Catecholestradiol Activation of Adrenergic Receptors Induces Endometrial Cell Survival via p38 MAPK Signaling

2020 ◽  
Author(s):  
Rachel Sprague ◽  
Joung W Kim ◽  
Esma Kirimlioglu ◽  
Xiaofang Guo ◽  
Nihan Günay ◽  
...  
Keyword(s):  
Cell Survival ◽  
P38 Mapk ◽  
Adrenergic Receptors ◽  
Estrogenic Activity ◽  
Mapk Signaling ◽  
Endometrial Cell ◽  
Ishikawa Cell ◽  
Ishikawa Cells ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

Abstract Context Enhanced levels of catecholestradiols, 2-hydroxyestradiol (2-OHE2) or 4-hydroxyestradiol (4-OHE2), are reported in endometriosis. During gestation, catecholestradiol activation of adrenergic receptors (AR) elevates estrogen receptor (ER)-independent proliferation of uterine arterial endothelial cells. Objective To investigate β-AR-mediated catecholestradiol effects on human endometrial stromal cell (HESC) and epithelial cell survival in endometriosis. Design β-AR immunostaining of eutopic and ectopic endometria (n = 9). Assays for cell viability, 5-bromo-2′-deoxyuridine proliferation, apoptosis, quantitative PCR, and estrogenicity (alkaline phosphatase activity), as well as siRNA β-AR silencing and immunoblot analyses of cultured HESCs or Ishikawa cells treated with control or 2-OHE2 or 4-OHE2 ±β-AR antagonist or ±p38 MAPK inhibitor. Setting University research institution. Patients Women with or without endometriosis. Interventions None. Main Outcome Measures β-AR expression in eutopic vs ectopic endometria and regulation of HESC survival by 2-OHE2 and 4-OHE2. Results Eutopic and ectopic endometrial stromal and epithelial cells displayed β2-AR immunoreactivity with increased staining in the functionalis vs basalis layer (P < 0.05). Both 2-OHE2 and 4-OHE2 enhanced HESC and Ishikawa cell survival (P < 0.05), an effect abrogated by β-AR antagonist propranolol, but not ER antagonist ICI182,780. 2-OHE2 or 4-OHE2 failed to induce cell survival and estrogenic activity in ADRB2-silenced HESCs and in Ishikawa cells, respectively. Although 2-OHE2 inhibited apoptosis and BAX mRNA expression, 4-OHE2 induced proliferation and decreased apoptosis (P < 0.05). Both catecholestradiols elevated phospho-p38 MAPK levels (P < 0.05), which was blocked by propranolol, and p38 MAPK inhibitor reversed catecholestradiol-enhanced HESC survival. Conclusions Catecholestradiols increase endometrial cell survival by an ER-independent β-AR-mediated p38 MAPK activation, suggesting that agents blocking β-AR (e.g., propranolol) or inhibiting 2-OHE2- or 4-OHE2-generating enzymes (i.e., CYP1A1/B1) could treat endometriosis.

Vandetanib combined with a p38 MAPK inhibitor synergistically reduces glioblastoma cell survival

2013 ◽  
Vol 30 (3) ◽  
Author(s):  
Linda Sooman ◽  
Johan Lennartsson ◽  
Joachim Gullbo ◽  
Michael Bergqvist ◽  
Georgios Tsakonas ◽  
...  
Keyword(s):  
Cell Survival ◽  
P38 Mapk ◽  
Glioblastoma Cell ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

scholarly journals Heat Shock Protein 70 Protects the Heart from Ischemia/Reperfusion Injury through Inhibition of p38 MAPK Signaling

2020 ◽  
Vol 2020 ◽  
pp. 1-19 ◽  
Author(s):  
Nan Song ◽  
Jiao Ma ◽  
Xiao-wen Meng ◽  
Hong Liu ◽  
Hui Wang ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Heat Shock Protein 70 ◽  
Myocardial Injury ◽  
Cell Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Mapk Signaling ◽  
Myocardial Infarct Size ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

Background. Heat shock protein 70 (Hsp70) has been shown to exert cardioprotection. Intracellular calcium ([Ca2+]i) overload induced by p38 mitogen-activated protein kinase (p38 MAPK) activation contributes to cardiac ischemia/reperfusion (I/R) injury. However, whether Hsp70 interacts with p38 MAPK signaling is unclear. Therefore, this study investigated the regulation of p38 MAPK by Hsp70 in I/R-induced cardiac injury. Methods. Neonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation for 6 h followed by 2 h reoxygenation (OGD/R), and rats underwent left anterior artery ligation for 30 min followed by 30 min of reperfusion. The p38 MAPK inhibitor (SB203580), Hsp70 inhibitor (Quercetin), and Hsp70 short hairpin RNA (shRNA) were used prior to OGD/R or I/R. Cell viability, lactate dehydrogenase (LDH) release, serum cardiac troponin I (cTnI), [Ca2+]i levels, cell apoptosis, myocardial infarct size, mRNA level of IL-1β and IL-6, and protein expression of Hsp70, phosphorylated p38 MAPK (p-p38 MAPK), sarcoplasmic/endoplasmic reticulum Ca2+-ATPase2 (SERCA2), phosphorylated signal transducer and activator of transcription3 (p-STAT3), and cleaved caspase3 were assessed. Results. Pretreatment with a p38 MAPK inhibitor, SB203580, significantly attenuated OGD/R-induced cell injury or I/R-induced myocardial injury, as evidenced by improved cell viability and lower LDH release, resulted in lower serum cTnI and myocardial infarct size, alleviation of [Ca2+]i overload and cell apoptosis, inhibition of IL-1β and IL-6, and modulation of protein expressions of p-p38 MAPK, SERCA2, p-STAT3, and cleaved-caspase3. Knockdown of Hsp70 by shRNA exacerbated OGD/R-induced cell injury, which was effectively abolished by SB203580. Moreover, inhibition of Hsp70 by quercetin enhanced I/R-induced myocardial injury, while SB203580 pretreatment reversed the harmful effects caused by quercetin. Conclusions. Inhibition of Hsp70 aggravates [Ca2+]i overload, inflammation, and apoptosis through regulating p38 MAPK signaling during cardiac I/R injury, which may help provide novel insight into cardioprotective strategies.

Additive effects of heat and p38 mapk inhibitor treatment on melanin synthesis

2007 ◽  
Vol 30 (5) ◽  
pp. 581-586 ◽  
Author(s):  
Dong-Seok Kim ◽  
Seo-Hyoung Park ◽  
Sun-Bang Kwon ◽  
Jung-Im Na ◽  
Chang-Hun Huh ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Additive Effects ◽  
Melanin Synthesis ◽  
P38 Mapk Inhibitor ◽  
Inhibitor Treatment ◽  
Mapk Inhibitor

scholarly journals Protective effects of the p38 MAPK inhibitor SB203580 on NMDA-induced injury in primary cerebral cortical neurons

2014 ◽  
Vol 10 (4) ◽  
pp. 1942-1948 ◽  
Author(s):  
XUE-WEN LIU ◽  
EN-FEI JI ◽  
PENG HE ◽  
RUI-XIAN XING ◽  
BU-XIAN TIAN ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Cortical Neurons ◽  
Protective Effects ◽  
Cerebral Cortical Neurons ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

scholarly journals Metformin combined with p38 MAPK inhibitor improves cisplatin sensitivity in cisplatin-resistant ovarian cancer

2014 ◽  
Vol 10 (5) ◽  
pp. 2346-2350 ◽  
Author(s):  
YA XIE ◽  
ZHENG PENG ◽  
MINGXING SHI ◽  
MEI JI ◽  
HONGJUN GUO ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
P38 Mapk ◽  
Cisplatin Sensitivity ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

scholarly journals Overexpression of long non coding RNA OR3A4 is associated with altered p38 signalling, morphological and phenotypic changes, and reduced immunogenicity in Barretts Oesophagus

2021 ◽  
Author(s):  
Thomas Nieto ◽  
Yash Sinha ◽  
Qin Qin Zhuang ◽  
Mathew Coleman ◽  
Joanne D Stockton ◽  
...  
Keyword(s):  
T Cells ◽  
P38 Mapk ◽  
Significant Risk ◽  
Oesophageal Adenocarcinoma ◽  
Cellular Phenotype ◽  
Over Expression ◽  
Non Coding Rna ◽  
P38 Mapk Inhibitor ◽  
Long Non Coding Rna ◽  
Mapk Inhibitor

Background: Barretts Oesophagus (BO) presents a particular pathological dilemma, in that patients who have no dysplasia within their BO experience a small but significant risk of malignant progression each year. Screening programmes have attempted to reduce the mortality from BO associated oesophageal adenocarcinoma but cannot predict which BO patients will progress to invasive malignancy. We have previously identified the long non coding RNA, OR3A4, is differentially hypomethylated in progressive BO. We aimed to understand its role in BO pathogenicity Methods: The stable BO cell line CP-A, as well as the oesophageal adenocarcinoma cells line OE-33 was transfected with a lentiviral OR3A4 over-expression vector, and underwent high resolution microscopy, immunofluorescence, RT-qPCR, RNA sequencing, and targeted drug screening with the p38-MAPK inhibitor domipramod to understand the effects of OR3A4 expression on progression. We then compared progressive vs. non-progressive BO samples using quantitative multi-fluorophore (Vectra) immunohistochemistry. Results: Over-expression of OR3A4 in CP-A lines resulted in a hyperproliferative, dysplastic cellular phenotype, with strong over-expression of MAPK and anti-apoptotic pathways at the RNA and protein level, which was sensitive to the p38-MAPK inhibitor domipramod. Vectra immunohistochemistry demonstrated that progressive BO had reduced visibility associated with a reduction in CD8+ T-cells and CD68+ macrophages and reduced CD4+ T-cells in the stomal compartment. Conclusion: The overexpression of OR3A4, which we have previously shown is associated with progressive BO leads to a proliferative dysplastic cellular phenotype associated with increased, reversible MAPK signalling and loss of immune visibility.

scholarly journals Role of Mitogen-Activated Protein Kinases in Activation of Human Neutrophils by Antineutrophil Cytoplasmic Antibodies

2001 ◽  
Vol 12 (1) ◽  
pp. 37-46
Author(s):  
RALPH KETTRITZ ◽  
ADRIAN SCHREIBER ◽  
FRIEDRICH C. LUFT ◽  
HERMANN HALLER
Keyword(s):  
Flow Cytometry ◽  
Cell Surface ◽  
P38 Mapk ◽  
Respiratory Burst ◽  
Antineutrophil Cytoplasmic Antibodies ◽  
Human Neutrophils ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

Abstract. Antineutrophil cytoplasmic antibodies (ANCA) may be important in the pathophysiology of necrotizing vasculitis. ANCA activate human neutrophils primed with tumor necrosis factor-α (TNF-α) in vitro. TNF-α priming results in translocation of ANCA antigens to the cell surface, where they are recognized by the antibodies. The signaling mechanisms involved in TNF-α priming and subsequent ANCA-induced activation were investigated. TNF-α-primed neutrophils were stimulated with monoclonal antibodies (MAb) to human myeloperoxidase (MPO) and proteinase 3 (PR3), and with preparations of human ANCA (three patients with PR3-ANCA and two patients with MPO-ANCA). Respiratory burst was measured with superoxide dismutase-inhibitable ferricytochrome C reduction and using dihydro-rhodamine-1,2,3. Phosphorylation of p38 mitogen-activated protein kinase (p38-MAPK) and the extracellular signal-regulated kinase (ERK) were assessed by immunoblotting. ANCA-antigen translocation was studied by flow cytometry. The tyrosine phosphorylation inhibitor genistein, but not calphostin or staurosporin, resulted in a significant dose-dependent superoxide generation inhibition (11.6 ± 1.7 nmol to 2.1 ± 0.5 for PR3-ANCA, and 16.0 ± 2.8 to 3.3 ± 1.3 for MPO-ANCA). The p38-MAPK inhibitor (SB202190) and the ERK inhibitor (PD98059) diminished PR3-ANCA-mediated superoxide production dose dependently (11.6 ± 1.7 nmol O2- to 1.9 ± 0.6 with 50 μM SB202190 and 4.0 ± 0.6 with 50 μM PD098059, respectively). For MPO-ANCA, the results were similar (16.0 ± 2.8 nmol to 0.9 ± 1.0 nmol with SB202190 and 6.4 ± 2.4 nmol with PD98059, respectively). Western blot showed phosphorylation of both p38-MAPK and ERK during TNF-α priming. The p38-MAPK inhibitor and the ERK inhibitor showed the strongest effect on respiratory burst when added before TNF-α priming, further supporting an important role for both signaling pathways in the priming process. Flow cytometry showed that p38-MAPK inhibition decreased the translocation of PR3 (by 93 ± 2%) and of MPO (by 64 ± 2%). In contrast, no such effect was seen when ERK was inhibited. Thus, p38-MAPK and ERK are important for the TNF-α-mediated priming of neutrophils enabling subsequent ANCA-induced respiratory burst. However, both pathways show differential effects, whereby p38-MAPK controls the translocation of ANCA antigens to the cell surface.

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