transcriptional activity of URAT1/SLC22A12. We also found that 27HC increased the protein and gene expression of URAT1/SLC22A12 in mouse kidneys and human kidney organoids, respectively. These results strongly suggest the role of 27HC for URAT1/SLC22A12 expression in renal proximal tubules and upregulation of serum uric acid levels and also show the relationship between cholesterol metabolism and serum uric acid regulation. Significance Statement The elevated levels of serum uric acid cause various diseases, and the excretion/reabsorption of uric acid to/from urine is tightly regulated by the uric acid transporters. We found that despite the role in serum uric acid regulation, only a small number of cells express URAT1/SLC22A12. We also found that URAT1/SLC22A12 gene promoter region has effective estrogen response elements, and endogenous Selective estrogen receptor (ER) Modulator 27-hydroxycholesterol (27HC) increased URAT1/SLC22A12 expression in the mice kidneys and human kidney organoids. These suggest that 27HC increases URAT1/SLC22A12 expression and upregulate serum uric acid levels. Since 27HC connects cholesterol metabolism, our study indicates the important link between cholesterol metabolism and serum uric acid regulation, and also provides a novel therapeutic approach to hyperuricemia.