Mifepristone-Exposured Human Endometrial Endothelial Cells In Vitro

Helmestam, Malin; Lindgren, Karin E; Stavréus-Evers, Anneli; Olovsson, Matts

doi:10.1177/1933719113497284

Cited by 11 publications

(10 citation statements)

References 37 publications

(72 reference statements)

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“…Pretreatment of cells with the GR inhibitor mifepristone (MF; Sigma Aldrich, St. Louis, Missouri; catalog M8046) was selected as an alternative approach to understand the role of GR in EPI‐ECs. A 10‐mmol/L stock of MF was prepared in dimethyl sulfoxide (Fisher Scientific, Rockford, Illinois; catalog BP231‐100) and diluted to 50 μmol/L in media . The effects of MF on EPI‐ECs were validated by immunocytochemistry after 24 hours of incubation (n = 4 donors in triplicate per condition).…”

Section: Methodsmentioning

confidence: 99%

Modulation of glucocorticoid receptor in human epileptic endothelial cells impacts drug biotransformation in an in vitro blood–brain barrier model

et al. 2018

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SummaryObjectiveNuclear receptors and cytochrome P450 (CYP) regulate hepatic metabolism of several drugs. Nuclear receptors are expressed at the neurovascular unit of patients with drug‐resistant epilepsy. We studied whether glucocorticoid receptor (GR) silencing or inhibition in human epileptic brain endothelial cells (EPI‐ECs) functionally impacts drug bioavailability across an in vitro model of the blood–brain barrier (BBB) by CYP‐multidrug transporter (multidrug resistance protein 1, MDR1) mechanisms.MethodsSurgically resected brain specimens from patients with drug‐resistant epilepsy, primary EPI‐ECs, and control human brain microvascular endothelial cells (HBMECs) were used. Expression of GR, pregnane X receptor, CYP3A4, and MDR1 was analyzed pre‐ and post‐GR silencing in EPI‐ECs. Endothelial cells were co‐cultured with astrocytes and seeded in an in vitro flow‐based BBB model (DIV‐BBB). Alternatively, the GR inhibitor mifepristone was added to the EPI‐EC DIV‐BBB. Integrity of the BBB was monitored by measuring transendothelial electrical resistance. Cell viability was assessed by glucose‐lactate levels. Permeability of [3H]sucrose and [14C]phenytoin was quantified. CYP function was determined by measuring resorufin formation and oxcarbazepine (OXC) metabolism.ResultsSilencing and inhibition of GR in EPI‐ECs resulted in decreased pregnane X receptor, CYP3A4, and MDR1 expression. GR silencing or inhibition did not affect BBB properties in vitro, as transendothelial electrical resistance and Psucrose were unaltered, and glucose metabolism was maintained. GR EPI‐EC silencing or inhibition led to (1) increased Pphenytoin BBB permeability as compared to control; (2) decreased CYP function, indirectly evaluated by resorufin formation; (3) improved OXC bioavailability with increased abluminal (brain‐side) OXC levels as compared to control.SignificanceOur results suggest that modulating GR expression in EPI‐ECs at the BBB modifies drug metabolism and penetration by a mechanism encompassing P450 and efflux transporters. The latter could be exploited for future drug design and to overcome pharmacoresistance.

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Section: Methodsmentioning

confidence: 99%

Modulation of glucocorticoid receptor in human epileptic endothelial cells impacts drug biotransformation in an in vitro blood–brain barrier model

et al. 2018

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“…For this reason, pathologists not familiar with these unique changes may mistake them as “hyperplasia” 172. A comparison of endometria from women treated with low-dose MFP and normal subjects evidenced the presence of nonsynchronous endometrium, large fluid-filled glands, and abnormal blood vessels, with cell injury and cell death in capillary endothelial cells,173 but no detectable effects on their mRNA expression for several markers 174…”

Section: Selective Progesterone Receptor Modulators (Sprms)mentioning

confidence: 99%

<p>Uterine fibroids: an update on current and emerging medical treatment options</p>

Farris

Bastianelli

Rosato

et al. 2019

TCRM

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Uterine fibroids are the most common gynecological disorder, classically requiring surgery when symptomatic. Although attempts at finding a nonsurgical cure date back to centuries, it is only around the middle of the last century that serious attempts at a medical treatment were carried out. Initially, both progestins and estrogen–progestin combinations have been utilized, although proof of their usefulness is lacking. A major step forward was achieved when peptide analogs of the GnRH were introduced, first those with superagonist properties and subsequently those acting as antagonists. Initially, the latter produced side effects preventing their routine utilization; eventually, this problem was overcome following the synthesis of cetrorelix. Because both types of analogs produce hypoestrogenism, their use is limited to a maximum of 6 months and, for this reason, today they are utilized as an adjuvant treatment before surgery with overall good results. Over the last decade, new, nonpeptidic, orally active GnRH-receptor blockers have also been synthesized. One of them, Elagolix, is in the early stages of testing in women with fibroids. Another fundamental development has been the utilization of the so-called selective progesterone receptor modulators, sometimes referred to as “antiprogestins”. The first such compound to be applied to the long-term treatment of fibroids was Mifepristone; today, this compound is mostly used outside of Western Countries, where the substance of choice is Ulipristal acetate. Large clinical trials have proven the effectiveness of Ulipristal in the long-term medical therapy of fibroids, although some caution must be exercised because of the rare occurrence of liver complications. All selective progesterone receptor modulators produce unique endometrial changes that are today considered benign, reversible, and without negative consequences. In conclusion, long-term medical treatment of fibroids seems possible today, especially in premenopausal women.

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“…[ 12 ] Cd 2+ ‐induced defect in VFGF‐A and PLGF expression leads to endothelial dysfunction, lack of proper implantation, premature delivery, subinfertility, and pre‐eclampsia. [ 12,84 ] Cd 2+ administration changes the rate of glucocorticoid production during pregnancy and causes pre‐eclampsia. [ 20 ]…”

Section: Nonessential Heavy Metalmentioning

confidence: 99%

Effects of heavy metals on reproduction owing to infertility

Bhardwaj

Paliwal

Saraf

2021

J Biochem & Molecular Tox

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The reproductive performance of most of the species is adversely affected by hazardous heavy metals like lead, cadmium, mercury, arsenic, zinc, and copper. Heavy metals are liberated in the environment by natural sources like rock weathering, volcanic eruption, and other human activities like industrial discharge, mineral mining, automobile exhaust, and so forth. Heavy metals alter several reproductive functions in both males and females like a decrease in sperm count, motility, viability, spermatogenesis, hormonal imbalance, follicular atresia, and delay in oocyte maturation, and so forth, and thus, forms an important aspect of reproductive toxicology. The present review compiles toxicity aspects of various heavy metals and their efficacy and mechanism of action in mammals.

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Mifepristone-Exposured Human Endometrial Endothelial Cells In Vitro

Cited by 11 publications

References 37 publications

Modulation of glucocorticoid receptor in human epileptic endothelial cells impacts drug biotransformation in an in vitro blood–brain barrier model

Modulation of glucocorticoid receptor in human epileptic endothelial cells impacts drug biotransformation in an in vitro blood–brain barrier model

<p>Uterine fibroids: an update on current and emerging medical treatment options</p>

Effects of heavy metals on reproduction owing to infertility

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