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Background/Aim: As prostaglandin E2 (PGE2) and its receptors (EP2) are over-expressed on tumor cells and microenvironment, radiolabeled cyclodextrins targeting such biomolecules are valuable vector candidates in molecular cancer diagnostics. Using experimental melanoma models, we evaluated the in vivo imaging behavior of novel Manganese-52-labeled (52Mn) randomly methylated beta-cyclodextrin ([52Mn]Mn-DOTA-GA-RAMEB) and compared it with the following well-established tumor-specific probes: melanocortin-1 receptor (MC1-R)-affine [68Ga]Ga-DOTANAPamide and PGE2 selective [68Ga]Ga-DOTA-GA-RAMEB cyclodextrin. Materials and Methods: Post-injection of [68Ga]Ga-DOTA-NAPamide, [68Ga]Ga-DOTAGA-RAMEB, and [52Mn]Mn-DOTAGA-RAMEB into MC1-R positive B16F10 melanoma-bearing mice, tumor radio-pharmaceutical uptake was quantified in vivo and ex vivo using preclinical positron emission tomography (PET) and high-performance gamma counter. Results: Although all tracers performed well in tumor identification, the highest standardized uptake values were detected in the [68Ga]Ga-DOTA-NAPamide scans. Corresponding to the ex vivo data, meaningful [52Mn]Mn-DOTAGA-RAMEB accumulation 1 h post-injection confirmed the tumor-targeting potential of the tracer. Temporal changes in PGE2/EP2 expression of the neoplasms may explain the significant differences observed between the tumor uptake of the two cyclodextrin probes and that of the 52Mn-labelled compound measured 1 h, 4 h, and 3 days post-injection (p≤0.01, p≤0.05). Conclusion: Although further pharmacokinetical optimization may be required, 52Mn-labelled cyclodextrin holds potential in melanoma diagnostics and the PET-based longitudinal assessment of tumor-associated PGE2/EP2 expression. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionNeurodegenerative disorders such as Alzheimer’s and Parkinson’s disease inflict economic and health burdens on societies. Alzheimer’s disease (AD), the most prevalent form of dementia, is accompanied by progressive degradation of memory, decision-making, and judgment. Parkinson’s disease (PD) is characterized by resting tremor, rigidity, bradykinesia, and loss of balance. Extensive research has pinpointed inflammation as a cause of the onset and progression of both diseases. However, it has not been confirmed which one is more formidable in terms of inflammation.To assess the extent of inflammation that is implicated in AD and PD and answer the question of which one is more inflammatory, serum levels of inflammatory biomarkers, including cytokines, chemokines, and prostaglandin E2 (PEG2), were measured in AD and PD patients as well as a healthy group.Our results showed a significant increase in IL-1α, IL-1β, IL-4, IL-6, IL-10, IL-12p70, IP-10, MCP-1, PEG2, and TNF-α in AD and PD patients compared with the control. Interestingly, IFN-γ did not manifest any significant difference in AD or PD patients compared with the control.As a hallmark of our results, it could be inferred that inflammation, as the underlying etiological cause, plays a more crucial role in PD compared with AD. Based on our results, it is proposed that anti-inflammatory remedies would be putatively more effective in PD rather than AD. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the anti-inflammatory properties of Drynariae rhizome (Polypodiaceae) extract (DRE) on lipopolysaccharide RAW264.7 macrophage cells and its protective effects on interleukin (IL)-1β-stimulated SW1353 chondrocyte cells. Methods: The anti-inflammatory effect of DRE (12.5, 25, 50, and 100 μg/mL) were measured by 5-lipooxygenase (LO) and cyclooxygenase (COX)-2 enzyme inhibitory activities, nitric oxide (NO) production in LPS-stimulated RAW264.7 cells using Griess reagent assay. Prostaglandins (PGE2) and leukotriene (LTB4) production were measured using enzyme-linked immunosorbent assay (ELISA). To investigate the protective effect on chondrocytes, the level of matrix metalloproteinases (MMP)-3, -9, and tissue inhibitor of matrix metalloproteinase (TIMP)-1 was determined using zymography assay and ELISA kit in SW1353 cells stimulated with IL-1β. Results: Drynariae rhizome (Polypodiaceae) extract (DRE) had a significant (p < 0.05) inhibitory effect on 5-LO and COX-2 enzymes in a concentration-dependent manner compared to untreated group. In RAW264.7 cells, levels of NO, PGE2 and LTB4 of DRE group were significantly (p < 0.05) decreased in study group (treated with DRE) at 12.5 μg/mL compared to the group treated with LPS (100 ng/mL) alone. Additionally, in SW1353 human chondrocytes stimulated with IL-1β, MMP-3 and MMP-9 were significantly (p < 0.05) suppressed in DRE-treated group compared to IL-1β group alone, with no significant impact on TIMP-1 production. Conclusion: Drynariae rhizome (Polypodiaceae) extract (DRE) possesses anti-inflammatory and cartilage protection effects. It therefore has the potential to be developed as an effective natural pharmaceutical agent for inflammation or osteoarthritis. [ABSTRACT FROM AUTHOR]

Abstract Background Mesenchymal stem cells (MSCs) have demonstrated remarkable therapeutic promise for acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS). MSC secretomes contain various immunoregulatory mediators that modulate both innate and adaptive immune responses. Priming MSCs has been widely considered to boost their therapeutic efficacy for a variety of diseases. Prostaglandin E2 (PGE2) plays a vital role in physiological processes that mediate the regeneration of injured organs. Methods This work utilized PGE2 to prime MSCs and investigated their therapeutic potential in ALI models. MSCs were obtained from human placental tissue. MSCs were transduced with firefly luciferase (Fluc)/eGFP fusion protein for real-time monitoring of MSC migration. Comprehensive genomic analyses explored the therapeutic effects and molecular mechanisms of PGE2-primed MSCs in LPS-induced ALI models. Results Our results demonstrated that PGE2-MSCs effectively ameliorated lung injury and decreased total cell numbers, neutrophils, macrophages, and protein levels in bronchoalveolar lavage fluid (BALF). Meanwhile, treating ALI mice with PGE2-MSCs dramatically reduced histopathological changes and proinflammatory cytokines while increasing anti-inflammatory cytokines. Furthermore, our findings supported that PGE2 priming improved the therapeutic efficacy of MSCs through M2 macrophage polarization. Conclusion PGE2-MSC therapy significantly reduced the severity of LPS-induced ALI in mice by modulating macrophage polarization and cytokine production. This strategy boosts the therapeutic efficacy of MSCs in cell-based ALI therapy.

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 (68Ga) and Bismuth-205/206 (205/206Bi)-appended β-CD compounds conjugated with chelator NODAGA or DOTAGA: [68Ga]Ga-NODAGA-2-hydroxypropyl-β-cyclodextrin/HPBCD, [68Ga]Ga-NODAGA-RAMEB, [68Ga]Ga-DOTAGA-RAMEB, and [205/206Bi]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. [ABSTRACT FROM AUTHOR]

Epilepsy is a group of chronic neurological disorders that have diverse etiologies but are commonly characterized by spontaneous seizures and behavioral comorbidities. Although the mechanisms underlying the epileptic seizures mostly remain poorly understood and the causes often can be idiopathic, a considerable portion of cases are known as acquired epilepsy. This form of epilepsy is typically associated with prior neurological insults, which lead to the initiation and progression of epileptogenesis, eventually resulting in unprovoked seizures. A convergence of evidence in the past two decades suggests that inflammation within the brain may be a major contributing factor to acquired epileptogenesis. As evidenced in mounting preclinical and human studies, neuroinflammatory processes, such as activation and proliferation of microglia and astrocytes, elevated production of pro-inflammatory cytokines and chemokines, blood–brain barrier breakdown, and upregulation of inflammatory signaling pathways, are commonly observed after seizure-precipitating events. An increased knowledge of these neuroinflammatory processes in the epileptic brain has led to a growing list of inflammatory mediators that can be leveraged as potential targets for new therapies of epilepsy and/or biomarkers that may provide valued information for the diagnosis and prognosis of the otherwise unpredictable seizures. In this review, we mainly focus on the most recent progress in understanding the roles of these inflammatory molecules in acquired epilepsy and highlight the emerging evidence supporting their candidacy as novel molecular targets for new pharmacotherapies of acquired epilepsy and the associated behavioral deficits. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) have demonstrated remarkable therapeutic promise for acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS). MSC secretomes contain various immunoregulatory mediators that modulate both innate and adaptive immune responses. Priming MSCs has been widely considered to boost their therapeutic efficacy for a variety of diseases. Prostaglandin E2 (PGE2) plays a vital role in physiological processes that mediate the regeneration of injured organs. Methods: This work utilized PGE2 to prime MSCs and investigated their therapeutic potential in ALI models. MSCs were obtained from human placental tissue. MSCs were transduced with firefly luciferase (Fluc)/eGFP fusion protein for real-time monitoring of MSC migration. Comprehensive genomic analyses explored the therapeutic effects and molecular mechanisms of PGE2-primed MSCs in LPS-induced ALI models. Results: Our results demonstrated that PGE2-MSCs effectively ameliorated lung injury and decreased total cell numbers, neutrophils, macrophages, and protein levels in bronchoalveolar lavage fluid (BALF). Meanwhile, treating ALI mice with PGE2-MSCs dramatically reduced histopathological changes and proinflammatory cytokines while increasing anti-inflammatory cytokines. Furthermore, our findings supported that PGE2 priming improved the therapeutic efficacy of MSCs through M2 macrophage polarization. Conclusion: PGE2-MSC therapy significantly reduced the severity of LPS-induced ALI in mice by modulating macrophage polarization and cytokine production. This strategy boosts the therapeutic efficacy of MSCs in cell-based ALI therapy. [ABSTRACT FROM AUTHOR]

Status epilepticus (SE) in humans is characterized by prolonged convulsive seizures that are generalized and often difficult to control. The current antiseizure drugs (ASDs) aim to stop seizures quickly enough to prevent the SE-induced brain inflammation, injury, and long-term sequelae. However, sole reliance on acute therapies is imprudent because prompt treatment may not always be possible under certain circumstances. The pathophysiological mechanisms underlying the devastating consequences of SE are presumably associated with neuroinflammatory reactions, where prostaglandin E2 (PGE2) plays a pivotal role. As the terminal synthase for pathogenic PGE2, the microsomal prostaglandin E synthase-1 (mPGES-1) is rapidly and robustly induced by prolonged seizures. Congenital deletion of mPGES-1 in mice is neuroprotective and blunts gliosis following chemoconvulsant seizures, suggesting the feasibility of mPGES-1 as a potential antiepileptic target. Herein, we investigated the effects of a dual species mPGES-1 inhibitor in a mouse pilocarpine model of SE. Treatment with the mPGES-1 inhibitor in mice after SE that was terminated by diazepam, a fast-acting benzodiazepine, time-dependently abolished the SE-induced PGE2 within the brain. Its negligible effects on cyclooxygenases, the enzymes responsible for the initial step of PGE2 biosynthesis, validated its specificity to mPGES-1. Post-SE inhibition of mPGES-1 also blunted proinflammatory cytokines and reactive gliosis in the hippocampus and broadly prevented neuronal damage in a number of brain areas. Thus, pharmacological inhibition of mPGES-1 by small-molecule inhibitors might provide an adjunctive strategy that can be implemented hours after SE, together with first-line ASDs, to reduce SE-provoked brain inflammation and injury. [ABSTRACT FROM AUTHOR]

Abstract Background The promising therapeutic strategy for the treatment of peripheral artery disease (PAD) is to restore blood supply and promote regeneration of skeletal muscle regeneration. Increasing evidence revealed that prostaglandin E2 (PGE2), a lipid signaling molecule, has significant therapeutic potential for tissue repair and regeneration. Though PGE2 has been well reported in tissue regeneration, the application of PGE2 is hampered by its short half-life in vivo and the lack of a viable system for sustained release of PGE2. Results In this study, we designed and synthesized a new PGE2 release matrix by chemically bonding PGE2 to collagen. Our results revealed that the PGE2 matrix effectively extends the half-life of PGE2 in vitro and in vivo. Moreover, the PGE2 matrix markedly improved neovascularization by increasing angiogenesis, as confirmed by bioluminescence imaging (BLI). Furthermore, the PGE2 matrix exhibits superior therapeutic efficacy in the hindlimb ischemia model through the activation of MyoD1-mediated muscle stem cells, which is consistent with accelerated structural recovery of skeletal muscle, as evidenced by histological analysis. Conclusions Our findings highlight the chemical bonding strategy of chemical bonding PGE2 to collagen for sustained release and may facilitate the development of PGE2-based therapies to significantly improve tissue regeneration. Graphical Abstract

Non-resolving inflammation plays a critical role during the transition from renal injury towards end-stage renal disease. The glucocorticoid-inducible protein annexin A1 has been shown to function as key regulator in the resolution phase of inflammation, but its role in immune-mediated crescentic glomerulonephritis has not been studied so far. Methods: Acute crescentic glomerulonephritis was induced in annexin A1- deficient and wildtype mice using a sheep serum against rat glomerular basement membrane constituents. Animals were sacrificed at d5 and d10 after nephritis induction. Renal leukocyte abundance was studied by immunofluorescence and flow cytometry. Alterations in gene expression were determined by RNA-Seq and gene ontology analysis. Renal levels of eicosanoids and related lipid products were measured using lipid mass spectrometry. Results: Histological analysis revealed an increased number of sclerotic glomeruli and aggravated tubulointerstitial damage in the kidneys of annexin A1-deficient mice compared to the wildtype controls. Flow cytometry analysis confirmed an increased number of CD45+ leukocytes and neutrophil granulocytes in the absence of annexin A1. Lipid mass spectrometry showed elevated levels of prostaglandins PGE2 and PGD2 and reduced levels of antiinflammatory epoxydocosapentaenoic acid regioisomers. RNA-Seq with subsequent gene ontology analysis revealed induction of gene products related to leukocyte activation and chemotaxis as well as regulation of cytokine production and secretion. Conclusion: Intrinsic annexin A1 reduces proinflammatory signals and infiltration of neutrophil granulocytes and thereby protects the kidney during crescentic glomerulonephritis. The annexin A1 signaling cascade may therefore provide novel targets for the treatment of inflammatory kidney disease. [ABSTRACT FROM AUTHOR]

Background/aim: As prostaglandin E2 (PGE2) and its receptors (EP2) are over-expressed on tumor cells and microenvironment, radiolabeled cyclodextrins targeting such biomolecules are valuable vector candidates in molecular cancer diagnostics. Using experimental melanoma models, we evaluated the in vivo imaging behavior of novel Manganese-52-labeled ( 52 Mn) randomly methylated beta-cyclodextrin ([ 52 Mn]Mn-DOTAGA-RAMEB) and compared it with the following well-established tumor-specific probes: melanocortin-1 receptor (MC1-R)-affine [ 68 Ga]Ga-DOTA-NAPamide and PGE2 selective [ 68 Ga]Ga-DOTAGA-RAMEB cyclodextrin., Materials and Methods: Post-injection of [ 68 Ga]Ga-DOTA-NAPamide, [ 68 Ga]Ga-DOTAGA-RAMEB, and [ 52 Mn]Mn-DOTAGA-RAMEB into MC1-R positive B16F10 melanoma-bearing mice, tumor radio-pharmaceutical uptake was quantified in vivo and ex vivo using preclinical positron emission tomography (PET) and high-performance gamma counter., Results: Although all tracers performed well in tumor identification, the highest standardized uptake values were detected in the [ 68 Ga]Ga-DOTA-NAPamide scans. Corresponding to the ex vivo data, meaningful [ 52 Mn]Mn-DOTAGA-RAMEB accumulation 1 h post-injection confirmed the tumor-targeting potential of the tracer. Temporal changes in PGE2/EP2 expression of the neoplasms may explain the significant differences observed between the tumor uptake of the two cyclodextrin probes and that of the 52 Mn-labelled compound measured 1 h, 4 h, and 3 days post-injection (p≤0.01, p≤0.05)., Conclusion: Although further pharmacokinetical optimization may be required, 52 Mn-labelled cyclodextrin holds potential in melanoma diagnostics and the PET-based longitudinal assessment of tumor-associated PGE2/EP2 expression., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Various studies have described the roles of myeloid-derived suppressor cells (MDSCs) in pathological conditions, but relatively few have described them under normal physiological conditions. Accumulation of MDSCs is important creating an anti-inflammation environment, which is essential for fertilized egg implantation. This study was designed to record the dynamic changes in MDSC-like cells composition during the menstrual period (MP) and ovulation period (OP) in healthy volunteers over the course of a single menstrual cycle to explore the association between MDSCs and the menstrual cycle under normal physiological conditions. The ratio of MDSC-like cells was higher in MP samples, whereas the activity of Arg-1 was higher during the OP window. There was a negative correlation between the ratio of MDSC-like cells and the percentage of lymphocytes and a positive correlation between MDSC-like cells and prostaglandin E2 (PGE2). Furthermore, regular changes in the ratio and function of MDSC-like cells in the peripheral blood were observed during menstruation, all of which corresponded to the cycle stage. During menstruation, MDSCs may promote endometrial repair, whereas they promote pregnancy during the OP. These findings may help to better understand the pathophysiology of pregnancy-related complications and lay a foundation for improving perinatal outcomes.

Non-resolving inflammation plays a critical role during the transition from renal injury towards end-stage renal disease. The glucocorticoid-inducible protein annexin A1 has been shown to function as key regulator in the resolution phase of inflammation, but its role in immune-mediated crescentic glomerulonephritis has not been studied so far.Methods: Acute crescentic glomerulonephritis was induced in annexin A1-deficient and wildtype mice using a sheep serum against rat glomerular basement membrane constituents. Animals were sacrificed at d5 and d10 after nephritis induction. Renal leukocyte abundance was studied by immunofluorescence and flow cytometry. Alterations in gene expression were determined by RNA-Seq and gene ontology analysis. Renal levels of eicosanoids and related lipid products were measured using lipid mass spectrometry.Results: Histological analysis revealed an increased number of sclerotic glomeruli and aggravated tubulointerstitial damage in the kidneys of annexin A1-deficient mice compared to the wildtype controls. Flow cytometry analysis confirmed an increased number of CD45+ leukocytes and neutrophil granulocytes in the absence of annexin A1. Lipid mass spectrometry showed elevated levels of prostaglandins PGE2 and PGD2 and reduced levels of antiinflammatory epoxydocosapentaenoic acid regioisomers. RNA-Seq with subsequent gene ontology analysis revealed induction of gene products related to leukocyte activation and chemotaxis as well as regulation of cytokine production and secretion.Conclusion: Intrinsic annexin A1 reduces proinflammatory signals and infiltration of neutrophil granulocytes and thereby protects the kidney during crescentic glomerulonephritis. The annexin A1 signaling cascade may therefore provide novel targets for the treatment of inflammatory kidney disease.

Prostaglandin E2 (PGE2) is a potent lipid mediator of inflammation that modulates immune cell function by binding to unique G protein‐coupled receptors (EP receptors). PGE2 production increases during microbial infection and inflammation. In this study, we assessed the effect of PGE2 on the phagocytosis of bacteria by neutrophils, which are key players during infection and inflammation. We also looked for specific EP receptor signaling pathways that contributed to the neutrophil phagocytic activity. PGE2 (50–1000 ng/ml) inhibited the phagocytosis of Escherichia coli by HL‐60 human neutrophils in a concentration‐dependent manner. Inhibition of neutrophil phagocytosis by PGE2 correlated with increased intracellular cyclic adenosine monophosphate (cAMP) production, and forskolin, an adenosyl cyclase agonist, confirmed the inhibitory effect of cAMP stimulation on neutrophil phagocytosis. The expression of EP2 receptors by HL‐60 cells was confirmed by western blot analysis, and selective agonism of EP2 receptors mimicked the inhibition of phagocytosis by PGE2. The EP2 receptor antagonist AH‐6089 partially blocked the inhibition of neutrophil phagocytosis PGE2. Specific inhibition of phosphatase and tensin homolog (PTEN) enzyme attenuated the inhibition of neutrophil phagocytosis by PGE2, and both PGE2 and increased intracellular cAMP increased neutrophil PTEN activity, which was associated with decreased PTEN phosphorylation. The results support negative regulation of the antimicrobial activity of neutrophils (i.e., phagocytosis), which has important implications for the future management of bacterial infections. [ABSTRACT FROM AUTHOR]

Abstract Prostaglandin E2 (PGE2) is a potent lipid mediator of inflammation that modulates immune cell function by binding to unique G protein‐coupled receptors (EP receptors). PGE2 production increases during microbial infection and inflammation. In this study, we assessed the effect of PGE2 on the phagocytosis of bacteria by neutrophils, which are key players during infection and inflammation. We also looked for specific EP receptor signaling pathways that contributed to the neutrophil phagocytic activity. PGE2 (50–1000 ng/ml) inhibited the phagocytosis of Escherichia coli by HL‐60 human neutrophils in a concentration‐dependent manner. Inhibition of neutrophil phagocytosis by PGE2 correlated with increased intracellular cyclic adenosine monophosphate (cAMP) production, and forskolin, an adenosyl cyclase agonist, confirmed the inhibitory effect of cAMP stimulation on neutrophil phagocytosis. The expression of EP2 receptors by HL‐60 cells was confirmed by western blot analysis, and selective agonism of EP2 receptors mimicked the inhibition of phagocytosis by PGE2. The EP2 receptor antagonist AH‐6089 partially blocked the inhibition of neutrophil phagocytosis PGE2. Specific inhibition of phosphatase and tensin homolog (PTEN) enzyme attenuated the inhibition of neutrophil phagocytosis by PGE2, and both PGE2 and increased intracellular cAMP increased neutrophil PTEN activity, which was associated with decreased PTEN phosphorylation. The results support negative regulation of the antimicrobial activity of neutrophils (i.e., phagocytosis), which has important implications for the future management of bacterial infections.

Inflammation in infants can cause respiratory dysfunction and is potentially life-threatening. Prostaglandin E2 (PGE2) is released during inflammatory events and perturbs breathing behavior in vivo. Here we study the effects of PGE2 on inspiratory motor rhythm generated by the preBötzinger complex (preBötC). We measured the concentration dependence of PGE2 (1 nM-1 μM) on inspiratory-related motor output in rhythmic medullary slice preparations. Low concentrations (1–10 nM) of PGE2 increased the duration of the inspiratory burst period, while higher concentrations (1 μM) decreased the burst period duration. Using specific pharmacology for prostanoid receptors (EP1-4R, FPR, and DP2R), we determined that coactivation of both EP2R and EP3R is necessary for PGE2 to modulate the inspiratory burst period. Additionally, biased activation of EP3 receptors lengthened the duration of the inspiratory burst period, while biased activation of EP2 receptors shortened the burst period. To help delineate which cell populations are affected by exposure to PGE2, we analyzed single-cell RNA-Seq data derived from preBötC cells. Transcripts encoding for EP2R (Ptger2) were differentially expressed in a cluster of excitatory neurons putatively located in the preBötC. A separate cluster of mixed inhibitory neurons differentially expressed EP3R (Ptger3). Our data provide evidence that EP2 and EP3 receptors increase the duration of the inspiratory burst period at 1–10 nM PGE2 and decrease the burst period duration at 1 μM. Further, the biphasic dose response likely results from differences in receptor binding affinity among prostanoid receptors. [ABSTRACT FROM AUTHOR]

Background: Fully functional regeneration of skeletal defects by multipotent progenitor cells requires that differentiating cells gain the specific mechano-competence needed in the target tissue. Using cartilage neogenesis as an example, we asked whether proper phenotypic differentiation of mesenchymal stromal cells (MSC) into chondrocytes in vitro will install the adequate biological mechano-competence of native articular chondrocytes (AC). Methods: The mechano-competence of human MSC- and AC-derived neocartilage was compared during differentiation for up to 35 days. The neocartilage layer was subjected to physiologic dynamic loading in a custom-designed bioreactor and assayed for mechano-sensitive gene and pathway activation, extracellular matrix (ECM) synthesis by radiolabel incorporation, nitric oxide (NO) and prostaglandin E2 (PGE2) production. Input from different pathways was tested by application of agonists or antagonists. Results: MSC and AC formed neocartilage of similar proteoglycan content with a hardness close to native tissue. Mechano-stimulation on day 21 and 35 induced a similar upregulation of mechano-response genes, ERK phosphorylation, NO production and PGE2 release in both groups, indicating an overall similar transduction of external mechanical signals. However, while AC maintained or enhanced proteoglycan synthesis after loading dependent on tissue maturity, ECM synthesis was always significantly disturbed by loading in MSC-derived neocartilage. This was accompanied by significantly higher COX2 and BMP2 background expression, > 100-fold higher PGE2 production and a weaker SOX9 stimulation in response to loading in MSC-derived neocartilage. Anabolic BMP-pathway activity was not rate limiting for ECM synthesis after loading in both groups. However, NFκB activation mimicked the negative loading effects and enhanced PGE2 production while inhibition of catabolic NFκB signaling rescued the load-induced negative effects on ECM synthesis in MSC-derived neocartilage. Conclusions: MSC-derived chondrocytes showed a higher vulnerability to be disturbed by loading despite proper differentiation and did not acquire an AC-like mechano-competence to cope with the mechanical stress of a physiologic loading protocol. Managing catabolic NFκB influences was one important adaptation to install a mechano-resistance closer to AC-derived neocartilage. This new knowledge asks for a more functional adaptation of MSC chondrogenesis, novel pharmacologic co-treatment strategies for MSC-based clinical cartilage repair strategies and may aid a more rational design of physical rehabilitation therapy after AC- versus MSC-based surgical cartilage intervention. [ABSTRACT FROM AUTHOR]

Periodontal ligament derived stem cells (PDLSC) are adult multipotent mesenchymal-like stem cells (MSCs) that can induce a promising immunomodulation to interact with immune cells for disease treatment. Metabolic reconfiguration has been shown to be involved in the immunomodulatory activity of MSCs. However, the underlying mechanisms are largely unknown, and it remains a challenging to establish a therapeutic avenue to enhance immunomodulation of endogenous stem cells for disease management. In the present study, RNA-sequencing (RNA-seq) analysis explores that curcumin significantly promotes PDLSC function through activation of MSC-related markers and metabolic pathways. In vitro stem cell characterization further confirms that self-renewal and multipotent differentiation capabilities are largely elevated in curcumin treated PDLSCs. Mechanistically, RNA-seq reveals that curcumin activates ERK and mTOR cascades through upregulating growth factor pathways for metabolic reconfiguration toward glycolysis. Interestingly, PDLSCs immunomodulation is significantly increased after curcumin treatment through activation of prostaglandin E2-Indoleamine 2,3 dioxygenase (PGE2-IDO) signaling, whereas inhibition of glycolysis activity by 2-deoxyglucose (2-DG) largely blocked immunomodulatory capacity of PDLSCs. Taken together, this study provides a novel pharmacological approach to activate endogenous stem cells through metabolic reprogramming for immunomodulation and tissue regeneration. [ABSTRACT FROM AUTHOR]

Inflammation in infants can cause respiratory dysfunction and is potentially life-threatening. Prostaglandin E2 (PGE2) is released during inflammatory events and perturbs breathing behavior in vivo. Here we study the effects of PGE2 on inspiratory motor rhythm generated by the preBötzinger complex (preBötC). We measured the concentration dependence of PGE2 (1 nM-1 μM) on inspiratory-related motor output in rhythmic medullary slice preparations. Low concentrations (1–10 nM) of PGE2 increased the duration of the inspiratory burst period, while higher concentrations (1 μM) decreased the burst period duration. Using specific pharmacology for prostanoid receptors (EP1-4R, FPR, and DP2R), we determined that coactivation of both EP2R and EP3R is necessary for PGE2 to modulate the inspiratory burst period. Additionally, biased activation of EP3 receptors lengthened the duration of the inspiratory burst period, while biased activation of EP2 receptors shortened the burst period. To help delineate which cell populations are affected by exposure to PGE2, we analyzed single-cell RNA-Seq data derived from preBötC cells. Transcripts encoding for EP2R (Ptger2) were differentially expressed in a cluster of excitatory neurons putatively located in the preBötC. A separate cluster of mixed inhibitory neurons differentially expressed EP3R (Ptger3). Our data provide evidence that EP2 and EP3 receptors increase the duration of the inspiratory burst period at 1–10 nM PGE2 and decrease the burst period duration at 1 μM. Further, the biphasic dose response likely results from differences in receptor binding affinity among prostanoid receptors.

Background: The promising therapeutic strategy for the treatment of peripheral artery disease (PAD) is to restore blood supply and promote regeneration of skeletal muscle regeneration. Increasing evidence revealed that prostaglandin E2 (PGE2), a lipid signaling molecule, has significant therapeutic potential for tissue repair and regeneration. Though PGE2 has been well reported in tissue regeneration, the application of PGE2 is hampered by its short half-life in vivo and the lack of a viable system for sustained release of PGE2. Results: In this study, we designed and synthesized a new PGE2 release matrix by chemically bonding PGE2 to collagen. Our results revealed that the PGE2 matrix effectively extends the half-life of PGE2 in vitro and in vivo. Moreover, the PGE2 matrix markedly improved neovascularization by increasing angiogenesis, as confirmed by bioluminescence imaging (BLI). Furthermore, the PGE2 matrix exhibits superior therapeutic efficacy in the hindlimb ischemia model through the activation of MyoD1-mediated muscle stem cells, which is consistent with accelerated structural recovery of skeletal muscle, as evidenced by histological analysis. Conclusions: Our findings highlight the chemical bonding strategy of chemical bonding PGE2 to collagen for sustained release and may facilitate the development of PGE2-based therapies to significantly improve tissue regeneration. [ABSTRACT FROM AUTHOR]

Previously, we demonstrated that extracts of the ripe fruit (rPM) and unripe fruit (uPM) of Prunus mume (Siebold) Siebold & Zucc. and citric acid have a laxative effect, which is at least partially mediated by the increase in fecal parameters as seen in the low-fiber diet-induced constipation model rats. This study aims at investigating the laxative effects of citric acid-enriched aqueous extracts of rPM, uPM, and its active compounds, such as citric acid and malic acid, on loperamide-induced constipation rat models. Animal studies were conducted with loperamide-induced constipation animal models. The results showed that rPM and citric acid, the major organic acid compounds, significantly improved stool parameters (number, weight, and water content of the stools) generated in loperamide-induced constipation rats, without adverse effects of diarrhea. The gastrointestinal (GI) motility was activated fully in the rPM- and citric acid-treated rats than in rats treaded with loperamide alone. In addition, when rPM and citric acid were added to RAW264.7 cells and used to treat loperamide-induced constipation model rats, the secretion of prostaglandin E2 (PGE2) increased significantly in cells and tissue. Furthermore, rPM and citric acid decreased the expression of the aquaporin 3 (AQP3) in the rat colons. Our results demonstrated that rPM and citric acid, the major organic acid compound in rPM, can effectively promote defecation frequency and regulate PGE2 secretion and AQP3 expression in the colon, providing scientific evidence to support the use of rPM as a therapeutic application. [ABSTRACT FROM AUTHOR]

Negative therapeutic feedback of inflammation would extensively attenuate the antitumor effect of photodynamic therapy (PDT). In this work, tumor homing chimeric peptide rhomboids (designated as NP-Mel) are fabricated to improve photodynamic performance by inhibiting PDT-upregulated cyclooxygenase-2 (COX-2). The hydrophobic photosensitizer of protoporphyrin IX (PpIX) and palmitic acid are conjugated onto the neuropilin receptors (NRPs) targeting peptide motif (CGNKRTR) to obtain tumor homing chimeric peptide (Palmitic-K(PpIX)CGNKRTR), which can encapsulate the COX-2 inhibitor of meloxicam. The well dispersed NP-Mel not only improves the drug stability and reactive oxygen species (ROS) production ability, but also increase the breast cancer targeted drug delivery to intensify the PDT effect. In vitro and in vivo studies verify that NP-Mel will decrease the secretion of prostaglandin E2 (PGE2) after PDT treatment, inducing the downregulation of IL-6 and TNF-α expressions to suppress PDT induced inflammation. Ultimately, an improved PDT performance of NP-Mel is achieved without inducing obvious systemic toxicity, which might inspire the development of sophisticated nanomedicine in consideration of the feedback induced therapeutic resistance., (© 2024 Wiley‐VCH GmbH.)

Intercellular communication plays an essential role in lung cancer (LC). One of the major players in cell‐cell‐communication is small extracellular vesicles (sEV). SEV trigger various biological responses by transporting cellular cargo to target cells. One essential sEV component are microRNAs (miRs), whose transport has recently attracted increasing research interest. We report that prostaglandin E2 (PGE2), a key inflammatory lipid mediator, specifically induces the sorting of miR‐574‐5p in sEV of A549 and 2106T cells. We found that sEV‐derived miR‐574‐5p activates Toll‐like receptors (TLR) 7/8, thereby decreasing PGE2‐levels. In contrast, intracellular miR‐574‐5p induces PGE2‐biosynthesis. Consequently, the combination of intracellular and sEV‐derived miR‐574‐5p controls PGE2‐levels via a feedback loop. This was only observed in adeno‐ but not in squamous cell carcinoma, indicating a cell‐specific response to sEV‐derived miRs, which might be due to unique tetraspanin compositions. Hence, we describe a novel function of miR‐574‐5p unique to adenocarcinoma. Intracellular miR‐574‐5p induces PGE2 and thus the secretion of sEV‐derived miR‐574‐5p, which in turn decreases PGE2‐biosynthesis in recipient cells. [ABSTRACT FROM AUTHOR]

Abstract Intercellular communication plays an essential role in lung cancer (LC). One of the major players in cell‐cell‐communication is small extracellular vesicles (sEV). SEV trigger various biological responses by transporting cellular cargo to target cells. One essential sEV component are microRNAs (miRs), whose transport has recently attracted increasing research interest. We report that prostaglandin E2 (PGE2), a key inflammatory lipid mediator, specifically induces the sorting of miR‐574‐5p in sEV of A549 and 2106T cells. We found that sEV‐derived miR‐574‐5p activates Toll‐like receptors (TLR) 7/8, thereby decreasing PGE2‐levels. In contrast, intracellular miR‐574‐5p induces PGE2‐biosynthesis. Consequently, the combination of intracellular and sEV‐derived miR‐574‐5p controls PGE2‐levels via a feedback loop. This was only observed in adeno‐ but not in squamous cell carcinoma, indicating a cell‐specific response to sEV‐derived miRs, which might be due to unique tetraspanin compositions. Hence, we describe a novel function of miR‐574‐5p unique to adenocarcinoma. Intracellular miR‐574‐5p induces PGE2 and thus the secretion of sEV‐derived miR‐574‐5p, which in turn decreases PGE2‐biosynthesis in recipient cells.

Macrophage polarization is mainly steered by metabolic reprogramming in the tissue microenvironment, thus leading to distinct outcomes of various diseases. However, the role of lipid metabolism in the regulation of macrophage alternative activation is incompletely understood. Using human THP-1 and mouse bone marrow derived macrophage polarization models, we revealed a pivotal role for arachidonic acid metabolism in determining the phenotype of M2 macrophages. We demonstrated that macrophage M2 polarization was inhibited by arachidonic acid, but inversely facilitated by its derived metabolite prostaglandin E2 (PGE2). Furthermore, PPARγ bridges these two seemingly unrelated processes via modulating oxidative phosphorylation (OXPHOS). Through inhibiting PPARγ, PGE2 enhanced OXPHOS, resulting in the alternative activation of macrophages, which was counterweighted by the activation of PPARγ. This connection between PGE2 biosynthesis and macrophage M2 polarization also existed in human and mouse esophageal squamous cell carcinoma. Our results highlight the critical role of arachidonic acid and metabolic PGE2 as immune regulators in modulating tissue homeostasis and pathological process.

Clinical and animal studies have suggested a possible beneficial effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH). Although SGLT2 inhibitors have been shown to reduce hepatic fat deposition in association with loss of body weight, the mechanism of this action has remained unknown. We here show that the SGLT2 inhibitor canagliflozin ameliorated fatty liver and hyperglycemia without affecting body weight or epididymal fat weight in obese diabetic KKAy mice. Lipidomics analysis based on liquid chromatography and tandem mass spectrometry revealed that canagliflozin treatment increased the amounts of prostaglandin E 2 (PGE 2) and resolvin E3 in the liver of these mice. We also found that PGE 2 attenuated fat deposition in mouse primary hepatocytes exposed to palmitic acid. Our results thus suggest that PGE 2 may play an important role in the amelioration of hepatic fat deposition by canagliflozin, with elucidation of its mechanism of action potentially providing a basis for the development of new therapeutics for NAFLD-NASH. • Canagliflozin attenuates hepatic fat deposition in obese diabetic KKAy mice. • Canagliflozin increases the amounts of PGE 2 and resolvin E3 in the KKAy mouse liver. • PGE 2 inhibits deposition of lipid droplets in mouse primary hepatocytes. • PGE 2 may mediate a beneficial effect of SGLT2 inhibitors on NAFLD. [ABSTRACT FROM AUTHOR]

Macrophage polarization is mainly steered by metabolic reprogramming in the tissue microenvironment, thus leading to distinct outcomes of various diseases. However, the role of lipid metabolism in the regulation of macrophage alternative activation is incompletely understood. Using human THP-1 and mouse bone marrow derived macrophage polarization models, we revealed a pivotal role for arachidonic acid metabolism in determining the phenotype of M2 macrophages. We demonstrated that macrophage M2 polarization was inhibited by arachidonic acid, but inversely facilitated by its derived metabolite prostaglandin E2 (PGE2). Furthermore, PPARγ bridges these two seemingly unrelated processes via modulating oxidative phosphorylation (OXPHOS). Through inhibiting PPARγ, PGE2 enhanced OXPHOS, resulting in the alternative activation of macrophages, which was counterweighted by the activation of PPARγ. This connection between PGE2 biosynthesis and macrophage M2 polarization also existed in human and mouse esophageal squamous cell carcinoma. Our results highlight the critical role of arachidonic acid and metabolic PGE2 as immune regulators in modulating tissue homeostasis and pathological process. [ABSTRACT FROM AUTHOR]

Abstract Background Triggering receptor expressed on myeloid cells-1 (TREM-1) is inducible on monocyte/macrophages and neutrophils and amplifies the inflammatory response. The aim of this study was to determine whether rheumatoid arthritis synovial fibroblasts (RASF) promote the expression of TREM-1 in monocytes and its potential regulatory mechanism. Methods Synovial fluid and paired peripheral blood from rheumatoid arthritis (RA) patients were analyzed using flow cytometry. Expression of TREM-1 in monocytes was detected after co-culture with RASF, with or without pre-treatment with toll-like receptor (TLR) ligands. Whether RASF-regulated TREM-1 level in monocytes require direct cell contact or soluble factors was evaluated by transwell experiment. COX-2 expression and PGE2 secretion in RASF were determined by quantitative PCR (qPCR) and ELISA. RASF, with and without TLR ligand stimulation, were treated with COX-2 inhibitors, COX-2 siRNA (siCOX-2) or EP1–4 antagonists, and the resulting TREM-1 level in CD14+ monocytes was measured using flow cytometry. Results TREM-1 was highly expressed in CD14+ cells from peripheral blood and especially synovial fluid from RA patients. The expression of TREM-1 in monocytes was increased by co-culture with RASF. TLR-ligand-activated RASF further elevated TREM-1 level. Transwell assay indicated that soluble factors played a key role in RASF-promoted expression of TREM-1 in monocytes. RASF, with or without stimulation by TLR ligands, increased secretion of PGE2 in a cyclooxygenase (COX)-2-dependent manner. PGE2 enhanced the increase in TREM-1 level in monocytes. Finally, studies using COX-2 inhibitors, COX-2 siRNA (siCOX-2) and EP1–4 antagonists, showed that RASF promotion of TREM-1 expression in monocytes was mediated by COX-2/PGE2/EP2,4 signaling. Conclusions Our data is the first report to reveal the critical role of RASF in upregulating TREM-1 expression in monocytes, which indicates that TREM-1 might be a novel target for RA therapy.

Chemical constituents and biological activities of the Mitrella kentii leaf oil were investigated in this study. Gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) were used to determine the chemical constituents of the oil. The oil was evaluated for its ability to inhibit prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) productions in human whole blood using a radioimmunoassay technique. Its inhibitory effect on plateletactivating factor (PAF) receptor binding with rabbit platelets using 3H-PAF as a ligand and its free radical scavenging effect on DPPH were also investigated. Caryophyllene oxide (33.8%w/w), E,Z-farnesol (6.9%), benzyl benzoate (6.5%w/w) and viridiflorol (6.5%w/w) were among the major components of the oil. Even though weak inhibitory activities were observed in both PGE2 and TXB2 assays, significant results were obtained in both PAF receptor binding inhibition and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging effect with IC50 value of 6.6 μg/mL and 155.6 μg/mL respectively. These promising activities warrant the development of the oil as an anti-inflammatory agent. [ABSTRACT FROM AUTHOR]

The outbreak of a new, potentially fatal virus, SARS‐COV‐2, which started in December 2019 in Wuhan, China, and since developed into a pandemic has stimulated research for an effective treatment and vaccine. For this research to be successful, it is necessary to understand the pathology of the virus. So far, we know that this virus can harm different organs of the body. Although the exact mechanisms are still unknown, this phenomenon may result from the body's secretion of prostaglandin E2 (PGE2), which is involved in several inflammation and immunity pathways. Noticeably, the expression of this molecule can lead to a cytokine storm causing a variety of side effects. In this paper, we discuss those side effects in SARS‐COV‐2 infection separately to determine whether PGE2 is, indeed, an important causative factor. Lastly, we propose a mechanism by which PGE2 production increases in response to COVID‐19 disease and suggest the possible direct relation between PGE2 levels and the severity of this disease. Also see the video abstract here: https://youtu.be/SnPFAcjxxKw. [ABSTRACT FROM AUTHOR]

We evaluated the mechanism by which high-molecular-weight hyaluronan (HMWH) attenuates nociceptor sensitization, in the setting of inflammation. HMWH attenuated mechanical hyperalgesia induced by the inflammatory mediator prostaglandin E2 (PGE2) in male and female rats. Intrathecal administration of an oligodeoxynucleotide antisense (AS-ODN) to mRNA for cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, and intradermal administration of A5G27, a CD44 receptor antagonist, both attenuated antihyperalgesia induced by HMWH. In male rats, HMWH also signals via Toll-like receptor 4 (TLR4), and AS-ODN for TLR4 mRNA administered intrathecally, attenuated HMWH-induced antihyperalgesia. Since HMWH signaling is dependent on CD44 clustering in lipid rafts, we pretreated animals with methyl-/i-cyclodextrin (M/1CD), which disrupts lipid rafts. M/fCD markedly attenuated HMWH-induced antihyperalgesia. Inhibitors for components of intracellular signaling pathways activated by CD44, including phospholipase C and phosphoinositide 3-kinase (PI3K), also attenuated HMWH-induced antihyperalgesia. Furthermore, in vitro application of HMWH attenuated PGE2-induced sensitization of tetrodotoxin-resistant sodium current, in small-diameter dorsal root ganglion neurons, an effect that was attenuated by a PI3K inhibitor. Our results indicate a central role of CD44 signaling in HMWH-induced antihyperalgesia and suggest novel therapeutic targets, downstream of CD44, for the treatment of pain generated by nociceptor sensitization. [ABSTRACT FROM AUTHOR]

There is recent evidence that the dysfunctional responses of a peculiar visceral fat deposit known as epicardial adipose tissue (EAT) can directly promote cardiac enlargement in the case of obesity. Here, we observed a newer molecular pattern associated with LV dysfunction mediated by prostaglandin E2 (PGE2) deregulation in EAT in a cardiovascular disease (CVD) population. A series of 33 overweight CVD males were enrolled and their EAT thickness, LV mass, and volumes were measured by echocardiography. Blood, plasma, EAT, and SAT biopsies were collected for molecular and proteomic assays. Our data show that PGE2 biosynthetic enzyme (PTGES-2) correlates with echocardiographic parameters of LV enlargement: LV diameters, LV end diastolic volume, and LV masses. Moreover, PTGES-2 is directly associated with EPAC2 gene (r = 0.70, p < 0.0001), known as a molecular inducer of ST2/IL-33 mediators involved in maladaptive heart remodelling. Furthermore, PGE2 receptor 3 (PTEGER3) results are downregulated and its expression is inversely associated with ST2/IL-33 expression. Contrarily, PGE2 receptor 4 (PTGER4) is upregulated in EAT and directly correlates with ST2 molecular expression. Our data suggest that excessive body fatness can shift the EAT transcriptome to a pro-tissue remodelling profile, may be driven by PGE2 deregulation, with consequent promotion of EPAC2 and ST2 signalling. [ABSTRACT FROM AUTHOR]

One of the proinflammatory agents in the human body is lead (Pb), which can enter the blood through the skin, respiratory tract and digestive tract, causing poisoning. Its most significant target is the central nervous system (CNS). Although studies on Pb neurotoxicity have been conducted for many years, the proinflammatory effect of Pb on the brain is rarely reported in contrast to other human tissues and organs. Lead neurotoxicity has been defined as a significant paediatric health problem as the foetal stage is a very susceptible period for Pb exposure at whole blood levels below 10 µg/dL (Pb neurotoxicity threshold in children). However, the mechanisms of the neurotoxic action of Pb in causing brain defects remain unclear. In this review we discuss the role of the blood-brain barrier in the neurotoxicity of Pb, and the role of cytokines as inflammatory mediators (specially interleukin-1 and interleukin-6, nuclear transcription factor κB, cyclooxygenase-1 and cyclooxygenase-2, prostaglandin E2, transforming growth factor β. We also discuss the influence of pre- and neonatal exposure to Pb on inflammatory reactions in the brain. [ABSTRACT FROM AUTHOR]

Prostaglandin (PG)-E2 is essential for growth and development of vertebrates. PGE2 binds to G-coupled receptors to regulate embryonic stem cell differentiation and maintains tissue homeostasis. Overproduction of PGE2 by breast tumor cells promotes aggressive breast cancer phenotypes and tumor-associated lymphangiogenesis. In this study, we investigated novel roles of PGE2 in early embryonic vascular development and maturation with the microinjection of PGE2 in fertilized zebrafish (Danio rerio) eggs. We injected Texas Red dextran to trace vascular development. Embryos injected with the solvent of PGE2 served as vehicle. Distinct developmental changes were noted from 28–96 h post fertilization (hpf), showing an increase in embryonic tail flicks, pigmentation, growth, hatching and larval movement post-hatching in the PGE2-injected group compared to the vehicle. We recorded a significant increase in trunk vascular fluorescence and maturation of vascular anatomy, embryo heartbeat and blood vessel formation in the PGE2 injected group. At 96 hpf, all larvae were euthanized to measure vascular marker mRNA expression. We observed a significant increase in the expression of stem cell markers efnb2a, ephb4a, angiogenesis markers vegfa, kdrl, etv2 and lymphangiogenesis marker prox1 in the PGE2-group compared to the vehicle. This study shows the novel roles of PGE2 in promoting embryonic vascular maturation and angiogenesis in zebrafish. This article has an associated First Person interview with the first author of the paper.

Highlights • Higher baseline PTGS2 mRNA expression was a significant predictor of decreases in prostaglandin (PG)E 2 in the colon of healthy volunteers after ω−3 fatty acid supplementation that was personalized using blood fatty acid responses. • Decreases in colon total fatty acid concentrations post-supplementation predicted greater reduction in colonic PGE 2 and point to the importance of lipid stores within the colonic mucosa in governing the anti-inflammatory effects of ω−3 fatty acid supplementation. • Dose of ω−3 fatty acids, baseline BMI, baseline expression of PTGS2 and change in colonic total fatty acids accounted for 48% of the inter-individual variability in the change in colonic PGE 2 in linear regression models. Abstract This study evaluated whether mRNA expression of major genes regulating formation of prostaglandin (PG)E 2 in the colon and colonic fatty acid concentrations are associated with the reduction in colonic mucosal PGE 2 after dietary supplementation with omega-3 (ω-3) fatty acids. Supplementation with ω-3 fatty acids was done for 12 weeks using personalized dosing that was expected to reduce colonic PGE 2 by 50%. In stepwise linear regression models, the ω-3 fatty acid dose and baseline BMI explained 16.1% of the inter-individual variability in the fold change of colonic PGE 2 post-supplementation. Increases in mRNA gene expression after supplementation were, however, modest and were not associated with changes in PGE 2. When baseline expression of PTGS1, PTGS2 and HPGD genes was included in the linear regression model containing dose and BMI, only PTGS2 , the gene coding for the inducible form cyclooxygenase, was a significant predictor. Higher relative expression of PTGS2 predicted greater decreases in colonic PGE 2 , accounting for an additional 13.6% of the inter-individual variance. In the final step of the regression model, greater decreases in total colonic fatty acid concentrations predicted greater decreases in colonic PGE 2 , contributing to an additional 18.7% of the variance. Overall, baseline BMI, baseline expression of PTGS2 and changes in colonic total fatty acids together accounted for 48% of the inter-individual variability in the change in colonic PGE 2. This is consistent with biochemical data showing that fatty acids which are not substrates for cyclooxygenases can activate cyclooxygenase-2 allosterically. Further clinical trials are needed to elucidate the factors that regulate the fatty acid milieu of the human colon and how this interacts with key lipid metabolizing enzymes. Given the central role of PGE 2 in colon carcinogenesis, these pathways may also impact on colon cancer prevention by other dietary and pharmacological approaches. [ABSTRACT FROM AUTHOR]

In clinical practice, inflammatory pain is an important, unresolved health problem, despite the utilization of non-steroidal anti-inflammatory drugs (NSAIDs). In the last decade, different studies have proven that reactive oxygen species (ROS) and reactive nitrogen species (RNS) are involved in the development and maintenance of inflammatory pain and hyperalgesia via the post-translation modification of key proteins, such as manganese superoxide dismutase (MnSOD). It is well-known that inducible cyclooxygenase 2 (COX-2) plays a crucial role at the beginning of the inflammatory response by converting arachidonic acid into proinflammatory prostaglandin PGE2 and then producing other proinflammatory chemokines and cytokines. Here, we investigated the impact of oxidative stress on COX-2 and prostaglandin (PG) pathways in paw exudates, and we studied how this mechanism can be reversed by using antioxidants during hyperalgesia in a well-characterized model of inflammatory pain in rats. Our results reveal that during the inflammatory state, induced by intraplantar administration of carrageenan, the increase of PGE2 levels released in the paw exudates were associated with COX-2 nitration. Moreover, we showed that the inhibition of ROS with Mn (III) tetrakis (4-benzoic acid) porphyrin(MnTBAP) antioxidant prevented COX-2 nitration, restored the PGE2 levels, and blocked the development of thermal hyperalgesia.

Proliferative diabetic retinopathy (PDR) is the leading cause of blindness and accounts for approximately 12 % of all new cases of blindness. Prostaglandin E2 (PGE2) and nucleotide-binding domain and Leucine-rich repeat Receptor containing a Pyrin domain 3 (NLRP3) inflammasomes have been long considered to be associated with PDR. Levels of pro-inflammatory mediators were examined by Enzyme-linked immunosorbent assay (ELISA) measurements. PGE2 levels were analyzed by using the Prostaglandin E2 Monoclonal EIA Kit. Human retinal microvascular endothelial cells (HRMECs) were stained with Annexin V/ propidium iodide and analyzed by flow cytometry for testing the apoptosis. Expression levels of NLRP3 inflammasome components under various conditions were detected by Western blot and real-time PCR. Inflammasome markers and PGE2 were highly expressed in the vitreous of PDR patients. PGE2 and NLRP3 induced apoptosis of HRMECs. PGE2 upregulated the expression of NLRP3 inflammasome components and inflammatory chemokines. Knockdown of NLRP3 attenuated the expression of NLRP3 inflammasome components and inhibited the effect of PGE2. Our results suggest that PGE2 levels and NLRP3 inflammasome activation are closely related to the pathogenesis of PDR and nonsteroidal anti-inflammatory drugs may have a potential therapeutic effect on PDR. [ABSTRACT FROM AUTHOR]

Juniperonic acid (JPA; Δ5,11,14,17-20:4), originally identified in certain gymnosperm seeds, is a rare n-3 polyunsaturated fatty acid (PUFA) with lipid-modulating effects on rats and anti-proliferative effects on fibroblast cell proliferation. However, little is known how JPA exerted its immunosuppressive effect. The objective of this study was to investigate whether JPA inhibited the production of inflammatory mediators through the modulation of cellular phospholipid fatty acid compositions. Using standard lipid chemistry techniques in conjunction with argentated column chromatography, high-purity JPA (> 98%) was extracted, isolated, and purified from Biota kernels. When murine RAW264.7 macrophages were incubated with increasing concentrations of JPA, amounts of cellular phospholipid total PUFA, JPA, and Δ7-docosatetraenoic acid (Δ7-DTA; elongation product of JPA) increased in a dose-dependent manner; however, the proportions of total monounsaturated fatty acid (MUFA) and arachidonic acid (AA) decreased. JPA suppressed the production of nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) and the expression of inducible nitric oxide synthase (iNOS) up to 21, 75, 30, and 44%, respectively. The induction of cyclooxygenase-2 (COX-2) over-expression by JPA could account for the doubling of the PGE2 level. Furthermore, JPA suppressed the expression of phosphorylated mitogen-activated protein kinases (MAPK). In a separate study using the mouse ear edema model, we demonstrated that JPA also significantly suppressed inflammation, as measured by ear thickness and biopsy weight. The anti-inflammatory properties of JPA could be due, in part, to the incorporation of JPA into cellular phospholipids with subsequent modulation of membrane-mediated MAPK signaling. [ABSTRACT FROM AUTHOR]

Little is known about the pathomechanism of pulmonary infections caused by Acanthamoeba sp. Therefore, the aim of this study was to determine whether Acanthamoeba sp. may affect the expression and activity of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), resulting in the altered levels of their main products, prostaglandins (PGE2) and thromboxane B2 (TXB2), in lungs of immunocompetent or immunosuppressed hosts. Acanthamoeba sp. induced a strong expression of COX-1 and COX-2 proteins in the lungs of immunocompetent mice, which, however, did not result in significant differences in the expression of PGE2 and TXB2. Our immunohistochemical analysis showed that immunosuppression induced by glucocorticoids in Acanthamoeba sp.-infected mice caused a decrease in COX-1 and COX-2 (not at the beginning of infection) in lung tissue. These results suggest that similar to COX-2, COX-1 is an important mediator of the pathophysiology in experimental pulmonary acanthamoebiasis. We suggest that the signaling pathways important for Acanthamoeba sp. induction of lung infection might interact with each other and depend on the host immune status. [ABSTRACT FROM AUTHOR]

Microsomal prostaglandin synthetase-1 (mPGES-1) is an inducible terminal enzyme that produces prostaglandin E2 (PGE2). In our previous study, we investigated the role of mPGES-1 in the inflammation and demyelination observed in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, using mPGES-1-deficient (mPGES-1-/-) and wild-type (wt) mice. We found that mPGES-1 facilitated inflammation, demyelination, and paralysis and was induced in vascular endothelial cells and macrophages and microglia around inflammatory foci. Here, we investigated the role of interleukin-1β (IL-1β) in the intercellular mechanism stimulated by mPGES-1 in EAE spinal cords in the presence of inflammation. We found that the area invaded by CD4-positive (CD4+) T cells was extensive, and that PGE2 receptors EP1-4 were more induced in activated CD4+ T cells of wt mice than in those of mPGES-1-/- mice. Moreover, IL-1β and IL-1 receptor 1 (IL-1r1) were produced by 65% and 48% of CD4+ T cells in wt mice and by 44% and 27% of CD4+ T cells in mPGES-1-/- mice. Furthermore, interleukin-17 (IL-17) was released from the activated CD4+ T cells. Therefore, mPGES-1 stimulates an intercellular interaction between CD4+ T cells by upregulating the autocrine function of IL-1β in activated CD4+ T cells, which release IL-17 to facilitate axonal and myelin damage in EAE mice. [ABSTRACT FROM AUTHOR]

Recent studies have shown promising results concerning the effectiveness of 3D plates in terms of stabilization of condylar fractures. Despite the use of new techniques and new materials, we can still observe certain side effects, including the immune reaction of the body, which may lead to the excessive inflammation. The aim of this paper was to determine how the production of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) in THP-1 monocytes/macrophages is influenced by the titanium 3D plates and dedicated screws. The experiments were conducted on THP-1 monocytic cell line and macrophages derived from a THP-1cells. The concentrations of PGE2 and TXB2 released were measured by using immunoassay kit. Verification of plate-induced activation of THP-1 monocytes and macrophages and initiation of inflammatory reaction was conducted by flow cytometry. Despite some differences in the content of the implant devices our results showed that these plates did not statistically significantly increase the production of these prostanoids. Osteosynthesis of condylar fractures using 3D titanium mini-plates seems to be a good alternative to traditional plates due to their lack of stimulating the cyclooxygenase-dependent production of prostanoids; limiting the development of inflammatory reactions. [ABSTRACT FROM AUTHOR]