MiR-144 and targets, c-fos and cyclooxygenase-2 (COX2), modulate synthesis of PGE2 in the amnion during pregnancy and labor.
Ontology highlight
ABSTRACT:
SUBMITTER: Li H
PROVIDER: S-EPMC4906292 | biostudies-other | 2016
REPOSITORIES: biostudies-other
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Project description:The amnion is remodeled during pregnancy to protect the growing fetus it contains, and it is particularly dynamic just before and during labor. By combining ultrastructural, immunohistochemical, and Western blotting analyses, we found that human and mouse amnion membranes during labor were subject to epithelial-to-mesenchymal transition (EMT), mediated, in part, by the p38 mitogen-activated protein kinase (MAPK) pathway responding to oxidative stress. Primary human amnion epithelial cell cultures established from amnion membranes from nonlaboring, cesarean section deliveries exhibited EMT after exposure to oxidative stress, and the pregnancy maintenance hormone progesterone (P4) reversed this process. Oxidative stress or transforming growth factor-? (TGF-?) stimulated EMT in a manner that depended on TGF-?-activated kinase 1 binding protein 1 (TAB1) and p38 MAPK. P4 stimulated the reverse transition, MET, in primary human amnion mesenchymal cells (AMCs) through progesterone receptor membrane component 2 (PGRMC2) and c-MYC. Our results indicate that amnion membrane cells dynamically transition between epithelial and mesenchymal states to maintain amnion integrity and repair membrane damage, as well as in response to inflammation and mechanical damage to protect the fetus until parturition. An irreversible EMT and the accumulation of AMCs characterize the amnion membranes at parturition.
| S-EPMC7092701 | biostudies-literature
Project description:Throughout most of pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, whereas spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and have a negative impact on PR function. In this study, we uncovered a previously undescribed regulatory pathway whereby micro-RNAs (miRNAs) serve as hormonally modulated and conserved mediators of contraction-associated genes in the pregnant uterus in the mouse and human. Using miRNA and gene expression microarray analyses of uterine tissues, we identified a conserved family of miRNAs, the miR-200 family, that is highly induced at term in both mice and humans as well as two coordinately down-regulated targets, zinc finger E-box binding homeobox proteins ZEB1 and ZEB2, which act as transcriptional repressors. We also observed up-regulation of the miR-200 family and down-regulation of ZEB1 and ZEB2 in two different mouse models of preterm labor. We further demonstrated that ZEB1 is directly up-regulated by the action of progesterone (P(4))/PR at the ZEB1 promoter. Excitingly, we observed that ZEB1 and ZEB2 inhibit expression of the contraction-associated genes, oxytocin receptor and connexin-43, and block oxytocin-induced contractility in human myometrial cells. Together, these findings implicate the miR-200 family and their targets, ZEB1 and ZEB2, as unique P(4)/PR-mediated regulators of uterine quiescence and contractility during pregnancy and labor and shed light on the molecular mechanisms involved in preterm birth.
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Project description:Plants of the Asteraceae family have been used in traditional medicine for centuries due to their main antimicrobial and analgesic activities. A liniment from Artemisia californica has recently been tested on patients affected by either acute pain or chronic pain conditions with great success. The aim of this study was to evaluate the anti-inflammatory activity of sesquiterpene lactones (SLs), representing the majority in the Asteraceae family. Leucodin, α-santonin and sclareolide (three SLs) were chosen to undergo chemical modifications. This pool of molecules underwent molecular modeling experiments using an in-house program, WATGEN, predicting the water network and its contribution to the overall affinity of the enzyme-ligand complex. The anti-inflammatory activity and the ability of compounds to modulate COX-2 expression have been evaluated in LPS-stimulated RAW 264.7 cells and in RIF-1 cells treated according to the Photodynamic Therapy (PDT) protocols using Photoprin (PH) as photosensitizer. Furthermore, commercially available assay kits were used to evaluate the concentration of PGE-2 and the direct inhibition of COX-2. All the tested molecules fit well in the enzyme binding pocket, but to get a substantial inhibition of the expression and activity of the enzyme as well as a reduction in the PGE2 concentration, high concentrations of the compounds are needed. The only exceptions being leucodin itself and FP6, one of the α-santonin derivatives, presenting a CF3 functional group. We believe that this class of compounds has some interesting potential in the treatment of pain and inflammation. Although, the activity seems to be due to a mechanism related to the expression of the COX enzymes rather than on a direct inhibition.
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Project description:Throughout most of pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, while spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and negatively impact PR function. In this study, we uncovered a new regulatory pathway whereby miRNAs serve as hormonally-modulated and conserved mediators of contraction-associated genes in the pregnant uterus from mouse to human. Using miRNA and gene expression microarray analyses of uterine tissues, we identified a conserved family of miRNAs, the miR-200 family, that is highly induced at term in both mice and humans, as well as two coordinately downregulated targets, zinc finger E-box binding homeobox proteins, ZEB1 and ZEB2, which act as transcriptional repressors. We also observed upregulation of the miR-200 family and downregulation of ZEB1 and ZEB2 in two different mouse models of preterm labor. We further demonstrated that ZEB1 is directly upregulated by the action of P4/PR at the ZEB1 promoter. Excitingly, we observed that ZEB1 and ZEB2 inhibit expression of the contraction- associated genes, oxytocin receptor and connexin-43 and block oxytocin-induced contractility in human myometrial cells. Together, these findings implicate the miR-200 family and their targets ZEB1 and ZEB2 as novel progesterone/PR- mediated regulators of uterine quiescence and contractility during pregnancy and labor, and shed new light on the molecular mechanisms involved in preterm birth. RNA was purified from mouse myometrium (miRNeasy kit, Qiagen). miRNA microarray was performed (LC Sciences) on 18 biological replicates of murine myometrium at 15.5 dpc and an equal number of replicates at 18.5 dpc. Gene expression microarray assays were performed (UT Southwestern Medical Center) on the same 36 samples as detailed further in SI Materials and Methods.
2010-10-30 | E-GEOD-25017 | biostudies-arrayexpress
Project description:Throughout most of pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, while spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and negatively impact PR function. In this study, we uncovered a new regulatory pathway whereby miRNAs serve as hormonally-modulated and conserved mediators of contraction-associated genes in the pregnant uterus from mouse to human. Using miRNA and gene expression microarray analyses of uterine tissues, we identified a conserved family of miRNAs, the miR-200 family, that is highly induced at term in both mice and humans, as well as two coordinately downregulated targets, zinc finger E-box binding homeobox proteins, ZEB1 and ZEB2, which act as transcriptional repressors. We also observed upregulation of the miR-200 family and downregulation of ZEB1 and ZEB2 in two different mouse models of preterm labor. We further demonstrated that ZEB1 is directly upregulated by the action of P4/PR at the ZEB1 promoter. Excitingly, we observed that ZEB1 and ZEB2 inhibit expression of the contraction- associated genes, oxytocin receptor and connexin-43 and block oxytocin-induced contractility in human myometrial cells. Together, these findings implicate the miR-200 family and their targets ZEB1 and ZEB2 as novel progesterone/PR- mediated regulators of uterine quiescence and contractility during pregnancy and labor, and shed new light on the molecular mechanisms involved in preterm birth.
2010-10-30 | GSE25017 | GEO
Project description:BACKGROUND:Interleukin-33 (IL-33) participates in various types of diseases including cancers. Previous studies of this cytokine in cancers mainly focused on its regulation on immune responses by which IL-33 modulated cancer progression. The IL-33 triggered signals in cancer cells remain unclear. METHODS:We analyzed IL-33 gene expression in human colorectal cancer (CRC) tissues and carried out gene enrichment analysis with TCGA Data Portal. We studied CRC proliferation in vivo by inoculating MC38 tumors in IL-33 transgenic mice. We investigated the cell proliferation in vitro with primary CRC cells isolated from fresh human CRC tissues, human CRC cell line HT-29 and mouse CRC cell line MC38. To evaluate the proliferation modulating effects of recombinant IL-33 incubation and other administrated factors, we measured tumor growth, colony formation, cell viability, and the expression of Ki67 and proliferating cell nuclear antigen (PCNA). We used several inhibitors, prostaglandin E2 (PGE2) neutralizing antibody, ST2 blocking antibody and specific shRNA expressing plasmid to study the pathway mediating IL-33-induced CRC proliferation. The IL-33 receptor ST2 in human CRC tissues was detected by immunohistochemistry staining and western blotting. The ST2-positive or negative subsets of primary CRC cells were acquired by flow cytometry sorting. RESULTS:We found that IL-33 expression was correlated with the gene signature of cell proliferation in 394 human CRC samples. The MC38 tumors grew more rapidly and the tumor Ki67 and PCNA were expressed at higher levels in IL-33 transgenic mice than in wild-type mice. IL-33 promoted cell growth, colony formation and expression of Ki67 and PCNA in primary CRC cells as well as CRC cell lines. IL-33 activated cycloxygenase-2 (COX2) expression and increased PGE2 production, whereas the COX2 selective inhibitor and PGE2 neutralizing antibody abolished the proliferation promoting effect of IL-33. ST2 blockade, ST2-negative sorting, NF-?B specific inhibitor and NF-?B specific shRNA (shP65) abrogated the COX2 induction caused by IL-33. CONCLUSION:IL-33 facilitates proliferation of colorectal cancer dependent on COX2/PGE2. IL-33 functions via its receptor ST2 and upregulates COX2 expression through NF-?B signaling. Understanding the IL-33 signal transduction in CRC cells provides potential therapeutic targets for clinical treatment.
| S-EPMC6098640 | biostudies-literature
Project description:Inflammation is a major risk factor for neonatal white matter injury (NWMI), which is associated with later development of cerebral palsy. Although recent studies have demonstrated maturation arrest of oligodendrocyte progenitor cells (OPCs) in NWMI, the identity of inflammatory mediators with direct effects on OPCs has been unclear. Here, we investigated downstream effects of pro-inflammatory IL-1β to induce cyclooxygenase-2 (COX2) and prostaglandin E2 (PGE2) production in white matter. First, we assessed COX2 expression in human fetal brain and term neonatal brain affected by hypoxic-ischemic encephalopathy (HIE). In the developing human brain, COX2 was expressed in radial glia, microglia, and endothelial cells. In human term neonatal HIE cases with subcortical WMI, COX2 was strongly induced in reactive astrocytes with "A2" reactivity. Next, we show that OPCs express the EP1 receptor for PGE2, and PGE2 acts directly on OPCs to block maturation in vitro. Pharmacologic blockade with EP1-specific inhibitors (ONO-8711, SC-51089), or genetic deficiency of EP1 attenuated effects of PGE2. In an IL-1β-induced model of NWMI, astrocytes also exhibit "A2" reactivity and induce COX2. Furthermore, in vivo inhibition of COX2 with Nimesulide rescues hypomyelination and behavioral impairment. These findings suggest that neonatal white matter astrocytes can develop "A2" reactivity that contributes to OPC maturation arrest in NWMI through induction of COX2-PGE2 signaling, a pathway that can be targeted for neonatal neuroprotection.
| S-EPMC5753598 | biostudies-literature
Project description:BackgroundSufficient information from in vitro and in vivo studies has become available to permit computer modeling of the processes that occur in the myometrium during labor. This development allows the in silico investigation of pathological mechanisms and the trialing of potential treatments.Methods/resultsBased on the human literature, we developed a computer model of the immune-endocrine environment of the myometrial cell. The interactions between molecules are represented by differential equations. The model is designed to simulate the estrogen and progesterone receptor changes during pregnancy and particularly the changes in the progesterone receptor (PR) isoforms A and B that are thought to mediate functional progesterone withdrawal in the human at labor. Parturition is represented by an increase in the PRA to PRB ratio to levels seen in women in labor. Infection is shown by inducing inflammation in the system by increasing phospho-IkB kinase concentration (IKK) levels; which lead to increased NF-kappaB activation, causing an increase in the PRA/PRB ratio. We examined the effects of progesterone or cyclo-oxygenase 2 (Cox2) inhibitor treatments on the PRA/PRB ratio in silico. The model predicted that high doses of progesterone and Cox2 inhibition would be effective in preventing an NF-kappaB-induced PRA/PRB ratio increase to the levels found during labor.ConclusionsOur data illustrate the use of dynamic biological computer simulations to test the effectiveness of therapeutic interventions. This may allow the early rejection of ineffective therapies prior to expensive field trials.
| S-EPMC2811723 | biostudies-literature
Project description:Transcription is a stochastic process occurring mostly in episodic bursts. Although the local chromatin environment is known to influence the bursting behavior on long timescales, the impact of transcription factors (TFs)--especially in rapidly inducible systems--is largely unknown. Using fluorescence in situ hybridization and computational models, we quantified the transcriptional activity of the proto-oncogene c-Fos with single mRNA accuracy at individual endogenous alleles. We showed that, during MAPK induction, the TF concentration modulates the burst frequency of c-Fos, whereas other bursting parameters remain mostly unchanged. By using synthetic TFs with TALE DNA-binding domains, we systematically altered different aspects of these bursts. Specifically, we linked the polymerase initiation frequency to the strength of the transactivation domain and the burst duration to the TF lifetime on the promoter. Our results show how TFs and promoter binding domains collectively act to regulate different bursting parameters, offering a vast, evolutionarily tunable regulatory range for individual genes.
| S-EPMC5555219 | biostudies-literature
Project description:PURPOSE:Microsomal prostaglandin E2 synthase 1 (mPGES1) was evaluated as an important downstream effector of the COX2 pathway responsible for tumor-mediated immunosuppression in melanoma. EXPERIMENTAL DESIGN:The analysis of a stage III melanoma tissue microarray (n = 91) was performed to assess the association between mPGES1, COX2, CD8, and patient survival. Pharmacologic inhibitors and syngeneic mouse models using PTGES-knockout (KO) mouse melanoma cell lines were used to evaluate the mPGES1-mediated immunosuppressive function. RESULTS:We observed correlations in expression and colocalization of COX2 and mPGES1, which are associated with increased expression of immunosuppressive markers in human melanoma. In a syngeneic melanoma mouse model, PTGES KO increased melanoma expression of PD-L1, increased infiltration of CD8a+ T cells, and CD8a+ dendritic cells into tumors and suppressed tumor growth. Durable tumor regression was observed in mice bearing PTGES KO tumors that were given anti-PD-1 therapy. Analysis of a stage III melanoma tissue microarray revealed significant associations between high mPGES1 expression and low CD8+ infiltration, which correlated with a shorter patient survival. CONCLUSIONS:Our results are the first to illustrate a potential role for mPGES1 inhibition in melanoma immune evasion and selective targeting in supporting the durability of response to PD-1 checkpoint immunotherapy. More research effort in this drug development space is needed to validate the use of mPGES1 inhibitors as safe treatment options.
| S-EPMC6397703 | biostudies-literature