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Highlights: [•] Lipocalin (L)-prostaglandin D2 (PGD2) synthase (S) was identified in human OA. [•] PGD2 augmented IL-1β induced PGE2 but inhibited NO in human chondrocytes. [•] PGD2 shows pro and anti-inflammatory properties in OA chondrocytes and cartilage. [•] Celecoxib exerts “Disease Modifying Drug” role in human arthritis. [Copyright &y& Elsevier]

Digital clubbing, which has been recognized as a sign of systemic disease, is one of the most ancient diseases. However, the pathogenesis of clubbing and hypertrophic osteoarthropathy has hitherto been poorly understood. The study of a clinically indistinguishable idiopathic form (primary hypertrophic osteoarthropathy, PHO) provides an opportunity to understand the pathogenesis of hypertrophic osteoarthropathy. Current advances in the study of PHO are discussed. The impaired metabolism of prostaglandin E2 (PGE2) plays a central role in its pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Microsomal prostaglandin synthetase-1 (mPGES-1) is an inducible terminal enzyme required for prostaglandin E2 (PGE2) biosynthesis. In this study, we examined the role of mPGES-1 in the inflammation and demyelination observed in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We induced EAE with myelin oligodendrocyte glycoprotein35–55 peptide in mPGES-1-deficient (mPGES-1−/− ) and wild-type (WT) mice. First, we examined the histopathology in the early and late phases of EAE progression. Next, we measured the concentration of PGE2 in the spinal cord and investigated the expression of mPGES-1 using immunohistochemistry. In addition, we examined the progression of the severity of EAE using an EAE score to investigate a correlation between pathological features and paralysis. In this paper, we demonstrate that WT mice showed extensive inflammation and demyelination, whereas mPGES-1−/− mice exhibited significantly smaller and more localized changes in the perivascular area. The mPGES-1 protein was induced in vascular endothelial cells and microglia around inflammatory foci, and PGE2 production was increased in WT mice but not mPGES-1−/− mice. Furthermore, mPGES-1−/− mice showed a significant reduction in the maximum EAE score and improved locomotor activity. These results suggest that central PGE2 derived from non-neuronal mPGES-1 aggravates the disruption of the vessel structure, leading to the spread of inflammation and local demyelination in the spinal cord, which corresponds to the symptoms of EAE. The inhibition of mPGES-1 may be useful for the treatment of human MS. [Copyright &y& Elsevier]

Abstract: Baicalin, a major constituent of flavonoids isolated from Scutellariae Radix, has been previously confirmed to decrease the duration of immobility in mice exposed to the forced swimming test (FST) and tail suspension test (TST). However, its antidepressant effects and mechanisms are still seldom studied in chronic mild stress (CMS) model of depression. In the present study, we attempted to investigate the effects of baicalin on the depressive-like behavior, the mRNA expression and activity of cyclooxygenase-2 (COX-2), as well as prostaglandin E2 (PGE2) levels in the frontal cortex and hippocampus. Moreover, the serum corticosterone levels were also examined. We found that CMS procedure not only decreased the sucrose preference and increased serum corticosterone levels, but also elevated the activity and mRNA expression of COX-2, and increased PGE2 levels in rat brain regions. Treatment with baicalin (10, 20, 40mg/kg) prevented these abnormalities induced by CMS. These results confirmed that baicalin exerted antidepressant-like effects, and suggested its mechanisms at least partially related to decease COX-2 activity and expression, subsequently resulted in reduction of PGE2 levels in brain. Our findings may provide a new aspect to understand the antidepressant action of baicalin, which is targeted on the COX-2 system in brain. [Copyright &y& Elsevier]

Inflammatory tenosynovitis is an inflammation that involves the tendons and synovial sheaths caused by minor trauma repeated for a long period of time. This inflammatory disease may be involved in the onset of tunnel carpal syndrome (CTS), because of the thickening of the tendon sheath that may produce an increase in the carpal canal pressure and damage of the median nerve in the wrist. Recent studies suggest that in patients with CTS pathological changes occur in the subsynovial connective tissue, such as vascular proliferation and non-inflammatory synovial fibrosis. However, little is known about the pathological mechanism of tenosynovial thickening. The aim of this study is to evaluate the potential role of vascular endothelial growth factor (VEGF), prostaglandin E2 (PGE2) and trasforming growth factor-beta (TGF-β) in the modifications of connective synovial tissue of CTS specimens in order to determine whether these factors play a role in the development of this disease. Ten specimens from patients with CTS and four control tissues (cadavers) were analyzed by immunohistochemistry using specific antibodies against these growth factors. A temporary increase in the production of these molecules was found in cells within the vessels and synovial lining during the intermediate phase of the syndrome, when the histology of the tenosynovium changes from oedematous to fibrotic. Our data confirm a close correlation between the expression of PGE2 and VEGF. Recent histological examinations have shown a marked increase in vascular proliferation and reduction of fibroblast density in specimens from CTS patients during the intermediate phase. Our study indicates that the expression of TGF-β in fibroblasts and vascular endothelial cells of synovial connective tissues of CTS patients was significantly higher than in those of controls. These findings suggest that angiogenesis appears to take place as a part of a regenerative reaction that results in fibrosis. We believe that VEGF, TGF-β and PGE2 may be potential therapeutic targets in the treatment of this disease although proof of this evidence requires further studies. [ABSTRACT FROM AUTHOR]

Abstract: Adipokine leptin reportedly acts on the kidney in pathophysiological states. However, the influence of leptin on renal tubular epithelial cells is still unclear. Gentamicin, a widely used antibiotic for the treatment of bacterial infection, can cause nephrotoxicity. This study aims to investigate the influence of long-term leptin treatment on gentamicin-induced apoptosis in rat renal tubular cells (NRK-52E) and mice. We monitored apoptosis and molecular mechanisms using annexin V/ propidium iodide staining and small interfering RNA transfection. In NRK-52E cells, leptin reduced gentamicin-induced apoptosis at 24h, but significantly increased apoptosis at 48h. Long-term treatment of leptin decreased Bcl-x L expression and increased caspase activity in gentamicin-treated NRK-52E cells. Leptin also increased the expression of cyclooxygenase-2 (COX-2) and its product, prostaglandin E2 (PGE2), in a dose-dependent manner. The COX-2 inhibitor, NS398 (N-[2-(Cyclohexyloxy)-4- nitrophenyl]methanesulfonamide), blocked PGE2 augmentation and the pro-apoptotic effects of leptin. The addition of PGE2 recovered the pro-apoptotic effect of leptin in NS398-treated NRK-52E cells. In a mouse animal model, a 10 day leptin treatment significantly increased gentamicin-induced apoptotic cells in proximal tubules. NS398 treatment inhibited this in vivo pro-apoptotic effect of leptin. Results reveal that long-term elevation of leptin induces COX-2-mediated PGE2 augmentation in renal tubular cells, and then increases these cells'' susceptibility to gentamicin-induced apoptosis. [Copyright &y& Elsevier]

Thymoquinone (TQ), a drug extracted from the black seeds of Nigella sativa, has been shown to exhibit anti-inflammatory, anti-oxidant, and anti-neoplastic effects in numerous cancer cells. The effects of TQ on cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production in MDA-MB-231, however, remain poorly understood. Western blot analysis and immunofluorescence staining were performed to study the expression levels of inflammation regulatory proteins in MDA-MB-231. PGE2 assay was conducted to explore the TQ-induced production of PGE2. In this study, we investigated the effects of TQ on COX-2 expression and PGE2 production in MDA-MB-231. TQ significantly induced COX-2 expression and increased PGE2 production in a dose-dependent manner, as determined by a Western blot analysis and PGE2 assay. Furthermore, the activation of Akt and p38 kinase, respectively, was up-regulated in TQ treated cells. Inhibition of p38 kinase with SB203580 and PI3kinase (PI3K) with LY294002 abolished TQ-caused COX-2 expression and decreased PGE2 production. These results collectively demonstrate that TQ effectively modulates COX-2 expression and PGE2 production via PI3K and p38 kinase pathways in the human breast cancer cell line MDA-MB-231. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: Taraxasterol, a pentacyclic-triterpene, was isolated from the Chinese medicinal herb Taraxacum officinale. In the present study, we investigated the in vitro anti-inflammatory activity of taraxasterol in lipopolysaccharide (LPS)-induced RAW 264.7 murine macrophages. Materials and methods: RAW 264.7 cells were pretreated with 2.5, 5, or 12.5μg/ml of taraxasterol 1h prior to treatment with 1μg/ml of LPS. Nitric oxide (NO) level in supernatants from cells was examined by Griess reaction, the concentrations of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) were measured by ELISA. Nuclear factor kappa B (NF-κB) activation was evaluated by immunocytochemical analysis. Results: We found that taraxasterol inhibited NO, PGE2, TNF-α, IL-1β and IL-6 production in LPS-induced RAW 264.7 macrophages in a dose-dependent manner. Further studies revealed that taraxasterol prevented the LPS-induced NF-κB translocation from cytoplasm into nuclear. Conclusions: These results indicate that taraxasterol has anti-inflammatory effect by blocking NF-κB pathway. [Copyright &y& Elsevier]

Acetylmelodorinol, chrysin and polycarpol, together with benzoic acid, benzoquinone and stigmasterol were isolated from the leaves of Mitrella kentii (Bl.) Miq. The compounds were evaluated for their ability to inhibit prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) production in human whole blood using a radioimmunoassay technique. Their inhibitory effect on platelet activating factor (PAF) receptor binding to rabbit platelet was determined using 3H-PAF as a ligand. Among the compounds tested, chrysin showed a strong dose-dependent inhibitory activity on PGE2 production (IC50 value of 25.5 μM), which might be due to direct inhibition of cyclooxygenase-2 (COX-2) enzymatic activity. Polycarpol, acetylmelodorinol and stigmasterol exhibited significant and concentration-dependent inhibitory effects on TXB2 production with IC50 values of 15.6, 19.1 and 19.4 μM, respectively, suggesting that they strongly inhibited COX-1 activity. Polycarpol and acetylmelodorinol showed strong dose-dependent inhibitory effects on PAF receptor binding with IC50 values of 24.3 and 24.5 μM, respectively. [ABSTRACT FROM AUTHOR]

Ultraviolet C (UVC) is a DNA damage inducer, and 20 J/m² of UVC irradiation caused cell growth inhibition and induced cell death after exposure for 24-36 h. The growth of NIH 3T3 cells was significantly suppressed at 24 h after UVC irradiation whereas the proliferation of A431 cells was inhibited until 36 h after UVC irradiation. UVC irradiation increased COX-2 expression and such up-regulation reached a maximum during 3-6 h in NIH 3T3 cells. In contrast, UVC-induced COX-2 reached a maximum after 24-36 h in A431 cells. Measuring prostaglandin E2 (PGE2) level showed a biphasic profile that PGE2 release was rapidly elevated in 1-12 h after UVC irradiation and increased again at 24 h in both cell lines. Treatment with the selective COX-2 inhibitor, SC-791, during maximum expression of COX-2 induction, attenuated the UVC induced-growth inhibition in NIH 3T3 cells. In contrast, SC-791 treatment after UVC irradiation enhanced death of A431 cells. These data showed that the patterns of UVC-induced PGE2 secretion from NIH 3T3 cells and A431 cells were similar despite the differential profile in UVC-induced COX-2 up-regulation. Besides, COX-2 might play different roles in cellular response to UVC irradiation in various cell lines. [ABSTRACT FROM AUTHOR]

IL (interleukin)-1β plays an important role in cartilage extracellular matrix degradation and bone resorption in OA (osteoarthritis) through the induction of degradative enzymes and proinflammatory mediators. In the present study, we have determined the consequences of HO-1 (haem oxygenase-1) induction on markers of inflammation and senescence in the functional unit cartilage–subchondral bone stimulated with IL-1β. Cartilage–subchondral bone specimens were obtained from the knees of osteoarthritic patients. Treatment with the HO- 1 inducer CoPP (cobalt protoporphyrin IX) counteracted the stimulatory effects of IL-1β on IL-6, nitrite, PGE2 (prostaglandin E2), TGF (transforming growth factor) β2, TGFβ3 and osteocalcin. Immunohistochemical analyses indicated that CoPP treatment of explants downregulated iNOS (inducible nitric oxide synthase), COX-2 (cyclooxygenase-2) and mPGES-1 (microsomal prostaglandin E synthase-1) induced by IL-1β. In contrast, the expression of HMGB1 (high-mobility group box 1) was not significantly modified. In addition, CoPP decreased the expression of iNOS and mPGES-1 in cells isolated from the explants and stimulated with IL-1β, which was counteracted by an siRNA (small interfering RNA) specific for human HO-1. In isolated primary chondrocytes, we determined senescence-associated β-galactosidase activity and the expression of senescence markers by real-time PCR.We have found that HO-1 induction could regulate senescence markers in the presence of IL-1β and significantly affected telomerase expression, as well as β-galactosidase activity and hTERT (human telomerase reverse transcriptase) and p21 expression in chondrocytes. The findings of the present study support the view that HO-1 induction results in the down-regulation of inflammatory and senescence responses in OA articular tissues. [ABSTRACT FROM AUTHOR]

Abstract: Low-intensity pulsed ultrasound (LIPUS) has been used as a safe and effective modality to enhance fracture healing. As the most abundant cells in bone, osteocytes orchestrate biological activities of effector cells via direct cell-to-cell contacts and by soluble factors. In this study, we have used the osteocytic MLO-Y4 cells to study the effects of conditioned medium from LIPUS-stimulated MLO-Y4 cells on proliferation and differentiation of osteoblastic MC3T3-E1 cells. Conditioned media from LIPUS-stimulated MLO-Y4 cells (LIPUS-Osteocyte-CM) were collected and added on MC3T3-E1 cell cultures. MC3T3-E1 cells cultured in LIPUS-Osteocyte-CM demonstrated a significant inhibition of proliferation and an increased alkaline phosphatase activity. The results of PGE2 and NO assay showed that LIPUS could enhance PGE2 and NO secretion from MLO-Y4 cells at all time points within 24h after LIPUS stimulation. We conclude that LIPUS regulates proliferation and differentiation of osteoblasts through osteocytes in vitro. Increased secretion of PGE2 from osteocytes may play a role in this effect. [Copyright &y& Elsevier]

Background: The molecular mechanisms of dietary oils (such as fish oil) and unsaturated fatty acids, which are widely used by the public for anti-inflammation and vascular protection, have not been settled yet. In this study, prostaglandin E2 (PGE2)-mediated calcium signaling was used to screen dietary oils and eight unsaturated fatty acids for identification of their anti-inflammatory mechanisms. Isolated fat/stromal cells expressing endogenous PGE2 receptors and an HEK293 cell line specifically expressing the recombinant human PGE2 receptor subtype-1 (EP1) were cultured and used in live cell calcium signaling assays. The different dietary oils and unsaturated fatty acids were used to affect cell signaling under the specific stimulation of a pathological amount of inflammatory PGE2. Results: It was identified that fish oil best inhibited the PGE2 signaling in the primary cultured stromal cells. Second, docosahexaenoic acid (DHA), found in abundance in fish oil, was identified as a key factor of inhibition of PGE2 signaling. Eicosapentaenoic acid (EPA), another major fatty acid found in fish oil and tested in this study was found to have small effect on EP1 signaling. The study suggested one of the four PGE2 subtype receptors, EP2 as the key target for the fish oil and DHA target. These findings were further confirmed by using the recombinant EP1 expressed in HEK293 cells as a target. Conclusion: This study demonstrated the new mechanism behind the positive effects of dietary fish oils in inhibiting inflammation originates from the rich concentration of DHA, which can directly inhibit the inflammatory EP1-mediated PGE2 receptor signaling, and that the inflammatory response stimulated by PGE2 in the fat stromal cells, which directly related to metabolic diseases, could be down regulated by fish oil and DHA. These findings also provided direct evidence to support the use of dietary oils and unsaturated fatty acids for protection against heart disease, pain, and cancer resulted from inflammatory PGE2. [ABSTRACT FROM AUTHOR]

Sulfur dioxide (SO2) pollution in atmospheric environment is involved in neurotoxicity and increased risk for hospitalization and mortality of many brain disorders; however, our understanding of the mechanisms by which SO2 caused harmful insults on neurons remains elusive. Here, we show that SO2 exposure produced a neuronal insult, and the neurotoxic effect was likely via stimulating cyclooxygenase-2 (COX-2) elevation by activation of nuclear factor-κB (NF-κB) activity and its acting on the promoter-distal NF-κB–binding site of COX-2 promoter. The action of SO2 on elevating COX-2 ultimately appeared to be dependent on the increased production of arachidonic acid–derived prostaglandins, mainly prostaglandin E2 (PGE2), and functioning of its EP2/4 receptors. Also, the molecular modulating process might be triggered by free radical attack from SO2 metabolism in vivo and followed by activating cyclic adenosine monophosphate/protein kinase A pathway and enhancing probability of the release of glutamate, upregulating N-methyl-D-aspartic acid receptor expression and causing neuronal apoptosis. Our results reveal a mechanistic basis for exploring an association between SO2 inhalation and increased risk for neurological disorders and opening up therapeutic approaches of treating, ameliorating, or preventing brain injuries resulting from SO2 exposure in atmospheric polluting environment. [ABSTRACT FROM AUTHOR]

Abstract: Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in arachidonic acid cascade, plays a key role in the biosynthesis of prostaglandin E2 (PGE2) upon inflammatory insults. Overproduction of PGE2 stimulates proliferation of various cancer cells, confers resistance to apoptosis of cancerous or transformed cells, and accelerates metastasis and angiogenesis. Excess PGE2 undergoes metabolic inactivation which is catalyzed by NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). In this context, 15-PGDH has been speculated as a physiological antagonist of COX-2 and a tumor suppressor. Thus, overexpression of 15-PGDH has been known to protect against experimentally induced carcinogenesis and renders the cancerous or transformed cells susceptible to apoptosis by counteracting oncogenic action of PGE2. In contrast, silence of 15-PGDH is observed in some cancer cells, which is associated with epigenetic modification, such as DNA methylation and histone deacetylation, in the promoter region of 15-PGDH. A variety of compounds capable of inducing the expression of 15-PGDH have been reported, which include the histone deacetylase inhibitors, nonsteroidal anti-inflammatory drugs, and peroxisome proliferator-activated receptor-gamma agonists. Therefore, 15-PGDH may be considered as a novel molecular target for cancer chemoprevention and therapy. This review highlights the role of 15-PGDH in carcinogenesis and its regulation. [Copyright &y& Elsevier]

Abstract: Extracellular matrix degradation in mandibular condylar cartilage is mediated by various cytokines in the temporomandibular joint (TMJ). Interleukin-1 beta (IL-1β) is detected in joint structures with pathologic status, and participates in catabolic action in the extracellular matrix. The purpose of this study was to investigate the effects of IL-1β on cyclooxygenase-2 (COX-2) expression and cartilage metabolism using cultured chondrocytes from mandibular condyle. Articular chondrocytes from the porcine mandibular condylar cartilage around the surface were cultured and treated with 0–10ng/ml IL-1β or 0–1000ng/ml prostaglandin (PGE2) for 0–24h. The mRNA levels of COX-2, MMP-1, -3, and -13 were evaluated by real-time PCR analysis. The protein levels of PGE2 and MMPs were examined by ELISA and Western blot analysis, respectively. The expression levels of COX-2 and PGE2 were enhanced by exogenous IL-1β in chondrocytes. The mRNA levels of MMP-1, -3, and -13 were up-regulated by PGE2 treatment dose-dependently. It is shown that the expression of COX-2/PGE2 was enhanced by IL-1β in articular chondrocytes from mandibular condyle, and that MMP-1, -3, and -13 were induced by PGE2, suggesting that IL-1β-induced COX-2/PGE2 play a crucial role in catabolic processes of mandibular condylar cartilage under inflammatory conditions. [Copyright &y& Elsevier]

BACKGROUND: Tumor-derived cytokines play a significant role in the progression of head and neck squamous cell carcinoma (HNSCC). Targeting proteins, such as tristetraprolin (TTP), that regulate multiple inflammatory cytokines may inhibit the progression of HNSCC. However, TTP's role in cancer is poorly understood. The goal of the current study was to determine whether TTP regulates inflammatory cytokines in patients with HNSCC. METHODS: TTP messenger RNA (mRNA) and protein expression were determined by quantitative real-time-polymerase chain reaction (Q-RT-PCR) and Western blot analysis, respectively. mRNA stability and cytokine secretion were evaluated by quantitative RT-PCR and enzyme-linked immunoadsorbent assay, respectively, after overexpression or knockdown of TTP in HNSCC. HNSCC tissue microarrays were immunostained for interleukin-6 (IL-6) and TTP. RESULTS: TTP expression in HNSCC cell lines was found to be inversely correlated with the secretion of IL-6, vascular endothelial growth factor (VEGF), and prostaglandin E2 (PGE2). Knockdown of TTP increased mRNA stability and the secretion of cytokines. Conversely, overexpression of TTP in HNSCC cells led to decreased secretion of IL-6, VEGF, and PGE2. Immunohistochemical staining of tissue microarrays for IL-6 demonstrated that staining intensity is prognostic for poor disease-specific survival (P = .023), tumor recurrence and development of second primary tumors (P = .014), and poor overall survival (P = .019). CONCLUSIONS: The results of the current study demonstrated that down-regulation of TTP in HNSCC enhances mRNA stability and promotes secretion of IL-6, VEGF, and PGE2. Furthermore, high IL-6 secretion in HNSCC tissue is a biomarker for poor prognosis. In as much as enhanced cytokine secretion is associated with poor prognosis, TTP may be a therapeutic target to reduce multiple cytokines concurrently in patients with HNSCC. [ABSTRACT FROM AUTHOR]

Abstract: Pinolenic acid (PNA), a naturally-occurring polyunsaturated fatty acid (PUFA), is found mainly in pine seeds. Although many studies have demonstrated beneficial effects of pine seed oil, there are no reports of the biological effects of PNA on cancer metastasis. The objective of this study was to investigate the effect of PNA on human breast cancer MDA-MB-231 cell proliferation and metastasis in vitro. We found that PNA did not affect cell viability and cell-matrix adhesion, but it inhibited cell metastasis by suppressing cell invasiveness and motility. Suppression could in part be associated with the modification of the n−6 PUFA composition of cells by PNA which significantly decreased the percentage of arachidonic acid (AA) in phospholipids from 12.6% to 4.9%. The lower AA content of the cancer cells might result in less synthesis of prostaglandin E2 (PGE2), and subsequent down-regulation of inducible cyclooxygenase (COX-2) expression. Thus, PNA represents a potential anti-cancer agent. [Copyright &y& Elsevier]

Abstract: Recurrent seizures may cause neuronal damage in the hippocampus. As neurons form intimate interactions with astrocytes via glutamate, this neuron–glia circuit may play a pivotal role in neuronal excitotoxicity following such seizures. On the other hand, astrocytes contact vascular endothelia with their endfeet. Recently, we found kainic acid (KA) administration induced microsomal prostaglandin E synthase-1 (mPGES-1) and prostaglandin E2 (PGE2) receptor EP3 in venous endothelia and on astrocytes, respectively. In addition, mice deficient in mPGES-1 exhibited an improvement in KA-induced neuronal loss, suggesting that endothelial PGE2 might modulate neuronal damage via astrocytes. In this study, we therefore investigated whether the functional associations between endothelia and astrocytes via endothelial mPGES-1 lead to neuronal injury using primary cultures of hippocampal slices. We first confirmed the delayed induction of endothelial mPGES-1 in the wild-type (WT) slices after KA-treatment. Next, we examined the effects of endothelial mPGES-1 on Ca2+ levels in astrocytes, subsequent glutamate release and neuronal injury using cultured slices prepared from WT and mPGES-1 knockout mice. Moreover, we investigated which EP receptor on astrocytes was activated by PGE2. We found that endothelial mPGES-1 produced PGE2 that enhanced astrocytic Ca2+ levels via EP3 receptors and increased Ca2+-dependent glutamate release, aggravating neuronal injury. This novel endothelium–astrocyte–neuron signaling pathway may be crucial for neuronal damage after repetitive seizures, and hence could be a new target for drug development. [Copyright &y& Elsevier]

Abstract: Due to their immunomodulatory properties, adipose tissue (AT) and Wharton’s Jelly (WJ) constitute valuable alternatives to BM as sources of MSCs for managing graft-versus-host disease. To ensure the efficiency of AT- and WJ-MSCs implies the characterization of their immunomodulatory functions in comparison to those of BM. In this study, we investigated the capacity of AT- and WJ-MSCs to modulate lymphocyte reactions in response to different stimuli as well as the specificity of this immunomodulation. AT- and WJ-MSC displayed potent immunosuppressive effects on lymphocyte responses in a dose-dependent manner. These effects included the prevention of lymphocyte activation as well as the suppression of T-cell proliferation regardless of the stimuli used to activate lymphocytes. These effects were mediated through the expression of COX1/COX2 enzymes and by the production of PGE2. CD4+ and CD8+ T-lymphocytes were equally targeted by MSCs demonstrating that the immunomodulation was not restricted to a specific T-cell subpopulation. [Copyright &y& Elsevier]

Abstract: β1-Integrins mediate cell attachment to different extracellular matrix proteins, intracellular proteins, and intercellular adhesions. Recently, it has been reported that prostaglandin E2 (PGE2) has anti-inflammatory properties such as inhibition of the expression of adhesion molecules or production of chemokines. However, the effect of PGE2 on the expression of β1-integrin remains unknown. In this study, we investigated the effects of PGE2 on the expression of β1-integrin in the human monocytic cell line THP-1 and in CD14+ monocytes/macrophages in human peripheral blood. For this, we examined the role of four subtypes of PGE2 receptors and E-prostanoid (EP) receptors on PGE2-mediated inhibition. We found that PGE2 significantly inhibited the expression of β1-integrin, mainly through EP4 receptors in THP-1 cells and CD14+ monocytes/macrophages in human peripheral blood. We suggest that PGE2 has anti-inflammatory effects, leading to the inhibited expression of β1-integrin in human monocytes/macrophages, and that the EP4 receptor may play an important role in PGE2-mediated inhibition. [Copyright &y& Elsevier]

Abstract: Prostaglandin E2 (PGE2) is a key lipid-derived compound which mediates important physiological functions in the nervous system via activation of four EP receptors (EP1–4). Recent studies have shown that altered PGE2 signalling due to abnormal lipid peroxidation and oxidative stress may underlie some pathologies of the nervous system. The prenatal exposure to the drug misoprostol, a prostaglandin type E analogue, has also been linked to a number of neurodevelopmental defects. In the present study, we use ratiometric calcium imaging with fura-2AM as a calcium indicator to determine the effects of PGE2 and misoprostol on calcium homeostasis in growth cones of mouse neuroblastoma (Neuro-2a) cells. Our results show that both drugs increase the amplitude of calcium transients in growth cones of Neuro-2a cells and induce neurite retraction. Moreover, quantitative real-time PCR also revealed that the mRNA expression level of the four EP receptors was significantly higher during the neurogenesis period in mouse indicating the importance of PGE2 signalling in the nervous system. [ABSTRACT FROM AUTHOR]

Abstract: To test whether mechanical loading produces faster healing in aged mice, fractured femurs of aged 1-year-old mice were subjected to low-intensity pulsed ultrasound (LIPUS), a treatment that is routinely used to help heal fractures in humans. Cyclooxygenase-2 knockout mice (COX-2−/−), which lack an immediate early mediator of mechanical stimulation, were also studied by histochemistry, microcomputed tomography and quantitative polymerase chain reaction to determine the role of COX-2. The healing in the aged COX-2−/− mice is slow during the endochondral bone remodeling (>30 d), a period generally prolonged in senescence. For aged wild-type mice, LIPUS halved the endochondral phase to about 10 d, whereas that was not the case for aged COX-2−/− mice, which showed no apparent shortening of the prolonged endochondral-phase healing time. Injecting prostaglandin E2 receptor agonists, however, rescued the COX-2−/− callus from insensitivity to LIPUS. In conclusion, COX-2 is a limiting factor in the delayed endochondral bone healing and is induced by LIPUS, which normalizes healing rate to the wild-type level. (E-mail: yukomtak@kdcnet.ac.jp) [Copyright &y& Elsevier]

Abstract: Human umbilical-cord-derived mesenchymal stem cells (hUC-MSCs) constitute an attractive alternative to bone-marrow-derived MSCs for potential clinical applications because of easy preparation and lower risk of viral contamination. In this study, both proliferation of human peripheral blood mononuclear cells (hPBMCs) and their IFN-γ production in response to mitogenic or allogeneic stimulus were effectively inhibited by hUC-MSCs. Co-culture experiments in transwell systems indicated that the suppression was largely mediated by soluble factor(s). Blocking experiments identified prostaglandin E2 (PGE2) as the major factor, because inhibition of PGE2 synthesis almost completely mitigated the immunosuppressive effects, whereas neutralization of TGF-β, IDO, and NO activities had little effects. Moreover, the inflammatory cytokines, IFN-γ and IL-1β, produced by hPBMCs upon activation notably upregulated the expression of cyclooxygenase-2 (COX-2) and the production of PGE2 by hUC-MSCs. In conclusion, our data have demonstrated for the first time the PGE2-mediated mechanism by which hUC-MSCs exert their immunomodulatory effects. [Copyright &y& Elsevier]

Seaweed has been used in traditional cosmetics and as a herbal medicine in treatments for cough, boils, goiters, stomach ailments, and urinary diseases, and for reducing the incidence of tumors, ulcers, and headaches. Despite the fact that seaweeds are frequently used in the practice of human health, little is known about the role of seaweed in the context of inflammation. This study aimed to investigate the influence of Jeju endemic seaweed on a mouse macrophage cell line (RAW 264.7) under the stimulation of lipopolysaccharide (LPS). Ethyl acetate extracts obtained from 14 different kinds of Jeju seaweeds were screened for inhibitory effects on pro-inflammatory mediators. Our results revealed that extracts from five seaweeds, Laurencia okamurae, Grateloupia elliptica, Sargassum thunbergii, Gloiopeltis furcata, and Hizikia fusiformis, were potent inhibitors of the production of pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Based on these results, the anti-inflammatory effects and low cell toxicity of these seaweed extracts suggest potential therapeutic applications in the regulation of the inflammatory response. [ABSTRACT FROM AUTHOR]

Passafaro D, Reina S, Sterin-Borda L, Borda E. Cholinergic autoantibodies from primary Sjögren’s syndrome modulate submandibular gland Na + /K + -ATPase activity via prostaglandin E 2 and cyclic AMP. Eur J Oral Sci 2010; 118: 131–138. © 2010 The Authors. Journal compilation © 2010 Eur J Oral Sci We demonstrate that patients with primary Sjögren’s syndrome (pSS) produce functional IgG autoantibodies that interact with the glandular M3 muscarinic acetylcholine receptors (mAChRs). These autoantibodies act as a partial muscarinic agonist, increasing prostaglandin E2 (PGE2) and cyclic AMP production through modifying Na+/K+-ATPase activity, but also interfere with the secretory effect of the parasympathetic neurotransmitter. The IgG from patients with pSS has two effects on the submandibular gland. On the one hand, it may act as an inducer of the proinflammatory molecule (PGE2) that, in turn, inhibits Na+/K+-ATPase activity. On the other hand, it plays a role in the pathogenesis of dry mouth, abolishing the Na+/K+-ATPase inhibition and the net K+ efflux stimulation of the salivary gland in response to the authentic agonist pilocarpine, decreasing salivary fluid production. [ABSTRACT FROM AUTHOR]

CD40, a member of the tumour necrosis factor-α receptor family, is constitutively expressed by cells of haematopoietic and non-haematopoietic origin, including fibroblasts. Signalling through this receptor molecule regulates inflammatory mediator secretion by many cell types. The work has been performed in healthy subjects and the authors studied, by cellular culture, flow cytometric analysis and ELISA assay, the expression of CD40 and PGE2 (prostaglandin E2) generation on gingival fibroblasts stimulated by β-AR (β-adrenoceptor) agonists. Herein, the authors demonstrate that β-AR subtype activation via their own specific agonists markedly increased CD40 expression on human gingival fibroblasts. This effect was prevented by β-AR subtype-specific antagonists. In addition, gingival fibroblast β-AR stimulation resulted in an increase in PGE2 generation. The inhibition of PLA2 (phospholipase A2) and COX-1 (cyclo-oxygenase-1) but not COX-2 impaired β-AR increase of PGE2, an effect that was restored by the addition of low concentrations of PGE2, suggesting that PGE2 generation is implicated in the mechanism underlying β-AR-agonist-mediated CD40 overexpression. Our work has revealed an endogenous β-AR mediator network involving gingival fibroblasts. [ABSTRACT FROM AUTHOR]

CD40, a member of the tumour necrosis factor-α receptor family, is constitutively expressed by cells of haematopoietic and non-haematopoietic origin, including fibroblasts. Signalling through this receptor molecule regulates inflammatory mediator secretion by many cell types. The work has been performed in healthy subjects and the authors studied, by cellular culture, flow cytometric analysis and ELISA assay, the expression of CD40 and PGE2 (prostaglandin E2) generation on gingival fibroblasts stimulated by β-AR (β-adrenoceptor) agonists. Herein, the authors demonstrate that β-AR subtype activation via their own specific agonists markedly increased CD40 expression on human gingival fibroblasts. This effect was prevented by β-AR subtype-specific antagonists. In addition, gingival fibroblast β-AR stimulation resulted in an increase in PGE2 generation. The inhibition of PLA2 (phospholipase A2) and COX-1 (cyclo-oxygenase-1) but not COX-2 impaired β-AR increase of PGE2, an effect that was restored by the addition of low concentrations of PGE2, suggesting that PGE2 generation is implicated in the mechanism underlying β-AR-agonist-mediated CD40 overexpression. Our work has revealed an endogenous β-AR mediator network involving gingival fibroblasts. [ABSTRACT FROM AUTHOR]

Figuero E, Carrillo-de-Albornoz A, Herrera D, Bascones-Martínez A. Gingival changes during pregnancy: I. Influence of hormonal variations on clinical and immunological parameters. J Clin Periodontol 2009; 37: 220–229. doi: 10.1111/j.1600-051X.2009.01516.x. Aim: To test whether exacerbated gingival inflammation in pregnancy is associated with increased salivary hormone levels and changes in gingival crevicular fluid (GCF) interleukin-1 β (IL-1 β) and prostaglandin-E2 (PGE2) levels. Material and methods: In this cohort study, 48 pregnant women without periodontitis were evaluated in the first, second, and third trimesters and at 3 months postpartum. Twenty-eight non-periodontitis non-pregnant women were evaluated twice, with a 6-month interval. Plaque and gingival indices (PlI, GI), salivary progesterone and estradiol and GCF IL-1 β and PGE2 levels were determined.anova for repeated measures or Friedman's test were used for intragroup analyses. Inter-group comparisons were analysed with t-test or Mann–Whitney U-test. Correlations were evaluated with Pearson's and Spearman's test. Results: Pregnant women showed an increase in GI ( p<0.05) despite maintaining low PlI values. No changes in IL-1 β and PGE2 levels were observed during pregnancy. No significant correlation was found between the GI increase and salivary hormone levels. GI ( p<0.05) and IL-1 β levels ( p<0.001) were lower in non-pregnant than in pregnant women. Conclusions: This study confirms the presence of an exacerbated gingival inflammation during pregnancy, but this phenomenon could not be associated with an increase in progesterone or estradiol or with changes in PGE2 or IL-1 β. [ABSTRACT FROM AUTHOR]

Abstract: Thiazolidinediones, known as peroxisome proliferator-activated receptor-γ (PPARγ) agonists, may modify prostaglandin formation and exert gastroprotective effects. Since activation of proteinase-activated receptor-1 (PAR1) reveals endogenous prostanoid-dependent gastroprotection, we investigated if two thiazolidinediones, ciglitazone and troglitazone, modulate the prostaglandin E2 (PGE2) release caused by activation of PAR1 in normal rat gastric mucosal epithelial RGM1 cells. Ciglitazone dramatically facilitated the PAR1-triggered PGE2 production and cyclooxygenase-2 (COX-2) upregulation, although it had no effect by itself. In contrast, troglitazone suppressed the PAR1-triggered PGE2 production and COX-2 upregulation. Either effect of ciglitazone and troglitazone was resistant to GW9662, a PPARγ antagonist. The facilitation of the PGE2 release by ciglitazone was blocked by inhibitors of MEK, p38 MAP kinase (p38MAPK) and PI3-kinase (PI3K), but not JNK. Nonetheless, ciglitazone failed to enhance the PAR1-triggered phosphorylation of ERK and p38MAPK. In conclusion, ciglitazone and troglitazone, exert opposite effects on the PAR1-triggered PGE2 production and COX-2 upregulation by targeting molecules other than PPARγ. [Copyright &y& Elsevier]

Cyclooxygenase isoform-2 (COX-2) and microsomal prostaglandin E2 synthase-1 (mPGES-1) are inducible enzymes that become up-regulated in inflammation and some cancers. It has been demonstrated that their coupling reaction of converting arachidonic acid (AA) into prostaglandin (PG) E2 (PGE2) is responsible for inflammation and cancers. Understanding their coupling reactions at the molecular and cellular levels is a key step toward uncovering the pathological processes in inflammation. In this paper, we describe a structure-based enzyme engineering which produced a novel hybrid enzyme that mimics the coupling reactions of the inducible COX-2 and mPGES-1 in the native ER membrane. Based on the hypothesized membrane topologies and structures, the C-terminus of COX-2 was linked to the N-terminus of mPGES-1 through a transmembrane linker to form a hybrid enzyme, COX-2-10aa-mPGES-1. The engineered hybrid enzyme expressed in HEK293 cells exhibited strong triple-catalytic functions in the continuous conversion of AA into PGG2 (catalytic-step 1), PGH2 (catalytic-step 2) and PGE2 (catalytic-step 3), a pro-inflammatory mediator. In addition, the hybrid enzyme was also able to directly convert dihomo-gamma-linolenic acid (DGLA) into PGG1, PGH1 and then PGE1 (an anti-inflammatory mediator). The hybrid enzyme retained similar Kd and Vmax values to that of the parent enzymes, suggesting that the configuration between COX-2 and mPGES-1 (through the transmembrane domain) could mimic the native conformation and membrane topologies of COX-2 and mPGES-1 in the cells. The results indicated that the quick coupling reaction between the native COX-2 and mPGES-1 (in converting AA into PGE2) occurred in a way so that both enzymes are localized near each other in a face-to-face orientation, where the COX-2 C-terminus faces the mPGES-1 N-terminus in the ER membrane. The COX-2-10aa-mPGES-1 hybrid enzyme engineering may be a novel approach in creating inflammation cell and animal models, which are particularly valuable targets for the next generation of NSAID screening. [ABSTRACT FROM PUBLISHER]

Abstract: Clinical evidence from paediatric neurology supports the possibility that a protracted inflammatory state in the central nervous system (CNS) may enhance the predisposition of brain tissue to develop seizures. Consequently, non-steroidal anti-inflammatory drugs (NSAIDs) as well as selective cyclooxygenase-2 (COX-2) inhibitors were expected to positively modulate seizure susceptibility during a systemic inflammatory response. Nevertheless, experimental findings and clinical evidence provide controversial results. As a possible explanation for these apparent discrepancies, it is hypothesised that the amount of prostaglandin E2 (PGE2) induced in the immature brain parenchyma during systemic inflammatory response is crucial since PGE2 plays a dual role. Indeed, on the one hand, this prostaglandin increases seizure susceptibility by stimulation of glutamate release from neurons and astrocytes. On the other hand, however, the same prostaglandin induces a massive release of corticosterone, being this hormone known to inhibit efficiently the seizure susceptibility of the immature brain. Hence, the dose–response curve of any given NSAID/COX-2 inhibitor on seizure susceptibility is expected to show different patterns, depending on the amount of PGE2 levels produced in the brain parenchyma during the effect of drug. The proposed hypothesis also suggests that mild to moderate increase of PGE2 levels in the immature brain parenchyma may act as a ‘preconditioning’ stimulus, i.e., it may confer a transient resistance to develop seizure-induced brain injury, besides to efficiently counteract seizure susceptibility. [Copyright &y& Elsevier]

Abstract: Chebulagic acid (CA), a natural anti-oxidant, showed potent anti-inflammatory effects in LPS-stimulated RAW 264.7, a mouse macrophage cell line. These effects were exerted via inhibition of NO and PGE2 production and down-regulation of iNOS, COX-2, 5-LOX, TNF-α and IL-6. CA inhibited NF-κB activation by LPS, and this was associated with the abrogation of IκB-α phosphorylation and subsequent decreases in nuclear p50 and p65 protein levels. Further, the phosphorylation of p38, ERK 1/2 and JNK in LPS-stimulated RAW 264.7 cells was suppressed by CA in a concentration-dependent manner. LPS-induced generation of reactive oxygen species (ROS) was also effectively inhibited by CA. These results suggest that CA exerts anti-inflammatory effects in LPS-stimulated RAW 264.7 macrophages by inhibition of NF-κB activation and MAP kinase phosphorylation. [Copyright &y& Elsevier]

The molecular mechanism of discogenic low back pain (LBP) involves nonphysiological nerve invasion into a degenerated intervertebral disc (IVD), induced by nerve growth factor (NGF). Selective cyclooxygenase (COX)-2 inhibitors are mainly used in the treatment of LBP, and act by suppressing the inflammatory mediator prostaglandin E2 (PGE2), which is induced by inflammatory stimuli, such as interleukin-1β (IL-1β). However, in our previous in vitro study using cultured human IVD cells, we demonstrated that the induction of NGF by IL-1β is augmented by a selective COX-2 inhibitor, and that PGE2 and PGE1 suppress NGF expression. Therefore, in this study, to elucidate the mechanism of NGF suppression by PGE2 and PGE1, we focused on mitogen-activated protein kinases (MAPKs) and its phosphatase, dual-specificity phosphatase (DUSP)-1. IL-1β-induced NGF expression was altered in human IVD cells by MAPK pathway inhibitors. PGE2 and PGE1 enhanced IL-1β-induced DUSP-1 expression, and suppressed the phosphorylation of MAPKs in human IVD cells. In DUSP-1 knockdown cells established using small interfering RNA, IL-1β-induced phosphorylation of MAPKs was enhanced and prolonged, and NGF expression was significantly enhanced. These results suggest that PGE2 and PGE1 suppress IL-1β-induced NGF expression by suppression of the MAPK signaling pathway, accompanied by increased DUSP-1 expression. [ABSTRACT FROM AUTHOR]

Abstract: The induced synthesis of bioactive prostanoids downstream of cyclooxygenase-2 (COX-2) and prostaglandin H2 (PGH2) exerts a critical event in colorectal carcinogenesis. Here we demonstrate that APCMin/+ mice with genetic deletion of microsomal prostaglandin E synthase-1 (mPGES-1), which catalyses the terminal conversion of PGH2 into PGE2, surprisingly develop more and generally larger intestinal tumors than do mPGES-1 wild type littermates (mean number of tumors/intestine 80 vs. 38, p <0.0005, mean tumor diameter 1.64 vs. 1.12mm, p <0.0005). No deviation regarding the expression of other PGE2 related enzymes (COX-1, COX-2, mPGES-2, cPGES, and 15-PGDH) or receptors (EP1–4) was obvious among the mPGES-1 deficient mice. PGE2 levels were suppressed in tumors of mPGES-1 deficient animals, but the concentrations of other PGH2 derived prostanoids were generally enhanced, being most prominent for TxA2 and PGD2. Thus, we hypothesise that a redirected synthesis towards other lipid mediators might (over)compensate for loss of mPGES-1/PGE2 during intestinal tumorigenesis. Nevertheless, our results question the suitability for mPGES-1 targeting therapy in the treatment or prevention of colorectal cancer. [Copyright &y& Elsevier]

Abstract: Activation of the prostaglandin E2 (PGE2) EP4 receptor, a G-protein-coupled receptor (GPCR), results in increases in intracellular cyclic AMP (cAMP) levels via stimulation of adenylate cyclase. Here we describe the in vitro pharmacological characterization of a novel EP4 receptor antagonist, CJ-042794 (4-{(1S)-1-[({5-chloro-2-[(4-fluorophenyl)oxy]phenyl}carbonyl)amino]ethyl}benzoic acid). CJ-042794 inhibited [3H]-PGE2 binding to the human EP4 receptor with a mean pK i of 8.5, a binding affinity that was at least 200-fold more selective for the human EP4 receptor than other human EP receptor subtypes (EP1, EP2, and EP3). CJ-042794 did not exhibit any remarkable binding to 65 additional proteins, including GPCRs, enzymes, and ion channels, suggesting that CJ-042794 is highly selective for the EP4 receptor. CJ-042794 competitively inhibited PGE2-evoked elevations of intracellular cAMP levels in HEK293 cells overexpressing human EP4 receptor with a mean pA 2 value of 8.6. PGE2 inhibited the lipopolysaccharide (LPS)-induced production of tumor necrosis factor α (TNFα) in human whole blood (HWB); CJ-042794 reversed the inhibitory effects of PGE2 on LPS-induced TNFα production in a concentration-dependent manner. These results suggest that CJ-042794, a novel, potent, and selective EP4 receptor antagonist, has excellent pharmacological properties that make it a useful tool for exploring the physiological role of EP4 receptors. [Copyright &y& Elsevier]

Abstract: Cyclooxygenase (COX) is a rate-limiting enzyme in prostaglandin synthesis. COX consists of two isoforms, constitutive COX-1 and inducible COX-2. We have first found that COX-2 expression in the brain is tightly regulated by neuronal activity under physiological conditions, and electroconvulsive seizure robustly induces COX-2 mRNA in the brain. Our recent in-depth studies reveal COX-2 expression is divided into two phases, early in neurons and late in non-neuronal cells, such as endothelial cells or astrocytes. In this review, we present that early synthesized COX-2 facilitates the recurrence of hippocampal seizures in rapid kindling model, and late induced COX-2 stimulates hippocampal neuron loss after kainic acid treatment. Hence, we consider the potential role of COX-2 inhibitors as a new therapeutic drug for a neuronal loss after seizure or focal cerebral ischemia. The short-term and sub-acute medication of selective COX-2 inhibitors that suppresses an elevation of prostaglandin E2 (PGE2) may be an effective treatment to prevent neuronal loss after onset of neuronal excitatory diseases. This review also discusses a novel role of vascular endothelial cells in brain diseases. We found that these cells produce PGE2 by synthesizing COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) in response to excitotoxicity and neuroinflammation. We also show a possible mechanisms of neuronal damage associated with seizure via astrocytes and endothelial cells. Further analysis of the interaction among neurons, astrocytes and endothelial cells may provide a better understanding of the processes of neuropathological disorders, as well as facilitating the development of new treatments. [Copyright &y& Elsevier]

Abstract: The effect of Collybia dryophila polysaccharide (CDP), a (1→3), (1→4)-β-d-glucan extracted from the mushroom C. dryophila, was evaluated on nitric oxide (NO) production induced by lipopolysaccharide (LPS) and gamma interferon (IFNγ) or by LPS alone in RAW 264.7 cells. CDP significantly inhibited NO production in a dose-dependent manner without affecting cell viability. The inhibition of NO by CDP was consistent with decreases in both inducible nitric oxide synthase (iNOS) protein and mRNA expression suggesting that CDP exerts its effect by inhibiting iNOS gene expression. In addition, CDP at concentrations of 400 and 800 μg/ml was shown to significantly increase prostaglandin E2 (PGE2) production in LPS- and IFNγ-induced macrophages when compared to the control. [Copyright &y& Elsevier]

Bidens pilosa ( BP) Linn. var. radiata is a plant used in traditional folk medicine. It is clinically effective in various diseases; the pathogenesis of most of these involves cyclooxygenase (COX)-2. To investigate the mechanism on which the clinical effectiveness of BP is based, we examined its effects on COX-2 expression and its major product, prostaglandin (PG)E2, under conditions of inflammation. We induced inflammation in normal human dermal fibroblasts with interleukin (IL)-1β and examined the effects of BP on COX-2 expression and PGE2 production using Western blotting and competitive enzyme immunoassay, respectively. The functional involvements of mitogen activated protein kinases (MAPK) ERK1/2, p38, and JNK in COX-2 expression were also examined by Western blotting. IL-1β-induced COX-2 expression was regulated by MAPK pathways, especially by p38. BP inhibited the phosphorylation of MAPKs, COX-2 expression, and subsequent PGE2 production. The physiological activities and clinical effectiveness of BP observed under diverse conditions may be partly attributable to its ability to inhibit MAPK, mainly p38, activity, COX-2 expression, and subsequent PGE2 production. [ABSTRACT FROM AUTHOR]

Abstract: The number of adults in the US affected by bipolar disorder, depression, or schizophrenia is approaching 15 million. Despite decades of research, etiologies of these illnesses remain elusive. Theories of aberrant brain morphology, neurotransmission, and signal conduction have provided the heuristic framework for a large body of literature, with attention focused upon hypotheses of monoamine signaling underlying psychiatric disease. More recently, attention has turned to potential contributions of other signaling pathways, including the arachidonic acid cascade and generation of prostaglandins (PG). To determine the potential involvement of the pathways leading to PGE2 synthesis in psychiatric disease, immunohistochemistry and immunoblotting were performed to measure regional expression of the cyclooxygenases (COX) and one of the terminal PGE2 synthases (PGES) in postmortem tissue provided by The Stanley Medical Research Institute. For normal, bipolar, depressed, and schizophrenic subjects, COX-1 and COX-2 protein levels did not differ across region and patient populations. In contrast, there was a significant effect of diagnosis on cytosolic PGES (cPGES) protein levels in the frontal cortex, with remarkable decreases observed in all psychiatric groups relative to normal tissue (P < 0.05). Significant reduction of cPGES expression was also found in the temporal cortex of bipolar subjects. Evaluation of medicated vs. non-medicated subjects revealed a significant effect of medication on cPGES expression in the frontal cortex of bipolar, but not depressed or schizophrenic subjects. These novel findings further support hypotheses of abnormalities in fatty acid and phospholipid metabolism in regions associated with psychiatric disease. [Copyright &y& Elsevier]

Abstract: Partial and generalized status epilepticus (pSE and gSE) trigger the same level of progenitor cell proliferation in adult dentate gyrus, but survival of new neurons is poor after gSE. Here, we show markedly elevated levels of prostaglandin E2 (PGE2) and brain-derived neurotrophic factor (BDNF) in rat hippocampal formation at 7 days following pSE but not gSE. Administration of the cyclooxygenase (COX) inhibitor flurbiprofen for 1 week, starting at day 8 post-SE, abated PGE2 and decreased BDNF levels, but did not affect survival of new neurons 4 weeks later. Thus, high PGE2 and BDNF levels induced by pSE are probably not of major importance for survival of new neurons during the first days after formation. We propose that they modulate other aspects of synaptic and cellular plasticity, and thereby may influence epileptogenesis. [Copyright &y& Elsevier]

Enhanced prostaglandin production via upregulated cyclooxygenase-2 (COX-2) expression is a likely contributing factor in ultraviolet B (UVB)-induced non-melanoma skin cancer (NMSC), which consists primarily of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). The four E prostanoid (EP) receptors, designated EP1 through EP4, are known to bind prostaglandin E2 (PGE2), the major prostaglandin present in the skin. We used murine models of UVB-induced SCC and BCC, as well as human NMSC from sun-exposed sites, to investigate the expression of EP receptors during UVB-induced tumorigenesis. We observed that UVB-induced murine SCC are associated with markedly altered expression patterns of the EP receptors when compared with non-irradiated skin. In contrast, expression of all EP receptors was largely absent in UVB-induced murine BCC. We also observed expression of all four EP receptors in human SCC, with altered expression of their mRNA levels as compared with adjacent tumor-free skin. Consistent with our murine studies, no EP receptor expression was detected in human BCC, and their mRNA expression levels showed no change from the adjacent non-tumor-bearing skin. These data suggest that altered EP receptor expression may play a differential role in the development of UVB-induced SCC and BCC in murine and human skin. [ABSTRACT FROM AUTHOR]

Abstract: We examined the effect of Buthus martensi Karsch (BMK) extract on IL-1β-induced production of nitrogen oxide (NO) in primary human osteoarthritis (OA) chondrocytes. The cells were treated with BMK (10μg/ml) and IL-1β (2ng/ml) for different periods, and inducible nitric oxide synthase (iNOS) mRNA and protein expression were determined by real-time quantitative reverse transcriptase–polymerase chain reaction and Western blotting, respectively. The cytotoxicity of BMK on human OA chondrocytes was very low (IC50 >250μg/ml) as measured by the XTT assay method. Production of NO was determined as nitrite in culture supernatant. Human chondrocytes cotreated with BMK produced significantly less NO compared with chondrocytes stimulated with IL-1β alone. Activation and translocation of and NF-κB DNA binding activity were determined by Western blotting and specific enzyme-linked immunosorbent assay. The inhibition of NO production correlated with the suppression of induction and expression of nuclear factor-κB (NF-κB) and activation protein-1 (AP-1)-dependent gene. BMK inhibited the activation and translocation of NF-κB to the nucleus, indicating that BMK inhibits the IL-1β-induced production of NO in human chondrocytes by interfering with the activation of NF-κB through a novel mechanism. In addition, BMK reduced prostaglandin E2 (PGE2) production in mouse peritoneal macrophages stimulated with lipopolysaccharide, whereas no influence on the activity of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2) or cyclooxygenase-1 (COX-1) was observed. Our data, therefore, suggest that BMK may be a therapeutically effective inhibitor of IL-1β-induced inflammatory effects that are dependent on NF-κB activation in human OA chondrocytes. The results indicate that BMK exerts anti-inflammatory effects related to the inhibition of neutrophil functions and of NO and PGE2 production, which could be due to a decreased expression of iNOS and COX-2 through the transcription factors NF-κB and AP-1. [Copyright &y& Elsevier]

Abstract: Prostaglandin endoperoxide synthases (PTGS), commonly referred to as cyclooxygenases (COX-1 and COX-2), catalyze the key step in the synthesis of biologically active prostaglandins (PGs), the conversion of arachidonic acid (AA) into prostaglandin H2 (PGH2). Although COX and prostaglandins have been implicated in a wide variety of physiologic processes, an evaluation of the role of prostaglandins in early mammalian development has been difficult due to the maternal contribution of prostaglandins from the uterus: COX null mouse embryos develop normally during embryogenesis. Here, we verify that inhibition of COX-1 results in zebrafish gastrulation arrest and shows that COX-1 expression becomes restricted to the posterior mesoderm during somitogenesis and to posterior mesoderm organs at pharyngula stage. Inhibition of COX-1 signaling after gastrulation results in defective vascular tube formation and shortened intersomitic vessels in the posterior body region. These defects are rescued completely by PGE2 treatment or, to a lesser extent, by PGF2α , but not by other prostaglandins, such as PGI2, TxB2, or PGD2. Functional knockdown of COX-1 using antisense morpholino oligonucleotide translation interference also results in posterior vessel defect in addition to enlarged posterior nephric duct, phenocopying the defects caused by inhibition of COX-1 activity. Together, we provide the first evidence that COX-1 signaling is required for development of posterior mesoderm organs, specifically in the vascular tube formation and posterior nephric duct development. [Copyright &y& Elsevier]

Abstract: In ambient aerosols, ultrafine particles (UFP) and their agglomerates are considered to be major factors contributing to adverse health effects. Reactivity of agglomerated UFP of elemental carbon (EC), Printex 90, Printex G, and diesel exhaust particles (DEP) was evaluated by the capacity of particles to oxidize methionine in a cell-free in vitro system for determination of their innate oxidative potential and by alveolar macrophages (AMs) to determine production of arachidonic acid (AA), including formation of prostaglandin E2 (PGE2), leukotriene B4 (LTB4), reactive oxygen species (ROS), and oxidative stress marker 8-isoprostane. EC exhibiting high oxidative potential induced generation of AA, PGE2, LTB4, and 8-isoprostane in canine and human AMs. Printex 90, Printex G, and DEP, showing low oxidative capacity, still induced formation of AA and PGE2, but not that of LTB4 or 8-isoprostane. Aging of EC lowered oxidative potential while still inducing production of AA and PGE2 but not that of LTB4 and 8-isoprostane. Cellular ROS production was stimulated by all particles independent of oxidative potential. Particle-induced formation of AA metabolites and ROS was dependent on mitogen-activated protein kinase kinase 1 activation of cytosolic phospholipase A2 (cPLA2) as shown by inhibitor studies. In conclusion, cPLA2, PGE2, and ROS formation was activated by all particle types, whereas LTB4 production and 8-isoprostane were strongly dependent on particles'' oxidative potential. Physical and chemical parameters of particle surface correlated with oxidative potential and stimulation of AM PGE2 and 8-isoprostane production. [Copyright &y& Elsevier]

Abstract: The effects of dietary soy isoflavones aglycone and glucoside on lipid metabolism were compared in male Sprague–Dawley rats (4 weeks old) given purified diets containing 0.3% cholesterol. The rats were fed a diet supplemented with either isoflavone aglycone-rich powder (IF-A group) or isoflavone glucoside-rich powder (IF-G group) or isoflavone-free diet (control group) for 40 days. The additional level of isoflavone aglycone moiety in the diet was prepared to the same level (approximately 0.096 g/100 g: approximately 0.1% in diet). The activity of hepatic cholesterol 7α-hydroxylase tended to be slightly higher in the rats fed isoflavones than in those fed the isoflavone-free diet. On the other hand, the activity of hepatic Δ6 desaturase in the IF-A group was lower than that of the control group. Reflecting this effect, the Δ6 desaturation indices [(20:3n-6+20:4n-6)/18:2n-6] in liver phospholipids of the IF-A group were lower than those in the control group. Liver and serum total cholesterol levels and liver TG level were also reduced by consumption of isoflavone aglycone. Moreover, serum TG level was lowered by consumption of both isoflavones aglycone and glucoside. The level of serum total isoflavones in the IF-A group was significantly higher than that in the IF-G group. Therefore, we speculate that the absorption speed of isoflavone aglycones might be faster than that of isoflavone glucosides in rats. This study suggests that dietary soy isoflavones, particularly their aglycone form, may exert a beneficial effect on lipid metabolism in rats fed cholesterol. [Copyright &y& Elsevier]

Abstract: The interactions between dendritic cells (DCs) and T cells determine the fate of an immune response to pathogenic microbes and to harmless allergens alike. The interactions between DCs and T cells is dependent on the maturation and differentiation status of DCs. This status is affected by the cellular lineage of the DCs and by signals that the cells receive from the environment and from T cells. A specific subpopulation of DCs (dendritic cell type 2 [DC2]) induces the development of T helper 2 (Th2) responses. Unregulated Th2 responses induce and cause inflammation in allergy and asthma. If it would be possible to target DC2 cells for prophylactic or therapeutic measures, then it may be possible to change the T cell response to allergens on a long-term basis. In the past few years, there have been major research efforts to elucidate molecular determinants of DC maturation. This review summarizes the new findings and their potential for future clinical application. [Copyright &y& Elsevier]

Abstract: Previous studies have demonstrated that human astrocytes express mRNA and receptor protein for group I and II metabotropic glutamate receptors (mGluRs). Whether these receptors can influence the inflammatory and immune response and can modulate the capacity of astrocytes to produce inflammatory cytokines is still unclear. Inflammatory cytokines can be produced by activated glial cells and play a critical role in several neurological disorders. Astrocyte-enriched human cell cultures growing in a serum-free chemically defined medium were used to study the regulation of IL (interleukin)-1β and IL-6 in response to mGluR activation. Astrocytes cultured in the absence or in the presence of epidermal growth factor (EGF), did not secrete significant IL-1β and IL-6, as determined by specific enzyme-linked immunosorbent assay (ELISA). Activation of mGluRs using (S)-3,5-dihydroxyphenylglycine (DHPG; selective group I agonist) or DCG-IV (selective group II agonist) did not affect the production of interleukins under both growth conditions. On exposure to IL-1β high levels of IL-6 were detected. Activation of mGluR3 with DCG-IV (but not of mGluR5 with DHPG) enhanced, in the presence of IL-1β, the release of IL-6 in a dose dependent manner in astrocytes cultured under conditions (+EGF) in which the mGluR expression is known to be upregulated. The effect of mGluR3 activation on IL-1β stimulated release of IL-6 was prevented by selective group II mGluR antagonists. The capacity of mGluR3 to modulate the release of IL-6 in the presence of IL-1β supports the possible involvement of this receptor subtype in the regulation of the inflammatory and immune response under pathological conditions associated with glial cell activation. [Copyright &y& Elsevier]