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Cancer Science Oct 2009The development of gastric cancer is closely associated with Helicobacter pylori (H. pylori) infection. The expression of cylooxigenase-2 (COX-2), a rate-limiting enzyme... (Review)
Review
The development of gastric cancer is closely associated with Helicobacter pylori (H. pylori) infection. The expression of cylooxigenase-2 (COX-2), a rate-limiting enzyme for prostaglandin biosynthesis, is induced in H. pylori-associated chronic gastritis, which thus results in the induction of proinflammatory prostaglandin, PGE(2). The COX-2/PGE(2) pathway plays a key role in gastric tumorigenesis. On the other hand, several oncogenic pathways have been shown to trigger gastric tumorigenesis. The activation of Wnt/beta-catenin signaling is found in 30-50% of gastric cancers, thus suggesting that Wnt signaling plays a causal role in gastric cancer development. Mutations in the bone morphogenetic protein (BMP) signaling pathway are responsible for the subset of juvenile polyposis syndrome (JPS) that develops hamartomas in the gastrointestinal tract. BMP suppression appears to contribute to gastric cancer development because gastric cancer risk is increased in JPS. Wnt signaling is important for the maintenance of gastrointestinal stem cells, while BMP promotes epithelial cell differentiation. Accordingly, it is possible that both Wnt activation and BMP suppression can cause gastric tumorigenesis through enhancement of the undifferentiated status of epithelial cells. Recent mouse model studies have indicated that induction of the PGE(2) pathway is required for the development of both gastric adenocarcinoma and hamartoma in the Wnt-activated and BMP-suppressed gastric mucosa, respectively. This article reviews the involvement of the PGE(2), Wnt, and BMP pathways in the development of gastric cancer, and gastric phenotypes that are found in transgenic mouse models of PGE(2) induction, Wnt activation, BMP suppression, or a combination of these pathways.
Topics: Animals; Bone Morphogenetic Proteins; Dinoprostone; Disease Models, Animal; Mice; Mice, Transgenic; Signal Transduction; Stomach Neoplasms; Wnt Proteins
PubMed: 19622104
DOI: 10.1111/j.1349-7006.2009.01258.x -
BMC Molecular and Cell Biology Aug 2019The EP prostanoid receptor is one of four GPCRs that mediate the diverse actions of prostaglandin E (PGE). Novel selective EP receptor agonists would assist to further...
BACKGROUND
The EP prostanoid receptor is one of four GPCRs that mediate the diverse actions of prostaglandin E (PGE). Novel selective EP receptor agonists would assist to further elucidate receptor sub-type function and promote development of therapeutics for bone healing, heart failure, and other receptor associated conditions. The rat EP (rEP) receptor has been used as a surrogate for the human EP (hEP) receptor in multiple SAR studies. To better understand the validity of this traditional approach, homology models were generated by threading for both receptors using the RaptorX server. These models were fit to an implicit membrane using the PPM server and OPM database with refinement of intra and extracellular loops by Prime (Schrödinger). To understand the interaction between the receptors and known agonists, induced-fit docking experiments were performed using Glide and Prime (Schrödinger), with both endogenous agonists and receptor sub-type selective, small-molecule agonists. The docking scores and observed interactions were compared with radioligand displacement experiments and receptor (rat & human) activation assays monitoring cAMP.
RESULTS
Rank-ordering of in silico compound docking scores aligned well with in vitro activity assay EC and radioligand binding K. We observed variations between rat and human EP binding pockets that have implications in future small-molecule receptor-modulator design and SAR, specifically a S103G mutation within the rEP4 receptor. Additionally, these models helped identify key interactions between the EP receptor and ligands including PGE and several known sub-type selective agonists while serving as a marked improvement over the previously reported models.
CONCLUSIONS
This work has generated a set of novel homology models of the rEP and hEP receptors. The homology models provide an improvement upon the previously reported model, largely due to improved solvation. The hEP docking scores correlates best with the cAMP activation data, where both data sets rank order Rivenprost>CAY10684 > PGE ≈ PGE > 11-deoxy-PGE ≈ 11-dexoy-PGE > 8-aza-11-deoxy-PGE. This rank-ordering matches closely with the rEP receptor as well. Species-specific differences were noted for the weak agonists Sulprostone and Misoprostol, which appear to dock more readily within human receptor versus rat receptor.
Topics: Amino Acid Sequence; Animals; Decapodiformes; Dinoprostone; Humans; Ligands; Models, Molecular; Molecular Docking Simulation; Rats; Receptors, Prostaglandin E, EP4 Subtype; Rhodopsin; Structural Homology, Protein
PubMed: 31455205
DOI: 10.1186/s12860-019-0212-5 -
The Journal of Pediatrics Dec 2015To determine whether infection, with associated eicosanoid release, is a main cause of respiratory disruption in neonates, by measuring levels of prostaglandin E2 (PGE2)...
OBJECTIVE
To determine whether infection, with associated eicosanoid release, is a main cause of respiratory disruption in neonates, by measuring levels of prostaglandin E2 (PGE2) and its metabolite (PGEM) in cerebrospinal fluid (CSF).
STUDY DESIGN
Of 59 eligible infants, 25 preterm infants (mean gestational age, 28 ± 0.5 weeks) and 22 full-term infants (mean gestational age, 40 ± 0.5 weeks) from a level 3 neonatal intensive care unit and the general maternity neonatal ward were enrolled prospectively. Infants with a condition that can cause secondary apnea were excluded. Cardiorespiratory disturbances, such as apnea, bradycardia, and desaturation (ABD) events, were quantified. All infants were subjected to standard laboratory analysis of blood and CSF concentrations of biomarkers, including PGE2 and PGEM, within 24 hours of lumbar puncture, which were correlated with ABD events and culture-verified infections.
RESULTS
PGEM levels were highest in infants with culture-verified sepsis and meningitis (P < .01). In infants without culture-verified bacterial infections, PGEM levels were higher in preterm infants compared with term infants (P < .05). The numbers of desaturation events and apnea events in neonates were positively associated with PGE2 levels in CSF (P < .05).
CONCLUSION
PGE2 and PGEM are rapidly elevated in CSF during an infectious event and may explain cardiorespiratory disturbances, which are the major presenting symptoms of neonatal infections. PGE2 and PGEM are released during bacterial infections and could serve as biomarkers for sepsis and autonomic dysfunction in neonates.
Topics: Apnea; Bacterial Infections; Biomarkers; Bradycardia; Dinoprostone; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Intensive Care Units, Neonatal; Male; Prospective Studies
PubMed: 26434370
DOI: 10.1016/j.jpeds.2015.08.053 -
Shock (Augusta, Ga.) Sep 2020High levels of PGE2 have been implicated in the pathogenesis of intestinal inflammatory disorders such as necrotizing enterocolitis (NEC) and peritonitis. However, PGE2...
High levels of PGE2 have been implicated in the pathogenesis of intestinal inflammatory disorders such as necrotizing enterocolitis (NEC) and peritonitis. However, PGE2 has a paradoxical effect: its low levels promote intestinal homeostasis, whereas high levels may contribute to pathology. These concentration-dependent effects are mediated by four receptors, EP1-EP4. In this study, we evaluate the effect of blockade of the low affinity pro-inflammatory receptors EP1 and EP2 on expression of COX-2, the rate-limiting enzyme in PGE2 biosynthesis, and on gut barrier permeability using cultured enterocytes and three different models of intestinal injury. PGE2 upregulated COX-2 in IEC-6 enterocytes, and this response was blocked by the EP2 antagonist PF-04418948, but not by the EP1 antagonist ONO-8711 or EP4 antagonist E7046. In the neonatal rat model of NEC, EP2 antagonist and low dose of COX-2 inhibitor Celecoxib, but not EP1 antagonist, reduced NEC pathology as well as COX-2 mRNA and protein expression. In the adult mouse endotoxemia and cecal ligation/puncture models, EP2, but not EP1 genetic deficiency decreased COX-2 expression in the intestine. Our results indicate that the EP2 receptor plays a critical role in the positive feedback regulation of intestinal COX-2 by its end-product PGE2 during inflammation and may be a novel therapeutic target in the treatment of NEC.
Topics: Animals; Cell Line; Cyclooxygenase 2; Dinoprostone; Enterocolitis, Necrotizing; Immunoblotting; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Peritonitis; Rats; Real-Time Polymerase Chain Reaction
PubMed: 31490357
DOI: 10.1097/SHK.0000000000001444 -
Digestive Diseases and Sciences Jun 2015
Topics: Animals; Dinoprostone; Female; Humans; Inflammatory Bowel Diseases; Myofibroblasts; Phosphatidylcholines
PubMed: 25902749
DOI: 10.1007/s10620-015-3668-y -
PloS One 2021The SARS-CoV-2 coronavirus has led to a pandemic with millions of people affected. The present study finds that risk-factors for severe COVID-19 disease courses, i.e....
The SARS-CoV-2 coronavirus has led to a pandemic with millions of people affected. The present study finds that risk-factors for severe COVID-19 disease courses, i.e. male sex, older age and sedentary life style are associated with higher prostaglandin E2 (PGE2) serum levels in blood samples from unaffected subjects. In COVID-19 patients, PGE2 blood levels are markedly elevated and correlate positively with disease severity. SARS-CoV-2 induces PGE2 generation and secretion in infected lung epithelial cells by upregulating cyclo-oxygenase (COX)-2 and reducing the PG-degrading enzyme 15-hydroxyprostaglandin-dehydrogenase. Also living human precision cut lung slices (PCLS) infected with SARS-CoV-2 display upregulated COX-2. Regular exercise in aged individuals lowers PGE2 serum levels, which leads to increased Paired-Box-Protein-Pax-5 (PAX5) expression, a master regulator of B-cell survival, proliferation and differentiation also towards long lived memory B-cells, in human pre-B-cell lines. Moreover, PGE2 levels in serum of COVID-19 patients lowers the expression of PAX5 in human pre-B-cell lines. The PGE2 inhibitor Taxifolin reduces SARS-CoV-2-induced PGE2 production. In conclusion, SARS-CoV-2, male sex, old age, and sedentary life style increase PGE2 levels, which may reduce the early anti-viral defense as well as the development of immunity promoting severe disease courses and multiple infections. Regular exercise and Taxifolin treatment may reduce these risks and prevent severe disease courses.
Topics: Adolescent; Adult; Animals; COVID-19; Case-Control Studies; Cells, Cultured; Chlorocebus aethiops; Dinoprostone; Disease Progression; Female; Humans; Immunity; Male; Middle Aged; SARS-CoV-2; Vero Cells; Young Adult
PubMed: 34347801
DOI: 10.1371/journal.pone.0255335 -
Physiological Reports Apr 2022Type 2 diabetes (T2D) affects >30 million Americans and nearly 70% of individuals with T2D will die from cardiovascular disease (CVD). Circulating levels of the...
Type 2 diabetes (T2D) affects >30 million Americans and nearly 70% of individuals with T2D will die from cardiovascular disease (CVD). Circulating levels of the inflammatory signaling lipid, prostaglandin E (PGE ), are elevated in the setting of obesity and T2D and are associated with decreased cardiac function. The EP3 and EP4 PGE receptors have opposing actions in several tissues, including the heart: overexpression of EP3 in cardiomyocytes impairs function, while EP4 overexpression improves function. Here we performed complementary studies in vitro with isolated cardiomyocytes and in vivo using db/db mice, a model of T2D, to analyze the effects of EP3 inhibition or EP4 activation on cardiac function. Using echocardiography, we found that 2 weeks of systemic treatment of db/db mice with 20 mg/kg of EP3 antagonist, beginning at 6 weeks of age, improves ejection fraction and fractional shortening (with no effect on heart rate). We further show that either EP3 blockade or EP4 activation enhances contractility and calcium cycling in isolated mouse cardiomyocytes cultured in both normal and high glucose. Thus, peak [Ca ] transient amplitude was increased, while time to peak [Ca ] and [Ca ] decay were decreased. These data suggest that modulation of EP3 and EP4 activity has beneficial effects on cardiomyocyte contractility and overall heart function.
Topics: Animals; Diabetes Mellitus, Type 2; Dinoprostone; Humans; Hyperglycemia; Mice; Myocytes, Cardiac; Receptors, Prostaglandin E, EP3 Subtype; Receptors, Prostaglandin E, EP4 Subtype
PubMed: 35403369
DOI: 10.14814/phy2.15212 -
Scientific Reports Jun 2021Prostaglandin E2 (PGE2), an active lipid compound derived from arachidonic acid, regulates different stages of the immune response of the host during several pathologies... (Clinical Trial)
Clinical Trial
Prostaglandin E2 (PGE2), an active lipid compound derived from arachidonic acid, regulates different stages of the immune response of the host during several pathologies such as chronic infections or cancer. In fact, manipulation of PGE2 levels was proposed as an approach for countering the Type I IFN signature of tuberculosis (TB). However, very limited information regarding the PGE2 pathway in patients with active TB is currently available. In the present work, we demonstrated that PGE2 exerts a potent immunosuppressive action during the immune response of the human host against Mycobacterium tuberculosis (Mtb) infection. Actually, we showed that PGE2 significantly reduced the surface expression of several immunological receptors, the lymphoproliferation and the production of proinflammatory cytokines. In addition, PGE2 promoted autophagy in monocytes and neutrophils cultured with Mtb antigens. These results suggest that PGE2 might be attenuating the excessive inflammatory immune response caused by Mtb, emerging as an attractive therapeutic target. Taken together, our findings contribute to the knowledge of the role of PGE2 in the human host resistance to Mtb and highlight the potential of this lipid mediator as a tool to improve anti-TB treatment.
Topics: Adult; Dinoprostone; Female; Humans; Immunosuppressive Agents; Male; Monocytes; Mycobacterium tuberculosis; Neutrophils; Tuberculosis
PubMed: 34193890
DOI: 10.1038/s41598-021-92667-1 -
Mapping the Binding Sites of UDP and Prostaglandin E2 Glyceryl Ester in the Nucleotide Receptor P2Y.ChemMedChem Apr 2022Cyclooxygenase-2 catalyzes the biosynthesis of prostaglandins from arachidonic acid and the biosynthesis of prostaglandin glycerol esters (PG-Gs) from...
Cyclooxygenase-2 catalyzes the biosynthesis of prostaglandins from arachidonic acid and the biosynthesis of prostaglandin glycerol esters (PG-Gs) from 2-arachidonoylglycerol. PG-Gs are mediators of several biological actions such as macrophage activation, hyperalgesia, synaptic plasticity, and intraocular pressure. Recently, the human UDP receptor P2Y was identified as a target for the prostaglandin E2 glycerol ester (PGE -G). Here, we show that UDP and PGE -G are evolutionary conserved endogenous agonists at vertebrate P2Y orthologs. Using sequence comparison of P2Y orthologs, homology modeling, and ligand docking studies, we proposed several receptor positions participating in agonist binding. Site-directed mutagenesis and functional analysis of these P2Y mutants revealed that both UDP and PGE -G share in parts one ligand-binding site. Thus, the convergent signaling of these two chemically very different agonists has already been manifested in the evolutionary design of the ligand-binding pocket.
Topics: Binding Sites; Dinoprostone; Humans; Nucleotides; Uridine Diphosphate
PubMed: 35034430
DOI: 10.1002/cmdc.202100683 -
International Journal of Molecular... Apr 2023As malignancies still represent one of the major health concerns worldwide, early tumor identification is among the priorities of today's science. Given the strong... (Review)
Review
As malignancies still represent one of the major health concerns worldwide, early tumor identification is among the priorities of today's science. Given the strong association between cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2), PGE2 receptors (EPs), and carcinogenesis, target-specific molecules directed towards the components of the COX2/PGE2/EP axis seem to be promising imaging probes in the diagnostics of PGE2pos. neoplasms and in the design of anti-cancer drugs. Featured with outstanding inclusion forming capability, β-cyclodextrins (CDs) including randomly methylated β-CD (RAMEB) were reported to complex with PGE2. Therefore, radiolabelled β-CDs could be valuable vectors in the molecular imaging of PGE2-related tumorigenesis. In vivo preclinical small animal model systems applying positron emission tomography (PET) ensure a well-suited scenario for the assessment of PGE2-affine labelled CD derivatives. Previous translational studies dealt with the evaluation of the tumor-homing capability of Gallium-68 (Ga) and Bismuth-205/206 (Bi)-appended β-CD compounds conjugated with chelator NODAGA or DOTAGA: [Ga]Ga-NODAGA-2-hydroxypropyl-β-cyclodextrin/HPBCD, [Ga]Ga-NODAGA-RAMEB, [Ga]Ga-DOTAGA-RAMEB, and [Bi]Bi-DOTAGA-RAMEB in experimental tumors with different PGE2 expression. These imaging probes project the establishment of tailor-made PET diagnostics of PGE2pos. malignancies. In the present review, we provide a detailed overview of the in vivo investigations of radiolabelled PGE2-directed CDs, highlighting the importance of the integration of translational discoveries into routine clinical usage.
Topics: Animals; Gallium Radioisotopes; Dinoprostone; Heterocyclic Compounds, 1-Ring; Neoplasms; beta-Cyclodextrins
PubMed: 37108106
DOI: 10.3390/ijms24086942