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Cureus Mar 2024One of the rarest types of ectopic pregnancy, with an incidence of 1:1,800, is cesarean scar ectopic pregnancy. Here, we report the case of a 28-year-old woman who had...
One of the rarest types of ectopic pregnancy, with an incidence of 1:1,800, is cesarean scar ectopic pregnancy. Here, we report the case of a 28-year-old woman who had undergone two previous cesarean sections. She arrived at our labor room with per vaginal spotting and abdominal pain with an ultrasound that revealed a cesarean scar ectopic pregnancy. The initial beta-human chorionic gonadotropin (β-hCG) value upon admission was 27,133 mIU/mL. Her ultrasound findings were confirmed with magnetic resonance imaging. Opting for combined medical management, we successfully treated her using systemic methotrexate and mifepristone, avoiding surgical intervention despite high β-hCG values. There is currently no established standardized treatment for cesarean scar ectopic pregnancies, and we feel that treatment must be tailored to every patient's individual needs. Our experience suggests that combining mifepristone and systemic methotrexate can be an effective approach with better curative effects, emphasizing the need for further research.
PubMed: 38571849
DOI: 10.7759/cureus.55481 -
Journal of Reproductive Immunology Jun 2024Implantation and maintenance of pregnancy involve intricate immunological processes that enable the developing fetus to coexist with the maternal immune system....
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.
Topics: Humans; Receptors, Progesterone; Female; Pregnancy; Progesterone; Membrane Proteins; Trophoblasts; Placenta; Signal Transduction; Maternal-Fetal Exchange; Embryo Implantation
PubMed: 38555747
DOI: 10.1016/j.jri.2024.104244 -
Neurological Research May 2024The serotonin (5-hydroxytryptamine, 5-HT) receptor 1A (5-HT1AR) is closely associated with serotonergic neurotransmission in the brain, being the most prevalent and...
OBJECTIVES
The serotonin (5-hydroxytryptamine, 5-HT) receptor 1A (5-HT1AR) is closely associated with serotonergic neurotransmission in the brain, being the most prevalent and widely distributed receptor of its kind. The purpose of this study is to investigate the regulation mechanism of 5-HT1AR by GSK4716.
METHODS
To investigate the mechanism of GSK4716-mediated 5-HT1AR regulation, we used hippocampus-derived HT22 cells expressing 5-HT1AR. The expression level of 5-HT1AR and associated proteins, were detected by reporter gene assay and western blotting.
RESULTS
GSK4716, an estrogen-related receptor gamma agonist increased 5-HT1AR expression by interacting with the GR, a repressor of 5-HT1AR transcription. Dexamethasone, a GR agonist, decreased the GSK4716-induced increase in 5-HT1AR, which was associated with an alteration in nuclear GR. Furthermore, GR antagonist RU486 reversed the effects induced by dexamethasone, including the elevation of nuclear GR levels and the reduction of 5-HT1AR transcription and expression.
CONCLUSION
The results could provide insight into the potential applications of small molecules, such as GSK4716, in the regulation of 5-HT1AR expression, which plays a role in serotonergic neurotransmission.
Topics: Animals; Mice; Cell Line; Dexamethasone; Estrogens; Hippocampus; Mifepristone; Receptor, Serotonin, 5-HT1A; Receptors, Glucocorticoid; Signal Transduction
PubMed: 38555524
DOI: 10.1080/01616412.2024.2322180 -
International Review of Neurobiology 2024Repurposing drugs for the treatment of alcohol dependence involves the use of drugs that were initially developed for other conditions, but have shown promise in... (Review)
Review
Repurposing drugs for the treatment of alcohol dependence involves the use of drugs that were initially developed for other conditions, but have shown promise in reducing alcohol use or preventing relapse. This approach can offer a more cost-effective and time-efficient alternative to developing new drugs from scratch. Currently approved medications for alcohol use disorder (AUD) include acamprosate, disulfiram, naltrexone, nalmefene, baclofen, and sodium oxybate. Acamprosate was developed specifically for AUD, while disulfiram's alcohol-deterrent effects were discovered incidentally. Naltrexone and nalmefene were originally approved for opioids but found secondary applications in AUD. Baclofen and sodium oxybate were repurposed from neurological conditions. Other drugs show promise. Topiramate and zonisamide, anticonvulsants, demonstrate efficacy in reducing alcohol consumption. Another anticonvulsant, gabapentin has been disappointing overall, except in cases involving alcohol withdrawal symptoms. Varenicline, a nicotinic receptor agonist, benefits individuals with less severe AUD or concurrent nicotine use. Ondansetron, a 5-HT3 antagonist, has potential for early-onset AUD, especially when combined with naltrexone. Antipsychotic drugs like aripiprazole and quetiapine have limited efficacy. Further investigation is needed for potential repurposing of α1 adrenergic receptor antagonists prazosin and doxazosin, glucocorticoid receptor antagonist mifepristone, the phosphodiesterase inhibitor Ibudilast, the cysteine prodrug N-acetylcysteine, and the OX1R and OX2R blocker Suvorexant. This review supports repurposing drugs as an effective strategy for expanding treatment options for AUD.
Topics: Humans; Alcoholism; Acamprosate; Naltrexone; Disulfiram; Sodium Oxybate; Baclofen; Drug Repositioning; Substance Withdrawal Syndrome; Alcohol Drinking
PubMed: 38555115
DOI: 10.1016/bs.irn.2024.02.002 -
The Journal of Steroid Biochemistry and... Jul 2024The development of antiprogestins was initially a gynecological purpose. However, since mifepristone was developed, its application for breast cancer treatment was... (Review)
Review
The development of antiprogestins was initially a gynecological purpose. However, since mifepristone was developed, its application for breast cancer treatment was immediately proposed. Later, new compounds with lower antiglucocorticoid and antiandrogenic effects were developed to be applied to different pathologies, including breast cancer. We describe herein the studies performed in the breast cancer field with special focus on those reported in recent years, ranging from preclinical biological models to those carried out in patients. We highlight the potential use of antiprogestins in breast cancer prevention in women with BRCA1 mutations, and their use for breast cancer treatment, emphasizing the need to elucidate which patients will respond. In this sense, the PR isoform ratio has emerged as a possible tool to predict antiprogestin responsiveness. The effects of combined treatments of antiprogestins together with other drugs currently used in the clinic, such as tamoxifen, CDK4/CDK6 inhibitors or pembrolizumab in preclinical models is discussed since it is in this scenario that antiprogestins will be probably introduced. Finally, we explain how transcriptomic or proteomic studies, that were carried out in different luminal breast cancer models and in breast cancer samples that responded or were predicted to respond to the antiprogestin therapy, show a decrease in proliferative pathways. Deregulated pathways intrinsic of each model are discussed, as well as how these analyses may contribute to a better understanding of the mechanisms involved.
Topics: Humans; Breast Neoplasms; Female; Receptors, Progesterone; Animals; Mifepristone; Hormone Antagonists
PubMed: 38554981
DOI: 10.1016/j.jsbmb.2024.106515 -
Cellular & Molecular Biology Letters Mar 2024Both glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ) play a critical role in adipocyte differentiation. Mifepristone is not only an...
BACKGROUND
Both glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ) play a critical role in adipocyte differentiation. Mifepristone is not only an antagonist of the glucocorticoid receptor but also an agonist of PPARγ. Therefore, the present study investigated the effect of mifepristone on adipocyte differentiation.
METHODS
Mouse 3T3-L1 cells were used as a model for adipocyte differentiation. The lipid droplet formation was evaluated with Bodipy493/503 staining and the expression of adipocyte markers [adiponectin and adipocyte fatty acid binding protein-4 (Fabp4)] was evaluated with quantitative PCR and immunoblot analyses for indication of adipocyte differentiation. siRNA and neutralizing antibodies were used to elucidate the molecular mechanism of mifepristone-induced adipocyte differentiation. Luciferase reporter assay was used to examine the effect of mifepristone on the promoter activity of PPAR-response element (PPRE). The DNA microarray analysis was used to characterize the transcriptome of the mifepristone-induced adipocytes. In vivo adipogenic effect of mifepristone was examined in mice.
RESULTS
Mifepristone not only enhanced adipocyte differentiation induced by the conventional protocol consisting of insulin, dexamethasone and 3-isobutyl-1-methylxanthine but also induced adipocyte differentiation alone, as evidenced by lipid droplets formation and induction of the expression of adiponectin and Fabp4. These effects were inhibited by an adiponectin-neutralizing antibody and a PPARγ antagonist. Mifepristone activated the promoter activity of PPRE in a manner sensitive to PPARγ antagonist. A principal component analysis (PCA) of DNA microarray data revealed that the mifepristone-induced adipocytes represent some characteristics of the in situ adipocytes in normal adipose tissues to a greater extent than those induced by the conventional protocol. Mifepristone administration induced an increase in the weight of epididymal, perirenal and gluteofemoral adipose tissues.
CONCLUSIONS
Mifepristone alone is capable of inducing adipocyte differentiation in 3T3-L1 cells and adipogenesis in vivo. PPARγ plays a critical role in the mifepristone-induced adipocyte differentiation. Mifepristone-induced adipocytes are closer to the in situ adipocytes than those induced by the conventional protocol. The present study proposes a single treatment with mifepristone as a novel protocol to induce more physiologically relevant adipocytes in 3T3-L1 cells than the conventional protocol.
Topics: Mice; Animals; Adiponectin; Mifepristone; PPAR gamma; 3T3-L1 Cells; Receptors, Glucocorticoid; Cell Differentiation; Adipogenesis; Adipocytes
PubMed: 38553665
DOI: 10.1186/s11658-024-00559-9 -
Cancers Mar 2024Tissue-specificity for fimbrial fallopian tube ovarian carcinogenesis remains largely unknown in mutation carriers. We aimed to assess the cell autonomous and...
BACKGROUND
Tissue-specificity for fimbrial fallopian tube ovarian carcinogenesis remains largely unknown in mutation carriers. We aimed to assess the cell autonomous and cell-nonautonomous implications of a germline mutation in the context of cancer immunosurveillance of CD3 CD56 natural killer (NK) cells.
METHODS
Premenopausal mutation carriers versus age-matched non-carriers were compared. Daily urinary 5β-pregnanediol levels were used to determine progesterone metabolomics across an ovarian cycle. Using peripherally acquired NK cells the cell-mediated cytotoxicity of tumor targets (OVCAR-3, K-562) was determined using live cellular impedance (xCELLigence) and multicolor flow cytometry. Hypoxia-inducible factor 1-alpha (HIF-1α) immunohistochemistry of cancer-free fallopian tube specimens allowed a comparison of proximal versus distal portions. Utilizing these findings the role of environmental factors relevant to the fimbrial fallopian tube (progesterone, hypoxia) on NK cell functional activity were studied in an ovarian phase-specific manner.
RESULTS
mutation carriers demonstrate a differential progesterone metabolome with a phase-specific reduction of peripheral NK cell functional activity. Progesterone exposure further impairs NK cell-mediated cytotoxicity in a dose-dependent manner, which is reversed with the addition of mifepristone (1.25 µM). The fimbrial fallopian tube demonstrated significantly higher HIF-1α staining, particularly in mutation carriers, reflecting a site-specific 'hypoxic niche'. Exposure to hypoxic conditions (1% O) can further impair tumor cytotoxicity in high-risk carriers.
CONCLUSIONS
Phase-specific differential NK cell activity in mutation carriers, either systemically or locally, may favor site-specific pre-invasive carcinogenesis. These cumulative effects across a reproductive lifecycle in high-risk carriers can have a detrimental effect further supporting epidemiological evidence for ovulation inhibition.
PubMed: 38539519
DOI: 10.3390/cancers16061186 -
Nature Apr 2024
Topics: Female; Humans; Pregnancy; Abortion, Induced; Family Planning Services; United States; Mifepristone; Supreme Court Decisions; Legislation, Drug
PubMed: 38538891
DOI: 10.1038/d41586-024-00938-4 -
BMJ (Clinical Research Ed.) Mar 2024
Topics: Humans; United States; Female; Pregnancy; Mifepristone; Abortion, Induced; Family Planning Services; Supreme Court Decisions
PubMed: 38538006
DOI: 10.1136/bmj.q763 -
JAMA May 2024
Topics: Humans; Abortifacient Agents; Abortion, Induced; Abortion, Legal; Health Services Accessibility; Mifepristone; Nonprescription Drugs; Reproductive Health Services; Supreme Court Decisions; United States; United States Food and Drug Administration
PubMed: 38526871
DOI: 10.1001/jama.2024.5376