scholarly journals Premature senescence of placental decidua cells as a possible cause of miscarriage produced by mycophenolic acid

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Paz de la Torre ◽  
Miguel Fernández-de la Torre ◽  
Ana I. Flores
Keyword(s):  
Mycophenolic Acid ◽  
Stromal Cells ◽  
Immunosuppressive Drug ◽  
Rrna Synthesis ◽  
Molecular Pathways ◽  
Proliferation Capacity ◽  
Nucleolar Stress ◽  
Mammalian Embryos ◽  
Underlying Mechanisms ◽  
Embryotoxic Effects

Abstract Background Successful pregnancy is supported by a healthy maternal–fetal interface (i.e., the decidual tissues) which holds the conceptus and safeguards it against stressors from the beginning of pregnancy. Any disturbance of this interface can presumably lead to the loss of pregnancy. The use of the immunosuppressive drug mycophenolic acid (MPA) should be discontinued in pregnancy given its abortive and embryotoxic effects. Direct teratogenic effects have been observed in mammalian embryos cultured in MPA, but the underlying mechanisms of abortion by MPA are less understood. Methods Decidual stromal cells isolated from human placentas are cultured in the presence of clinically relevant doses of MPA. Data regarding the effects of MPA on the proliferation and viability of decidua cultures are first analysed and then, molecular pathways contributing to these effects are unravelled. Results MPA treatment of decidual stromal cells results in loss of proliferation capacity and a decrease in the viability of decidua cultures. The molecular pathways involved in the effects of MPA on decidual stromal cells are a reduction in pre-rRNA synthesis and subsequent disruption of the nucleolus. The nucleolar stress stabilizes p53, which in turn, leads to a p21–mediated cell cycle arrest in late S and G2 phases, preventing the progression of the decidua cells into the mitosis. Furthermore, MPA does not induce apoptosis but activate mechanisms of autophagy and senescence in decidual stromal cells. Conclusion The irreversible growth arrest of decidua cells, whose role in the maintenance of the pregnancy microenvironment is known, may be one cause of miscarriage in MPA treated pregnant women.

Population pharmacokinetics of mycophenolic acid in Mexican patients with lupus nephritis

Lupus ◽  
2020 ◽  
Vol 29 (9) ◽  
pp. 1067-1077
Author(s):  
Melissa Romano-Aguilar ◽  
Juan Eduardo Reséndiz-Galván ◽  
Susanna Edith Medellín-Garibay ◽  
Rosa del Carmen Milán-Segovia ◽  
Marco Ulises Martínez-Martínez ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Mycophenolic Acid ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Immunosuppressive Drug ◽  
Stochastic Simulations ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Variability ◽  
Clinical Genetic ◽  
Post Dose

Background Mycophenolic acid (MPA) is an effective oral immunosuppressive drug used to treat lupus nephritis (LN), which exhibits large pharmacokinetic variability. This study aimed to characterize MPA pharmacokinetic behaviour in Mexican LN patients and to develop a population pharmacokinetic model which identified factors that influence MPA pharmacokinetic variability. Methods Blood samples from LN patients treated with mycophenolate mofetil (MMF) were collected pre dose and up to six hours post dose. MPA concentrations were determined by a validated ultra-performance liquid chromatography tandem mass spectrometry technique. Patients were genotyped for polymorphisms in enzymes (UGT1A8, 1A9 and 2B7) and transporters (ABCC2 and SLCO1B3). The anthropometric, clinical, genetic and co-medication characteristics of each patient were considered as potential covariates to explain the variability. Results A total of 294 MPA concentrations from 40 LN patients were included in the development of the model. The data were analysed using NONMEM software and were best described by a two-compartment linear model. MPA CL, Vc, Vp, Ka and Q were 15.4 L/h, 22.86 L, 768 L, 1.28 h−1 and 20.3 L/h, respectively. Creatinine clearance and prednisone co-administration proved to have influence on clearance, while body weight influenced Vc. The model was internally validated, proving to be stable. MMF dosing guidelines were obtained through stochastic simulations performed with the final model. Conclusions This is the first MPA population pharmacokinetic model to have found that co-administration of prednisone results in a considerable increase on clearance. Therefore, this and the other covariates should be taken into account when prescribing MMF in order to optimize the immunosuppressant therapy in patients with LN.

Mice Lacking Transcription Factor NF-E2 Provide In Vivo Validation of the Proplatelet Model of Thrombocytopoiesis and Show a Platelet Production Defect That Is Intrinsic to Megakaryocytes

Blood ◽  
1998 ◽  
Vol 92 (5) ◽  
pp. 1608-1616 ◽  
Author(s):  
Patrick Lecine ◽  
Jean-Luc Villeval ◽  
Paresh Vyas ◽  
Bethany Swencki ◽  
Yuhui Xu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stromal Cells ◽  
Cultured Cells ◽  
Platelet Production ◽  
Physiologic Mechanism ◽  
Platelet Release ◽  
Proplatelet Formation ◽  
Underlying Mechanisms ◽  
American Society

Mechanisms of platelet production and release by mammalian megakaryocytes are poorly understood. We used thrombocytopenic knockout mice to better understand these processes. Proplatelets are filamentous extensions of terminally differentiated megakaryocytes that are thought to represent one mechanism of platelet release; however, these structures have largely been recognized in cultured cells and there has been no correlation between thrombocytopoiesis in vivo and proplatelet formation. Mice lacking transcription factor NF-E2 have a late arrest in megakaryocyte maturation, resulting in profound thrombocytopenia. In contrast to normal megakaryocytes, which generate abundant proplatelets, cells from these mice never produce proplatelets, even after prolonged stimulation with c-Mpl ligand. Similarly, megakaryocytes from thrombocytopenic mice with lineage-selective loss of transcription factor GATA-1 produce proplatelets very rarely. These findings establish a significant correlation between thrombocytopoiesis and proplatelet formation and suggest that the latter represents a physiologic mechanism of platelet release. We further show that proplatelet formation by normal megakaryocytes and its absence in cells lacking NF-E2 are independent of interactions with adherent (stromal) cells. Similarly, thrombocytopenia in NF-E2−/− mice reflects intrinsic defects in the megakaryocyte lineage. These observations improve our understanding of platelet production and validate the study of proplatelets in probing the underlying mechanisms. © 1998 by The American Society of Hematology.

scholarly journals Lipidomic Alterations and PPARα Activation Induced by Resveratrol Lead to Reduction in Lesion Size in Endometriosis Models

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Zhengyun Chen ◽  
Chunyan Wang ◽  
Cuicui Lin ◽  
Lifeng Zhang ◽  
Huimei Zheng ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Therapeutic Potential ◽  
Lesion Size ◽  
Chronic Inflammatory Disease ◽  
Reproductive Age ◽  
Valuable Insight ◽  
Endometrial Stromal Cells ◽  
Proliferation Capacity ◽  
Significant Efficacy ◽  
Insight Into

Endometriosis is an estrogen-dependent chronic inflammatory disease that affects approximately 10% of women of reproductive age and up to 50% of women with infertility. The heterogeneity of the disease makes accurate diagnosis and treatment a clinical challenge. In this study, we generated two models of endometriosis: the first in rats and the second using human ectopic endometrial stromal cells (HEcESCs) derived from the lesion tissues of endometriosis patients. We then applied resveratrol to assess its therapeutic potential. Resveratrol intervention had significant efficacy to attenuate lesion size and to rectify aberrant lipid profiles of model rats. Lipidomic analysis revealed significant lipidomic alterations, including notable increases of sphingolipids and decreases of both glycerolipids and most phospholipids. Upon resveratrol application, both proliferation capacity and invasiveness parameters decreased, and the early apoptosis proportion increased for HEcESCs. The activation of PPARα was also noted as a factor potentially contributing to recovery from endometriosis in both models. Our study provides valuable insight into the mechanisms of resveratrol in endometriosis and therefore strengthens the potential for optimizing resveratrol treatment for this disease.

scholarly journals Secretome of Mesenchymal Stromal Cells Prevents Myofibroblasts Differentiation by Transferring Fibrosis-Associated microRNAs within Extracellular Vesicles

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1272 ◽  
Author(s):  
Nataliya Basalova ◽  
Georgy Sagaradze ◽  
Mikhail Arbatskiy ◽  
Evgeniy Evtushenko ◽  
Konstantin Kulebyakin ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Transforming Growth Factor Beta ◽  
Stromal Cells ◽  
High Throughput Sequencing ◽  
Transforming Growth Factor ◽  
Multipotent Mesenchymal Stromal Cells ◽  
Matrix Proteins ◽  
Direct Transfer ◽  
Underlying Mechanisms

Fibroblasts differentiation into myofibroblasts is a central event of tissue fibrosis. Multipotent mesenchymal stromal cells (MSCs) secretome can interfere with fibrosis development; despite precise underlying mechanisms remain unclear. In this study, we tested the hypothesis that MSC secretome can affect fibroblast’ differentiation into myofibroblasts by delivering regulatory RNAs, including microRNAs to these cells. Using the model of transforming growth factor-beta (TGFbeta)-induced fibroblast differentiation into myofibroblasts, we tested the activity of human MSC secretome components, specifically extracellular vesicles (MSC-EV). We showed that MSC-EV down-regulated secretion of extracellular matrix proteins by fibroblasts as well as suppressed their contractility resulting in prevention as well as reversion of fibroblasts differentiation to myofibroblasts. High-throughput sequencing of RNAs extracted from MSC-EV has revealed many fibrosis-associated microRNAs. Fibroblast treatment with MSC-EV led to direct transfer of microRNAs, which resulted in the elevation of most prominent fibrosis-associated microRNAs, including microRNA-21 and microRNA-29c. Using MSC-EV transfection by antagomirs to these microRNAs we demonstrated their involvement in the suppression of fibroblast differentiation in our model. Taken together, MSC secretome can suppress fibrosis by prevention of fibroblast differentiation into myofibroblasts as well as induce de-differentiation of the latter by direct transfer of specific microRNAs.

scholarly journals Mycophenolic Acid Inhibits Migration and Invasion of Gastric Cancer Cells via Multiple Molecular Pathways

PLoS ONE ◽  
2013 ◽  
Vol 8 (11) ◽  
pp. e81702 ◽  
Author(s):  
Boying Dun ◽  
Ashok Sharma ◽  
Yong Teng ◽  
Haitao Liu ◽  
Sharad Purohit ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Mycophenolic Acid ◽  
Migration And Invasion ◽  
Molecular Pathways ◽  
Gastric Cancer Cells

scholarly journals 4-thiouridine inhibits rRNA synthesis and causes a nucleolar stress response

RNA Biology ◽  
2013 ◽  
Vol 10 (10) ◽  
pp. 1623-1630 ◽  
Author(s):  
Kaspar Burger ◽  
Bastian Mühl ◽  
Markus Kellner ◽  
Michaela Rohrmoser ◽  
Anita Gruber-Eber ◽  
...  
Keyword(s):  
Stress Response ◽  
Rrna Synthesis ◽  
Nucleolar Stress

scholarly journals Down-Regulating Hexokinase 2 Inhibits Proliferation of Endometrial Stromal Cells Through a Noncanonical Pathway Involving Phosphorylated-STAT1 in Endometriosis

2021 ◽  
Author(s):  
Shuhui Hou ◽  
Shating Lei ◽  
Haiyan Peng ◽  
Lichun Weng ◽  
Siji Lv ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Cell Function ◽  
Malignant Tumors ◽  
Reproductive Age ◽  
Endometrial Stromal Cells ◽  
Hexokinase 2 ◽  
Proliferation Capacity ◽  
Glycolysis Pathway ◽  
Elevated Expression

Abstract Background: Endometriosis is a benign gynecologic disease that causes chronic pelvic pain, dysmenorrhea and infertility and shares several characteristics with malignant tumors, afflicting women of reproductive age. Hexokinase 2 (HK2) plays a pivotal role as the first rate-limiting enzyme in the metabolic glycolysis pathway, and its abnormal elevation in tumors is associated with tumor genesis and metastasis. However, the expression and role of HK2 in endometriosis remain unclear.Methods: We sequenced the primary endometrial stromal cells from patients with endometrioma and adopted immunohistochemistry, quantitative real-time PCR and western blot to determine the expression of HK2. Then wound healing assays, cell invasion assays, cell proliferation assays were performed to explore the functions of HK2 in endometrial stromal cells. Furthermore, mice models of endometriosis were recruited to observe the effects of HK2 inhibitors in vivo. Lastly, glycolysis metabolism detection and transcriptome sequencing were carried out in HK2-knockdown endometrial stromal cells to analyze the mechanism of HK2 affecting cell function.Results: Endometriotic stromal cells displayed active glycolysis metabolism and elevated expression of HK2. Downregulating HK2 reduced the migration, invasion and proliferation capacity of endometrial stromal cells. Knockdown of HK2 induced upregulation of signal transducer and activator of transcription 1 (STAT1) and their phosphorylation to attenuate the proliferation of endometrial stromal cells.Conclusions: HK2 was associated with the migration, invasion and proliferation of endometrial stromal cells, which might provide new insights into the pathogenesis and treatment of endometriosis.

scholarly journals Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids

2021 ◽  
Author(s):  
Thomas M. Rawlings ◽  
Komal Makwana ◽  
Deborah M. Taylor ◽  
Matteo A. Molè ◽  
Katherine J. Fishwick ◽  
...  
Keyword(s):  
Stress Responses ◽  
Stromal Cells ◽  
Embryo Implantation ◽  
Implantation Window ◽  
Decidual Cells ◽  
Uterine Mucosa ◽  
Underlying Mechanisms ◽  
New Treatments ◽  
The Impact ◽  
Mesenchymal Epithelial Transition

AbstractDecidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust matrix that accommodates the placenta throughout pregnancy. To gain insights into the underlying mechanisms, we established and characterised endometrial assembloids, consisting of gland organoids and primary stromal cells. Single-cell transcriptomics revealed that decidualized assembloids closely resemble midluteal endometrium, harbouring differentiated and senescent subpopulations in both glands and stroma. We show that acute senescence in glandular epithelium drives secretion of multiple canonical implantation factors, whereas in the stroma it calibrates the emergence of anti-inflammatory decidual cells and pro-inflammatory senescent decidual cells. Pharmacological inhibition of stress responses in pre-decidual cells accelerated decidualization by inhibiting senescence and mesenchymal-epithelial transition, processes involved in endometrial breakdown and regeneration, respectively. Accelerated decidualization resulted in entrapment of co-cultured human blastocysts in a largely static decidual matrix. By contrast, the presence of senescent decidual cells created a dynamic implantation environment, enabling embryo expansion and attachment, although their persistence led to gradual disintegration of assembloids. Our findings demonstrate that senescence controls endometrial fate decisions at implantation and highlight how endometrial assembloids may accelerate the discovery of new treatments to prevent reproductive failure.

scholarly journals Distinct Molecular Pathways to X4 Tropism for a V3-Truncated Human Immunodeficiency Virus Type 1 Lead to Differential Coreceptor Interactions and Sensitivity to a CXCR4 Antagonist

2010 ◽  
Vol 84 (17) ◽  
pp. 8777-8789 ◽  
Author(s):  
Gregory Q. Del Prete ◽  
George J. Leslie ◽  
Beth Haggarty ◽  
Andrea P. O. Jordan ◽  
Josephine Romano ◽  
...  
Keyword(s):  
Viral Evolution ◽  
Viral Envelope ◽  
Structural Basis ◽  
Molecular Pathways ◽  
V3 Loop ◽  
Cxcr4 Antagonist ◽  
Starting Point ◽  
Coreceptor Switch ◽  
Underlying Mechanisms ◽  
Hiv 1

ABSTRACT During the course of infection, transmitted HIV-1 isolates that initially use CCR5 can acquire the ability to use CXCR4, which is associated with an accelerated progression to AIDS. Although this coreceptor switch is often associated with mutations in the stem of the viral envelope (Env) V3 loop, domains outside V3 can also play a role, and the underlying mechanisms and structural basis for how X4 tropism is acquired remain unknown. In this study we used a V3 truncated R5-tropic Env as a starting point to derive two X4-tropic Envs, termed ΔV3-X4A.c5 and ΔV3-X4B.c7, which took distinct molecular pathways for this change. The ΔV3-X4A.c5 Env clone acquired a 7-amino-acid insertion in V3 that included three positively charged residues, reestablishing an interaction with the CXCR4 extracellular loops (ECLs) and rendering it highly susceptible to the CXCR4 antagonist AMD3100. In contrast, the ΔV3-X4B.c7 Env maintained the V3 truncation but acquired mutations outside V3 that were critical for X4 tropism. In contrast to ΔV3-X4A.c5, ΔV3-X4B.c7 showed increased dependence on the CXCR4 N terminus (NT) and was completely resistant to AMD3100. These results indicate that HIV-1 X4 coreceptor switching can involve (i) V3 loop mutations that establish interactions with the CXCR4 ECLs, and/or (ii) mutations outside V3 that enhance interactions with the CXCR4 NT. The cooperative contributions of CXCR4 NT and ECL interactions with gp120 in acquiring X4 tropism likely impart flexibility on pathways for viral evolution and suggest novel approaches to isolate these interactions for drug discovery.

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