The impact of progesterone and RU-486 on classic pro-labour proteins &amp; contractility in human myometrial tissues during 24-hour exposure to tension &amp; interleukin-1β

Lai, Pei F.; Georgiou, Ektoras X; Tribe, Rachel M.; Johnson, Mark R.

doi:10.1016/j.mce.2019.110633

Cited by 3 publications

(7 citation statements)

References 84 publications

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“…In agreement with our previous study, 31 24-h TC with vehicle controls can increase COX-2 and Cx43 abundance, when compared to t = 0. PR was previously found to decrease after 24-h TC with only vehicle treatment 31 but unaffected in the present study; the vehicles used were different between these studies, which may responsible for this inconsistency.…”

Section: Discussionsupporting

confidence: 93%

“…Chemiluminescence imaging undertaken using a G:BOX Chemical XL system (Syngene). ImageJ v1.5 used for histogram‐based densitometry as described previously 31 …”

Section: Methodsmentioning

confidence: 99%

“…Total protein extracts (same as those prepared for PKA activity assays) were used as previously described for detecting Ser16phosphorylated and total heat shock protein 20 (HSP20), 15 as well as PR, CAPs (cyclooxygenase-2 (COX-2), connexin-43 (Cx43) and oxytocin receptor (OTR)) and housekeeping proteins (glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and β-tubulin) 31 ; 10 and 25 μg total protein per sample was used to detect CAPs and PR, respectively. Specificity validation for primary antibodies shown in Figure S2.…”

Section: Immunoblottingmentioning

confidence: 99%

“…The rationale was mid-range inhibition (250 μM) permitted observation of additional or synergistic effects from P4, and near-full inhibition (750 μM) was useful for observing duration of maximal suppression (according to acute response data) of contractions when applied before their spontaneous onset. P4 at 100 nM maintained a physiologically relevant state at tissue level, 31 whereas 300 nM was used to model a theoretically therapeutic state that would exist with vaginal progesterone prophylaxis 36 or alternative (myometriumtargeted) drug delivery methods. 37 Together, these Ami and P4 concentrations were used for three sets of experimental conditions for 24-h treatment with continuous ITM of spontaneous contractions: 250 μM Ami ± 300 nM P4, 750 μM Ami ± 100 nM P4, and 250 μM Ami ± 100 nM P4.…”

Section: Spontaneous Contractility During 24-h Ami ± P4mentioning

confidence: 99%

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Evaluating aminophylline and progesterone combination treatment to modulate contractility and labor‐related proteins in pregnant human myometrial tissues

Lai

Young²,

Tribe

et al. 2021

Pharmacology Res & Perspec

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Section: Discussionsupporting

confidence: 93%

“…Chemiluminescence imaging undertaken using a G:BOX Chemical XL system (Syngene). ImageJ v1.5 used for histogram‐based densitometry as described previously 31 …”

Section: Methodsmentioning

confidence: 99%

Section: Immunoblottingmentioning

confidence: 99%

Section: Spontaneous Contractility During 24-h Ami ± P4mentioning

confidence: 99%

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Evaluating aminophylline and progesterone combination treatment to modulate contractility and labor‐related proteins in pregnant human myometrial tissues

Lai

Young²,

Tribe

et al. 2021

Pharmacology Res & Perspec

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“…This apparent synergistic effect against inflammation-driven transcriptional activity is likely to be mediated via modulation of MAPKs, whereby cAMP and progesterone together (via CREB [ 65 ] and PR-B [ 66 ], respectively) increase dual specificity phosphatase 1 (DUSP1) expression that represses SAPK/JNK activity [ 67 , 68 ] to reduce PR-A Ser344/345 phosphorylation [ 62 ]. PR-A and PR-B abundance has been observed to exist at a 1 : 1 ratio in myometrium biopsies from non-labouring pregnant women at term gestation [ 69 , 70 ]; when this is modelled in vitro using the human myometrium hTERT-HM A/B cell line [ 48 ], treatment with a combination of forskolin and progesterone can maintain a transcriptome profile that resembles the in vivo non-labouring state more closely than treatment with either agent alone [ 71 ].…”

Section: Combined Effects Of Camp and Progesterone On Gene Expressionmentioning

confidence: 99%

Transcription factors regulated by cAMP in smooth muscle of the myometrium at human parturition

Lai

Tribe

et al. 2021

Biochemical Society Transactions

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Cyclic adenosine monophosphate (cAMP) contributes to maintenance of a quiescent (relaxed) state in the myometrium (i.e. uterine smooth muscle) during pregnancy, which most commonly has been attributed to activation of protein kinase A (PKA). PKA-mediated phosphorylation of cytosolic contractile apparatus components in myometrial smooth muscle cells (mSMCs) are known to promote relaxation. Additionally, PKA also regulates nuclear transcription factor (TF) activity to control expression of genes important to the labour process; these are mostly involved in actin-myosin interactions, cell-to-cell connectivity and inflammation, all of which influence mSMC transition from a quiescent to a contractile (pro-labour) phenotype. This review focuses on the evidence that cAMP modulates the activity of TFs linked to pro-labour gene expression, predominantly cAMP response element (CRE) binding TFs, nuclear factor κB (NF-κB), activator protein 1 (AP-1) family and progesterone receptors (PRs). This review also considers the more recently described exchange protein directly activated by cAMP (EPAC) that may oppose the pro-quiescent effects of PKA, as well as explores findings from other cell types that have the potential to be of novel relevance to cAMP action on TF function in the myometrium.

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Molecular Evaluation of PROGINS Mutation in Progesterone Receptor Gene and Determination of its Frequency, Distribution Pattern and Association with Breast Cancer Susceptibility in Saudi Arabia

Albalawi

Mir

Abuduhier

2020

EMIDDT

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Aims: Experimental and clinical evidence demonstrate that progesterone hormone and its nuclear receptor, the Progesterone Receptor (PR), play critical role in controlling mammary gland tumorigenesis and breast cancer development. Hormonal therapy (Tomaxifen) is the frontline treatment for hormone-dependent breast cancers. Progesterone hormone induces its action on the target cells by binding with its Progesterone receptor (PgR) therefore any genetic variations, which might induce alienation in the progesterone receptor, can result in an increased susceptibility of gynecological cancers. Alu insertion (PROGINS) mutation in PgR gene is reported to be associated with an increased risk of ovarian cancer and a decreased risk of breast cancer. However, its association with breast cancer risk remains inconclusive. Therefore, we investigated the association of PROGINS allele and its link with breast cancer risk. Methods: This case control study was performed on 200 subjects in which 100 were breast cancer cases and 100 gender matched healthy controls.The mutation was detected by using mutation specific PCR and results were confirmed by direct Sanger sequencing. Results: A clinically significant difference was reported in genotype distribution of PROGINs allele among the cases and gender-matched healthy controls (P<0. 032). Genotype frequencies of A1/A1, A1/A2, A2/A2 reported in cases was 81%, 19% (18% & 1%) and in matched healthy controls were 93%, 7% (6% & 1%). The higher frequency of PROGINs allele (19%) was observed in cases than the healthy controls (7%). The findings indicated that PgR variants (CC vs CT) increased the risk of Breast cancer in codominant inheritance model with OR= 3.44, 95% CI =1. 30-9.09, P<0.021) whereas nonsignificant association was found for CC vs TT genotypes with OR=1.14, 95% CI=0.07-18.658, P=0. 92. However, subgroup analysis revealed that CT + TT vs CC genotype increased the risk of breast cancer in dominant inheritance model tested OR = 3. 11, 95% CI = (1.24-7.79), P = 0.015). A nonsignificant association for PgR (CC+CT) vs TT) genotypes were reported in breast cancer OR = 1. 0, 95% CI= (0. 061-16.21), P=1) in recessive inheritance model tested. However, analysis with clinicalpathological variables revealed that the PROGINs allele is significantly associated with the distant metastasis and advanced stage of the disease. Conclusion: The mutation specific PCR was successfully developed as an alternative to Sanger sequencing for the cost-effective detection for PROGINS allele of progesterone receptor gene. A clinically significant correlation of PROGINs allele was reported with the distant metastasis and advanced stage of the disease. Taken together, these results demonstrated that PROGINS variant is associated with an increased susceptibility to Breast cancer, providing novel insights into the genetic etiology and underlying biology of Breast carcinogenesis. Further studies with large sample sizes are required to validate our findings.

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The impact of progesterone and RU-486 on classic pro-labour proteins & contractility in human myometrial tissues during 24-hour exposure to tension & interleukin-1β

Cited by 3 publications

References 84 publications

Evaluating aminophylline and progesterone combination treatment to modulate contractility and labor‐related proteins in pregnant human myometrial tissues

Evaluating aminophylline and progesterone combination treatment to modulate contractility and labor‐related proteins in pregnant human myometrial tissues

Transcription factors regulated by cAMP in smooth muscle of the myometrium at human parturition

Molecular Evaluation of PROGINS Mutation in Progesterone Receptor Gene and Determination of its Frequency, Distribution Pattern and Association with Breast Cancer Susceptibility in Saudi Arabia

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