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Neonates with critical congenital heart disease of the ductal-dependent pulmonary circulation type (CCHD-DDPC) require prostaglandin E1 (PGE1) to maintain oxygen saturation until surgery. However, the factors contributing to the maintenance doses of PGE1 remain unclear. This study aimed to determine the predictors of high maintenance PGE1 doses in these neonates. This retrospective cohort study included neonates with CCHD-DDPC at Songklanagarind Hospital between January 1, 2006, and December 31, 2021. Factors associated with high maintenance PGE1 doses (> 0.01 mcg/kg/min) were analyzed to identify predictors. Odds ratios were calculated using tabulation and logistic regression analysis. A prediction score was developed for high maintenance PGE1 doses. Among 96 neonates with CCHD-DDPC, 55 % required high maintenance doses of PGE1. Three factors significantly associated with high maintenance PGE1 doses were patent ductus arteriosus (PDA) size-to-birthweight ratio ≤1.3 mm/kg, initial PGE1 dose >0.03 mcg/kg/min, and preoperative invasive mechanical ventilation. The area under the receiver operating characteristic curve for these three predictors was 0.7409. A predictive score of 0–3 was created based on these factors. The probabilities of receiving a high maintenance dose of PGE1 for patients with overall scores of 0, 1, 2, and 3 were 0.19 (95 % CI: 0.04–0.33), 0.42 (95 % CI: 0.30–0.54), 0.69 (95 % CI: 0.57–0.81), and 0.87 (95 % CI: 0.76–0.99), respectively. In neonates with CCHD-DDPC, a PDA size-to-birth weight ratio ≤1.3 mm/kg, an initial dose of PGE1 > 0.03 mcg/kg/min, and preoperative invasive mechanical ventilation were predictors of high maintenance PGE1 doses during the preoperative period. [ABSTRACT FROM AUTHOR]

Background: The Pro-inflammatory mediators such as prostaglandin E2, nitric oxide and TNF-α are the key players in the stimulation of the inflammatory responses. Thus, the pro-inflammatory mediators are considered to be potential targets for screening nutraceutical with anti-inflammatory activity. Methods: In this context, we explored the anti-inflammatory potency of seagrass extract with western blot (Bio-Rad) analysis by using LPS induced RAW macrophages as in-vitro models, western blot analysis, In-silico methods using Mastero 13.0 software. Results: The anti-inflammatory activity of Seagrass was demonstrated through down regulation of Pro-inflammatory markers such as Cyclooxygenase-2, induced Nitric oxide synthase and prostaglandin E synthase-1. The results were validated by docking the phytochemical constituents of seagrass namely Isocoumarin, Hexadecanoic acid, and Cis-9 Octadecenoic acid, 1,2 Benzene dicarboxylic acid and beta-sitosterol with TNF-alpha, COX-2, iNOS and PGES-1. Conclusion: The methanolic extract of seagrass Halophila beccarii is a potential nutraceutical agent for combating against inflammation with a significant anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

Objective: The clinical advantage of alprostadil [prostaglandin E1 (PGE1)] in the treatment of microcirculatory disturbances (defined as no-reflow or slow-flow) in acute percutaneous coronary intervention (PCI) is still disputed. The purpose of our study was to review the efficacy of PGE1 supplements in patients with acute myocardial infarction (AMI) who had urgent PCI. Design: This study was a meta-analysis of randomized controlled trials. Data Sources: PubMed, Embase, the Cochrane Library, Ovid, ProQuest, Scopus, the Chinese BioMedical Literature Database, China National Knowledge Internet, the China Science and Technology Journal Database, and the Wanfang Data Knowledge Service Platform were used as sources. Eligibility Criteria for Selecting Studies: We included randomized controlled trials including PGE1 for the treatment of intraoperative microcirculatory disorders and major cardiovascular adverse events in emergency PCI in people with AMI. Independent data extraction was conducted, and study quality was assessed. The meta-analysis was carried out by using random effects models to calculate the risk ratio (RR) of microcirculatory disorders between groups receiving PGE1 and those receiving placebo, nitroglycerin, or tirofiban. Main Outcome Measures: The primary endpoint of the study was the incidence of microcirculatory disturbances. Secondary outcomes included corrected thrombolysis in myocardial infarction (TIMI) frame count (cTFC), the percentage of patients with TIMI myocardial perfusion grade 3 (TMPG3), and the percentage of patients with myocardial blush grade 3 (MBG3) as efficacy indicators. Additionally, major adverse cardiovascular events (MACE) at 30 days and 180 days were assessed as safety indicators. Results: There were 18 trials involving a total of 1458 participants. PGE1 significantly reduced the occurrence of microcirculation disorders compared with conventional medications and placebo [risk ratio 0.48, 95% confidence interval (CI) 0.36–0.63, I2 = 46%; cTFC (RR −4.74, 95% −6.85 to −2.63, I2 93%); percentage of patients with TMPG3 (RR 1.34, 95% CI 1.07–1.68, I2 70%) or MBG3 (RR 1.33, 95% CI 1.19–1.49, I2 0%); major adverse cardiovascular events (MACEs) in 30 days (RR 0.48, 95% CI 0.27–0.86, I2 0%); and MACEs in 180 days (RR 0.41, 95% CI 0.28–0.60, I2 0%)]. Conclusions: We found that PGE1 decreased the occurrence of micro-circulation disturbance in AMI and enhanced the outcome of PCI. Additional studies should be conducted to confirm these findings. [ABSTRACT FROM AUTHOR]

The primary goal of the investigation was to analyse the anti-inflammatory and antioxidant properties of Gamma-linolenic acid (GLA) on rats with indomethacin (IND)-induced gastric ulcers. Thirty rats were divided into five groups: Control, IND (50 mg/kg, p.o.), IND pretreated with GLA 100 mg/kg (p.o. for 14 d), IND pretreated with GLA 150 mg/kg (p.o. for 14 d) and IND pretreated with omeprazole (20 mg/kg, p.o. for 14 d). The stomach tissues were examined to calculate the ulcer index and pH and analyse biochemical markers (prostaglandin E2 (PGE2), cyclooxygenase 1 (COX1), TNF-1, IL-6 and intercellular adhesion molecule-1 (ICAM1)) and oxidative stress parameters (malondialdehyde: (MDA), superoxide dismutase (SOD), glutathione (GSH) and CAT (catalase)) as well as undergo histopathological assessment. GLA 100 and 150 mg/kg showed a protective effect against IND-induced gastric damage. It reduced levels of COX1, TNF-1, IL-6 and ICAM and increased PGE2 levels. GLA also normalised antioxidant function by modulating MDA, SOD, GSH and CAT. GLA intervention protects against IND-induced gastric ulcers by restoring oxidant/antioxidant balance and reducing inflammation. [ABSTRACT FROM AUTHOR]

Congenital diverticulum is an uncommonly detected cardiac lesion, especially in infancy. However, its association with cyanotic congenital heart disease is extremely rare. In the current work, we report a case diagnosed in the neonatal period with tetralogy of Fallot and pulmonary valve atresia associated with a large congenital diverticulum originating from the right ventricle. [ABSTRACT FROM AUTHOR]

Background and objective Tumor microenvironment (TME) is one of the important factors in tumorigenesis and progression, in which tumor-associated macrophages (TAMs) play an important role in non-small cell lung cancer (NSCLC) progression. However, the mechanism of TAMs in NSCLC progression remains unclear, so this study aimed to investigate the role of TAMs in NSCLC progression and to find potential therapeutic targets. Methods Gene Expression Profiling Interactive Analysis (GEPIA) database was used to analyze the expression of prostaglandin E2 receptor 4 (EP4) mRNA in NSCLC and normal lung tissues; the protein expression levels of cyclooxygenase-2 (COX-2), EP4, cluster of differentiation 86 (CD86), CD163 and CD31 were detected by immunohistochemistry (IHC) in 120 NSCLC tissues and 24 paracancerous tissues specimens. The nude mouse lung adenocarcinoma cell A549 and macrophage RAW264.7 co-transplanted tumor model was established. And the samples were collected by gavage with EP4 inhibitor E7046, and then stained with hematoxylin-eosin (HE), IHC, and immunofluorescence (IF), and then detected by Western blot for the epithelial mesenchymal transformation (EMT) of the tumor tissues of the nude mice in each group. Western blot was used to detect the expressions of EMT related protiens in each group of nude mice; full-length transcriptome sequencing was used to screen the key genes causing liver metastasis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed. Results EP4 mRNA expression level in NSCLC tissues was generally lower than that in normal lung tissues (P<0.05); COX-2, EP4, CD163, CD31 proteins were differentially expressed in NSCLC tissues and adjacent tissues, and differences were observed in many clinicopathological parameters of NSCLC patients; RAW264.7 shortened the latency period of tumorigenesis of A549 and promoted the proliferation of tumors and liver metastasis of tumors, and E7046 could reduce tumor cell proliferation activity, tumor tissue vascular density and M2-type macrophage infiltration in nude mice; IF staining showed that macrophages were mainly distributed around the metastatic foci of tumors; Western blot results showed that compared with A549 alone transplantation group, the relative expression of E-cadherin protein in tumor tissues of mice in A549 and RAW264.7 co-transplantation group was significantly decreased, and the difference was statistically significant (P<0.05), while the relative expression of N-cadherin protein was up-regulated, but the difference was not statistically significant (P>0.05); the main pathways enriched in the differential genes of the full-length transcriptome were the PI3K-AKT and MAPK signaling pathways. Conclusion During NSCLC development, the COX-2/PGE2/EP4 axis may promote tumor progression by inducing macrophage functional activation, and EP4 may be a potential new target for tumor immunotherapy. This study provides new perspectives and ideas for in-depth exploration of the mechanisms of NSCLC development, as well as a theoretical basis for the development of new therapeutic strategies for NSCLC. [ABSTRACT FROM AUTHOR]

Grapiprant is a prostaglandin E2 receptor antagonist that has been found to be an effective anti-inflammatory in dogs and that is devoid of some of the adverse effects associated with traditional NSAIDs that elicit their effects through inhibition of PGE2 production. Previously published reports have described the pharmacokinetics of this drug in horses when administered at 2 mg/kg; however, pharmacodynamic effects in this species have yet to be described. The objective of the current study was to describe the pharmacokinetics and pharmacodynamics of grapiprant at a higher dose. Eight horses received a single oral administration of 15 mg/kg. Plasma concentrations were determined for 96 h using liquid chromatography-tandem mass spectrometry. Non-compartmental analysis was used to determine pharmacokinetic parameters. Pharmacodynamic effects were assessed ex vivo by stimulating blood samples with PGE2 and determining TNF-ɑ concentrations. Maximum concentration, time to maximum concentration and area under the curve were 327.5 (188.4-663.0) ng/ml, 1 (0.75-2.0) hour and 831.8 (512.6-1421.6) h*ng/ml, respectively. The terminal half-life was 11.1 (8.27-21.2) hr. Significant stimulation of TNF alpha was noted for 2-4 h post-drug administration. Results of this study suggest a short duration of EP4 receptor engagement when administered at a dose of 15 mg/kg.

Simple Summary: Glioblastoma is a lethal primary brain tumor, and so far, immunotherapeutic strategies have not significantly improved patients' prognosis, both in newly diagnosed and recurrent settings. Understanding the features of the immune environment of the central nervous system is crucial to designing new treatment strategies able to counteract site-specific immunosuppressive and pro-tumorigenic factors. Here, we review next-generation immunomodulating therapeutic strategies such as immune check-point blockade, vaccinations, and adoptive cell therapies, aiming to re-shape the tumor microenvironment and restore active anti-tumor immunity. The door for immunotherapeutic strategies in glioblastoma treatment is not completely closed; researchers should test combinatorial treatments and design trials with solid translational analyses to gain more close and deep insight into on-treatment modifications of the tumor microenvironment. Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor, bearing a survival estimate below 10% at five years, despite standard chemoradiation treatment. At recurrence, systemic treatment options are limited and the standard of care is not well defined, with inclusion in clinical trials being highly encouraged. So far, the use of immunotherapeutic strategies in GBM has not proved to significantly improve patients' prognosis in the treatment of newly diagnosed GBM, nor in the recurrent setting. Probably this has to do with the unique immune environment of the central nervous system, which harbors several immunosuppressive/pro-tumorigenic factors, both soluble (e.g., TGF-β, IL-10, STAT3, prostaglandin E2, and VEGF) and cellular (e.g., Tregs, M2 phenotype TAMs, and MDSC). Here we review the immune composition of the GBMs microenvironment, specifically focusing on the phenotype and function of the T cell compartment. Moreover, we give hints on the therapeutic strategies, such as immune checkpoint blockade, vaccinations, and adoptive cell therapy, that, interacting with tumor-infiltrating lymphocytes, might both target in different ways the tumor microenvironment and potentiate the activity of standard therapies. The path to be followed in advancing clinical research on immunotherapy for GBM treatment relies on a twofold strategy: testing combinatorial treatments, aiming to restore active immune anti-tumor responses, tackling immunosuppression, and additionally, designing more phase 0 and window opportunity trials with solid translational analyses to gain deeper insight into the on-treatment shaping of the GBM microenvironment. [ABSTRACT FROM AUTHOR]

The quest for novel agents to regulate the generation of prostaglandin E2 (PGE2) is of high importance because this eicosanoid is a key player in inflammatory diseases. We synthesized a series of N-acylated and N-alkylated 2-aminobenzothiazoles and related heterocycles (benzoxazoles and benzimidazoles) and evaluated their ability to suppress the cytokine-stimulated generation of PGE2 in rat mesangial cells. 2-Aminobenzothiazoles, either acylated by the 3-(naphthalen-2-yl)propanoyl moiety (GK510) or N-alkylated by a chain carrying a naphthalene (GK543) or a phenyl moiety (GK562) at a distance of three carbon atoms, stand out in inhibiting PGE2 generation, with EC50 values ranging from 118 nM to 177 nM. Both GK510 and GK543 exhibit in vivo anti-inflammatory activity greater than that of indomethacin. Thus, N-acylated or N-alkylated 2-aminobenzothiazoles are novel leads for the regulation of PGE2 formation.

Objective(s): To evaluate the gastroprotective potential of zafirlukast against indomethacin-induced gastric ulcers in rats.Materials and Methods: Thirty-two male Wistar rats were included in this study and randomly divided into 4 equal groups (n=8); control (normal) group, indomethacin group, Ranitidine group, and Zafirlukast group. Indomethacin was given as a single oral dose of (20 mg/kg) for the induction of ulcers. Both ranitidine (50 mg/kg) and zafirlukast (20 mg/ kg) were given orally for seven days after inducing the ulcer. All animals were sacrificed by an overdose of anesthesia at the end of the experimental period and their gastric tissues have been collected for histopathological and biological assay. Levels of prostaglandin E2 (PGE2), thiobarbituric acid reactive substances (TBARS), and interleukin 1β (IL-1β ) were measured as well as a histopathological study to evaluate the effect of zafirlukast on gastric tissues.Results: Significant abnormalities were found in both the histological and biochemical parameters of the indomethacin group reflecting the changes seen with gastric ulcers. Significant improvement was found in the Zafirlukast group as reflected by the morphological improvement seen in the gastric tissues. An effect that was associated with an increase in the PGE2 levels along with reductions in IL-1β expression and TBARS concentrations.Conclusion: As per the results of this study, zafirlukast shows promising gastroprotective properties possibly through enhancement of PGE2 levels as well as having anti-inflammatory and anti-oxidant properties.

Background and Aim: PGE2 plays a very important role in the mediation of orthodontic therapies and dental reactions. Laser therapy in dentistry can be used to reduce pain, increase genetic bone, stimulate teeth, and reduce localized pain in time periods. The purpose of this study was to determine the effect of low-power laser therapy on the surface of PGE2 gingival fluid during orthodontic treatment. Material and Methods: In this double blind clinical trial study, 15 patients with crowning or protrusion of teeth requiring constant orthodontic treatment, along with pulling of the first two right and left prime mules, and then retracting the anterior teeth, were selected. After the first periodontal period examinations was performed in patients undergoing orthodontic treatment. One quadrant was selected as the experimental group and the opposite quadrant was selected as the control group. In the experimental group, low power diode laser irradiation was performed along the entire length of the gingival groove on days 0 (start of treatment), 2, 18 and 30 (total 4 days) after orthodontic treatment and sampling. The samples were transferred to the laboratory and determined at PGE2 level using an ELISAR device. Data were analyzed by Repeated Measure test, Friedman test and paired t-test. Results: The mean the PGE2 fluid in the orthodontic treated teeth, In the days of treatment, 30,18,2 laser radiation was significantly different between the experimental and control groups (P <0.001). In laser therapy, with significant increase in time, there was a significant reduction in PGE2 (p<0.05). Conclusion: Regarding the effect of reducing the pain of using and not using the laser in orthodontic movement, adjuvant treatment with low power laser reduces PGE2 as a mediator causing pain. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to assess the association between treatment characteristics of prostaglandin E1 including initiation time and duration, maximal and cumulative doses, and adverse effects. Design: A retrospective cohort study in which medical records of neonates with duct-dependent lesions were studied for treatment parameters and adverse effects. Multivariable logistic regression model was applied for testing the effect PGE1 variables on outcomes. Main outcome measures: The primary outcomes of this study were association of adverse effects of PGE1 treatment with maximal dose, cumulative dose, and treatment duration. The secondary outcomes included safety of feeding in infants treated with PGE1. Results: Eighty-two infants with duct-dependent lesions receiving PGE1 were included. Several infants who received early PGE1 treatment required ventilation support. Feeds were ceased more often as the cumulative dose and duration of PGE1 treatment increased. Gastrointestinal adverse effects were significantly associated with the cumulative dose of PGE1 and treatment duration. Apneas, hyperthermia, and tachycardia were associated with maximal dose. Our data did not demonstrate a difference in the incidence of NEC associated with characteristics of PGE1 treatment. Conclusion: Cumulative PGE1 dose is associated with gastrointestinal adverse effects in neonates. Lower doses should be considered in neonates expecting prolonged PGE1 treatment. [ABSTRACT FROM AUTHOR]

Background: The role of pro-resolving mediators in inflammation is a new concern in research. The effect of low-dose aspirin on production of a special kind of these mediators named aspirin triggered lipoxin (ATL) has been studied on different tissues. This randomized clinical trial evaluated the effect of low-dose aspirin on ATL and pro-inflammatory mediators' level in periapical fluid of necrotic teeth with large lesions. Methods: Twenty-four patients with necrotic pulp and periapical lesion were randomly assigned to low-dose aspirin and placebo groups. In the first appointment, canals were shaped up to F3 size and #40 K-file and cleaned with 10 milliliters 2.5% sodium hypochlorite and 17% Ethylenediaminetetraacetic acid. Periapical fluid was sampled by a paper cone. The tooth was temporized without any intracanal medication. Tablets were administered for 7 days, then the teeth were re-opened and the sampling were repeated. Interleukin-1 beta (IL-1β), prostaglandin E2 (PGE2) and ATL were analyzed by enzyme-linked immunosorbent assay. Data were analyzed with paired t-test using SPSS statistical software, version 21 (α = 0.05). Results: A significant reduction in PGE2 and IL-1β was noted in the aspirin-treated group while an increase in ATL was observed (P < 0.001). There was no significant difference in the mediator scores before and after in the placebo-treated group (P > 0.05). Conclusion: Low-dose aspirin can influence the inflammatory process by reducing pro-inflammatory mediators such as PGE2 and IL-1β, as well as increasing the pro-resolving mediators such as ATL. Trial registration: IRCT20191211045702N1. [ABSTRACT FROM AUTHOR]

The major finding of this study is that the blood level of PGE2 may be a useful biomarker for the diagnosis of silicosis, while the level of hemoglobin, erythrocytes and hematocrit may be useful markers for prognostic purposes. Objective: Silicosis is a prevalent incurable pneumoconiosis caused by inhalation of silica dust. Study aimed to investigate inflammatory, hematological, and biochemical parameters as additional biomarkers for diagnosing or monitoring silicosis. Methods: Research enrolled 14 workers with silicosis and 7 healthy controls (without exposure and silicosis). The serum level of prostaglandin E2, C-reactive protein, fibrinogen, biochemical, and hematological parameters were measured. The receiver operating characteristic curve was used to determine diagnostic sensitivity of each biomarker. Results: Patients with silicosis have a significantly higher level of prostaglandin E2, erythrocyte, hemoglobin, and hematocrit than patients without silicosis. Prostaglandin E2, hemoglobin, and the erythrocyte count are significant in separating the silicosis cases from healthy controls. Conclusions: Prostaglandin E2 might be an adjuvant peripheral diagnostic biomarker for silicosis, while hematological parameters (erythrocytes, hemoglobin, and hematocrit) might be prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Objective(s): To evaluate the gastroprotective potential of zafirlukast against indomethacin-induced gastric ulcers in rats. Materials and Methods: Thirty-two male Wistar rats were included in this study and randomly divided into 4 equal groups (n=8); control (normal) group, indomethacin group, Ranitidine group, and Zafirlukast group. Indomethacin was given as a single oral dose of (20 mg/kg) for the induction of ulcers. Both ranitidine (50 mg/kg) and zafirlukast (20 mg/kg) were given orally for seven days after inducing the ulcer. All animals were sacrificed by an overdose of anesthesia at the end of the experimental period and their gastric tissues have been collected for histopathological and biological assay. Levels of prostaglandin E2 (PGE2), thiobarbituric acid reactive substances (TBARS), and interleukin 1ß (IL-1ß) were measured as well as a histopathological study to evaluate the effect of zafirlukast on gastric tissues. Results: Significant abnormalities were found in both the histological and biochemical parameters of the indomethacin group reflecting the changes seen with gastric ulcers. Significant improvement was found in the Zafirlukast group as reflected by the morphological improvement seen in the gastric tissues. An effect that was associated with an increase in the PGE2 levels along with reductions in IL-1ß expression and TBARS concentrations. Conclusion: As per the results of this study, zafirlukast shows promising gastroprotective properties possibly through enhancement of PGE2 levels as well as having anti-inflammatory and anti-oxidant properties. [ABSTRACT FROM AUTHOR]

Simple Summary: Inflammation is the biological response of the body to damaging and toxic stimuli, and is a positive event that evolves with the resolution of critical events (acute inflammation). However, when the process becomes chronic it acquires pathological characteristics, and is associated with detrimental diseases such as cancer. It is recognized that prostaglandin E2 (PGE2) is one key lipid mediator involved in chronic inflammation, and is directly implicated in tumor development by regulating cancer cell growth and migration, apoptosis, epithelial–mesenchymal transition, metastasis, angiogenesis, and immune escape. The enzymes' expression in PGE2 synthesis positively correlates with tumor progression and aggressiveness. This review describes the interplay between the PGE2 cascade and epidermal growth factor receptor that fuel cancer progression, and new therapeutic strategies that target these signaling pathways, to outline the importance of the modulation of the inflammatory process in cancer fighting. It is recognized that prostaglandin E2 (PGE2) is one key lipid mediator involved in chronic inflammation, and it is directly implicated in tumor development by regulating cancer cell growth and migration, apoptosis, epithelial–mesenchymal transition, angiogenesis, and immune escape. In addition, the expression of the enzymes involved in PGE2 synthesis, cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES1), positively correlates with tumor progression and aggressiveness, clearly indicating the crucial role of the entire pathway in cancer. Moreover, several lines of evidence suggest that the COX2/mPGES1/PGE2 inflammatory axis is involved in the modulation of epidermal growth factor receptor (EGFR) signaling to reinforce the oncogenic drive of EGFR activation. Similarly, EGFR activation promotes the induction of COX2/mPGES1 expression and PGE2 production. In this review, we describe the interplay between COX2/mPGES1/PGE2 and EGFR in cancer, and new therapeutic strategies that target this signaling pathway, to outline the importance of the modulation of the inflammatory process in cancer fighting. [ABSTRACT FROM AUTHOR]

Background. Cordia vignei Hutch and Dalziel (Fam. Boraginaceae) is a woody plant found in west tropical Africa. The aim of this research is to find out if the leaf extract of this plant prevents oedema in animal models. Methods. (a) Inflammation was induced in the animals by injecting 100 µl of 2% lambda carrageenan into the subplantar tissue of the right footpads of 7-day-old chicks 1 h before or after oral administration of 30–300 mgkg−1 CVE. Oedema was measured for 5 h using the water displacement method. (b) Oedema was induced in ICR mice by subplantar injection of prostaglandin E2 (PGE2) (50 µl of 1 nM) 30 minutes before or after CVE administration. Oedema was measured for 3 h. (c) Oedema was induced in ICR mice by subplantar injection of bradykinin (BK) (10 nmol/paw) 30 min before or after administration of extract. Results. We found that CVE significantly (P < 0.05) prevented inflammation that was induced by injecting carrageenan into the footpads of the chicks. Also, we observed that CVE prevented inflammation produced by injecting PGE2 into the subplantar tissue of mice. Finally, we also report that CVE prevented inflammation produced by injecting BK into the subplantar tissues of mice. All these effects were observed in both preventive and curative protocols. Conclusion. We conclude that Cordia vignei leaf extract has potential anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

Each Chinese medicine has its own properties and effects. However, the close connection between the medicinal properties and the effects of the medicine remains unclear. To export the scientific connection between the medicinal properties and efficacy of Rehmanniae Radix (RR), this study established a model and evaluated the therapeutic effects of RR on cold–heat syndrome to access the properties of RR, and then established a blood-heat syndrome model through the injection of rats with dry yeast combined with anhydrous ethanol. Related biochemical indicators (coagulation factors and central pyrogenic factor) were measured to assess the efficacy of RR. Finally, metabonomic technology was used to study the blood-cooling mechanism of RR from two aspects: medicinal properties and efficacy. The comprehensive results suggest that RR can significantly reduce the rectal temperature of blood-heat syndrome model rats and increase both the expression levels of coagulation factors (TNF- α , IL-1 β , and IL-6) and the central pyrogenic factors (c-AMP, PGE-2). RR also cools the blood through regulating arginine, proline, phenylalanine, taurine, hypotaurine, sulfur, glycerophospholipid, primary bile acid metabolic pathways, and the tricarboxylic acid cycle. Therefore, RR plays the role of cooling blood by virtue of its cold property. The medicinal property of RR has a guiding effect on the clinical application. Moreover, the integrated metabolomic approach is a powerful tool for studying the properties and efficacy of Chinese medicine. [ABSTRACT FROM AUTHOR]

Introduction: Osteoarthritis is a public health concern that leads to disability due to chronic pain, stiffness, sleep disturbance, and depression. D-limonene is a racemic mixture of limonene, a natural cyclic monoterpene, and the major component of the oil extracted from the citrus rind with chemo-preventive and anti-inflammatory activities. The purpose of this study was to investigate the anti-inflammatory properties of Dlimonene compared with dexamethasone and ibuprofen in bovine fibroblast-like synoviocyte cells (BFLSc) as well as Human THP-1 monocyte/macrophage-like cells. Materials and Methods: BFLSc was isolated from the synovial membrane of the metacarpal joint cartilage of an 8-month-old Holstein. THP-1 cells were prepared by the Pasteur Institute of Iran. Cells were cultivated and exposed to 20 ng/ml lipopolysaccharide (LPS) stimulation without, or in the presence of, ibuprofen, dexamethasone, or D-limonene (7.5µg/ml). The gene expressions of cyclooxygenase-2 (COX-2), Interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), and Tumor necrosis factor alpha (TNF-α) were evaluated by real-time PCR. Concentrations of Nitric Oxide (NO), and Prostaglandin-E2 (PGE2) were measured by ELISA methods. Results: The inhibitory effects of D-limonene included dose-dependent decreases in the expression of iNOS and COX-2 proteins (P < 0.05). The treated cells secreted increased amounts of COX-2, IL-1β, iNOS, TNF-α, NO, and PGE2 in response to LPS stimulation in all conditions. D-limonene quenched the gene expression of COX-2, iL-1β, iNOS, and TNF-α, in BFLSc, and the production of PGE2 and NO in monocyte/macrophage cells alike dexamethasone, and ibuprofen. Conclusion: The results obtained in this study show that D-limonene probably exerts anti-inflammatory effects through the suppression of TNF- α, IL-1β, COX-2, and iNOS and NO, PGE2 production. [ABSTRACT FROM AUTHOR]

Background: Curcuma longa has been used as spices, food preservative, coloring material, and traditional medicine. This plant also has long been used for a variety of diseases including dyslipidemia, stomach disorders, arthritis, and hepatic diseases. The aim of the present investigation was to examine the anti-neuroinflammatory effects of the 50% ethanolic extract of C. longa in lipopolysaccharide (LPS)-induced BV2 microglial cells. Methods: Griess reaction was employed to measure the production of nitric oxide (NO), and the levels of prostaglandin E2 (PGE2) and pro-inflammatory cytokines such as interleukin 1-beta (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) were determined by using profit ELISA kits. Western blotting was used to determine the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), mitogen activated protein kinases (MAPKs), heme oxygenase-1 (HO-1) and nuclear factor erythroid-2-related factor 2 (Nrf2). Results: Pre-treatment with CLE inhibited the overproduction and overexpression of pro-inflammatory mediators including NO, PGE2, iNOS, COX-2, and pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α in LPS-induced BV2 cells. In addition, CLE suppressed the activation of the NF-κB and three MAPK signaling pathways. Treatment with CLE induced HO-1 protein expression by activating Nrf2 pathway, and inhibiting the HO-1 expression reversed the anti-inflammatory effect of CLE. Conclusion: CLE showed anti-neuroinflammatory effects against LPS-induced microglial cells activation through the inhibition of production and expression of pro-inflammatory mediators by negative regulation of the NF-κB and MAPK signaling pathways. These anti-neuroinflammatory effects of CLE were mediated by HO-1/Nrf2 signaling pathway. Taken together, the present study suggests a potent effect of CLE to prevent neuroinflammatory diseases. It is necessary to perform additional efficacy evaluation through in vivo experiments. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a chronic degenerative disease that is one of the main causes of disability in middle-aged and elderly people. Adipose stem cell (ASC)-derived exosomes (ASC-Exo) could repair cartilage damage and treat OA. MiRNA-338-3p expression was confirmed to play a role in inhibiting proinflammatory cytokines. Herein, we aimed to explore the mechanism by which exosomes derived from miR-338-3p overexpressing ASCs protects chondrocytes from interleukin (IL)-1β-induced chondrocyte change. Methods: Exosomes were extracted from ASCs transfected with miR-338-3p or its antisense inhibitor. The ASC-Exos (miR-338-3p silencing/overexpression) were incubated with IL-1β-induced ATDC5 cells, followed by evaluation of the chondrocyte proliferation, degradation, and inflammation injury. Results: In vitro results revealed that ASC-Exos inhibited the expression of prostaglandin E2 (PGE2), IL-6, IL-1β, and TNF-α, as well as promoted the proliferation of ATDC5 cells. Moreover, ASC-Exos inhibited inflammation injury and degradation of ATDC5 cells by transferring miR-338-3p. Luciferase reporter assays showed that RUNX2 was a target gene of miR-338-3p. Additionally, RUNX2 overexpression in ATDC5 cells reversed the protective effect of miR-338-3p on chondrocytes. Taken together, this study demonstrated that exosomes secreted from miR-338-3p-modified ASCs were effective in the repair of IL-1β-induced chondrocyte change by inhibiting RUNX2 expression. Conclusions: Our result provided valuable data for understanding the mechanism of ASC-Exos in OA treatment. [ABSTRACT FROM AUTHOR]

Objectives: Billions of individuals worldwide suffer from periodontal disease, an inflammatory disease that results in hard‐tissue and soft‐tissue destruction. A viable therapeutic option to treat periodontal disease may be via cannabinoids that exert immunomodulatory effects, and the endocannabinoid system (ECS) is readily present in periodontal tissues that exhibit cannabinoid type 1 and 2 receptors (CB1R and CB2R). Phytocannabinoids (pCBs), which are a part of a heterogeneous group of molecules acting on cannabinoid receptors (CBR) derived from the cannabis plants, have been attributed to a wide variety of effects including anti‐inflammatory activity and some pro‐inflammatory effects depending on the cell type. Thus, this study aims to examine the effects of pCBs on primary human gingival fibroblasts (HGFs) in IL‐1β stimulated (simulated periodontal disease) HGFs. Materials and Methods: Human gingival fibroblasts (HGFs) obtained from ATCC were cultured per the manufacturer's recommendation. The functional activity of cannabinoid receptors was measured using ACTOne (cAMP)‐based CB1R and CB2R assay. The effects of three pCBs (0.1–10 μg/ml or 10–4.5–10−6.5 M) on cell viability were assessed using the CCK‐8 cellular dehydrogenase assay. IL‐1β (1 ng/ml) was added an hour before the treatment to stimulate inflammation in the HGFs before the addition of cannabinoid ligands. After 24‐h incubation, the production of INF‐γ, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13, and TNF‐α was measured using Mesoscale Discovery (MSD) Human Pro‐Inflammatory kit. To measure prostaglandin E 2 levels (PGE2), Cisbio HTRF PGE2 assay kit was used per the manufacturer's recommendation to measure after 24‐h incubation. The data were analyzed using GraphPad Prism 6.0. The analytes for each group were compared using a one‐way ANOVA test with Bonferroni's correction. Results: Cannabidivarin (CBVN or CBDV) (EC50 = 12 nM) and cannabigerol (CBG) (EC50 = 30 nM) exhibited agonist activity on CB2R with intermediate efficacy. Cannabidiol (CBD) did not exhibit activation of the CB2R, and the CB1R activation was not observed with any of the pCBs. Cytotoxicity results showed that concentrations of 2.50 μg/ml or greater for the pCBs were toxic except for CBVN. Lower concentrations of CBD and CBG (0.1–0.75 μg/ml), and CBVN at 2.50 μg/ml exhibited significant effects on HGF proliferation. In IL‐1β‐stimulated HGFs, prostaglandin E2 (PGE2) production was significantly suppressed only by CBG and CBVN. CBD and CBG treatment alone did, however, elevate PGE2 production significantly compared to control. IL‐1β stimulation resulted in a robust increase in the production of all cytokines tested. Treatment of IL‐β‐stimulated HGF with the three pCBs (1 μg/ml) significantly reduced INF‐ɣ, TNF‐α, and IL‐2. The significant suppression of IL‐4 was seen with CBD and CBVN, while only CBVN exerted suppression of IL‐13. The three pCBs significantly increased IL‐6, IL‐10, and IL‐12 levels, while none of the pCBs reduced the expression of IL‐8 in IL‐1β‐stimulated HGF. Conclusion: The effective inhibition of IL‐1β‐stimulated production of PGE2 and cytokines by the pCB in HGFs suggests that targeting the endocannabinoid system may lead to the development of therapeutic strategies for periodontal therapy. However, each pCB has its unique anti‐inflammatory profile, in which certain pro‐inflammatory activities are also exhibited. The pCBs alone or in combination may benefit and aid in improving public oral health. [ABSTRACT FROM AUTHOR]

Pain and inflammation are the most frequent reasons for which people seek medical care. Currently available analgesics against these conditions produce fatal adverse effects. NPK 500 capsules is an alternative herbal analgesic employed to treat dysmenorrhea, peptic ulcer and pain. NPK 500 is produced from Cassia sieberiana. A plant used in traditional medicine to treat pain and inflammation. This study reports the analysis, phytochemical characterization and mechanism of analgesic and anti-inflammatory activities of two NPK 500 capsules, called old and new NPK500 capsules (ONPK500 and NNPK500) respectively. Physicochemical, organoleptic, GC-MS and LC-MS methods were employed to analyze the NPK 500 capsules. Analgesic activity was evaluated using tail immersion, Randall-Selitto and acetic acid induced writing tests. Anti-inflammatory activity was evaluated using carrageenan-induced rat paw inflammation. Additionally, pro-inflammatory mediators such as prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase 1 and 2 (COX-2 and COX-1) were quantified in the sera of the rats using Enzyme Linked Immunosorbent Assay (ELISA) kits. Thirteen major compounds were characterized in the NNPK 500 capsules via the GC-MS and LC-MS spectroscopies. Kaempferol was the major compound characterized in addition to physcion, β-sitosterol 3-O-β-D-glucopyranoside, betulinic acid and nine others. Physicochemical and organoleptic indices of the capsules were also derived for its authentication and quality control. Furthermore, NNPK 500 0.5–1.5 mg/kg p.o. produce significant (P < 0.5) analgesic activity (160–197%) higher than that of ONPK500 (109.8%) and Morphine (101%) in the tail immersion test. The analgesic activity of NNPK 500 0.5–1.5 mg/kg p.o. (171.0–258.3%) and ONPK 500 (179.5%) were also significant (P < 0.01) and higher than that of Aspirin (103.00%) in the Randall-Selitto test. Both capsules also demonstrated significant (P < 0.5) analgesic and anti-inflammatory activities in the acetic acid-induced writhing and carrageenan-indued paw edema tests respectively. The two NPK500 capsules also, significantly (P < 0.5) inhibited PGE2 and iNOS but not COX-2 and COX-1 in the carrageenan-indued paw edema test. These results show that NNPK 500 and ONPK 500 capsules possessed potent analgesic and anti-inflammatory activities via inhibition of PGE2 and iNOS as a result of their chemical constituents. NPK500 capsules thus, relief acute pain and inflammation without causing gastrointestinal, renal or hepatic injuries, since they did not inhibit COX-1. [Display omitted] • The major active ingredient identified in NPK500 capsules was kaempferol. • Physcion, β-sitosterol 3-O-β-D-glucopyranoside and betulinic acid were also present. • Analgesic activity of NPK500 was 171.0–258.3% against 103.00% for Aspirin. • NPK500 also produced significant anti-inflammatory activity. • NPK500 capsules inhibited PGE2 and iNOS during inflammation. [ABSTRACT FROM AUTHOR]

Ficus erecta , a traditional Chinese She Ethnomedicine, has been historically utilized to treat various inflammatory conditions such as arthritis, nephritis, and osteoporosis. However, the underlying mechanisms accounting for its anti-inflammatory activity, as well as its active components, largely remain elusive. The purpose of this research was to investigate the chemical constituents of F. erecta that contribute to its anti-inflammatory effects. Coumarins and flavones were obtained from the 95% EtOH extract of F. erecta using virous column chromatography and reversed-phase semipreparative HPLC. The structures of the new compounds were elucidated by extensive analysis of spectroscopic methods, including HRESIMS, 1D and 2D NMR spectra, and CD experiments. Cultured macrophage RAW264.7 cells were utilized for the anti-inflammatory experiments. MTT cell viability assay, Griess reagent method, ELISA, and Western blot experiments were employed to evaluate the anti-inflammatory activity and investigate the related mechanism. Four new (1–4) and eleven previously identified (5–16) coumarins, together with one new (17) and six known flavones (18–23) were isolated from the whole plant of F. erecta. Compounds 7 and 17 significantly reduced nitric oxide (NO) and prostaglandin E2 (PGE 2) production without cytotoxic effects. Furthermore, compounds 7 and 17 reduced the production of proinflammatory cytokines including tumor necrosis factor (TNF)- α , interleukin (IL)-1 β , and IL-6 in a concentration-dependent manner. Western blot analysis indicated that compounds 7 and 17 suppressed the expression of iNOS, COX-2, and p-I κ B α in LPS-stimulated RAW264.7 macrophage cells. The current phytochemical investigations revealed that coumarins and flavones represent the primary chemical constituents of F. erecta. Compounds 7 and 17 exhibit potent anti-inflammatory properties, linked with the inhibition of NF- κ B activation by preventing the degradation of I κ B α phosphorylation. These compounds may serve as promising candidates for treating or preventing certain inflammatory diseases. [Display omitted] • Four new coumarins and one new flavone were isolation from Ficus erecta. • Their structures were elucidated on the basis of spectroscopic analyses. • Twelve selected isolates were evaluated for the in vitro anti-inflammatory activity. • 7 and 17 reduced the production of pro-inflammation mediators and cytokines. • 7 and 17 might exert their anti-inflammatory effects by inhibiting NF- κ B activation. [ABSTRACT FROM AUTHOR]

Swertia Mussotti is used as febrifuge, analgesic and to treat calculous cholecystitis, however, the underling mechanism remains unclear. This study investigates the therapeutic effect of the active fraction named iridoid and xanthone glycoside (IXG) extracted from S. mussotii on six animal models related to calculous cholecystitis and its complications, and to explore its potential target proteins. Four main compounds including swertiamarin (STR), sweroside (SRS), gentiopicroside (GPS) and mangiferin (MGR) were identified from the IXG by UHPLC-TOF-MS. The in vivo experiments results confirmed that IXG significantly decreased the level of total bilirubin (TBIL), direct bilirubin (DBIL) and cyclooxygenase-2 (COX2) in calculous cholecystitis. IXG treatment dramatically reduced the number of twists and the time of clicking foot in 2nd phase induced by glacial acetic acid and formalin, however, no effect was showed on central pain established by hot plate test. IXG also significantly decreased the anal temperature induced by yeast and 2,4-dinitrophenol. These results indicated that IXG alleviate calculous cholecystitis and its clinical symptom. In addition, IXG suppressed the expression of Prostaglandin E2 (PGE2) in vitro. Mechanistically, COX2 was identified as the direct target of IXG in RAW264.7 cells, and downregulated the protein levels of COX2. The results confirmed that IXG ameliorates calculous cholecystitis and its clinical symptom (pain and fever) by suppressing the production of PGE2 through targeting COX2. [Display omitted] • IXG protects against the liver injury induced by calculous cholecystitis. • IXG inhibits peripheral pain induced by glacial acetic acid and formalin, respectively. • IXG inhibits inflammatory fever induced by yeast and non-inflammatory fever induced by 2,4-dinitrophenol. • IXG exerts analgesia and antipyretic effect by targeting COX2 to reduce the production of PGE2 in vitro. [ABSTRACT FROM AUTHOR]

Background: The mechanism of action of Angelicae Pubescentis Radix in rheumatoid arthritis treatment is complex; the pathways and protein targets involved remain unclear. This study predicted the targets and signaling pathways of Angelicae Pubescentis Radix for rheumatoid arthritis treatment using network pharmacology and molecular docking technology and clarified its mechanism of action using in vitro cellular experiments. Methods: Angelicae Pubescentis Radix active components and related targets were retrieved from the traditional Chinese medicine systems pharmacology database. All human proteins were mined from the global protein database, and the network of active components and targets of Angelicae Pubescentis Radix was drawn using Cytoscape 3.7.1. GeneCard, Online Mendelian Inheritance in Man, and DrugBank databases were used to mine rheumatoid arthritis-related genes. Metascape was used for Gene Ontology function analysis and Kyoto Encyclopedia of Genes and Genomes enrichment pathways. β-sitosterol's molecular docking was determined using AutoDock Tools; pathway verification was performed in the Kyoto Encyclopedia of Genes and Genomes database, and the verified genes were input into the Human Protein Atlas database to observe the expression levels in various human body tissues. Results: Eight main active components were screened out of Angelicae Pubescentis Radix from the traditional Chinese medicine systems pharmacology database, and 60 targets related to major active ingredients were obtained. Forty-two core pathogenic rheumatoid arthritis-related genes were screened from GeneCard and other related databases. The enrichment of the Kyoto Encyclopedia of Genes and Genomes pathway included the vascular endothelial growth factor signaling pathway that proved to be the decisive pathway for rheumatoid arthritis treatment by a high degree value. In vitro experiments confirmed that Angelicae Pubescentis Radix mainly regulated cell proliferation and survival through the vascular endothelial growth factor signaling pathway and showed significant therapeutic effects on rheumatoid arthritis. The prostaglandin endoperoxide synthase 2 gene was associated with rheumatoid arthritis via pathway verification and monitoring of human gene expression levels. Conclusions: The mechanism of the multi-component, multi-target, and multi-channel treatment of rheumatoid arthritis via Angelicae Pubescentis Radix was explored using network pharmacology and molecular docking technology, providing new thinking and research directions for future rheumatoid arthritis treatment using Angelicae Pubescentis Radix. [ABSTRACT FROM AUTHOR]

Peucedanum japonicum Thunberg has been used to treat cold, cough, and inflammatory diseases in Southern and Eastern Asia. The effects of P. japonicum root aqueous extract (PJ) on lipopolysaccharide (LPS)-induced inflammation were investigated in RAW264.7 macrophages and an animal model of septic shock. Lipopolysaccharides are endotoxins that trigger excessive inflammatory responses, similar to those elicited by gram-negative bacteria. Inflammation is characterized by a primary defense system against pathogens and the onset of sundry diseases or illnesses, and macrophages are important components of the phagocytic system during inflammatory processes. The present study evaluated the effects of PJ on the production of pro-inflammatory mediators, such as nitric oxide and prostaglandin E2, and assessed the expression of enzymes that induce the production of pro-inflammatory mediators using western blotting. We also evaluated the production and mRNA expression of pro-inflammatory cytokines using enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction, respectively. Using western blotting, we determined whether nuclear factor-kappa B (NF- κ B) and c-Jun N-terminal kinase (JNK) are involved in the molecular mechanisms induced by PJ that suppressed LPS-induced inflammatory responses. We also found that PJ inhibited NF- κ B and JNK pathways in macrophages and reduced LPS-induced mortality in the mouse model of septic shock by inhibiting the activation of NF- κ B and JNK pathways that downregulated the expression of inflammatory mediators. These results indicated that PJ is an effective inflammatory suppressor. [ABSTRACT FROM AUTHOR]

Objective: Chronic periodontitis is caused by multiple risk factors. To predict chronic periodontitis in older people, we evaluated the association between a combination of major periodontal pathogens and salivary biomarkers and the presence of periodontitis. Methods: Stimulated saliva samples were collected to analyze the prevalence of Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Prevotella intermedia, as well as four biomarkers: interleukin (IL)‐1β, IL‐6, tumor necrosis factor‐α (TNF‐α), and prostaglandin E2 (PGE2). A total of 201 Japanese patients were recruited. Oral examinations ware performed to determine chronic periodontitis as measured by Community Periodontal Index. The sociodemographic and behavioral characteristics were also obtained, and the parameters were adjusted as potential confounders to employ statistical models. Results: The odds ratio (OR) for the presence of P. gingivalis and the third tertile level of IL‐1β as compared with the absence of P. gingivalis and the lowest tertile of IL‐1β was highest in individuals with periodontitis (OR = 13.98; 95% confidence interval [CI] 3.87–50.52) with the best level (0.79) of area under the curve (AUC) based on the receiver operating characteristic curve. The OR for the presence of P. gingivalis and the third tertile of PGE2 was 7.76 (CI 1.89–31.91) with an AUC of 0.78. The coexistence of more than two periodontal bacteria and the third tertile of PGE2 was also strongly associated with chronic periodontitis (OR = 9.23, 95% CI 2.38–35.79) with an AUC of 0.76. Conclusions: The combined information of the presence of P. gingivalis in stimulated saliva, and higher levels of salivary IL‐1β may play a vital role in the detection and prediction of chronic periodontitis in older adults. [ABSTRACT FROM AUTHOR]

Simple Summary: The early treatment of oral cancer is a high priority, as improvements in this area could lead to greater cure rates and reduced disability due to extensive surgery. Oral cancer is very difficult to detect in over 70% of cases as it develops unseen until quite advanced, sometimes rapidly. It has become apparent that there are at least two types of epithelial cells (keratinocytes) found in oral tissue on the road to cancer (premalignant). One type secretes molecules called prostaglandins but the other does not and the former may stimulate the latter to progress to malignancy, either by stimulating their proliferation or encouraging the influx of blood vessels to feed them. Additionally, we have identified regulators of prostaglandin secretion in premalignant oral cells that could be targeted in future therapies, such as inducers of cellular senescence, drugs which kill senescent cells (senolytics), steroid metabolism, cyclo-oxygenase 2 (COX2) and p38 mitogen-activated protein kinase. Potentially pre-malignant oral lesions (PPOLs) are composed of keratinocytes that are either mortal (MPPOL) or immortal (IPPOL) in vitro. We report here that MPPOL, but not generally IPPOL, keratinocytes upregulate various extracellular tumor-promoting cytokines (interleukins 6 and 8) and prostaglandins E1 (ePGE1) and E2 (ePGE2) relative to normal oral keratinocytes (NOKs). ePGE upregulation in MPPOL was independent of PGE receptor status and was associated with some but not all markers of cellular senescence. Nevertheless, ePGE upregulation was dependent on the senescence program, cyclo-oxygenase 2 (COX2) and p38 mitogen-activated protein kinase and was partially regulated by hydrocortisone. Following senescence in the absence of p16INK4A, ePGEs accumulated in parallel with a subset of tumor promoting cytokine and metalloproteinase (MMP) transcripts, all of which were ablated by ectopic telomerase. Surprisingly, ataxia telangiectasia mutated (ATM) function was not required for ePGE upregulation and was increased in expression in IPPOL keratinocytes in line with its recently reported role in telomerase function. Only ePGE1 was dependent on p53 function, suggesting that ePGEs 1 and 2 are regulated differently in oral keratinocytes. We show here that ePGE2 stimulates IPPOL keratinocyte proliferation in vitro. Therefore, we propose that MPPOL keratinocytes promote the progression of IPPOL to oral SCC in a pre-cancerous field by supplying PGEs, interleukins and MMPs in a paracrine manner. Our results suggest that the therapeutic targeting of COX-2 might be enhanced by strategies that target keratinocyte senescence. [ABSTRACT FROM AUTHOR]