Estrogen has important roles in the initiation and development of benign prostatic hyperplasia （BPH）. Regulators of the estrogen receptor （ER） are tissue- and cell-specific. We evaluated the effect of estrogen ant...Estrogen has important roles in the initiation and development of benign prostatic hyperplasia （BPH）. Regulators of the estrogen receptor （ER） are tissue- and cell-specific. We evaluated the effect of estrogen antagonist, raloxifene （Ral）, on the prevention and treatment of BPH by investigating its effect on the proliferation of two different prostate cell lines： a stromal cell line, WPMY-1, and a benign prostatic hyperplasia epithelial cell line, BPH-1. We additionally evaluated its effect on prostatic hyperplasia induced by estrogen and androgen in a rat model. The effect of Ral on the prevention of prostatic hyperplasia was analyzed by haematoxylin and eosin staining and quantitative immunohistochemistry （IHC） for proliferating cell nuclear antigen and α-smooth muscle actin. In vitro and in vivo, tamoxifen （Tam）, another anti-estrogen drug, and finasteride （Fin）, a drug for the clinical treatment of BPH, served as efficacy controls. The in vitro data showed that neither Ral nor Tam alone affected the proliferation of WPMY-1 and BPH-1, but both antagonized the effect of oestradiol in promoting the proliferation of the two cells. Results from the IHC staining of the rat prostates indicated that, similar to Tam and Fin, Ral inhibited the proliferation of stromal cells in vivo. Interestingly, in contrast to Tam, both Ral and Fin inhibited the proliferation of epithelial cells. Furthemore, Ral treatment much strongly decreased the number of prostatic acini and the surrounding layers of smooth muscle cells than Fin （P 〈 0.05）. Our data showed for the first time that Ral may have a role in the response of the rat prostate to selective ER modulators.展开更多
Objective To investigate the neuroprotective effects and the mechanism of this protection of raloxifene （RLX）, a selective estrogen receptor modulator.Methods MTT assay and flow cytometry with annexin V-FITC/PI stai...Objective To investigate the neuroprotective effects and the mechanism of this protection of raloxifene （RLX）, a selective estrogen receptor modulator.Methods MTT assay and flow cytometry with annexin V-FITC/PI staining were performed to evaluate the neuroprotective effects of RLX on Aβ25-35-induced toxicity. The potential mechanisms were studied by Western blotting in cultured rat pheochromocytoma cells （PC12 cells）.Results RLX（1 000 nmol/L）, in combination with Aβ25-35 （30 llmol/L）, increased the cell viability （P 〈0.001）, and reduced the number of apoptotic cells （P 〈0.05）. RLX attenuated Aβ25-35-induced loss of △ψm （P 〈0.01）. The changing of △ψm was similar to the variation of apoptosis. PD98059 （inhibitor of ERK1/2） inhibited the effects of RLX on cell viability and phosphorylation of cleaved caspase-9. No significant difference of cell viability or phosphorylation of cleaved caspase-9 had been found when PC12 cells were incubated with SB203580 （inhibitor of p38MAPK） or SP600125 （inhibitor of JNK）. Afl25.35 induced a time-dependent phosphorylation of p38MAPK and JNK. In PC12 cells treated solely with RLX, ERK1/2 was activated （P〈0.01）. In PC12 cells treated with Aβ25-35 and RLX, Aβ2545-induced phosphorylation of p38MAPK and JNK were inhibited （P〈0.01 and P〈0.001, respectively）.Conclusion RLX inhibited Af125.35-induced cell apoptosis by activating the ERK1/2 pathway in PC12 cells. RLX also attenuated Aβ25-35-induced activation of p38MAPK and JNK. The mitochondria pathway Was involved in this inhibitory effect.展开更多
Assigning causality in drug-induced liver injury is challenging particularly when more than one drug could be responsible. We report a woman on long-term therapy with raloxifen who developed acute cholestasis shortly ...Assigning causality in drug-induced liver injury is challenging particularly when more than one drug could be responsible. We report a woman on long-term therapy with raloxifen who developed acute cholestasis shortly after starting fenofibrate. The picture evolved into chronic cholestasis. We hypothesized that an interaction at the metabolic level could have triggered the presentation of hepatotoxicity after a very short time of exposure to fenofibrate in this patient. The findings of an overexpression of vascular endothelial growth factor in the liver biopsy suggest that angiogenesis might play a role in the persistance of toxic cholestasis.展开更多
Background:Raloxifene,a selective estrogen receptor modulator,is also known to be a lysosomotropic agent.The bioavailability of raloxifene is around 2%due to extensive hepatic transport.Exosomes are nanosized vesicles...Background:Raloxifene,a selective estrogen receptor modulator,is also known to be a lysosomotropic agent.The bioavailability of raloxifene is around 2%due to extensive hepatic transport.Exosomes are nanosized vesicles that are naturally released from cells.Method:In this study,exosomes released from HeLa cervical cancer cells were loaded with raloxifene to increase its bioavailability,and an aptamer was attached to the exosome membrane for targeting only HeLa cells.Characterization of exosomes isolated from HeLa cells was performed by transmission electron microscopy,zeta sizer,and western blotting.In addition,the cytotoxic,apoptotic,autophagic,and lysosomotropic effects of the prepared Exo-Apt-Ral formulation on HeLa cervical cancer cells were investigated.Results:According to zeta analysis,the sizes of the empty exosome and Exo-Apt-Ral formulation were measured as 66±12 and 120±21 nm,respectively.There was a rise in the lysosomal permeability of HeLa cells after the Exo-Apt-Ral application.In addition,both apoptotic and autophagic death mechanisms were triggered in HeLa cells after the Exo-Apt-Ral application.Conclusion:This study showed that raloxifene functionalized by loading into aptamer-bound exosomes can be a new targeted drug carrier system for cervical cancer.展开更多
Selective estrogen receptor modulators （SERMs） are structurally different com- pounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists and antagonists. Raloxifene is...Selective estrogen receptor modulators （SERMs） are structurally different com- pounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists and antagonists. Raloxifene is the only SERM approved worldwide for the prevention and treatment of postmenopausal osteoporosis. Raloxifene, which has estrogen-like actions on bone, lipids and the coagulation system, and estrogen antagonist effects on the breast and uterus, has undergone very extensive prospective, placebo-controlled, randomized trial evaluation.展开更多
Objective: To study the effects of raloxifene on the growth of the human ovarian cancer cell line Skov3 and on the expression of cell proliferative antigen Ki-67 in vitro.Methods: The proliferative capacity of the ova...Objective: To study the effects of raloxifene on the growth of the human ovarian cancer cell line Skov3 and on the expression of cell proliferative antigen Ki-67 in vitro.Methods: The proliferative capacity of the ovarian cancer cell line Skov3 in the culture medium with raloxifene was evaluated by the microculture tetrazolium assay (MTT) and the expression of cell proliferation was appraised by the immunohistochemical staining of ki-67.Results: The growth of ovarian cancer cell line Skov3 was inhibited by raloxifene at high concentrations, while a trend of growth promotion at initial then followed by growth inhibition was found when raloxifene was at low concentrations. Raloxifene at high concentrations not only significantly reduced the expression of Ki-67 but also destroyed the cell structure.Conclusion: Raloxifene does not stimulate the growth of human ovarian cancer cell line Skov3significantly.展开更多
Objective To determine the effects of raloxifene hydrochloride (RLX) on bone mineral density (BMD),bone metabolism markers and serum lipids in healthy postmenopausal women in Beijing.Methods A multicenter,randomized...Objective To determine the effects of raloxifene hydrochloride (RLX) on bone mineral density (BMD),bone metabolism markers and serum lipids in healthy postmenopausal women in Beijing.Methods A multicenter,randomized,double-blind,placebo-controlled study was conducted in a total of 204 healthy postmenopausal women (age 59.5±5.0 years and weight 62.8±8.7 kg) treated with either RLX 60 mg (n=102) or placebo (n=102) daily for 12 months. BMD,serum lipids,and bone markers were measured before and after drug administration.Results Compared with placebo,RLX produced a significant increase in both total lumbar spine and total hip BMD. For the lumbar spine,percentage increase in total BMD was 2.3% with RLX compared with a decrease of 0.1% with placebo ( P <0.001). Corresponding values for total hip BMD were a 2.5% increase for RLX and a 1.1% increase for placebo ( P =0.011). For biochemical markers of bone metabolism,serum osteocalcin and C-telopeptide,percentage decreases were 27.65% and 24.02% in RLX-treated subjects. Corresponding values in placebo were a 10.64% decrease and a 15.75% increase (RLX compared with placebo,both P <0.001). For total cholesterol and low-density lipoprotein cholesterol levels,percentage decreases were 6.44% and 34.58% in the RLX-treated group. Corresponding values in placebo-treated patients were a 1.44% increase and a 19.07% decrease (RLX compared with placebo,both P <0.001). No differences were found for high-density lipoprotein cholesterol or triglyceride levels between the two groups. Only 5 subjects discontinued early owing to an adverse event (3 in the RLX group and 2 in the placebo group). Conclusions This study confirms that RLX exerts positive effects on the skeleton,increasing BMD and decreasing biochemical markers of bone metabolism,and has a positive effect on the overall serum lipid profile in postmenopausal women in China.展开更多
The intensity of resonance Rayleigh scattering (RRS) of Evans blue (EB) or raloxifene hydrochloride (Ralo) is very weak, but it can be enhanced significantly and a new RRS spectrum appears when both of them interact t...The intensity of resonance Rayleigh scattering (RRS) of Evans blue (EB) or raloxifene hydrochloride (Ralo) is very weak, but it can be enhanced significantly and a new RRS spectrum appears when both of them interact to form an ion-association complex in sodium acetate-hydrochloric acid buffer solution at pH 1.8. The intensity of RRS is directly proportional to the concentration of Ralo in the range of 0–8.3 μg · mL?1, and the detection limit for Ralo (σ = 3) is 18.9 ng·mL?1. The method has high sensitivity and fairly good selectivity. Based on the above evidences, a new facile method for the determination of trace amount of Ralo has been established with satisfactory results.展开更多
Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer...Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer treatment and osteoporosis in postmenopausal women, as well as for the treatment of climacteric symptoms. Similar to estrogens, neuroprotective effects of estrogen receptor modulators have been described in different models. However, the mechanisms of action of these compounds in the central nervous system have not been fully described. We conducted a systematic search to investigate the effects of estrogen receptor modulators in the central nervous system, focusing on the modulation of cytoskeletal proteins. We found that raloxifene, tamoxifen, and tibolone modulate some cytoskeletal proteins such as tau, microtuble-associated protein 1（MAP1）, MAP2, neurofilament 38（NF38） by different mechanisms of action and at different levels： neuronal microfilaments, intermediate filaments, and microtubule-associated proteins. Finally, we emphasize the importance of the study of these compounds in the treatment of neurodegenerative diseases since they present the benefits of estrogens without their side effects.展开更多
基金Acknowledgment This research was funded by the following grants： the National Basic Research Programs, China （973 Programs, No. 2009CB918904, No. 2010CB945003）, the National Natural Science Foundation of China （No. 30872592）, Joint Research Fund for Overseas Chinese Scholars and Scholars in Hong Kong and Macao, China （No. 30928027）, and the key research project of Tianjin Municipal Science and Technology Commission, China （No. 09ZCKFSF00800）.
文摘Estrogen has important roles in the initiation and development of benign prostatic hyperplasia （BPH）. Regulators of the estrogen receptor （ER） are tissue- and cell-specific. We evaluated the effect of estrogen antagonist, raloxifene （Ral）, on the prevention and treatment of BPH by investigating its effect on the proliferation of two different prostate cell lines： a stromal cell line, WPMY-1, and a benign prostatic hyperplasia epithelial cell line, BPH-1. We additionally evaluated its effect on prostatic hyperplasia induced by estrogen and androgen in a rat model. The effect of Ral on the prevention of prostatic hyperplasia was analyzed by haematoxylin and eosin staining and quantitative immunohistochemistry （IHC） for proliferating cell nuclear antigen and α-smooth muscle actin. In vitro and in vivo, tamoxifen （Tam）, another anti-estrogen drug, and finasteride （Fin）, a drug for the clinical treatment of BPH, served as efficacy controls. The in vitro data showed that neither Ral nor Tam alone affected the proliferation of WPMY-1 and BPH-1, but both antagonized the effect of oestradiol in promoting the proliferation of the two cells. Results from the IHC staining of the rat prostates indicated that, similar to Tam and Fin, Ral inhibited the proliferation of stromal cells in vivo. Interestingly, in contrast to Tam, both Ral and Fin inhibited the proliferation of epithelial cells. Furthemore, Ral treatment much strongly decreased the number of prostatic acini and the surrounding layers of smooth muscle cells than Fin （P 〈 0.05）. Our data showed for the first time that Ral may have a role in the response of the rat prostate to selective ER modulators.
基金supported by the "Six Talents Peak" of Jiangsu Province,China 973 Program(No.2007CB944005)Science and Technology Development Foundation of Nanjing Medical University(No.2011NJMU152)
文摘Objective To investigate the neuroprotective effects and the mechanism of this protection of raloxifene （RLX）, a selective estrogen receptor modulator.Methods MTT assay and flow cytometry with annexin V-FITC/PI staining were performed to evaluate the neuroprotective effects of RLX on Aβ25-35-induced toxicity. The potential mechanisms were studied by Western blotting in cultured rat pheochromocytoma cells （PC12 cells）.Results RLX（1 000 nmol/L）, in combination with Aβ25-35 （30 llmol/L）, increased the cell viability （P 〈0.001）, and reduced the number of apoptotic cells （P 〈0.05）. RLX attenuated Aβ25-35-induced loss of △ψm （P 〈0.01）. The changing of △ψm was similar to the variation of apoptosis. PD98059 （inhibitor of ERK1/2） inhibited the effects of RLX on cell viability and phosphorylation of cleaved caspase-9. No significant difference of cell viability or phosphorylation of cleaved caspase-9 had been found when PC12 cells were incubated with SB203580 （inhibitor of p38MAPK） or SP600125 （inhibitor of JNK）. Afl25.35 induced a time-dependent phosphorylation of p38MAPK and JNK. In PC12 cells treated solely with RLX, ERK1/2 was activated （P〈0.01）. In PC12 cells treated with Aβ25-35 and RLX, Aβ2545-induced phosphorylation of p38MAPK and JNK were inhibited （P〈0.01 and P〈0.001, respectively）.Conclusion RLX inhibited Af125.35-induced cell apoptosis by activating the ERK1/2 pathway in PC12 cells. RLX also attenuated Aβ25-35-induced activation of p38MAPK and JNK. The mitochondria pathway Was involved in this inhibitory effect.
基金Supported by a research grant from the Agencia Espanola del Medicamento and Fondo de Investigaciones Sanitarias, No. FIS PI 04/1759 and PI 04/1688
文摘Assigning causality in drug-induced liver injury is challenging particularly when more than one drug could be responsible. We report a woman on long-term therapy with raloxifen who developed acute cholestasis shortly after starting fenofibrate. The picture evolved into chronic cholestasis. We hypothesized that an interaction at the metabolic level could have triggered the presentation of hepatotoxicity after a very short time of exposure to fenofibrate in this patient. The findings of an overexpression of vascular endothelial growth factor in the liver biopsy suggest that angiogenesis might play a role in the persistance of toxic cholestasis.
基金supported by a Grant(221S945)from the Scientific and Technological Research Council of Turkey(TUBITAK)an Aydin Adnan Menderes University Research Grant(ADU-TPF-20041).
文摘Background:Raloxifene,a selective estrogen receptor modulator,is also known to be a lysosomotropic agent.The bioavailability of raloxifene is around 2%due to extensive hepatic transport.Exosomes are nanosized vesicles that are naturally released from cells.Method:In this study,exosomes released from HeLa cervical cancer cells were loaded with raloxifene to increase its bioavailability,and an aptamer was attached to the exosome membrane for targeting only HeLa cells.Characterization of exosomes isolated from HeLa cells was performed by transmission electron microscopy,zeta sizer,and western blotting.In addition,the cytotoxic,apoptotic,autophagic,and lysosomotropic effects of the prepared Exo-Apt-Ral formulation on HeLa cervical cancer cells were investigated.Results:According to zeta analysis,the sizes of the empty exosome and Exo-Apt-Ral formulation were measured as 66±12 and 120±21 nm,respectively.There was a rise in the lysosomal permeability of HeLa cells after the Exo-Apt-Ral application.In addition,both apoptotic and autophagic death mechanisms were triggered in HeLa cells after the Exo-Apt-Ral application.Conclusion:This study showed that raloxifene functionalized by loading into aptamer-bound exosomes can be a new targeted drug carrier system for cervical cancer.
文摘Selective estrogen receptor modulators （SERMs） are structurally different com- pounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists and antagonists. Raloxifene is the only SERM approved worldwide for the prevention and treatment of postmenopausal osteoporosis. Raloxifene, which has estrogen-like actions on bone, lipids and the coagulation system, and estrogen antagonist effects on the breast and uterus, has undergone very extensive prospective, placebo-controlled, randomized trial evaluation.
文摘Objective: To study the effects of raloxifene on the growth of the human ovarian cancer cell line Skov3 and on the expression of cell proliferative antigen Ki-67 in vitro.Methods: The proliferative capacity of the ovarian cancer cell line Skov3 in the culture medium with raloxifene was evaluated by the microculture tetrazolium assay (MTT) and the expression of cell proliferation was appraised by the immunohistochemical staining of ki-67.Results: The growth of ovarian cancer cell line Skov3 was inhibited by raloxifene at high concentrations, while a trend of growth promotion at initial then followed by growth inhibition was found when raloxifene was at low concentrations. Raloxifene at high concentrations not only significantly reduced the expression of Ki-67 but also destroyed the cell structure.Conclusion: Raloxifene does not stimulate the growth of human ovarian cancer cell line Skov3significantly.
文摘Objective To determine the effects of raloxifene hydrochloride (RLX) on bone mineral density (BMD),bone metabolism markers and serum lipids in healthy postmenopausal women in Beijing.Methods A multicenter,randomized,double-blind,placebo-controlled study was conducted in a total of 204 healthy postmenopausal women (age 59.5±5.0 years and weight 62.8±8.7 kg) treated with either RLX 60 mg (n=102) or placebo (n=102) daily for 12 months. BMD,serum lipids,and bone markers were measured before and after drug administration.Results Compared with placebo,RLX produced a significant increase in both total lumbar spine and total hip BMD. For the lumbar spine,percentage increase in total BMD was 2.3% with RLX compared with a decrease of 0.1% with placebo ( P <0.001). Corresponding values for total hip BMD were a 2.5% increase for RLX and a 1.1% increase for placebo ( P =0.011). For biochemical markers of bone metabolism,serum osteocalcin and C-telopeptide,percentage decreases were 27.65% and 24.02% in RLX-treated subjects. Corresponding values in placebo were a 10.64% decrease and a 15.75% increase (RLX compared with placebo,both P <0.001). For total cholesterol and low-density lipoprotein cholesterol levels,percentage decreases were 6.44% and 34.58% in the RLX-treated group. Corresponding values in placebo-treated patients were a 1.44% increase and a 19.07% decrease (RLX compared with placebo,both P <0.001). No differences were found for high-density lipoprotein cholesterol or triglyceride levels between the two groups. Only 5 subjects discontinued early owing to an adverse event (3 in the RLX group and 2 in the placebo group). Conclusions This study confirms that RLX exerts positive effects on the skeleton,increasing BMD and decreasing biochemical markers of bone metabolism,and has a positive effect on the overall serum lipid profile in postmenopausal women in China.
文摘The intensity of resonance Rayleigh scattering (RRS) of Evans blue (EB) or raloxifene hydrochloride (Ralo) is very weak, but it can be enhanced significantly and a new RRS spectrum appears when both of them interact to form an ion-association complex in sodium acetate-hydrochloric acid buffer solution at pH 1.8. The intensity of RRS is directly proportional to the concentration of Ralo in the range of 0–8.3 μg · mL?1, and the detection limit for Ralo (σ = 3) is 18.9 ng·mL?1. The method has high sensitivity and fairly good selectivity. Based on the above evidences, a new facile method for the determination of trace amount of Ralo has been established with satisfactory results.
基金supported by FIS/IMSS project No.FIS/IMSS/PROT/G13/1216CGA received Beca de Excelencia en Investigación by Fundación IMSS,ACS+1 种基金JJSU received financial support from CIS/IMSSCONACy T,RPA received financial support from USC-CONACYT Postdoctoral Scholars Program
文摘Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer treatment and osteoporosis in postmenopausal women, as well as for the treatment of climacteric symptoms. Similar to estrogens, neuroprotective effects of estrogen receptor modulators have been described in different models. However, the mechanisms of action of these compounds in the central nervous system have not been fully described. We conducted a systematic search to investigate the effects of estrogen receptor modulators in the central nervous system, focusing on the modulation of cytoskeletal proteins. We found that raloxifene, tamoxifen, and tibolone modulate some cytoskeletal proteins such as tau, microtuble-associated protein 1（MAP1）, MAP2, neurofilament 38（NF38） by different mechanisms of action and at different levels： neuronal microfilaments, intermediate filaments, and microtubule-associated proteins. Finally, we emphasize the importance of the study of these compounds in the treatment of neurodegenerative diseases since they present the benefits of estrogens without their side effects.
