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Nephrology, Dialysis, Transplantation :... Jun 2024Glucocorticoids are the treatment of choice for proteinuric patients with minimal change disease (MCD) and primary focal segmental glomerulosclerosis (FSGS)....
BACKGROUND
Glucocorticoids are the treatment of choice for proteinuric patients with minimal change disease (MCD) and primary focal segmental glomerulosclerosis (FSGS). Immunosuppressive as well as direct effects on podocytes are believed to mediate their actions. In this study, we analyzed the anti-proteinuric effects of inhibition of the glucocorticoid receptor (GR) in glomerular epithelial cells, including podocytes.
METHODS
We employed genetic and pharmacological approaches to inhibit the GR. Genetically, we used Pax8-Cre/GRfl/fl mice to specifically inactivate the GR in kidney epithelial cells. Pharmacologically, we utilized a glucocorticoid antagonist called mifepristone.
RESULTS
Genetic inactivation of GR, specifically in kidney epithelial cells, using Pax8-Cre/GRfl/fl mice, ameliorated proteinuria following protein overload. We further tested the effects of pharmacological GR inhibition in three models and species: the puromycin aminonucleoside-induced nephrosis model in rats, the protein overload model in mice and the inducible transgenic NTR/MTZ zebrafish larvae with specific and reversible podocyte injury. In all three models, both pharmacological GR activation and inhibition consistently and significantly ameliorated proteinuria. Additionally, we translated our findings to humans, where three nephrotic adult patients with MCD or primary FSGS with contraindications or insufficient responses to corticosteroids were treated with mifepristone. This treatment resulted in a clinically relevant reduction of proteinuria.
CONCLUSIONS
Thus, across multiple species and proteinuria models, both genetic and pharmacological GR inhibition was at least as effective as pronounced GR activation. While the mechanism remains perplexing, GR inhibition may be a novel and targeted therapeutic approach to treat glomerular proteinuria potentially bypassing adverse actions of steroids.
Topics: Animals; Receptors, Glucocorticoid; Mice; Proteinuria; Humans; Rats; Podocytes; Zebrafish; Male; Mifepristone; Disease Models, Animal; Glomerulosclerosis, Focal Segmental; Female; Kidney Diseases; Puromycin Aminonucleoside; Hormone Antagonists; Nephrosis, Lipoid; Mice, Inbred C57BL; Mice, Transgenic
PubMed: 38037533
DOI: 10.1093/ndt/gfad254 -
Oncology Letters Jan 2024Breast cancer expressing the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) is known as triple-positive (TPBC)....
Breast cancer expressing the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) is known as triple-positive (TPBC). TPBC represents 9-11% of breast cancer cases worldwide and is a heterogeneous subtype. Notably, TPBC presents a therapeutic challenge due to the crosstalk between the hormonal (ER and PR) and HER2 pathways. Patients with TPBC are treated with trastuzumab (TTZ); however, several patients treated with TTZ tend to relapse. The present study aimed to investigate the effect of the PR on inhibitory effect of TTZ on cell viability. BT474 cells (a model of TPBC) and BT474 PR-silenced cells were treated with either TTZ, progesterone (Pg), the PR antagonist mifepristone (RU486) or estradiol (E2) alone or in combination for 144 h (6 days). Cell viability assays and western blotting were subsequently performed. The results showed that Pg and E2 interfered with the inhibitory effect of TTZ on cell viability and this effect was potentiated when both hormones were combined. Pg was revealed to act through the PR, mainly activating the PR isoform B (PR-B) and inducing the protein expression levels of CDK4 and cyclin D1; however, it did not reactivate the HER2/Akt pathway. By contrast, E2 was able to increase PR isoform A (PR-A) expression, which was inhibited by Pg. Notably, in most of the experiments, RU486 did not antagonize the effects of Pg. In conclusion, Pg and E2 may interfere with the inhibitory effect of TTZ on cell viability through PR-B activation and PR-A inactivation.
PubMed: 38034484
DOI: 10.3892/ol.2023.14152 -
Women's Health (London, England) 2023
Topics: Female; Humans; Pregnancy; Abortion, Induced; Japan; Mifepristone; Misoprostol; Abortifacient Agents, Nonsteroidal; Abortifacient Agents, Steroidal
PubMed: 38017657
DOI: 10.1177/17455057231216533 -
BioRxiv : the Preprint Server For... Nov 2023Dravet syndrome (DS) is a severe genetic epilepsy primarily caused by mutations in a voltage-activated sodium channel gene (SCN1A). Patients face life-threatening...
Dravet syndrome (DS) is a severe genetic epilepsy primarily caused by mutations in a voltage-activated sodium channel gene (SCN1A). Patients face life-threatening seizures that are largely resistant to available anti-seizure medications (ASM). Preclinical DS animal models are a valuable tool to identify candidate ASMs for these patients. Among these, mutant zebrafish exhibiting spontaneous seizure-like activity are particularly amenable to large-scale drug screening. Prior screening in a mutant zebrafish line generated using N-ethyl-Nnitrosourea (ENU) identified valproate, stiripentol, and fenfluramine e.g., Federal Drug Administration (FDA) approved drugs with clinical application in the DS population. Successful phenotypic screening in mutant zebrafish consists of two stages: (i) a locomotion-based assay measuring high-velocity convulsive swim behavior and (ii) an electrophysiology-based assay, using local field potential (LFP) recordings, to quantify electrographic seizure-like events. Using this strategy more than 3000 drug candidates have been screened in zebrafish mutants. Here, we curated a list of nine additional anti-seizure drug candidates recently identified in preclinical models: 1-EBIO, AA43279, chlorzoxazone, donepezil, lisuride, mifepristone, pargyline, soticlestat and vorinostat. First-stage locomotion-based assays in mutant zebrafish identified only 1-EBIO, chlorzoxazone and lisuride. However, second-stage LFP recording assays did not show significant suppression of spontaneous electrographic seizure activity for any of the nine anti-seizure drug candidates. Surprisingly, soticlestat induced frank electrographic seizure-like discharges in wild-type control zebrafish. Taken together, our results failed to replicate clear anti-seizure efficacy for these drug candidates highlighting a necessity for strict scientific standards in preclinical identification of ASMs.
PubMed: 38014342
DOI: 10.1101/2023.11.11.566723 -
Medicine Nov 2023Complete placenta previa often causes significant bleeding in a short period during second-trimester pregnancy termination. This can destabilize the mother's...
Clinical analysis of prophylactic uterine artery embolization combined with double balloon catheter for second-trimester pregnancy termination in cases of complete placenta previa: A retrospective study.
Complete placenta previa often causes significant bleeding in a short period during second-trimester pregnancy termination. This can destabilize the mother's circulation, threatening her life. Furthermore, the condition is complicated by an immature cervix, making it a challenging clinical problem. The aim of this study was to investigate the effect of prophylactic uterine artery embolization (UAE) combined with double balloon catheter (DBC) deal with those cases. A total of 7 patients who underwent pregnancy termination in the second-trimester in Maternal and Child Health Hospital of Hubei Province between March 1st, 2021 and August 31st, 2023 were retrospectively analyzed in this study. All patients were diagnosed with complete placenta previa status and placenta accreta spectrum, and were treated with prophylactic UAE combined with DBC, and/or dilation and evacuation. All the patients received mifepristone, and 5 of them underwent medical termination with ethacridine lactate. Following prophylactic UAE combined with DBC, 6 patients underwent dilation and evacuation, which was monitored by ultrasound. And one patient experienced natural delivery of their fetus and placenta. Only one patient (patient 3) developed an intrapartum fever after prolonged duration of 18 hours from ethacridine to UAE and 56 hours from UAE to DBC. The amount of intrapartum hemorrhage ranged from 20 mL to 300 mL. The combined therapy of prophylactic UAE and DBC is a preferred option for patients with complete placenta previa undergoing second-trimester pregnancy termination. The use of dilation and evacuation may depend on the cervical condition, bleeding, or infection.
Topics: Humans; Pregnancy; Female; Child; Retrospective Studies; Pregnancy Trimester, Second; Uterine Artery Embolization; Placenta Previa; Abortion, Induced; Placenta Accreta; Catheters
PubMed: 38013334
DOI: 10.1097/MD.0000000000036240 -
International Journal of Molecular... Nov 2023Investigating the impact of disease-causing mutations, their affected pathways, and/or potential therapeutic strategies using disease modeling often requires the...
Investigating the impact of disease-causing mutations, their affected pathways, and/or potential therapeutic strategies using disease modeling often requires the generation of different in vivo and in cellulo models. To date, several approaches have been established to induce transgene expression in a controlled manner in different model systems. Several rounds of subcloning are, however, required, depending on the model organism used, thus bringing labor-intensive experiments into the technical approach and analysis comparison. The GeneSwitch™ technology is an adapted version of the classical UAS-GAL4 inducible system, allowing the spatial and temporal modulation of transgene expression. It consists of three components: a plasmid encoding for the chimeric regulatory pSwitch protein, Mifepristone as an inducer, and an inducible plasmid. While the pSwitch-containing first plasmid can be used both in vivo and in cellulo, the inducible second plasmid can only be used in cellulo. This requires a specific subcloning strategy of the inducible plasmid tailored to the model organism used. To avoid this step and unify gene expression in the transgenic models generated, we replaced the backbone vector with standard pUAS-attB plasmid for both plasmids containing either the chimeric GeneSwitch™ cDNA sequence or the transgene cDNA sequence. We optimized this adapted system to regulate transgene expression in several mammalian cell lines. Moreover, we took advantage of this new system to generate unified cellular and fruit fly models for YARS1-induced Charco-Marie-Tooth neuropathy (CMT). These new models displayed the expected CMT-like phenotypes. In the N2a neuroblastoma cells expressing YARS1 transgenes, we observed the typical "teardrop" distribution of the synthetase that was perturbed when expressing the YARS1 mutation. In flies, the ubiquitous expression of YARS1 induced dose-dependent developmental lethality and pan-neuronal expression caused locomotor deficit, while expression of the wild-type allele was harmless. Our proof-of-concept disease modeling studies support the efficacy of the adapted transgenesis system as a powerful tool allowing the design of studies with optimal data comparability.
Topics: Animals; DNA, Complementary; Charcot-Marie-Tooth Disease; Drosophila; Mutation; Neurons; Tyrosine-tRNA Ligase; Disease Models, Animal; Mammals
PubMed: 38003325
DOI: 10.3390/ijms242216138 -
Diseases (Basel, Switzerland) Nov 2023Uterine leiomyomas are the most common benign tumors in women of childbearing age. They may lead to problems of conception or complications during the gestational... (Review)
Review
Uterine leiomyomas are the most common benign tumors in women of childbearing age. They may lead to problems of conception or complications during the gestational period. The methods of treatment include surgical (myomectomy and hysterectomy, embolization of arteries) and therapeutic treatment (ulipristal acetate, leuprolide acetate, cetrorelix, goserelin, mifepristone). Both approaches are efficient but incompatible with pregnancy planning. Therefore, there is a call for medical practice to develop therapeutical means of preventing leiomyoma onset in patients planning on becoming pregnant. Based on the analysis of GWAS data on the search for mononucleotide polymorphisms associated with the risk of leiomyoma, in meta-transcriptomic and meta-methylomic studies, target proteins have been proposed. Prospective therapeutic treatments of leiomyoma may be based on chemical compounds, humanized recombinant antibodies, vaccines based on markers of the uterine leiomyoma cells that are absent in the adult organism, or DNA and RNA preparations. Three different nosological forms of the disease associated with driver mutations in the , and genes should be considered when developing or prescribing drugs. For example, synthetic inhibitors and vaccines based on matrix metalloproteinases and are expected to be effective only for the prevention of the occurrence of -dependent nodules.
PubMed: 37987267
DOI: 10.3390/diseases11040156 -
The Linacre Quarterly Nov 2023The safety and efficacy of mifepristone antagonization with progesterone to avert medication abortion, also known as abortion pill rescue, is a subject of vigorous...
The safety and efficacy of mifepristone antagonization with progesterone to avert medication abortion, also known as abortion pill rescue, is a subject of vigorous debate. Two prominent medical associations have taken positions that either entirely reject or fully support its use. This scoping review aimed to gain insight into the safety and efficacy of its use. Analysis of 16 studies showed that the continuing pregnancy rate after ingesting mifepristone alone is ≦25 percent for gestational ages ≦49 days. Analysis of four studies showed that two-thirds of the women who changed their minds and received progesterone after initiating their medication abortion with mifepristone could safely continue their pregnancies. There is no increased maternal or fetal risk from using bioidentical progesterone in early pregnancy. If a woman has already taken mifepristone for her medication abortion and then changes her mind, timely supplementation with progesterone may allow her pregnancy to continue. The conclusion that mifepristone antagonization with progesterone is a safe and effective treatment has implications for medication abortion informed consent. Two-thirds of the women who changed their minds and received progesterone after initiating their medication abortion with mifepristone could safely continue their pregnancies. If a woman has already taken mifepristone for her medication abortion and then changes her mind, timely supplementation with progesterone may allow her pregnancy to continue. Physicians should disclose this treatment option to their patients at the time of informed consent.
PubMed: 37969420
DOI: 10.1177/00243639231176592 -
Endocrine-related Cancer Feb 2024Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have...
Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography-tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.
Topics: Humans; Mice; Animals; Female; Mifepristone; Breast Neoplasms; Receptors, Progesterone; Hormone Antagonists; Prognosis
PubMed: 37962553
DOI: 10.1530/ERC-23-0238 -
International Journal of Cell Biology 2023Inducible gene regulation methods are indispensable in diverse biological applications, yet many of them have severe limitations in their applicability. These include...
Inducible gene regulation methods are indispensable in diverse biological applications, yet many of them have severe limitations in their applicability. These include inducer toxicity, a limited variety of organisms the given system can be used in, and side effects of the induction method. In this study, a novel inducible system, the , was created using a mutant ligand-binding domain of the glucocorticoid receptor (CS1/CD), used together with various genetic elements such as the Gal4 DNA-binding domain or Cre recombinase. The RuX system is shown to be capable of over 1000-fold inducibility, has flexible applications, and is offered for use in cell cultures.
PubMed: 37941807
DOI: 10.1155/2023/7121512