|
1
|
Liu AH, Xu B, Li XW, Yu YW, Guan HX, Sun XL, Lin YZ, Zhang LL, Zhuo XD, Li J, Chen WQ, Hu WF, Ye MZ, Huang XM, Chen X. Development and validation of a risk assessment model for predicting the failure of early medical abortions: A clinical prediction model study based on a systematic review and meta-analysis. PLoS One 2024; 19:e0315025. [PMID: 39705275 PMCID: PMC11661585 DOI: 10.1371/journal.pone.0315025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 11/19/2024] [Indexed: 12/22/2024] Open
Abstract
OBJECTIVE As the first model in predicting the failure of early medical abortion (EMA) was inefficient, this study aims to develop and validate a risk assessment model for predicting the failure of EMAs more accurately in a clinical setting. METHODS The derivation cohort was obtained from a comprehensive systematic review and meta-analysis. The clinically significant risk factors were identified and combined with their corresponding odds ratios to establish a risk assessment model. The risk factors were assigned scores based on their respective weightings. The model's performance was evaluated by an external validation cohort obtained from a tertiary hospital. The outcome was defined as the incidence of EMA failure. RESULTS A total of 126,420 patients who had undergone medical abortions were included in the systematic review and meta-analysis, and the pooled failure rate was 6.7%. The final risk factors consisted of gestational age, maternal age, parity, previous termination of pregnancy, marital status, type of residence, and differences between gestational age calculated using the last menstrual period and that measured via ultrasound. The risk factors were assigned scores based on their respective weightings, with a maximum score of 19. The clinical prediction model exhibited a good discrimination, as validated by external verification (402 patients) with an area under the curve of 0.857 (95% confidence interval 0.804-0.910). The optimal cutoff value was determined to be 13.5 points, yielding a sensitivity of 83.3% and specificity of 75.4%. CONCLUSION This study effectively establishes a simple risk assessment model including seven routinely available clinical parameters for predicting EMA failure. In preliminary validation, this model demonstrates good performance in terms of predictive efficiency, accuracy, calibration, and clinical benefit. However, more research and validation are warranted for future application. TRIAL REGISTRATION NUMBER CRD42023485388.
Collapse
Affiliation(s)
- An-Hao Liu
- Department of Obstetrics and Gynecology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Bin Xu
- Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen, China
| | - Xiu-Wen Li
- Department of Obstetrics and Gynecology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Yue-Wen Yu
- Department of Obstetrics and Gynecology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Hui-Xin Guan
- Department of Obstetrics and Gynecology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Xiao-Lu Sun
- Department of Ultrasound, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Yan-Zhen Lin
- Department of Obstetrics and Gynecology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Li-Li Zhang
- Department of Obstetrics and Gynecology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Xian-Di Zhuo
- Department of Obstetrics and Gynecology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Jia Li
- Department of Obstetrics and Gynecology, Jianning General Hospital, Sanming, China
| | - Wen-Qun Chen
- Department of Obstetrics and Gynecology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Wen-Feng Hu
- Department of Obstetrics and Gynecology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Ming-Zhu Ye
- Department of Obstetrics and Gynecology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Xiu-Min Huang
- Department of Obstetrics and Gynecology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Xun Chen
- Department of Obstetrics and Gynecology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| |
Collapse
|
|
2
|
Kitawaki Y, Horie A, Ikeda A, Shitanaka S, Yanai A, Ohara T, Nakakita B, Sagae Y, Okunomiya A, Tani H, Mandai M. Intrauterine administration of peripheral blood mononuclear cells helps manage recurrent implantation failure by normalizing dysregulated gene expression including estrogen-responsive genes in mice. Cell Commun Signal 2024; 22:587. [PMID: 39639317 PMCID: PMC11619271 DOI: 10.1186/s12964-024-01904-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 10/22/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Intrauterine peripheral blood mononuclear cell (PBMC) therapy for recurrent implantation failure (RIF) has been reported to improve embryo implantation by acting on the endometrium. However, the exact mode of action of PBMC on the endometrium of patients with RIF remains unclear. In addition, the differences in the therapeutic effects of PBMC therapy with and without human chorionic gonadotropin (hCG) are unknown. Therefore, in this study, we investigated the changes in the endometrium during the implantation phase induced by PBMC administration and the differences in the efficacy of this therapy with and without hCG using a mouse model of implantation failure (IF). METHODS IF model was established by the subcutaneous administration of low-dose RU486. Pregnant mice were randomly divided into five groups: control, IF, culture medium, PBMC, and PBMC-hCG (the latter three groups were IF model mice with intrauterine administration). The pregnancy rate and the number and size of implantation sites were recorded during early pregnancy (day 7.5). Uteri from the preimplantation phase (evening of day 3.5) were collected and analyzed using RNA-sequencing (RNA-seq). RESULTS The pregnancy rate, the number of implantation sites, and the number of normal-sized implantation sites were significantly decreased in the IF model and were improved in the medium, PBMC, and PBMC-hCG groups. RNA-seq data showed that PBMC treatment normalized the expression of the majority of dysregulated genes in the endometrium during the preimplantation phase in the IF model, especially the overexpression of estrogen-activated genes. In addition, PBMC treatment increased the expression of local glucocorticoid receptors and suppressed the expression of inflammation-related genes, whereas no significant changes in blood estradiol and glucocorticoid levels were observed. These changes were more pronounced in the PBMC-hCG group and were consistent with the pregnancy outcomes. CONCLUSIONS Intrauterine administration of PBMC before embryo implantation promoted embryo implantation in the IF mouse model, and hCG enhanced pregnancy outcomes. PBMC modulated steroid receptor expression and suppressed inflammation and excessive estrogen action.
Collapse
Affiliation(s)
- Yoshimi Kitawaki
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-Cho, Sakyo, Kyoto, 606-8507, Japan
| | - Akihito Horie
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-Cho, Sakyo, Kyoto, 606-8507, Japan.
- Department of Gynecology and Obstetrics, Medical Research Institute Kitano Hospital, 2-4-20 Ohgimachi, Kita-Ku, Osaka, 530-8480, Japan.
| | - Asami Ikeda
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-Cho, Sakyo, Kyoto, 606-8507, Japan
| | - Shimpei Shitanaka
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-Cho, Sakyo, Kyoto, 606-8507, Japan
| | - Akihiro Yanai
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-Cho, Sakyo, Kyoto, 606-8507, Japan
| | - Tsutomu Ohara
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-Cho, Sakyo, Kyoto, 606-8507, Japan
| | - Baku Nakakita
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-Cho, Sakyo, Kyoto, 606-8507, Japan
| | - Yusuke Sagae
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-Cho, Sakyo, Kyoto, 606-8507, Japan
| | - Asuka Okunomiya
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-Cho, Sakyo, Kyoto, 606-8507, Japan
| | - Hirohiko Tani
- Department of Gynecology and Obstetrics, Shizuoka General Hospital, 4-27-1 Kita Ando Aoi-Ku, Shizuoka, 420-8527, Japan
| | - Masaki Mandai
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-Cho, Sakyo, Kyoto, 606-8507, Japan
| |
Collapse
|
|
3
|
Li M, Fu F, Wang T. Escin alleviates cerebral ischemia-induced intestinal pyroptosis via the GR-dependent p38 MAPK/NF-κB signaling and NLRP3 inflammasome activation. Int Immunopharmacol 2024; 138:112592. [PMID: 38955024 DOI: 10.1016/j.intimp.2024.112592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/04/2024]
Abstract
Cerebral ischemia-induced systemic inflammation and inflammasome-dependent pyroptotic cell death in ileum, causing serious intestinal injury. Glucocorticoid receptor (GR) mediates the effects of glucocorticoids and participates in inflammation. Escin has corticosteroid-like, neuroprotective, and anti-intestinal dysfunction effects. This study aimed to investigate the effect of Escin on the intestinal barrier injury in rats subjected to middle cerebral artery occlusion (MCAO) and on Caco-2 cells exposed to lipopolysaccharides. The MCAO-caused brain injury was evaluated by assessing neurological function, cerebral infarct volume, and plasma corticosterone (Cort) levels. Intestinal injury was evaluated by observing the histopathological changes, assessing the intestinal barrier function, and determining blood FD4, endotoxin and IL-1β levels. The levels of the tight-junction proteins such as claudin-1, occludin, and ZO-1, and proteins involved in the GR/p38 MAPK/NF-κB pathway and NLRP3-inflammasome activation were evaluated using western blotting or immunofluorescence. Administration of Escin suppressed the cerebral ischemia-induced increases in Garcia-test scores and infarct volume, alleviated the injury to the intestinal barrier, and decreased the levels of Cort, endotoxin, and IL-1β. Additionally, Escin upregulated GR and downregulated phospho(p)-p65, p-p38MAPK, NLRP3, GSDMD-N, and cleaved-caspase-1 in the intestine. The effects of Escin could be suppressed by the GR antagonist RU486 or enhanced by the p38 MAPK antagonist SB203580. We revealed details how Escin improves cerebral ischemia-induced intestinal barrier injury by upregulating GR and thereby inhibiting the pyroptosis induced by NF-κB-mediated NLRP3 activation. This study will provide a experimental foundation for the features of glucocorticoid-like activity and the discovery of new clinical application for Escin.
Collapse
Affiliation(s)
- Min Li
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, PR China; School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, PR China.
| | - Fenghua Fu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, PR China
| | - Tian Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, PR China.
| |
Collapse
|
|
4
|
Xiao Y, Zheng P, Xu W, Wu Z, Zhang X, Wang R, Huang T, Ming J. Progesterone receptor impairs immune respond and down-regulates sensitivity to anti-LAG3 in breast cancer. Transl Res 2024; 271:68-78. [PMID: 38795691 DOI: 10.1016/j.trsl.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 02/09/2024] [Accepted: 05/02/2024] [Indexed: 05/28/2024]
Abstract
BACKGROUND Progesterone receptor (PR) serves as a crucial prognostic and predictive marker in breast cancer. Nonetheless, the interplay between PR and the tumor immune microenvironment remains inadequately understood. This investigation employs bioinformatics analyses, mouse models, and clinical specimens to elucidate the impact of PR on immune microenvironment and identify potential targets for immunotherapy, furnishing valuable guidance for clinical practice. METHODS Analysis of immune infiltration score by Xcell between PR-positive and PR-negative breast cancer tumors. Construction of overexpression mouse progesterone receptor (mPgr) EMT-6 cell was to explore the tumor immune microenvironment. Furthermore, anti- Lymphocyte-activation gene 3 (LAG3) therapy aimed to investigate whether PR could influence the effectiveness of immune treatments. RESULTS Overexpression mPgr inhibited tumor growth in vitro, but promoted tumor growth in Balb/c mouse. Flow cytometry showed that the proportion and cytotoxicity of CD8+T cells in tumor of overexpressing mPgr group were significantly reduced. The significant reduction in overexpressing mPgr group was found in the proportions of LAG3+CD8+ T cells and LAG3+ Treg T cells. Anti-LAG3 treatment resulted in reduced tumor growth in EV group mouse rather than in overexpressing mPgr group. Patents derived tumor fragment (PDTF) also showed higher anti-tumor ability of CD3+T cell in patents' tumor with PR <20% after anti-human LAG3 treatment in vitro. CONCLUSIONS The mPgr promotes tumor growth by downregulating the infiltration and function of cytotoxic cell. LAG3 may be a target of ER-positive breast cancer immunotherapy. The high expression of PR hinders the sensitivity to anti-LAG3 treatment.
Collapse
Affiliation(s)
- Yunxiao Xiao
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, China
| | - Peng Zheng
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, China
| | - Wenjie Xu
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, China
| | - Zhenghao Wu
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, China
| | - Ximeng Zhang
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, China
| | - Rong Wang
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, China
| | - Tao Huang
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, China.
| | - Jie Ming
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, China.
| |
Collapse
|
|
5
|
Wang F, Ferreira LMR, Mazzanti A, Yu H, Gu B, Meissner TB, Li Q, Strominger JL. Progesterone-mediated remodeling of the maternal-fetal interface by a PGRMC1-dependent mechanism. J Reprod Immunol 2024; 163:104244. [PMID: 38555747 PMCID: PMC11151737 DOI: 10.1016/j.jri.2024.104244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 02/27/2024] [Accepted: 03/19/2024] [Indexed: 04/02/2024]
Abstract
Implantation and maintenance of pregnancy involve intricate immunological processes that enable the developing fetus to coexist with the maternal immune system. Progesterone, a critical hormone during pregnancy, is known to promote immune tolerance and prevent preterm labor. However, the mechanism by which progesterone mediates these effects remains unclear. In this study, we investigated the role of the non-classical progesterone receptor membrane component 1 (PGRMC1) in progesterone signaling at the maternal-fetal interface. Using JEG3 cells, a trophoblast model cell line, we observed that progesterone stimulation increased the expression of human leukocyte antigen-C (HLA-C) and HLA-G, key molecules involved in immune tolerance. We also found that progesterone upregulated the expression of the transcription factor ELF3, which is known to regulate trophoblast-specific HLA-C expression. Interestingly, JEG3 cells lacked expression of classical progesterone receptors (PRs) but exhibited high expression of PGRMC1, a finding we confirmed in primary trophoblasts by mining sc-RNA seq data from human placenta. To investigate the role of PGRMC1 in progesterone signaling, we used CRISPR/Cas9 technology to knockout PGRMC1 in JEG3 cells. PGRMC1-deficient cells showed a diminished response to progesterone stimulation. Furthermore, we found that the progesterone antagonist RU486 inhibited ELF3 expression in a PGRMC1-dependent manner, suggesting that RU486 acts as a progesterone antagonist by competing for receptor binding. Additionally, we found that RU486 inhibited cell invasion, an important process for successful pregnancy, and this inhibitory effect was dependent on PGRMC1. Our findings highlight the crucial role of PGRMC1 in mediating the immunoregulatory effects of progesterone at the maternal-fetal interface.
Collapse
Affiliation(s)
- Fang Wang
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, United States; Department of Obstetrics, Zhongnan Hospital, Wuhan University, Hubei 430072, China
| | - Leonardo M R Ferreira
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, United States; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
| | - Andrew Mazzanti
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, United States; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Huaxiao Yu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Bowen Gu
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, United States
| | - Torsten B Meissner
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, United States; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
| | - Qin Li
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, United States; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China.
| | - Jack L Strominger
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, United States.
| |
Collapse
|
|
6
|
Retis-Resendiz AM, Cid-Cruz Y, Velázquez-Hernández DM, Romero-Reyes J, León-Juárez M, García-Gómez E, Camacho-Arroyo I, Vázquez-Martínez ER. cAMP regulates the progesterone receptor gene expression through the protein kinase A pathway during decidualization in human immortalized endometrial stromal cells. Steroids 2024; 203:109363. [PMID: 38182066 DOI: 10.1016/j.steroids.2024.109363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 12/27/2023] [Accepted: 01/02/2024] [Indexed: 01/07/2024]
Abstract
Decidualization, a crucial process for successful pregnancy establishment and maintenance, involves endometrial stromal cell differentiation. This process is orchestrated by estradiol (E2), progesterone, and other stimuli that increase intracellular cyclic adenosine monophosphate (cAMP) levels. The intracellular progesterone receptor (PR), encoded by the PGR gene, has a key role in decidualization. This study aimed to understand the role of sex steroids and cAMP in regulating PGR expression during the in vitro decidualization of the human immortalized endometrial stromal cell line, T-HESC. We subjected the cells to individual and combined treatments of E2, medroxyprogesterone (MPA), and cAMP. Additionally, we treated cells with PR and estrogen receptor antagonists and a protein kinase A (PKA) inhibitor. We evaluated the expression of PGR isoforms and decidualization-associated genes by RT-qPCR. Our findings revealed that cAMP induced PGR-B and PGR-AB expression by activating the PKA signaling pathway, while MPA downregulated their expression through the PR. Furthermore, downstream genes involved in decidualization, such as those coding for prolactin (PRL), insulin-like growth factor-binding protein-1 (IGFBP1), and Dickkopf-1 (DKK1), exhibited positive regulation via the cAMP-PKA pathway. Remarkably, MPA-activated PR signaling induced the expression of IGFBP1 and DKK1 but inhibited that of PRL. In conclusion, we have demonstrated that the PKA signaling pathway induces PGR gene expression during in vitro decidualization of the T-HESC human endometrial stromal cell line. This study has unraveled some of the intricate regulatory mechanisms governing PGR expression during this fundamental process for implantation and pregnancy maintenance.
Collapse
Affiliation(s)
- Alejandra Monserrat Retis-Resendiz
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología (INPer)-Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Mexico City 11000, Mexico
| | - Yesenia Cid-Cruz
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología (INPer)-Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Mexico City 11000, Mexico
| | - Dora María Velázquez-Hernández
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología (INPer)-Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Mexico City 11000, Mexico
| | - Jessica Romero-Reyes
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología (INPer)-Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Mexico City 11000, Mexico
| | - Moisés León-Juárez
- Departamento de Inmunobioquímica, Instituto Nacional de Perinatología (INPer), Mexico City 11000, Mexico
| | - Elizabeth García-Gómez
- Consejo Nacional de Humanidades, Ciencias y Tecnologías (CONAHCYT)-Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología (INPer)-Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Mexico City 11000, Mexico
| | - Ignacio Camacho-Arroyo
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología (INPer)-Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Mexico City 11000, Mexico
| | - Edgar Ricardo Vázquez-Martínez
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología (INPer)-Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Mexico City 11000, Mexico.
| |
Collapse
|
|
7
|
Zhang Q, Xu W, Kong Z, Wu Y, Liu Y. Cadmium exposure-induced rat testicular dysfunction and its mechanism of chronic stress. Food Chem Toxicol 2023; 182:114181. [PMID: 37972751 DOI: 10.1016/j.fct.2023.114181] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 10/23/2023] [Accepted: 11/03/2023] [Indexed: 11/19/2023]
Abstract
Cadmium is a common environmental pollutant in daily life, the toxic mechanisms of chronic cadmium exposure on the testes have not been fully elucidated. This study aimed to explore the effects of cadmium exposure on male reproductive health and its mechanism. The results showed that cadmium exposure led widened interstitial spaces, abnormal seminiferous tubule morphology, and decreased Leydig cell numbers. Moreover, sperm quality was significantly reduced, along with a decrease in fertility rate. And cadmium exposure could activate the hypothalamic-pituitary-adrenal (HPA) axis, elevate blood glucocorticoid levels, subsequently increase glucocorticoid receptor (GR) expression and activation in testicular Leydig cells. Then GR act on the glucocorticoid receptor element (GRE) in the DNA methyltransferase 3 A (DNMT3A) promoter region and upregulate DNMT3A expression. Consequently, this led to an increase in DNA methylation levels in the angiotensin II receptor 2 (AT2R) promoter region, resulting in reduced AT2R expression and inhibiting testicular steroidogenesis. This study systematically elucidated that cadmium exposure could lead to testicular steroidogenesis suppression and decreased fertility through the GR/DNMT3A/AT2R signaling pathway. This research further provides theoretical and experimental evidence for confirming the threat of cadmium exposure to human reproduction, and contributes to the guidance and protection of male reproductive health.
Collapse
Affiliation(s)
- Qi Zhang
- Department of Clinical Pharmacy, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, Hubei, 445000, China
| | - Wei Xu
- Department of Neurology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, Hubei, 445000, China
| | - ZiYu Kong
- Department of Pharmacology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, 430071, China
| | - YuJiao Wu
- Department of Clinical Pharmacy, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, Hubei, 445000, China.
| | - Yi Liu
- China Tobacco HuBei Industrial LLC, Wuhan, 430071, China.
| |
Collapse
|
|
8
|
Behmagham F, Abdullah MN, Azimi SB, Ubaid M, Ali ATA, Adhab AH, Sami MH, Soleimani-Amiri S, Vessally E. Reductive coupling of nitro compounds with boronic acid derivatives: an overview. RSC Adv 2023; 13:33390-33402. [PMID: 37964904 PMCID: PMC10642445 DOI: 10.1039/d3ra05100e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 10/16/2023] [Indexed: 11/16/2023] Open
Abstract
The purpose of this review is to summarize the current literature on reductive C-N coupling of nitro compounds and boronic acids, with special emphasis on the mechanistic features of the reactions. The metal-catalyzed reactions are discussed first. This is followed by electro-synthesis and organophosphorus-catalyzed reactions. Finally, the available examples of catalyst-free reactions will be covered at the end of this review.
Collapse
Affiliation(s)
- Farnaz Behmagham
- Department of Chemistry, Miandoab Branch, Islamic Azad University Miandoab Iran
| | - Media Noori Abdullah
- Department of Chemistry, College of Science, Salahaddin University-Erbil Kurdistan Region Iraq
| | - Seyedeh Bahareh Azimi
- Assessment and Environment Risks Department, Research Center of Envirnment and Sustainable Development (RCESD) Tehran Iran
| | | | - Abbas Talib Abd Ali
- College of Health and Medical Technologies, National University of Science and Technology Dhi Qar Iraq
| | | | | | | | - Esmail Vessally
- Department of Chemistry, Payame Noor University P. O. Box 19395-3697 Tehran Iran
| |
Collapse
|
|
9
|
Pech M, Steinbach C, Kocour M, Prokopová I, Šandová M, Bořík A, Lutz I, Kocour Kroupová H. Effects of mifepristone, a model compound with anti-progestogenic activity, on the development of African clawed frog (Xenopus laevis). AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2023; 263:106694. [PMID: 37716317 DOI: 10.1016/j.aquatox.2023.106694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 08/23/2023] [Accepted: 09/09/2023] [Indexed: 09/18/2023]
Abstract
The objective of this study was to assess the effects of a model substance with anti-progestogenic activity on development of African clawed frog (Xenopus laevis) from tadpole to juvenile stage. Mifepristone, a synthetic progesterone receptor-blocking steroid hormone used in medicine as an abortifacient, was chosen as a model compound with anti-progestogenic activity. In the experiment, African clawed frog tadpoles were exposed to mifepristone at three concentrations (2, 21, and 215 ng L-1). A control group was exposed to dimethyl sulfoxide (DMSO; 0.001 %). The experiment started when tadpoles reached stages 47-48 according to Nieuwkoop and Faber (NF; 1994) and continued until stage NF 66, when metamorphosis was complete. Exposure to mifepristone had no significant effect on the rate of tadpole development, occurrence of morphological anomalies, weight, body length, or sex ratio. Mortality was within an acceptable range of 0-3.6 % throughout the test and did not differ among the groups. Histopathological examination of the gonads and thyroid gland revealed no significant changes. Therefore, we can conclude that mifepristone had no negative effect on development of the African clawed frog up to juvenile stage. Nevertheless, at the highest tested mifepristone concentration (215 ng L-1), gene expression analysis revealed up-regulation of mRNA expression of nuclear progesterone receptor (npr), membrane progesterone receptor (mpr), estrogen receptor beta (esrβ), and luteinizing hormone (lh) in the brain-pituitary complex of exposed frogs at stage NF 66. Higher mRNA expression of npr was also found in frogs exposed to 22 ng L-1 mifepristone compared to the solvent control. These findings confirmed the anti-progestogenic activity of mifepristone in frogs because the up-regulation of progesterone receptors occurs if progesterone availability in the body is reduced. All the observed changes in combination may have negative consequences for reproduction and reproductive behavior later in life.
Collapse
Affiliation(s)
- Michal Pech
- Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Research Institute of Fish Culture and Hydrobiology, University of South Bohemia in České Budějovice, Zátiší 728/II, Vodňany, 389 25, Czech Republic.
| | - Christoph Steinbach
- Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Research Institute of Fish Culture and Hydrobiology, University of South Bohemia in České Budějovice, Zátiší 728/II, Vodňany, 389 25, Czech Republic
| | - Martin Kocour
- Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Research Institute of Fish Culture and Hydrobiology, University of South Bohemia in České Budějovice, Zátiší 728/II, Vodňany, 389 25, Czech Republic
| | - Ilona Prokopová
- Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Research Institute of Fish Culture and Hydrobiology, University of South Bohemia in České Budějovice, Zátiší 728/II, Vodňany, 389 25, Czech Republic
| | - Marie Šandová
- Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Research Institute of Fish Culture and Hydrobiology, University of South Bohemia in České Budějovice, Zátiší 728/II, Vodňany, 389 25, Czech Republic
| | - Adam Bořík
- Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Research Institute of Fish Culture and Hydrobiology, University of South Bohemia in České Budějovice, Zátiší 728/II, Vodňany, 389 25, Czech Republic
| | - Ilka Lutz
- Leibniz-Institute of Freshwater Ecology and Inland Fisheries (IGB), Müggelseedamm 310, Berlin 12587, Federal Republic of Germany
| | - Hana Kocour Kroupová
- Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Research Institute of Fish Culture and Hydrobiology, University of South Bohemia in České Budějovice, Zátiší 728/II, Vodňany, 389 25, Czech Republic
| |
Collapse
|
|
10
|
Shimels T, Getnet M, Shafie M, Belay L. Comparison of mifepristone plus misoprostol with misoprostol alone for first trimester medical abortion: A systematic review and meta-analysis. Front Glob Womens Health 2023; 4:1112392. [PMID: 36970118 PMCID: PMC10038101 DOI: 10.3389/fgwh.2023.1112392] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 02/07/2023] [Indexed: 03/08/2023] Open
Abstract
ObjectiveTo compare mifepristone plus a misoprostol-combined regimen with misoprostol alone in the medical abortion of first trimester pregnancy.MethodsAn internet-based search of available literature was performed using text words contained in titles and abstracts. PubMed/Medline, Cochrane CENTRAL, EMBASE, and Google scholar were used to locate English-based articles published until December 2021. Studies fulfilling the inclusion criteria were selected, appraised, and assessed for methodological quality. The included studies were pooled for meta-analysis, and the results were presented in risk ratio at a 95% confidence interval.FindingsNine studies comprising 2,052 participants (1,035 intervention and 1,017 controls) were considered. Primary endpoints were complete expulsion, incomplete expulsion, missed abortion, and ongoing pregnancy. The intervention was found to more likely induce complete expulsion irrespective of gestational age (RR: 1.19; 95% CI: 1.14–1.25). The administration of misoprostol 800 mcg after 24 h of mifepristone pre-treatment in the intervention group more likely induced complete expulsion (RR: 1.23; 95% CI: 1.17–1.30) than after 48 h. The intervention group was also more likely to experience complete expulsion when misoprostol was used either vaginally (RR: 1.16; 95% CI: 1.09–1.17) or buccally (RR: 1.23; 95% CI: 1.16–1.30). The intervention was more effective in the subgroup with a negative foetal heartbeat at reducing incomplete abortion (RR: 0.45; 95% CI: 0.26–0.78) compared with the control group. The intervention more likely reduced both missed abortion (RR: 0.21; 95% CI: 0.08–0.91) and ongoing pregnancy (RR: 0.12; 95% CI: 0.05–0.26). Fever was less likely to be reported (RR: 0.78; 95% CI: 0.12–0.89), whereas the subjective experience of bleeding was more likely to be encountered (RR: 1.31; 95% CI: 1.13–1.53) by the intervention group.ConclusionThe review strengthened the theory that a combined mifepristone and misoprostol regimen can be an effective medical management for inducing abortions during first trimester pregnancy in all contexts. Specifically, there is a high-level certainty of evidence on complete expulsion during the early stage and its ability to reduce both missed and ongoing pregnancies.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019134213, identifier CRD42019134213.
Collapse
Affiliation(s)
- Tariku Shimels
- Research Directorate,St. Paul’s Hospital Millennium Medical College, Addis Ababa, Ethiopia
- Correspondence: Tariku Shimels
| | - Melsew Getnet
- Research Directorate,St. Paul’s Hospital Millennium Medical College, Addis Ababa, Ethiopia
| | - Mensur Shafie
- Department of Pharmacology, St. Paul’s Hospital Millennium Medical College, Addis Ababa, Ethiopia
| | - Lemi Belay
- Department of Obstetrics and Gynaecology, St. Paul’s Hospital Millennium Medical College, Addis Ababa, Ethiopia
| |
Collapse
|
|
11
|
Wang W, Kang Y, Jiang Y, Zhuang Y, Zhang G, Chen Y, Zhou F. Mifepristone increases AQP1 mRNA expression, angiogenesis, and cell permeability through the ERK MAPK pathway. Mol Biol Rep 2023; 50:1069-1077. [PMID: 36394707 DOI: 10.1007/s11033-022-08082-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 10/25/2022] [Indexed: 11/19/2022]
Abstract
AIMS The purpose of this study was to investigate the mechanism of mifepristone serves as an anti-implantation contraceptive drug on aquaporins 1 (AQP1) expression. METHODS Human umbilical vein endothelial cells (HUVECs) were used to detect the effects of different concentrations of mifepristone (0, 0.065, 0.2, and 1 μmol/L) on the activity of angiogenesis and AQP1 expression. The expression of AQP1 was tested by the real-time PCR. The angiogenesis and penetration function of HUVECs was investigated by Matrigel lumen formation and trans-well assay, respectively. RESULTS The expression of AQP1, angiogenesis and cell permeability were significantly higher than control groups in HUVECs treatment with mifepristone at 1 μmol/L for 12 h. Estrogen and progesterone decreased the up-regulation of AQP1 and cell permeability, not angiogenesis, induced by mifepristone. Mifepristone increased protein levels of p-ERK, not p-p38 or p-JNK, and pre-treatment with ERK MAPK-specific inhibitor significantly inhibited the up-regulation of AQP1 mRNA expression, angiogenesis and cell permeability induced by mifepristone. si-AQP1 significantly reduced the up-regulation of angiogenesis, cell permeability and p-ERK/ERK ratio expression induced by mifepristone treatment. Overexpression of AQP1 enhanced the increase of expression ratio of p-ERK/ERK induced by mifepristone. CONCLUSIONS Low-dose mifepristone increased cell permeability, angiogenesis and AQP1 expression, which was involved in MAPK pathways. This provides new insights into the molecular mechanism of mifepristone serves as an anti-implantation contraceptive drug.
Collapse
Affiliation(s)
- Wenwen Wang
- Department of Pathology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang Province, China
| | - Yuanyuan Kang
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Yu Jiang
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Yalin Zhuang
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Gensheng Zhang
- National Clinical Research Center for Child Health, National Children's Regional Medical Center, the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Yuezhou Chen
- Department of Reproductive Medicine Center, Zhongshan City People's Hospital, Zhongshan, 528403, China.
| | - Feng Zhou
- Department of Pathology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang Province, China.
| |
Collapse
|
|
12
|
Bensreti H, Alhamad DW, Gonzalez AM, Pizarro-Mondesir M, Bollag WB, Isales CM, McGee-Lawrence ME. Update on the Role of Glucocorticoid Signaling in Osteoblasts and Bone Marrow Adipocytes During Aging. Curr Osteoporos Rep 2023; 21:32-44. [PMID: 36564571 PMCID: PMC9936962 DOI: 10.1007/s11914-022-00772-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/15/2022] [Indexed: 12/25/2022]
Abstract
PURPOSE OF REVIEW Bone marrow adipose tissue (BMAT) in the skeleton likely plays a variety of physiological and pathophysiological roles that are not yet fully understood. In elucidating the complex relationship between bone and BMAT, glucocorticoids (GCs) are positioned to play a key role, as they have been implicated in the differentiation of bone marrow mesenchymal stem cells (BMSCs) between osteogenic and adipogenic lineages. The purpose of this review is to illuminate aspects of both endogenous and exogenous GC signaling, including the influence of GC receptors, in mechanisms of bone aging including relationships to BMAT. RECENT FINDINGS Harmful effects of GCs on bone mass involve several cellular pathways and events that can include BMSC differentiation bias toward adipogenesis and the influence of mature BMAT on bone remodeling through crosstalk. Interestingly, BMAT involvement remains poorly explored in GC-induced osteoporosis and warrants further investigation. This review provides an update on the current understanding of the role of glucocorticoids in the biology of osteoblasts and bone marrow adipocytes (BMAds).
Collapse
Affiliation(s)
- Husam Bensreti
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Dima W Alhamad
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Alejandro Marrero Gonzalez
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Manuel Pizarro-Mondesir
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Wendy B Bollag
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, USA
- Charlie Norwood VA Medical Center, Augusta, GA, USA
| | - Carlos M Isales
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
- Department of Orthopaedic Surgery, Medical College of Georgia, Augusta University, Augusta, GA, USA
- Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Meghan E McGee-Lawrence
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA.
- Department of Orthopaedic Surgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.
| |
Collapse
|
|
13
|
Check JH, Check DL. The role of progesterone and the progesterone receptor in cancer: progress in the last 5 years. Expert Rev Endocrinol Metab 2023; 18:5-18. [PMID: 36647582 DOI: 10.1080/17446651.2023.2166487] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 01/05/2023] [Indexed: 01/15/2023]
Abstract
INTRODUCTION Patients with various advanced cancers devoid of nuclear progesterone receptors (nPR) have demonstrated increased quality and length of life when treated with the PR modulator mifepristone, which likely works by interacting with membrane PRs (mPR). AREAS COVERED Two immunomodulatory proteins are discussed that seem to play a role in cancers that proliferate whether the malignant tumor is positive or negative for the nPR. These two proteins are the progesterone receptor membrane component-1 (PGRMC-1) and the progesterone-induced blocking factor (PIBF). Both PGRMC-1 and the parent form of PIBF foster increased tumor aggressiveness, whereas splice variants of the 90 kDa form of PIBF inhibit immune response against cancer cells. EXPERT OPINION The marked clinical improvement following 200-300 mg of mifepristone is likely related to blocking PIBF. In the low dosage used, mifepristone likely acts as an agonist for PGRMC-1 protein. Mifepristone may be less effective for cancers positive for the nPR because the nPR may be protective and blocking it may have detrimental effects. Based on this hypothetical model, the development of other potential treatment options to provide even greater efficacy for treating cancer are discussed.
Collapse
Affiliation(s)
- Jerome H Check
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Cooper Medical School of Rowan University, Camden, New Jersey, USA
- Cooper Institute for Reproductive Hormonal Disorders P.C, Mt. Laurel, New Jersey, USA
| | - Diane L Check
- Cooper Institute for Reproductive Hormonal Disorders P.C, Mt. Laurel, New Jersey, USA
| |
Collapse
|
|
14
|
Cruz JVR, Batista C, Afonso BDH, Alexandre-Moreira MS, Dubois LG, Pontes B, Moura Neto V, Mendes FDA. Obstacles to Glioblastoma Treatment Two Decades after Temozolomide. Cancers (Basel) 2022; 14:cancers14133203. [PMID: 35804976 PMCID: PMC9265128 DOI: 10.3390/cancers14133203] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/17/2022] [Accepted: 06/21/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Glioblastomas are the most common and aggressive brain tumors in adults, with a median survival of 15 months. Treatment is surgical removal, followed by chemotherapy and/or radiotherapy. Current chemotherapeutics do not kill all the tumor cells and some cells survive, leading to the appearance of a new tumor resistant to the treatment. These treatment-resistant cells are called tumor stem cells. In addition, glioblastoma cells have a high capacity for migration, forming new tumors in areas distant from the original tumor. Studies are now focused on understanding the molecular mechanisms of chemoresistance and controlling drug entry into the brain to improve drug performance. Another promising therapeutic approach is the use of viruses that specifically destroy glioblastoma cells, preserving the neural tissue around the tumor. In this review, we summarize the main biological features of glioblastoma and the therapeutic targets that are currently under study for new clinical trials. Abstract Glioblastomas are considered the most common and aggressive primary brain tumor in adults, with an average of 15 months’ survival rate. The treatment is surgery resection, followed by chemotherapy with temozolomide, and/or radiotherapy. Glioblastoma must have wild-type IDH gene and some characteristics, such as TERT promoter mutation, EGFR gene amplification, microvascular proliferation, among others. Glioblastomas have great heterogeneity at cellular and molecular levels, presenting distinct phenotypes and diversified molecular signatures in each tumor mass, making it difficult to define a specific therapeutic target. It is believed that the main responsibility for the emerge of these distinct patterns lies in subcellular populations of tumor stem cells, capable of tumor initiation and asymmetric division. Studies are now focused on understanding molecular mechanisms of chemoresistance, the tumor microenvironment, due to hypoxic and necrotic areas, cytoskeleton and extracellular matrix remodeling, and in controlling blood brain barrier permeabilization to improve drug delivery. Another promising therapeutic approach is the use of oncolytic viruses that are able to destroy specifically glioblastoma cells, preserving the neural tissue around the tumor. In this review, we summarize the main biological characteristics of glioblastoma and the cutting-edge therapeutic targets that are currently under study for promising new clinical trials.
Collapse
Affiliation(s)
- João Victor Roza Cruz
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro. Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde, Bloco F, Ilha do Fundão, Cidade Universitária, Rio de Janeiro 21941-590, Brazil; (J.V.R.C.); (C.B.); (B.d.H.A.); (B.P.); (V.M.N.)
| | - Carolina Batista
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro. Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde, Bloco F, Ilha do Fundão, Cidade Universitária, Rio de Janeiro 21941-590, Brazil; (J.V.R.C.); (C.B.); (B.d.H.A.); (B.P.); (V.M.N.)
| | - Bernardo de Holanda Afonso
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro. Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde, Bloco F, Ilha do Fundão, Cidade Universitária, Rio de Janeiro 21941-590, Brazil; (J.V.R.C.); (C.B.); (B.d.H.A.); (B.P.); (V.M.N.)
- Instituto Estadual do Cérebro Paulo Niemeyer, Rua do Rezende 156, Rio de Janeiro 20231-092, Brazil
| | - Magna Suzana Alexandre-Moreira
- Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, Campus A.C. Simões, Avenida Lourival Melo Mota, Maceio 57072-970, Brazil;
| | - Luiz Gustavo Dubois
- UFRJ Campus Duque de Caxias Professor Geraldo Cidade, Rodovia Washington Luiz, n. 19.593, km 104.5, Santa Cruz da Serra, Duque de Caxias 25240-005, Brazil;
| | - Bruno Pontes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro. Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde, Bloco F, Ilha do Fundão, Cidade Universitária, Rio de Janeiro 21941-590, Brazil; (J.V.R.C.); (C.B.); (B.d.H.A.); (B.P.); (V.M.N.)
| | - Vivaldo Moura Neto
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro. Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde, Bloco F, Ilha do Fundão, Cidade Universitária, Rio de Janeiro 21941-590, Brazil; (J.V.R.C.); (C.B.); (B.d.H.A.); (B.P.); (V.M.N.)
- Instituto Estadual do Cérebro Paulo Niemeyer, Rua do Rezende 156, Rio de Janeiro 20231-092, Brazil
| | - Fabio de Almeida Mendes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro. Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde, Bloco F, Ilha do Fundão, Cidade Universitária, Rio de Janeiro 21941-590, Brazil; (J.V.R.C.); (C.B.); (B.d.H.A.); (B.P.); (V.M.N.)
- Correspondence:
| |
Collapse
|
|
15
|
Wu L, Xiong W, Zeng M, Yan A, Song L, Chen M, Wei T, Zu Q, Zhang J. Different dosing intervals of mifepristone-misoprostol for second-trimester termination of pregnancy: A meta-analysis and systematic review. Int J Gynaecol Obstet 2021; 154:195-203. [PMID: 33332580 DOI: 10.1002/ijgo.13541] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 09/25/2020] [Accepted: 12/14/2020] [Indexed: 11/06/2022]
Abstract
OBJECTIVE To compare 1- and 2-day drug administration interval between mifepristone and misoprostol for second-trimester pregnancy termination and provide evidence-based recommendations. METHODS Search strategy: the search was performed in Pubmed, EMBASE, and Cochrane Library for the relevant published studies from their establishment to March 2020. SELECTION CRITERIA randomized controlled trials (RCTs) comparing 1- and 2-day time interval of mifepristone-misoprostol for termination of pregnancy during second-trimester pregnancy were considered. Data were processed using Revman 5.3 software. RESULTS Meta-analyses of three RCTs showed no significant difference was reported in the induction-to-abortion time and successful abortion rate between 1- and 2-day mifepristone and misoprostol intervals. Statistical difference was not identified in the induction-to-abortion time between the two drug administration intervals in nulliparous or parous women. CONCLUSIONS Both 1- and 2-day dosing intervals between mifepristone and misoprostol are suitable for clinical use for second-trimester medical termination of pregnancy.
Collapse
Affiliation(s)
- Limei Wu
- Department of Obstetrics and Gynecology, Chengdu Second People's Hospital, Chengdu, Sichuan, China
| | - Wanchun Xiong
- Department of Obstetrics and Gynecology, Chengdu Second People's Hospital, Chengdu, Sichuan, China
| | - Manman Zeng
- Department of Gynecology, Women and Children's Hospital of Guangdong, Guangzhou, Guangdong, China
| | - Aihua Yan
- Department of Obstetrics and Gynecology, Chengdu Second People's Hospital, Chengdu, Sichuan, China
| | - Ling Song
- Department of Obstetrics and Gynecology, Chengdu Second People's Hospital, Chengdu, Sichuan, China
| | - Meng Chen
- Department of Obstetrics and Gynecology, Chengdu Second People's Hospital, Chengdu, Sichuan, China
| | - Tianqin Wei
- Department of Obstetrics and Gynecology, Chengdu Second People's Hospital, Chengdu, Sichuan, China
| | - Qian Zu
- Department of Neurology, Chengdu Second People's Hospital, Chengdu, Sichuan, China
| | - Jiayin Zhang
- Department of Obstetrics and Gynecology, Chengdu Second People's Hospital, Chengdu, Sichuan, China
| |
Collapse
|
|
16
|
Girardelli S, Albano L, Mangili G, Valsecchi L, Rabaiotti E, Cavoretto PI, Mortini P, Candiani M. Meningiomas in Gynecology and Reproduction: an Updated Overview for Clinical Practice. Reprod Sci 2021; 29:2452-2464. [PMID: 33970444 DOI: 10.1007/s43032-021-00606-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/03/2021] [Indexed: 10/21/2022]
Abstract
There is various evidence to suggest a relationship between female hormones and meningiomas; as clinicians, we often come to face challenging situations involving female patients diagnosed with meningiomas during the post-pubertal phases of their life. We aimed to review the specific circumstances (pregnancy, postpartum, hormonal contraception and hormone replacement therapy, gender-affirming hormonal treatment) clinicians might come to face during their daily clinical practice, given the absence of available guidelines. We therefore conducted a narrative review on articles found in PubMed and Embase databases using appropriate keywords. Ninety-six relevant articles were included. The available evidence on managing meningiomas in post-pubertal women often implies personal strategies, highlighting the lack of a unified approach. The knowledge of the biological links between female hormones and meningiomas is fundamental to correctly counsel patients in various life phases. Prospective randomized studies are required to improve available guidelines on how to best manage meningiomas in female post-pubertal patients.
Collapse
Affiliation(s)
- Serena Girardelli
- Obstetrics and Gynecology Department, I.R.C.C.S. San Raffaele Scientific Institute, Vita-Salute University, Via Olgettina 60, 20132, Milan, Italy.
| | - Luigi Albano
- Neurosurgery and Radiosurgery Department, I.R.C.C.S. San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy
| | - Giorgia Mangili
- Obstetrics and Gynecology Department, I.R.C.C.S. San Raffaele Scientific Institute, Vita-Salute University, Via Olgettina 60, 20132, Milan, Italy
| | - Luca Valsecchi
- Obstetrics and Gynecology Department, I.R.C.C.S. San Raffaele Scientific Institute, Vita-Salute University, Via Olgettina 60, 20132, Milan, Italy
| | - Emanuela Rabaiotti
- Obstetrics and Gynecology Department, I.R.C.C.S. San Raffaele Scientific Institute, Vita-Salute University, Via Olgettina 60, 20132, Milan, Italy
| | - Paolo Ivo Cavoretto
- Obstetrics and Gynecology Department, I.R.C.C.S. San Raffaele Scientific Institute, Vita-Salute University, Via Olgettina 60, 20132, Milan, Italy
| | - Pietro Mortini
- Neurosurgery and Radiosurgery Department, I.R.C.C.S. San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy
| | - Massimo Candiani
- Obstetrics and Gynecology Department, I.R.C.C.S. San Raffaele Scientific Institute, Vita-Salute University, Via Olgettina 60, 20132, Milan, Italy
| |
Collapse
|
|
17
|
Kowalewski MP, Pereira MT, Papa P, Gram A. Progesterone receptor blockers: historical perspective, mode of function and insights into clinical and scientific applications. TIERAERZTLICHE PRAXIS AUSGABE KLEINTIERE HEIMTIERE 2020; 48:433-440. [PMID: 33276393 DOI: 10.1055/a-1274-9290] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Antigestagens (antiprogestins) are functional competitors of progesterone (P4) that prevent P4 from mediating its biological functions either by suppressing its production or blocking its function. Among the latter are progesterone antagonists, competitors of P4 binding to its nuclear receptor PGR, which have found application in both human and veterinary medicine, in particular in small animal practice for the prevention of nidation and the interruption of pregnancy. Depending on their mode of action, progesterone receptor antagonists can be divided into 2 classes. Class I antagonists bind to the PGR but fail to induce its binding to promoters of target genes (competitive inhibitors). Class II antigestagens, including aglepristone used in veterinary medicine, bind to the PGR, activate its association with a promoter, but interfere with the downstream signalling cascades, e. g., by recruiting transcriptional repressors. They act thereby as transdominant repressors exerting negative effects on target gene expression. Importantly for experimental sciences, as active antagonists, class II antagonists do not require the presence of the natural ligand for their action. Besides their clinical application, antigestagens are used in research for investigating P4-dependent physiological and pathological processes. Here an overview of the history and the current usage of progesterone receptor antagonists in veterinary medicine and research is presented.
Collapse
Affiliation(s)
| | | | - Paula Papa
- Institute of Veterinary Anatomy, Vetsuisse-Faculty, University of Zurich
| | - Aykut Gram
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Erciyes University
| |
Collapse
|
|
18
|
Gregory S, Hill D, Grey B, Ketelbey W, Miller T, Muniz-Terrera G, Ritchie CW. 11β-hydroxysteroid dehydrogenase type 1 inhibitor use in human disease-a systematic review and narrative synthesis. Metabolism 2020; 108:154246. [PMID: 32333937 DOI: 10.1016/j.metabol.2020.154246] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 04/01/2020] [Accepted: 04/20/2020] [Indexed: 11/20/2022]
Abstract
INTRODUCTION 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an intracellular enzyme that catalyses conversion of cortisone into cortisol; correspondingly, 11β-HSD1 inhibitors inhibit this conversion. This systematic review focuses on the use of 11β-HSD1 inhibitors in diseases known to be associated with abnormalities in hypothalamic pituitary adrenal (HPA) axis function. METHODS The databases screened for suitable papers were: MedLine, EMBASE, Web of Science, ClinicalTrials.gov, and Cochrane Central. RESULTS 1925 papers were identified, of which 29 were included in the final narrative synthesis. 11β-HSD1 and its inhibitors have been studied in diabetes, obesity, metabolic syndrome (MetS), and Alzheimer's disease (AD). Higher expression of 11β-HSD1 is seen in obesity and MetS, but has not yet been described in obesity or AD. Genetic studies identify 11β-HSD1 SNPs of interest in populations with diabetes, MetS, and AD. One phase II trial successfully reduced HbA1c in a diabetic population, however trials in MetS, obesity, and AD have not met primary endpoints. CONCLUSIONS Translation of this research from preclinical studies has proved challenging so far, however this is a growing area of research and more studies should focus on understanding the complex relationships between 11β-HSD1 and disease pathology, especially given the therapeutic potential of 11β-HSD1 inhibitors in development.
Collapse
Affiliation(s)
- Sarah Gregory
- Centre for Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
| | - David Hill
- Centre for Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Ben Grey
- Centre for Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | | | | | - Graciela Muniz-Terrera
- Centre for Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Craig W Ritchie
- Centre for Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| |
Collapse
|
|
19
|
Bray B, Clement KA, Bachmeier D, Weber MA, Forster GL. Corticosterone in the ventral hippocampus differentially alters accumbal dopamine output in drug-naïve and amphetamine-withdrawn rats. Neuropharmacology 2020; 165:107924. [PMID: 31881169 DOI: 10.1016/j.neuropharm.2019.107924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 12/19/2019] [Accepted: 12/20/2019] [Indexed: 12/26/2022]
Abstract
Dysregulation in glucocorticoid stress and accumbal dopamine reward systems can alter reward salience to increase motivational drive in control conditions while contributing to relapse during drug withdrawal. Amphetamine withdrawal is associated with dysphoria and stress hypersensitivity that may be mediated, in part, by enhanced stress-induced corticosterone observed in the ventral hippocampus. Electrical stimulation of the ventral hippocampus enhances accumbal shell dopamine release, establishing a functional connection between these two regions. However, the effects of ventral hippocampal corticosterone on this system are unknown. To address this, a stress-relevant concentration of corticosterone (0.24ng/0.5 μL) or vehicle were infused into the ventral hippocampus of urethane-anesthetized adult male rats in control and amphetamine withdrawn conditions. Accumbal dopamine output was assessed with in vivo chronoamperometry. Corticosterone infused into the ventral hippocampus rapidly enhanced accumbal dopamine output in control conditions, but produced a biphasic reduction of accumbal dopamine output in amphetamine withdrawal. Selectively blocking glucocorticoid-, mineralocorticoid-, or cytosolic receptors prevented the effects of corticosterone. Overall, these results suggest that the ability of corticosterone to alter accumbal dopamine output requires cooperative activation of mineralocorticoid and glucocorticoid receptors in the cytosol, which is dysregulated during amphetamine withdrawal. These findings implicate ventral hippocampal corticosterone in playing an important role in driving neural systems involved in positive stress coping mechanisms in healthy conditions, whereas dysregulation of this system may contribute to relapse during withdrawal.
Collapse
Affiliation(s)
- Brenna Bray
- Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark St., Vermillion, SD, 57069, USA.
| | - Kaci A Clement
- Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark St., Vermillion, SD, 57069, USA.
| | - Dana Bachmeier
- Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark St., Vermillion, SD, 57069, USA.
| | - Matthew A Weber
- Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark St., Vermillion, SD, 57069, USA; Department of Neurology, Iowa Neuroscience Institute, Pappajohn Biomedical Discovery Building, 169 Newton Road, Iowa City, IA, 52242, USA.
| | - Gina L Forster
- Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark St., Vermillion, SD, 57069, USA; Department of Anatomy and Brain Health Research Centre, University of Otago, PO Box 56, Dunedin, 9054, New Zealand.
| |
Collapse
|
|
20
|
First trimester termination of pregnancy. Best Pract Res Clin Obstet Gynaecol 2020; 63:13-23. [DOI: 10.1016/j.bpobgyn.2019.06.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 06/17/2019] [Indexed: 11/19/2022]
|
|
21
|
Progesterone signaling in myometrial cells: role in human pregnancy and parturition. CURRENT OPINION IN PHYSIOLOGY 2020. [DOI: 10.1016/j.cophys.2019.09.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
|
|
22
|
|
|
23
|
DeBono A, Thomas DR, Lundberg L, Pinkham C, Cao Y, Graham JD, Clarke CL, Wagstaff KM, Shechter S, Kehn-Hall K, Jans DA. Novel RU486 (mifepristone) analogues with increased activity against Venezuelan Equine Encephalitis Virus but reduced progesterone receptor antagonistic activity. Sci Rep 2019; 9:2634. [PMID: 30796232 PMCID: PMC6385310 DOI: 10.1038/s41598-019-38671-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 12/27/2018] [Indexed: 12/21/2022] Open
Abstract
There are currently no therapeutics to treat infection with the alphavirus Venezuelan equine encephalitis virus (VEEV), which causes flu-like symptoms leading to neurological symptoms in up to 14% of cases. Large outbreaks of VEEV can result in 10,000 s of human cases and mass equine death. We previously showed that mifepristone (RU486) has anti-VEEV activity (EC50 = 20 μM) and only limited cytotoxicity (CC50 > 100 μM), but a limitation in its use is its abortifacient activity resulting from its ability to antagonize the progesterone receptor (PR). Here we generate a suite of new mifepristone analogues with enhanced antiviral properties, succeeding in achieving >11-fold improvement in anti-VEEV activity with no detectable increase in toxicity. Importantly, we were able to derive a lead compound with an EC50 of 7.2 µM and no detectable PR antagonism activity. Finally, based on our SAR analysis we propose avenues for the further development of these analogues as safe and effective anti-VEEV agents.
Collapse
Affiliation(s)
- Aaron DeBono
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia
| | - David R Thomas
- Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology School of Biomedical Sciences, Monash University, Melbourne, Australia
| | - Lindsay Lundberg
- National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, USA
| | - Chelsea Pinkham
- National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, USA
| | - Ying Cao
- Centre for Cancer Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - J Dinny Graham
- Centre for Cancer Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Christine L Clarke
- Centre for Cancer Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Kylie M Wagstaff
- Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology School of Biomedical Sciences, Monash University, Melbourne, Australia
| | | | - Kylene Kehn-Hall
- National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, USA
| | - David A Jans
- Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology School of Biomedical Sciences, Monash University, Melbourne, Australia.
| |
Collapse
|
|
24
|
Bou Khalil R, Smayra V, Saliba Y, Hajal J, Bakhos JJ, Souaiby L, Richa S, Tamraz J, Farès N. Mifepristone reduces hypothalamo-pituitary-adrenal axis activation and restores weight loss in rats subjected to dietary restriction and methylphenidate administration. Neurosci Res 2017; 135:46-53. [PMID: 29288690 DOI: 10.1016/j.neures.2017.12.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 12/16/2017] [Accepted: 12/22/2017] [Indexed: 11/16/2022]
Abstract
This study evaluates the efficacy of mifepristone on weight restoration in rats subjected to dietary restriction and methylphenidate administration. 25 female rats aged between 9 and 12 months were divided into 2 groups: 5 controls (exposed only to dietary restriction) and 20 rats that were administered 5 mg/kg/d of methylphenidate before meal exposure, for 36 days. Among rats who responded to methylphenidate (weight loss of 15-25%) weeks after its administration, a group of 6 rats continued to receive only methylphenidate ("Met" group), and another group received 10 mg/kg/d of mifepristone in addition to methylphenidate for 18 days ("Met+Mif" group; n = 6). The mean weight of the "Met+Mif" group remained significantly lower when compared to the control group (87.63 ± 2.83% vs 96.29 ± 3.26%; p < 0.001 respectively) but was significantly higher than that of the "Met" group (87.63 ± 2.83% vs. 80.61 ± 3.52%; p < 0.001 respectively). Plasma concentrations of adiponectin and gene expression of its receptors in rats brain were significantly higher in the "Met" group as compared to the "Met+Mif" and control groups (p < 0.01). Accordingly, mifepristone reduces HPA axis activation and restores weight through adipose tissue recovering. It might be considered a promising treatment for anorexia nervosa patients in future studies.
Collapse
Affiliation(s)
- Rami Bou Khalil
- Saint Joseph University, Hôtel Dieu de France Hospital, Department of Psychiatry, Beirut, Lebanon; Saint Joseph University, Research Laboratory in Physiology and Physiopathology, LRPP, Beirut, Lebanon; Saint Joseph University, Faculty of Medicine, Beirut, Lebanon.
| | - Viviane Smayra
- Saint Joseph University, Faculty of Medicine, Beirut, Lebanon
| | - Youakim Saliba
- Saint Joseph University, Research Laboratory in Physiology and Physiopathology, LRPP, Beirut, Lebanon
| | - Joelle Hajal
- Saint Joseph University, Research Laboratory in Physiology and Physiopathology, LRPP, Beirut, Lebanon
| | - Jules-Joël Bakhos
- Saint Joseph University, Research Laboratory in Physiology and Physiopathology, LRPP, Beirut, Lebanon
| | - Lama Souaiby
- National mental health program, Ministry of public health, Beirut, Lebanon
| | - Sami Richa
- Saint Joseph University, Hôtel Dieu de France Hospital, Department of Psychiatry, Beirut, Lebanon; Saint Joseph University, Faculty of Medicine, Beirut, Lebanon; Saint Joseph University, Head of department of Psychiatry, Beirut, Lebanon
| | - Jean Tamraz
- Saint Joseph University, Faculty of Medicine, Beirut, Lebanon; Saint Joseph University, Hôtel Dieu de France Hospital, Department of Neuroimaging, Beirut, Lebanon
| | - Nassim Farès
- Saint Joseph University, Research Laboratory in Physiology and Physiopathology, LRPP, Beirut, Lebanon; Saint Joseph University, Faculty of Medicine, Beirut, Lebanon
| |
Collapse
|
|
25
|
Sant'Anna GDS, Brum IS, Branchini G, Pizzolato LS, Capp E, Corleta HVE. Ovarian steroid hormones modulate the expression of progesterone receptors and histone acetylation patterns in uterine leiomyoma cells. Gynecol Endocrinol 2017; 33:629-633. [PMID: 28300476 DOI: 10.1080/09513590.2017.1301924] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Uterine leiomyomas are the most common benign smooth muscle cell tumors in women. Estrogen (E2), progesterone (P4) and environmental factors play important roles in the development of these tumors. New treatments, such as mifepristone, have been proposed. We evaluated the gene expression of total (PRT) and B (PRB) progesterone receptors, and the histone acetyltransferase (HAT) and deacetylase (HDAC) activity after treatment with E2, P4 and mifepristone (RU486) in primary cell cultures from uterine leiomyoma and normal myometrium. Compared to myometrium, uterine leiomyoma cells showed an increase in PRT mRNA expression when treated with E2, and increase in PRB mRNA expression when treated with E2 and P4. Treatment with mifepristone had no significant impact on mRNA expression in these cells. The HDAC activity was higher in uterine leiomyoma compared to myometrial cells after treatment with E2 and E2 + P4 + mifepristone. HAT activity was barely detectable. Our results suggest that ovarian steroid hormones modulate PR, and mifepristone was unable to decrease PRT and PRB mRNA. The higher activity of HDAC leiomyoma cells could be involved in transcriptional repression of genes implicated in normal myometrium cell function, contributing to the maintenance and growth of uterine leiomyoma.
Collapse
Affiliation(s)
- Gabriela Dos Santos Sant'Anna
- a Programa de Pós-Graduação em Medicina: Ciências Médicas, Faculdade de Medicina da Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
- b Laboratório de biologia molecular endócrino e tumoral , Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
- c Hospital de Clínicas de Porto Alegre , Porto Alegre , Brazil
| | - Ilma Simoni Brum
- b Laboratório de biologia molecular endócrino e tumoral , Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
- c Hospital de Clínicas de Porto Alegre , Porto Alegre , Brazil
| | - Gisele Branchini
- b Laboratório de biologia molecular endócrino e tumoral , Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
- c Hospital de Clínicas de Porto Alegre , Porto Alegre , Brazil
- d Programa de Pós-Graduação em Patologia, Universidade Federal de Ciências da Saúde de Porto Alegre , Porto Alegre , Brazil , and
| | - Lolita Schneider Pizzolato
- b Laboratório de biologia molecular endócrino e tumoral , Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
- c Hospital de Clínicas de Porto Alegre , Porto Alegre , Brazil
| | - Edison Capp
- b Laboratório de biologia molecular endócrino e tumoral , Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
- c Hospital de Clínicas de Porto Alegre , Porto Alegre , Brazil
- e Departamento de Ginecologia e Obstetrícia , Faculdade de Medicina da UFRGS , Porto Alegre , Brazil
| | - Helena von Eye Corleta
- a Programa de Pós-Graduação em Medicina: Ciências Médicas, Faculdade de Medicina da Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
- b Laboratório de biologia molecular endócrino e tumoral , Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil
- c Hospital de Clínicas de Porto Alegre , Porto Alegre , Brazil
- e Departamento de Ginecologia e Obstetrícia , Faculdade de Medicina da UFRGS , Porto Alegre , Brazil
| |
Collapse
|
|
26
|
Bou Khalil R, Souaiby L, Farès N. The importance of the hypothalamo-pituitary-adrenal axis as a therapeutic target in anorexia nervosa. Physiol Behav 2017; 171:13-20. [PMID: 28043861 DOI: 10.1016/j.physbeh.2016.12.035] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Revised: 12/26/2016] [Accepted: 12/27/2016] [Indexed: 12/19/2022]
Abstract
Anorexia nervosa (AN) is an eating disorder, mainly affecting women, with a lifetime prevalence of about 1%, that can run a chronic course. While an effective pharmacotherapy is lacking, it is hypothesized that the progesterone and type II glucocorticoid receptor antagonist mifepristone (RU486) might be useful, as it is well known that the hypothalamo-pituitary-adrenal axis (HPA) is activated in AN. Even if secondary to the eating disorder, an active HPA axis may contribute to maintaining the neuroendocrine, emotional and behavioral effects observed in AN. More specifically, it is suggested that the HPA axis interacts with limbic structures, including the insular and prefrontal cortices, to uphold the changes in interoceptive and emotional awareness seen in AN. As such, it is proposed that mifepristone (RU486) reverses these effects by acting on these limbic regions. In conclusion, the theoretical efficacy of mifepristone (RU486) in improving symptoms of AN should be tested in randomized clinical trials.
Collapse
Affiliation(s)
- Rami Bou Khalil
- Hôtel Dieu de France, Department of psychiatry, Saint Joseph University, Beirut, Lebanon.
| | - Lama Souaiby
- Saint Joseph University, Department of psychiatry, Beirut, Lebanon
| | - Nassim Farès
- Saint Joseph University, Physiology and pathophysiology laboratory, PTS, Faculty of medicine, Beirut, Lebanon
| |
Collapse
|
|
27
|
A SNP in pri-miR-10a is associated with recurrent spontaneous abortion in a Han-Chinese population. Oncotarget 2016; 7:8208-22. [PMID: 26824181 PMCID: PMC4884987 DOI: 10.18632/oncotarget.7002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 01/01/2016] [Indexed: 11/25/2022] Open
Abstract
MicroRNA-10a (miR-10a) has a wide range of functions in nearly all mammalian tissues and is involved in the occurrence of many diseases. However, it remains unknown whether miR-10a is associated with human recurrent spontaneous abortion (RSA). In this study, we found that rs3809783 A > T in miR-10a coding region was significantly associated with the increase of the risk of human unexplained RSA (URSA) acquisition in a Han-Chinese population. The T allele of rs3809783 hindered the production of mature miR-10a. A to T substitution in miR-10a rs3809783 repressed cell proliferation and migratory capacity. Further investigation discovered that Bcl-2-interacting mediator (Bim) was the functional target of miR-10a and inversely regulated Bim expression. Dual-luciferase assay indicated that A allele in miR-10a rs3809783 could more effectively suppress Bim expression than T allele. In addition, A to T substitution in miR-10a rs3809783 attenuated the sensibility of cells to progesterone and its antagonist mifepristone. Collectively, our data suggest that rs3809783 A > T in pri-miR-10a may be conductive to the genetic predisposition to RSA by disrupting the production of mature miR-10a and reinforcing the expression of Bim.
Collapse
|
|
28
|
Zhang H, Wu F, Li Y, Yang X, Huang J, Lv T, Zhang Y, Chen J, Chen H, Gao Y, Liu G, Jia L. Chitosan-based nanoparticles for improved anticancer efficacy and bioavailability of mifepristone. BEILSTEIN JOURNAL OF NANOTECHNOLOGY 2016; 7:1861-1870. [PMID: 28144535 PMCID: PMC5238647 DOI: 10.3762/bjnano.7.178] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 11/06/2016] [Indexed: 05/10/2023]
Abstract
In addition to its well-known abortifacient effect, mifepristone (MIF) has been used as an anticancer drug for various cancers in many studies with an in-depth understanding of the mechanism of action. However, application of MIF is limited by its poor water solubility and low oral bioavailability. In this work, we developed a drug delivery system based on chitosan nanoparticles (CNs) to improve its bioavailability and anticancer activity. The MIF-loaded chitosan nanoparticles (MCNs) were prepared by convenient ionic gelation techniques between chitosan (Cs) and tripolyphosphate (TPP). The preparation conditions, including Cs concentration, TPP concentration, Cs/MIF mass ratio, and pH value of the TPP solution, were optimized to gain better encapsulation efficiency (EE) and drug loading capacity (DL). MCNs prepared with the optimum conditions resulted in spherical particles with an average size of 200 nm. FTIR and XRD spectra verified that MIF was successfully encapsulated in CNs. The EE and DL of MCNs determined by HPLC were 86.6% and 43.3%, respectively. The in vitro release kinetics demonstrated that MIF was released from CNs in a sustained-release manner. Compared with free MIF, MCNs demonstrated increased anticancer activity in several cancer cell lines. Pharmacokinetic studies in male rats that were orally administered MCNs showed a 3.2-fold increase in the area under the curve from 0 to 24 h compared with free MIF. These results demonstrated that MCNs could be developed as a potential delivery system for MIF to improve its anticancer activity and bioavailability.
Collapse
Affiliation(s)
- Huijuan Zhang
- College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Fuqiang Wu
- College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Yazhen Li
- College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Xiping Yang
- College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Jiamei Huang
- College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Tingting Lv
- College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Yingying Zhang
- College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Jianzhong Chen
- School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China
| | - Haijun Chen
- College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Yu Gao
- College of Chemistry, Fuzhou University, Fuzhou 350108, China
| | - Guannan Liu
- College of Life Sciences, China Jiliang University, Hangzhou, Zhejiang, 310018, China
| | - Lee Jia
- College of Chemistry, Fuzhou University, Fuzhou 350108, China
| |
Collapse
|
|
29
|
Nelson AL. Investigational hormone receptor agonists as ongoing female contraception: a focus on selective progesterone receptor modulators in early clinical development. Expert Opin Investig Drugs 2015; 24:1321-30. [PMID: 26289789 DOI: 10.1517/13543784.2015.1076791] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION As efforts are made to continue to increase the safety of contraceptive methods, those without estrogen have attracted new attention. Progestin-only options are available in many delivery systems, but most cause disturbed bleeding patterns. For gynecologic patients, selective progesterone receptor modulators (SPRMs) have been approved for medical abortion, for ovulation suppression in emergency contraception, and for the treatment of heavy menstrual bleeding due to leiomyoma. AREAS COVERED This article discusses the role of SPRMs in controlling fertility on an ongoing basis with particular emphasis on mifepristone and ulipristal acetate (UPA), since none of the other compounds has progressed out of early Phase I - II testing. It also discusses important information about the mechanisms of action and safety of these two SPRMs. EXPERT OPINION Of all the investigational hormone agonist/antagonists, SPRMs have demonstrated the greatest potential as ongoing female contraceptives. They have the ability to suppress ovulation after initiation of the luteinizing hormone (LH) surge without affecting ovarian production of estrogen or inducing any significant metabolic changes. SPRMs may well be able to provide longer term contraception as oral agents, vaginal rings, and perhaps even intrauterine devices. UPA has the greatest promise. Current research needs to be expanded.
Collapse
Affiliation(s)
- Anita L Nelson
- a Los Angeles BioMedical Research Institute, David Geffen School of Medicine at UCLA, Harbor-UCLA Medical Center, Department of Obstetrics and Gynecology , 1457 3rd Street, Manhattan Beach, CA 90266, USA +1 310 937 7226 ; +1 310 937 1416 ;
| |
Collapse
|
|
30
|
Hu Y, Huo ZH, Liu CM, Liu SG, Zhang N, Yin KL, Qi L, Ma X, Xia HF. Functional study of one nucleotide mutation in pri-miR-125a coding region which related to recurrent pregnancy loss. PLoS One 2014; 9:e114781. [PMID: 25479352 PMCID: PMC4257728 DOI: 10.1371/journal.pone.0114781] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Accepted: 10/28/2014] [Indexed: 11/18/2022] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs which modulate gene expression by binding to complementary segments present in the 3'UTR of the mRNAs of protein coding genes. MiRNAs play very important roles in maintaining normal human body physiology conditions, meanwhile, abnormal miRNA expressions have been found related to many human diseases spanning from psychiatric disorders to malignant cancers. Recently, emerging reports have indicated that disturbed miRNAs expression contributed to the pathogenesis of recurrent pregnancy loss (RPL). In this study, we identified a new mutation site (+29A>G, position relative to pre-miR-125a) by scanning pri-miR-125a coding region in 389 Chinese Han RPL patients. This site was co-existed with two polymorphisms (rs12976445 and rs41275794) in patients heterogeneously and changed the predicted secondary structures of pri-miR-125a. Subsequent in vitro analysis indicated that the A>G mutation reduced mature miR-125a expression, and further led to less efficient inhibition of verified target genes. Functional analysis showed that mutant pri-mir-125a can enhance endometrial stromal cells (ESCs) invasive capacity and increase the sensitivity of ESCs cells to mifepristone. Moreover, we further analyzed the possible molecular mechanism by RIP-chip assay and found that mutant pri-mir-125a disturbed the expression of miR-125a targetome, the functions of which includes embryonic development, cell proliferation, migration and invasion. These data suggest that A>G mutation in pri-miR-125a coding region contributes to the genetic predisposition to RPL by disordering the production of miR-125a, which consequently meddled in gene regulatory network between mir-125a and mRNA.
Collapse
Affiliation(s)
- Yi Hu
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China
- Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Zheng-Hao Huo
- Department of Biotechnology, School of Basic Medical Science, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Chun-Mei Liu
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China
| | - Shi-Guo Liu
- Affiliated hospital of medical college of Qing Dao university, Qingdao, China
| | - Ning Zhang
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China
- Graduate School; Peking Union Medical College, Beijing, China
| | - Kun-Lun Yin
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China
- Graduate School; Peking Union Medical College, Beijing, China
| | - Lu Qi
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China
| | - Xu Ma
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China
- Graduate School; Peking Union Medical College, Beijing, China
- * E-mail: (XM); (HFX)
| | - Hong-Fei Xia
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China
- Graduate School; Peking Union Medical College, Beijing, China
- * E-mail: (XM); (HFX)
| |
Collapse
|
|
31
|
Theron KE, Penny CB, Hosie MJ. Postcoital administration of RU486 induces a hormonally under-stimulated rat endometrium. Reprod Biol 2014; 14:224-33. [DOI: 10.1016/j.repbio.2014.04.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Revised: 03/21/2014] [Accepted: 04/25/2014] [Indexed: 01/04/2023]
|
|
32
|
Ritter HD, Mueller CR. Expression microarray identifies the unliganded glucocorticoid receptor as a regulator of gene expression in mammary epithelial cells. BMC Cancer 2014; 14:275. [PMID: 24755251 PMCID: PMC4021255 DOI: 10.1186/1471-2407-14-275] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Accepted: 04/14/2014] [Indexed: 12/25/2022] Open
Abstract
Background While glucocorticoids and the liganded glucocorticoid receptor (GR) have a well-established role in the maintenance of differentiation and suppression of apoptosis in breast tissue, the involvement of unliganded GR in cellular processes is less clear. Our previous studies implicated unliganded GR as a positive regulator of the BRCA1 tumour suppressor gene in the absence of glucocorticoid hormone, which suggested it could play a similar role in the regulation of other genes. Methods An shRNA vector directed against GR was used to create mouse mammary cell lines with depleted endogenous levels of this receptor in order to further characterize the role of GR in breast cells. An expression microarray screen for targets of unliganded GR was performed using our GR-depleted cell lines maintained in the absence of glucocorticoids. Candidate genes positively regulated by unliganded GR were identified, classified by Gene Ontology and Ingenuity Pathway Analysis, and validated using quantitative real-time reverse transcriptase PCR. Chromatin immunoprecipitation and dual luciferase expression assays were conducted to further investigate the mechanism through which unliganded GR regulates these genes. Results Expression microarray analysis revealed 260 targets negatively regulated and 343 targets positively regulated by unliganded GR. A number of the positively regulated targets were involved in pro-apoptotic networks, possibly opposing the activity of liganded GR targets. Validation and further analysis of five candidates from the microarray indicated that two of these, Hsd11b1 and Ch25h, were regulated by unliganded GR in a manner similar to Brca1 during glucocorticoid treatment. Furthermore, GR was shown to interact directly with and upregulate the Ch25h promoter in the absence, but not the presence, of hydrocortisone (HC), confirming our previously described model of gene regulation by unliganded GR. Conclusion This work presents the first identification of targets of unliganded GR. We propose that the balance between targets of liganded and unliganded GR signaling is responsible for controlling differentiation and apoptosis, respectively, and suggest that gene regulation by unliganded GR may represent a mechanism for reducing the risk of breast tumourigenesis by the elimination of abnormal cells.
Collapse
Affiliation(s)
| | - Christopher R Mueller
- Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada K7L 3N6.
| |
Collapse
|
|
33
|
Flores-Espinosa P, Pineda-Torres M, Vega-Sánchez R, Estrada-Gutiérrez G, Espejel-Nuñez A, Flores-Pliego A, Maida-Claros R, Paredes-Vivas Y, Morales-Méndez I, Sosa-González I, Chávez-Mendoza A, Zaga-Clavellina V. Progesterone elicits an inhibitory effect upon LPS-induced innate immune response in pre-labor human amniotic epithelium. Am J Reprod Immunol 2013; 71:61-72. [PMID: 24128422 DOI: 10.1111/aji.12163] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Accepted: 09/09/2013] [Indexed: 12/19/2022] Open
Abstract
PROBLEM Infection of human fetal membranes elicits secretion of pro-inflammatory modulators through its innate immune capacities. We investigated the effect of lipopolysacharide (LPS) and progesterone (P4) upon expression of TLR-4/MyD88, TNFα, IL-6, IL-8, IL-10, and HBD2 on the human amniotic epithelium. METHOD OF STUDY Explants of the human amniotic epithelium were pre-treated with 0.01, 0.1, and 1.0 μM of P4; then cotreated with 1000 ng/mL LPS. TLR-4 was immuno-detected, and concentrations of MyD88, TNFα, IL-6, IL-8, IL-10, and HBD2 were quantified by ELISA. RESULTS P4 significantly reduced the expression of LPS-induced TLR-4/MyD88. LPS increased the concentrations of TNFα, IL-6, IL-8, IL-10, and HBD2 by factors of 30-, eight, three, three, and fivefold, respectively. P4 at 1.0 μM was the most effective dose to blunt the secretion of TNFα, IL-6, and HBD-2. RU-486 blocks the effect of P4. CONCLUSION P4 inhibited LPS-induced TLR-4/MyD88 and pro-inflammatory factors in the human amniotic epithelium. These results could explain partially how P4 can protect the amniotic region of fetal membranes and generate a compensatory mechanism that limits the secretion of pro-inflammatory modulators, which could jeopardize the immune privilege during pregnancy.
Collapse
Affiliation(s)
- Pilar Flores-Espinosa
- Department of Cell Biology, Instituto Nacional de Perinatología 'Isidro Espinosa de los Reyes', Mexico City, Mexico; Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Theron KE, Penny CB, Hosie MJ. The Bax/Bcl-2 apoptotic pathway is not responsible for the increase in apoptosis in the RU486-treated rat uterus during early pregnancy. Reprod Biol 2013; 13:290-7. [PMID: 24287037 DOI: 10.1016/j.repbio.2013.09.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2012] [Revised: 09/20/2013] [Accepted: 09/23/2013] [Indexed: 11/29/2022]
Abstract
An increase in apoptotic activity has been observed in both the rabbit and the rat endometria following treatment with RU486. The aim of this study was to assess whether Bax and Bcl-2 signaling, in response to RU486, could be crucial role players mediating apoptosis in the rat uterus during early pregnancy. RU486 is a partial progesterone (P4) and estrogen receptor antagonist, functioning to actively silence P4 receptor gene-associated transcription. Although an increase in apoptosis as a result of RU486 administration has been previously reported in rabbits, the specific apoptotic factors and pathways involved in driving this process have not yet been established. Immunofluorescent techniques were used to determine protein expression levels of both Bax and Bcl-2 in RU486-treated endometria at days 4.5, 5.5 and 6.5 of pregnancy. The Bax/Bcl-2 index was used to determine the overall pro- or anti-apoptotic setting at each day of pregnancy, following RU486 administration. Changes in the Bax and Bcl-2 gene expression levels as a consequence of RU486 administration were evaluated using RT-qPCR. Both the protein and gene expression analyses suggest that RU486 induces a change toward an overall anti-apoptotic signal within the Bax/Bcl-2 pathway. These results suggest that the observed increase in apoptosis following RU486 administration is not driven by a shift in the Bax/Bcl-2 ratio toward cell death, when the P4 and estrogen receptors are partially inactivated by RU486, but is possibly regulated by another apoptotic pathway.
Collapse
Affiliation(s)
- Kathrine E Theron
- School of Anatomical Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown 2193, South Africa.
| | | | | |
Collapse
|
|
35
|
Abstract
The hypothalamic-pituitary-adrenal (HPA) axis is the body's main stress-response system, and cortisol is the major adrenal glucocorticoid hormone secreted in human beings. HPA axis activity and cortisol secretion is regulated by a negative feedback system involving glucocorticoid receptors. Dysregulation of the HPA axis and increased cortisol levels have been implicated in mood, psychotic, and other psychiatric disorders. Mifepristone, as a potent antagonist of glucocorticoid receptors, has been studied or is currently being investigated as a potential therapeutic agent for psychotic depression, posttraumatic stress disorder, and alcohol and cocaine dependence, as well as for mitigating the weight gain associated with the use of antipsychotic drugs and for improving cognitive dysfunction in schizophrenia and bipolar disorder. This article will review some of the work in these areas.
Collapse
Affiliation(s)
- Robert H Howland
- University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania 15213, USA.
| |
Collapse
|
|
36
|
Low-dose mifepristone increases uterine expression of aquaporin 1/aquaporin 2 at the time of implantation. Contraception 2013; 87:844-9. [DOI: 10.1016/j.contraception.2012.09.035] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2011] [Revised: 09/29/2012] [Accepted: 09/30/2012] [Indexed: 11/18/2022]
|
|
37
|
Kogan M, Deshmane S, Sawaya BE, Gracely EJ, Khalili K, Rappaport J. Inhibition of NF-κB activity by HIV-1 Vpr is dependent on Vpr binding protein. J Cell Physiol 2013; 228:781-90. [PMID: 23001849 DOI: 10.1002/jcp.24226] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2012] [Accepted: 09/06/2012] [Indexed: 01/22/2023]
Abstract
Numerous studies have reported that Vpr alters NF-κB signaling in various cell types, however, the findings have been largely conflicting with reports of both stimulatory and inhibitory effects of Vpr. Our aim was to investigate the role of Vpr signaling in myeloid cells using an adenovirus based expression and indicator system. Our results show that Vpr is inhibitory to NF-κB, however, this effect is dependent on the particular manner of NF-κB stimulation. Consistent with this notion, we report that Vpr has inhibitory effects that are specific to the TNF-α pathway, but not affecting the LPS pathway, suggesting that differential targets of Vpr may exist for NF-κB regulation. Further, we identify VprBP as one possible cellular component of Vpr's regulation of IκBα in response to TNF-α stimulation. We did not identify such a role for HSP27, which instead seems to inhibit Vpr functions. Chronically HIV-1 infected U1 cells with knockdown constructs for Vpr were unexpectedly less responsive to TNF-α mediated viral replication, perhaps suggesting that other HIV-1 components may antagonize these anti-NF-κB effects in infected cells. We hypothesize that Vpr may serve an important role in the context of viral infection and immune function in vivo, through its selective inhibition of NF-κB pathways.
Collapse
Affiliation(s)
- Michael Kogan
- Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA
| | | | | | | | | | | |
Collapse
|
|
38
|
RU486, a glucocorticoid receptor antagonist, induces apoptosis in U937 human lymphoma cells through reduction in mitochondrial membrane potential and activation of p38 MAPK. Oncol Rep 2013; 30:506-12. [PMID: 23624748 DOI: 10.3892/or.2013.2432] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Accepted: 04/04/2013] [Indexed: 11/05/2022] Open
Abstract
RU486 (mifepristone) exerts an anticancer effect on cancer cells via induction of apoptosis. However, the molecular mechanisms are not fully understood. Here, we investigated the effect of RU486 on the apoptosis of U937 human leukemia cells. RU486 markedly increased apoptosis in U937 cells as well as in MDA231 human breast carcinoma, A549 human lung adenocarcinoma epithelial and HCT116 human colorectal carcinoma cells. RU486 increased dose-dependent release of mitochondrial cytochrome c, and reduced the mitochondrial membrane potential (MMP, Δψm) in RU486-treated U937 cells. We also found that overexpression of Bcl-2 completely blocked RU486-mediated apoptosis. However, reactive oxygen species signaling had no effect on RU486-induced apoptosis. RU486 increased the phosphorylation of p38 MAPK and JNK, but p38 MAPK only was associated with RU486-mediated apoptosis. Taken together, RU486 induces apoptosis through reduction in the mitochondrial membrane potential and activation of p38 MAPK in U937 human leukemia cells.
Collapse
|
|
39
|
Aisemberg J, Vercelli CA, Bariani MV, Billi SC, Wolfson ML, Franchi AM. Progesterone is essential for protecting against LPS-induced pregnancy loss. LIF as a potential mediator of the anti-inflammatory effect of progesterone. PLoS One 2013; 8:e56161. [PMID: 23409146 PMCID: PMC3567061 DOI: 10.1371/journal.pone.0056161] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Accepted: 01/10/2013] [Indexed: 11/18/2022] Open
Abstract
Lipopolysaccharide (LPS) administration to mice on day 7 of gestation led to 100% embryonic resorption after 24 h. In this model, nitric oxide is fundamental for the resorption process. Progesterone may be responsible, at least in part, for a Th2 switch in the feto-maternal interface, inducing active immune tolerance against fetal antigens. Th2 cells promote the development of T cells, producing leukemia inhibitory factor (LIF), which seems to be important due to its immunomodulatory action during early pregnancy. Our aim was to evaluate the involvement of progesterone in the mechanism of LPS-induced embryonic resorption, and whether LIF can mediate hormonal action. Using in vivo and in vitro models, we provide evidence that circulating progesterone is an important component of the process by which infection causes embryonic resorption in mice. Also, LIF seems to be a mediator of the progesterone effect under inflammatory conditions. We found that serum progesterone fell to very low levels after 24 h of LPS exposure. Moreover, progesterone supplementation prevented embryonic resorption and LPS-induced increase of uterine nitric oxide levels in vivo. Results show that LPS diminished the expression of the nuclear progesterone receptor in the uterus after 6 and 12 h of treatment. We investigated the expression of LIF in uterine tissue from pregnant mice and found that progesterone up-regulates LIF mRNA expression in vitro. We observed that LIF was able to modulate the levels of nitric oxide induced by LPS in vitro, suggesting that it could be a potential mediator of the inflammatory action of progesterone. Our observations support the view that progesterone plays a critical role in a successful pregnancy as an anti-inflammatory agent, and that it could have possible therapeutic applications in the prevention of early reproductive failure associated with inflammatory disorders.
Collapse
Affiliation(s)
- Julieta Aisemberg
- Centro de Estudios Farmacológicos y Botánicos (CONICET-UBA), Buenos Aires, Argentina.
| | | | | | | | | | | |
Collapse
|
|
40
|
Rouiller Y, Périlleux A, Marsaut M, Stettler M, Vesin MN, Broly H. Effect of hydrocortisone on the production and glycosylation of an Fc-fusion protein in CHO cell cultures. Biotechnol Prog 2012; 28:803-13. [PMID: 22535835 DOI: 10.1002/btpr.1530] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2011] [Revised: 02/09/2012] [Indexed: 12/30/2022]
Abstract
Glucocorticoids are known to modulate various cellular functions such as cell proliferation, metabolism, glycosylation, and secretion of many proteins. We tested the effect of hydrocortisone (HC) on cell growth, viability, metabolism, protein production, and glycosylation of an Fc-protein expressing Chinese hamster ovary (CHO) cell culture. HC extended cell viability but impaired cell growth. The inhibitory effect on cell growth was dose-dependent and decreased when the glucocorticoid addition was delayed. When HC was added after 2 or 3 days of culture, an increase in glutamate consumption was observed, which was reversed by the glucocorticoid receptor antagonist mifepristone (Mif). Titer and specific productivity increased in the presence of HC. The increase in titer was only slightly reversed by Mif. On the other hand, Mif by itself induced an increase in titer to a level comparable to or higher than HC. Protein glycosylation was altered by the glucocorticoid in a dose- and time-dependent manner, with a shift to more acidic bands, which correlated with an increase in sialic acid moieties. This increase, which was not linked to a decrease in extracellular sialidase activity in HC-treated cultures, was reversed by Mif. Predictive models based on design of experiments enabled the definition of optimal conditions for process performance in terms of viability and titer and for the quality of the Fc-fusion protein in terms of glycosylation. The data obtained suggest a use of glucocorticoids for commercial production of Fc-fusion proteins expressed in CHO cells.
Collapse
Affiliation(s)
- Yolande Rouiller
- Merck Serono SA, Corsier-sur-Vevey, Biotech Process Sciences, ZI B, CH-1809 Fenil-sur-Corsier, Switzerland.
| | | | | | | | | | | |
Collapse
|
|
41
|
Simms JA, Haass-Koffler CL, Bito-Onon J, Li R, Bartlett SE. Mifepristone in the central nucleus of the amygdala reduces yohimbine stress-induced reinstatement of ethanol-seeking. Neuropsychopharmacology 2012; 37:906-18. [PMID: 22048462 PMCID: PMC3280651 DOI: 10.1038/npp.2011.268] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Chronic ethanol exposure leads to dysregulation of the hypothalamic-pituitary-adrenal axis, leading to changes in glucocorticoid release and function that have been proposed to maintain pathological alcohol consumption and increase vulnerability to relapse during abstinence. The objective of this study was to determine whether mifepristone, a glucocorticoid receptor antagonist, plays a role in ethanol self-administration and reinstatement. Male, Long-Evans rats were trained to self-administer either ethanol or sucrose in daily 30 min operant self-administration sessions using a fixed ratio 3 schedule of reinforcement. Following establishment of stable baseline responding, we examined the effects of mifepristone on maintained responding and yohimbine-induced increases in responding for ethanol and sucrose. Lever responding was extinguished in separate groups of rats and animals were tested for yohimbine-induced reinstatement and corticosterone release. We also investigated the effects of local mifepristone infusions into the central amygdala (CeA) on yohimbine-induced reinstatement of ethanol- and sucrose-seeking. In addition, we infused mifepristone into the basolateral amygdala (BLA) in ethanol-seeking animals as an anatomical control. We show that both systemic and intra-CeA (but not BLA) mifepristone administration suppressed yohimbine-induced reinstatement of ethanol-seeking, while only systemic injections attenuated sucrose-seeking. In contrast, baseline consumption, yohimbine-induced increases in responding, and circulating CORT levels were unaffected. The data indicate that the CeA plays an important role in the effects of mifepristone on yohimbine-induced reinstatement of ethanol-seeking. Mifepristone may be a valuable pharmacotherapeutic strategy for preventing relapse to alcohol use disorders and, as it is FDA approved, may be a candidate for clinical trials in the near future.
Collapse
Affiliation(s)
- Jeffrey A Simms
- Preclinical Development Group, Ernest Gallo Clinic and Research Center at University of California San Francisco, Emeryville, CA, USA
| | - Carolina L Haass-Koffler
- Preclinical Development Group, Ernest Gallo Clinic and Research Center at University of California San Francisco, Emeryville, CA, USA,Clinical Pharmacology and Experimental Therapeutics, University of California San Francisco, Byers Hall, San Francisco, CA, USA
| | - Jade Bito-Onon
- Preclinical Development Group, Ernest Gallo Clinic and Research Center at University of California San Francisco, Emeryville, CA, USA
| | - Rui Li
- Preclinical Development Group, Ernest Gallo Clinic and Research Center at University of California San Francisco, Emeryville, CA, USA
| | - Selena E Bartlett
- Preclinical Development Group, Ernest Gallo Clinic and Research Center at University of California San Francisco, Emeryville, CA, USA,Preclinical Development Group, Ernest Gallo Clinic and Research Center at University of California San Francisco, 5858 Horton Street, Suite 200, Emeryville, CA 94608 USA, Tel: +1 510 985 3133, Fax: +1 510 985 3101, E-mail:
| |
Collapse
|
|
42
|
Ritter HD, Antonova L, Mueller CR. The unliganded glucocorticoid receptor positively regulates the tumor suppressor gene BRCA1 through GABP beta. Mol Cancer Res 2012; 10:558-69. [PMID: 22328717 DOI: 10.1158/1541-7786.mcr-11-0423-t] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Loss of BRCA1 tumor suppressor function is a critical event in breast tumorigenesis. We have previously identified the stress hormone hydrocortisone as a negative regulator of BRCA1 expression in nonmalignant mammary cells. Here, we have identified a direct role for the unliganded glucocorticoid receptor (GR) in BRCA1 upregulation in the absence of hydrocortisone. The positive regulatory effect of GR is lost upon the addition of hydrocortisone. We have shown that GR interacts with the BRCA1 promoter only in the absence of hydrocortisone, and that this interaction is mediated through the β-subunit of the ets transcription factor GA-binding protein (GABP) at the RIBS promoter element. GR and GABPβ interact in both coimmunoprecipitation and mammalian two-hybrid assays, and this interaction involves the N-terminal to central regions of both proteins. This work presents the first evidence of a ligand-independent role for GR as a positive regulator of gene expression, and loss of GR from the BRCA1 promoter in response to stress hormones leads to decreased BRCA1 expression. Because low levels of BRCA1 have been implicated in the development of sporadic breast cancer, this may represent a novel mechanism through which prolonged stress signaling increases breast cancer risk.
Collapse
Affiliation(s)
- Heather D Ritter
- Department of Biochemistry, Queen's University, Kingston, Ontario K7L 3N6, Canada
| | | | | |
Collapse
|
|
43
|
Jung EM, An BS, Choi KC, Jeung EB. Potential estrogenic activity of triclosan in the uterus of immature rats and rat pituitary GH3 cells. Toxicol Lett 2012; 208:142-8. [DOI: 10.1016/j.toxlet.2011.10.017] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2011] [Revised: 10/24/2011] [Accepted: 10/24/2011] [Indexed: 12/31/2022]
|
|
44
|
He YH, Zhang HN, Zhang GP, Hou N, Xiao Q, Huang Y, Wu JH, Luo MS, Zhang GS, Yi Q, Chen MS, Luo JD. A physiological concentration of glucocorticoid inhibits the pro-inflammatory cytokine-induced proliferation of adult rat cardiac fibroblasts: Roles of extracellular signal-regulated kinase 1/2 and nuclear factor-κB. Clin Exp Pharmacol Physiol 2011; 38:739-46. [DOI: 10.1111/j.1440-1681.2011.05581.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
|
|
45
|
Min KJ, Jang JH, Lee JT, Choi KS, Kwon TK. Glucocorticoid receptor antagonist sensitizes TRAIL-induced apoptosis in renal carcinoma cells through up-regulation of DR5 and down-regulation of c-FLIP(L) and Bcl-2. J Mol Med (Berl) 2011; 90:309-19. [PMID: 22008998 DOI: 10.1007/s00109-011-0821-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Revised: 09/28/2011] [Accepted: 10/07/2011] [Indexed: 01/01/2023]
Abstract
RU486 (Mifepristone) has been known as antiprogesterone and antiglucocorticoid agent. RU486 is also used for treatment of several cancers, such as breast, ovarian, prostate, and glaucoma. Here, we investigated the effect of RU486 on TRAIL-induced apoptosis in human renal carcinoma Caki cells. Low dose of RU486 (30-50 μM) alone had no effect on apoptosis, but RU486 markedly sensitized Caki cells to TRAIL-induced apoptosis. We found that up-regulation of death receptor 5 (DR5; receptor for TRAIL ligand), and down-regulation of Bcl-2 and c-FLIP (caspase regulator) contributes to RU-486 induced TRAIL sensitization. Down-regulation of DR5 by siRNA also blocked RU486 induced TRAIL sensitization. Furthermore, overexpression of Bcl-1 or c-FLIP(L) inhibited the cell death induced by the combined treatment with RU486 and TRAIL. RU486 increased DR5 expression at the transcriptional levels through induction of CHOP expression. By contrast, RU486 did not sensitize normal human mesangial cells to TRAIL-mediated apoptosis. Effect of RU486 on TRAIL-induced cancer cell apoptosis was independent of glucocorticoid receptor and progesterone receptor. Taken together, RU486 enhances TRAIL-mediated apoptosis through down-regulation of Bcl-2 and c-FLIP(L) as well as CHOP-mediated DR5 up-regulation.
Collapse
Affiliation(s)
- Kyoung-Jin Min
- Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea
| | | | | | | | | |
Collapse
|
|
46
|
Effects of RU486 in the expression of progesterone receptor isoforms in the hypothalamus and the preoptic area of the rat during postpartum estrus. Neurosci Lett 2011; 504:127-130. [DOI: 10.1016/j.neulet.2011.09.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Revised: 09/09/2011] [Accepted: 09/12/2011] [Indexed: 11/23/2022]
|
|
47
|
Wabnitz GH, Michalke F, Stober C, Kirchgessner H, Jahraus B, van den Boomen DJH, Samstag Y. L-plastin phosphorylation: a novel target for the immunosuppressive drug dexamethasone in primary human T cells. Eur J Immunol 2011; 41:3157-69. [PMID: 21805466 DOI: 10.1002/eji.201041366] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2010] [Revised: 07/07/2011] [Accepted: 07/26/2011] [Indexed: 01/29/2023]
Abstract
Activation of naïve T cells requires costimulation via TCR/CD3 plus accessory receptors, which enables the dynamic rearrangement of the actin cytoskeleton and immune synapse maturation. Signaling events induced following costimulation may thus be valuable targets for therapeutic immunosuppression. Phosphorylation of the actin-bundling protein L-plastin represents such a costimulatory signal in primary human T cells. Phosphorylated L-plastin has a higher affinity toward F-actin. However, the importance of the L-plastin phosphorylation for actin cytoskeleton regulation upon antigen recognition remained unclear. Here, we demonstrate that phosphorylation of L-plastin is important for immune synapse maturation. Thus, expression of nonphosphorylatable L-plastin in untransformed human peripheral blood T cells leads to reduced accumulation of LFA-1 in the immune synapse and to a diminished F-actin increase upon T-cell activation. Interestingly, L-plastin phosphorylation is inhibited by the glucocorticoid dexamethasone. In line with this finding, dexamethasone treatment leads to a reduced F-actin content in stimulated T cells and prevents maturation of the immune synapse. This inhibitory effect of dexamethasone could be reverted by expression of a phospho-mimicking L-plastin mutant. In conclusion, our data introduce costimulation-induced L-plastin phosphorylation as an important event for immune synapse formation and its inhibition by dexamethasone as a novel mode of function of this immunosuppressive glucocorticoid.
Collapse
Affiliation(s)
- Guido H Wabnitz
- Institute for Immunology, Ruprecht-Karls-University, Heidelberg, Germany.
| | | | | | | | | | | | | |
Collapse
|
|
48
|
Low-dose mifepristone increases uterine natural killer cell cytotoxicity and perforin expression during the receptive phase. Fertil Steril 2011; 96:649-53. [DOI: 10.1016/j.fertnstert.2011.06.074] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Revised: 05/28/2011] [Accepted: 06/28/2011] [Indexed: 11/17/2022]
|
|
49
|
Abstract
Preclinical strategies that are used to identify potential drug candidates include target-based screening, phenotypic screening, modification of natural substances and biologic-based approaches. To investigate whether some strategies have been more successful than others in the discovery of new drugs, we analysed the discovery strategies and the molecular mechanism of action (MMOA) for new molecular entities and new biologics that were approved by the US Food and Drug Administration between 1999 and 2008. Out of the 259 agents that were approved, 75 were first-in-class drugs with new MMOAs, and out of these, 50 (67%) were small molecules and 25 (33%) were biologics. The results also show that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches - with 28 and 17 of these drugs coming from the two approaches, respectively - in an era in which the major focus was on target-based approaches. We postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.
Collapse
|
|
50
|
Tieszen CR, Goyeneche AA, Brandhagen BN, Ortbahn CT, Telleria CM. Antiprogestin mifepristone inhibits the growth of cancer cells of reproductive and non-reproductive origin regardless of progesterone receptor expression. BMC Cancer 2011; 11:207. [PMID: 21619605 PMCID: PMC3125282 DOI: 10.1186/1471-2407-11-207] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2011] [Accepted: 05/27/2011] [Indexed: 01/20/2023] Open
Abstract
Background Mifepristone (MF) has been largely used in reproductive medicine due to its capacity to modulate the progesterone receptor (PR). The study of MF has been expanded to the field of oncology; yet it remains unclear whether the expression of PR is required for MF to act as an anti-cancer agent. Our laboratory has shown that MF is a potent inhibitor of ovarian cancer cell growth. In this study we questioned whether the growth inhibitory properties of MF observed in ovarian cancer cells would translate to other cancers of reproductive and non-reproductive origin and, importantly, whether its efficacy is related to the expression of cognate PR. Methods Dose-response experiments were conducted with cancer cell lines of the nervous system, breast, prostate, ovary, and bone. Cultures were exposed to vehicle or increasing concentrations of MF for 72 h and analysed for cell number and cell cycle traverse, and hypodiploid DNA content characteristic of apoptotic cell death. For all cell lines, expression of steroid hormone receptors upon treatment with vehicle or cytostatic doses of MF for 24 h was studied by Western blot, whereas the activity of the G1/S regulatory protein Cdk2 in both treatment groups was monitored in vitro by the capacity of Cdk2 to phosphorylate histone H1. Results MF growth inhibited all cancer cell lines regardless of tissue of origin and hormone responsiveness, and reduced the activity of Cdk2. Cancer cells in which MF induced G1 growth arrest were less susceptible to lethality in the presence of high concentrations of MF, when compared to cancer cells that did not accumulate in G1. While all cancer cell lines were growth inhibited by MF, only the breast cancer MCF-7 cells expressed cognate PR. Conclusions Antiprogestin MF inhibits the growth of different cancer cell lines with a cytostatic effect at lower concentrations in association with a decline in the activity of the cell cycle regulatory protein Cdk2, and apoptotic lethality at higher doses in association with increased hypodiploid DNA content. Contrary to common opinion, growth inhibition of cancer cells by antiprogestin MF is not dependent upon expression of classical, nuclear PR.
Collapse
Affiliation(s)
- Chelsea R Tieszen
- Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, Vermillion, SD, USA
| | | | | | | | | |
Collapse
|