Plasma PGE2 Levels Research Articles

Oropharyngeal tumor cells induce COX-2 expression in peripheral blood monocytes by secretion of IL-1α.

Oropharyngeal squamous cell cancer (OPC) accounts for 3% of all cancers and greater than 1.5% of all cancer deaths in the United States, with marked treatment-associated morbidity in survivors. More than 80% of OPC is caused by HPV16. Tumors induced by HPV have been linked to impaired immune functions, with most studies focused on the local tumor microenvironment. Fewer studies have characterized the effects of these tumors on systemic responses in OPC, especially innate responses that drive subsequent adaptive responses, potentially creating feed-back loops favorable to the tumor. Here we report that elevated plasma levels of PGE2 are expressed in half of patients with OPC secondary to overexpression of COX-2 by peripheral blood monocytes, and this expression is driven by IL-1α secreted by the tumors. Monocytes from patients are much more sensitive to the stimulation than monocytes from controls, suggesting the possibility of enhanced immune-modulating feed-back loops. Furthermore, control monocytes pre-exposed to PGE2 overexpress COX-2 in response to IL-1α, simulating responses made by monocytes from some OPC patients. Disrupting the PGE2/IL-1α feed-back loop can have potential impact on targeted medical therapies.

Systemic Interleukin‐1β Elicits Cyclooxygenase‐Independent Fever

Interleukin‐1β (IL‐1β) induces neuroimmune responses that help to fight infections. IL‐1β‐induced fever is not abolished by cyclooxygenase (COX) inhibitors used to treat inflammation and the neural pathways responsible for COX‐independent fever are still unknown. Considering that neurons that reside in the rostral raphe pallidus area (rRPa) and in the dorsomedial hypothalamus (DMH) play a key role in the control of thermoeffectors, we hypothesized that neurons in these areas contribute to COX‐independent fever elicited by intravenous (iv) IL‐1β. Female and male Sprague Dawley rats were anesthetized with urethane and α‐chloralose (ur/ch) or isoflurane (iso) and treated with saline or indomethacin, prior to receiving iv IL‐1β. Systemic IL‐1β increased brown adipose tissue (BAT) sympathetic nerve activity (SNA) (+2852 ± 2020% baseline (BL), p = 0.003), BAT temperature (TBAT; +2.6 ± 1.3°C, p < 0.001), expired CO2 (+1.0 ± 0.4%, p < 0.001), core body temperature (TCORE; +0.6 ± 0.2°C, p < 0.001), heart rate (HR; +102 ± 42 bpm, p < 0.001), mean arterial pressure (MAP; +11 ± 7 mmHg, p = 0.002), and paw temperature (TPAW; ‐6.9 ± 1.2°C, p < 0.001), which is an index of cutaneous vasoconstriction (CVC). Indomethacin did not prevent IL‐1β‐evoked increases in BAT SNA (+2545 ± 756% BL, p < 0.001), TBAT (+2.9 ± 1.3°C, p < 0.001), expired CO2 (+1.2 ± 0.6%, p = 0.003), TCORE (+0.9 ± 0.5°C, p = 0.005), HR (+117 ± 47 bpm, p < 0.001), MAP (+27 ± 20 mmHg, p = 0.01), or TPAW (‐5.9 ± 3.4°C, p = 0.02). Nanoinjection of muscimol in the rRPa prevented IL‐1β‐evoked increases in BAT SNA (p < 0.01), TBAT (p < 0.01), expired CO2 (p < 0.01) and TCORE (p < 0.01), but not in HR (p = 0.08), in comparison to the group that received IL‐1β only. Nanoinjection of muscimol in the rRPa in indomethacin‐pretreated rats prevented IL‐1β‐evoked increases in BAT SNA (p < 0.01), TBAT (p < 0.01), expired CO2 (p < 0.01), TCORE (p < 0.01), and TPAW (p = 0.03), but not in HR (p = 0.12), in comparison to an indomethacin‐pretreated group that received IL‐1β. Nanoinjections of glutamate receptor antagonists in the DMH markedly reduced IL‐1β‐evoked increases in BAT SNA (‐838 ± 542% BL, p = 0.03), TBAT (‐1.1 ± 0.4°C, p = 0.003), expired CO2 (‐0.4 ± 0.1%, p = 0.009) and HR (‐38 ± 20 bpm, p = 0.01), and reduced MAP (‐4 ± ‐2 mmHg, p = 0.02). Plasma PGE2 levels following iv IL‐1β were significantly higher (by ~3 fold) in rats that were not anesthetized when receiving IL‐1b (263.1 ± 136.4 pg/ml) compared to all other groups of rats that were maintained under anesthesia for 2 h (ur/ch anesthetized, saline pretreated: 96.7 ± 30.8 pg/ml, p = 0.007, or indomethacin pretreated: 119.7 ± 51.9 pg/ml, p = 0.02; iso anesthetized, saline pretreated: 82.5 ± 21.2 pg/ml, p = 0.003, or indomethacin‐pretreated: 108.4 ± 39.1 pg/ml, p = 0.01). Therefore, we suggest that the anesthetics used inhibited the systemic production of PGE2. Together, our data suggest that a glutamatergic input to the DMH is necessary for providing the excitatory drive for increasing BAT thermogenesis and tachycardia in response to circulating IL‐1β, likely via rRPa neurons. Additionally, IL‐1β‐evoked CVC requires activation of neurons in the rRPa. These data define critical components of the neural circuit for systemic IL‐1β‐induced fever and provide a foundation for elucidating additional brain mechanisms responsible for COX‐independent fever.

Effect of treatment with resiniferatoxin in an experimental model of pulpal inflammatory in mice.

To evaluate whether treatment with resiniferatoxin (RTX) is capable of lowering the plasma levels of PGE2 and TNF-α, as well as histopathological parameters in inflammation of pulp tissue in a mouse experimental model. Ten groups of six BALB/c mice were formed as follows: healthy group (HC ), healthy group treated with RTX (HRTX ), two groups with pulp inflammation at 14 and 18hours (PI14 /PI18 ), six groups with pulpal inflammation plus treatment with Ibuprofen (IBU14 /IBU18 ), dexamethasone (DEX14 /DEX18 ) and resiniferatoxin (RTX14 /RTX18 ) at 14 and 18hours, respectively. Pulpal inflammation was induced through occlusal exposure of the pulp of the maxillary first molar. The plasma levels of PGE2 and TNF-α and the histological parameters of the pulp tissue of the HC and HRTX groups were evaluated at the time of acquiring the animals. In the other groups, the plasma levels of PGE2 and TNF-α and the histopathological parameters were evaluated at 14 and 18hours after pulp damage. Plasma levels of PGE2 and TNF-α were quantified by ELISA, and the histopathological parameters were evaluated by H/E staining. Statistical significance was determined by one-way analysis of variance (ANOVA) to test for overall differences between group means. A significant increase (*p<.05) in plasma levels of PGE2 and TNF-α occurred 14 and 18hours after pulp damage. In addition, treatment with RTX significantly decreased (*p<.05) the plasma levels of PGE2 and TNF-α at 14 and 18hours after pulp damage, as well as the infiltrate of inflammatory cells at 18hours after pulp damage, similarly to treatment with ibuprofen and dexamethasone. It was possible to detect systemic levels of PGE2 and TNF-α at 14 and 18hours after pulp damage. Likewise, treatment with RTX was associated with an anti-inflammatory effect similar to treatment with ibuprofen and dexamethasone. These findings place resiniferatoxin as a therapeutic alternative in the treatment of inflammatory diseases in Dentistry.

Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway

Background & AimsInfection is a major problem in advanced liver disease secondary to monocyte dysfunction. Elevated prostaglandin (PG)E2 is a mediator of monocyte dysfunction in cirrhosis; thus, we examined PGE2 signalling in outpatients with ascites and in patients hospitalised with acute decompensation to identify potential therapeutic targets aimed at improving monocyte dysfunction.MethodsUsing samples from 11 outpatients with ascites and 28 patients hospitalised with decompensated cirrhosis, we assayed plasma levels of PGE2 and lipopolysaccharide (LPS); performed quantitative real-time PCR on monocytes; and examined peripheral blood monocyte function. We performed western blotting and immunohistochemistry for PG biosynthetic machinery expression in liver tissue. Finally, we investigated the effect of PGE2 antagonists in whole blood using polychromatic flow cytometry and cytokine production.ResultsWe show that hepatic production of PGE2 via the cyclo-oxygenase 1–microsomal PGE synthase 1 pathway, and circulating monocytes contributes to increased plasma PGE2 in decompensated cirrhosis. Transjugular intrahepatic sampling did not reveal whether hepatic or monocytic production was larger. Blood monocyte numbers increased, whereas individual monocyte function decreased as patients progressed from outpatients with ascites to patients hospitalised with acute decompensation, as assessed by Human Leukocyte Antigen (HLA)–DR isotype expression and tumour necrosis factor alpha and IL6 production. PGE2 mediated this dysfunction via its EP4 receptor.ConclusionsPGE2 mediates monocyte dysfunction in decompensated cirrhosis via its EP4 receptor and dysfunction was worse in hospitalised patients compared with outpatients with ascites. Our study identifies a potential drug target and therapeutic opportunity in these outpatients with ascites to reverse this process to prevent infection and hospital admission.Lay summaryPatients with decompensated cirrhosis (jaundice, fluid build-up, confusion, and vomiting blood) have high infection rates that lead to high mortality rates. A white blood cell subset, monocytes, function poorly in these patients, which is a key factor underlying their sensitivity to infection. We show that monocyte dysfunction in decompensated cirrhosis is mediated by a lipid hormone in the blood, prostaglandin E2, which is present at elevated levels, via its EP4 pathway. This dysfunction worsens when patients are hospitalised with complications of cirrhosis compared with those in the outpatients setting, which supports the EP4 pathway as a potential therapeutic target for patients to prevent infection and hospitalisation.

Arachidonic Acid-Dependent Pathway Inhibition in Platelets: its Role in Multiple Injury-Induced Coagulopathy and the Potential Mechanisms.

Our previous study demonstrated the types of platelet dysfunction varied at early stage (∼3 h) in trauma-induced coagulopathy (TIC) caused by different types of injuries. And arachidonic acid (AA)-dependent pathway inhibition in platelet seemed to be specific for TIC caused by multiple injury (MI). The aim of this research was to further study AA-dependent pathway inhibition in platelets in a rat model of TIC caused by MI and to explore its potential mechanisms. Sprague-Dawley rat model of TIC caused by MI was established. We used thrombelastography with platelet mapping as a measure of platelet function to assess the inhibitory extent of AA-dependent activation pathway. Flow cytometry was used to determine the expression of activation-dependent granular protein P-selectin (CD62P). In addition, the plasma levels of 6-Keto-prostaglandin F1 alpha (6-Keto-PGF1α), Prostaglandin E2, and Thromboxane B2 were assessed by enzyme-linked immuno sorbent assay. The inhibition rate of AA-dependent pathway after injury was significantly higher than that of control. The maximum amplitude decreased in the MI group, compared with that of control. The percentage of CD62P expression in the MI group was remarkably lower than that of control after AA treatment. The plasma concentrations of 6-Keto-PGF1α and PGE2 increased in the MI group. Platelets inhibition was observed in TIC caused by MI at early stage after injury, which might be partially attributed to AA-dependent activation pathway dysfunction. The increase of plasma Prostacyclin and PGE2 levels may contribute to the inhibition process.

Association between plasma prostaglandin E2 level and colorectal cancer.

Evidences for the personalized use of nonsteroidal anti-inflammatory drugs (NSAIDs) in colorectal cancer (CRC) prevention and treatment that include consideration of prostaglandin E2 levels are necessary. This study was designed as a case-control study including 60 CRC patients and 120 cancer-free controls. A sensitive empirical method, precolumn derivatization HPLC, was used to determine plasma PGE2 levels. The TaqMan SNP Genotyping Assay was used for the genotyping of prostaglandin-endoperoxide synthase 2 (PTGS2) polymorphisms. Multivariate logistic regression analysis suggested that 1 log10(PGE2) increase would result in a 3.64-fold increase in the risk of CRC. Moreover, subjects with log10(PGE2) level in the 75th percentile had a significantly higher risk of CRC than those with log10(PGE2) levels in the 25th percentile [odds ratio (OR), 3.50; 95% confidence interval (CI), 1.35-9.05]. This association was more evident after adjustment for history of NSAIDs use (OR, 3.85; 95% CI, 1.46-10.16). Preliminarily, 260.02 and 414.95 pg/ml might be proposed as the preventive and warning cutoff values of plasma PGE2 for CRC. The preferred NSAIDs dose for patients with the AG+GG (rs689466) and CC+CT (rs5275) genotypes should be higher than that of patients carrying AA or TT genotypes, despite the presence of equal plasma PGE2 levels. We show for the first time that the plasma PGE2 level is associated with the risk of CRC. We provide a preliminary suggestion for NSAIDs doses adjustment according to PTGS2 genotypes after consideration of plasma PGE2 levels.

Increased hypothalamic hydrogen sulphide contributes to endotoxin tolerance by down-modulating PGE2 production.

Whereas some patients have important changes in body core temperature (Tb) during systemic inflammation, others maintain a normal Tb, which is intrinsically associated to immune paralysis. One classical model to study immune paralysis is the use of repeated administration of lipopolysaccharide (LPS), the so-called endotoxin tolerance. However, the neuroimmune mechanisms of endotoxin tolerance remain poorly understood. Hydrogen sulphide (H2 S) is a gaseous neuromodulator produced in the brain by the enzyme cystathionine β-synthase (CBS). The present study assessed whether endotoxin tolerance is modulated by hypothalamic H2 S. Rats with central cannulas (drug microinjection) and intraperitoneal datalogger (temperature record) received a low-dose of lipopolysaccharide (LPS; 100µgkg-1 ) daily for four consecutive days. Hypothalamic CBS expression and H2 S production rate were assessed, together with febrigenic signalling. Tolerant rats received an inhibitor of H2 S synthesis (AOA, 100pmol1µL-1 icv) or its vehicle in the last day. Antero-ventral preoptic area of the hypothalamus (AVPO) H2 S production rate and CBS expression were increased in endotoxin-tolerant rats. Additionally, hypothalamic H2 S inhibition reversed endotoxin tolerance reestablishing fever, AVPO and plasma PGE2 levels without altering the absent plasma cytokines surges. Endotoxin tolerance is not simply a reflection of peripheral reduced cytokines release but actually results from a complex set of mechanisms acting at multiple levels. Hypothalamic H2 S production modulates most of these mechanisms.

Seasonal expressions of COX-1, COX-2 and EP4 in the uteri of the wild Daurian ground squirrels (Spermophilus dauricus)

Prostaglandins (PGs) play a pivotal role in uterine reproductive process including maternal recognition of pregnancy, cell proliferation, and myometrium contractions in mammals. In this study, we investigated the immunolocalizations and expression levels of Prostaglandin E2 synthases cyclo-oxygenase (COX)-1 and COX-2, as well as one of PGE2 receptor subtypes 4 (EP4) in the uteri of the wild Daurian ground squirrels (Spermophilus dauricus) during the breeding and non-breeding seasons. Histologically, the thickness of endometrium: myometrium ratio in the uteri of the breeding season was higher than that of the non-breeding season. The immunostainings of COX-1, COX-2 and EP4 were observed in stromal cells, glandular cells and myometrium cells in the breeding and non-breeding seasons. The protein and mRNA expression levels of COX-1, COX-2 and EP4 were higher in the uteri of the breeding season than those of in the non-breeding season. The mean mRNA levels of COX-1, COX-2 and EP4 were positively correlated with uterine weights. In addition, the PGE2 concentration of uterine tissues as well as plasma PGE2, 17β-estradiol, progesterone, LH and FSH levels were also significantly higher in the breeding season compared to those of the non-breeding season. These results suggested that PGE2 might play an important autocrine or paracrine role in the regulation of seasonal changes in the uterine functions of the wild Daurian ground squirrels during the breeding and non-breeding seasons.

High mobility group box 1 protein released in the course of aseptic necrosis of tissues sensitizes rats to pyrogenic effects of lipopolysaccharide

It is still an open question as to whether or not aseptic injuries affect the generation of fever due to exogenous pyrogens including bacterial products. Therefore, in the present paper we have investigated the course of endotoxin fever in rats induced with lipopolysaccharide (LPS; given intraperitoneally in a dose of 50 μg/kg) 48 h after subcutaneous administration of turpentine oil (TRP; 0.1 mL per rat) that causes aseptic necrosis of tissues. We found that febrile response was significantly augmented in the animals pre-treated with turpentine compared to control rats (pre-treated with saline), and that observed excessive elevation of body temperature (Tb) was accompanied by enhanced release of fever mediators: interleukin-6 (IL-6) and prostaglandin E2 (PGE2) into plasma. Moreover, we found that sensitization to pyrogenic effects of lipopolysaccharide was associated with the increase in plasma level of high mobility group box 1 protein (HMGB1), one of the best-known damage-associated molecular patterns (DAMP), which was recently discovered as inflammatory mediator. Since the injection of anti-HMGB1 antibodies weakened observed hyperpyrexia in the animals pre-treated with turpentine, we conclude that HMGB1 is a plasma-derived factor released in the course of aseptic injury that enhances pyrogenic effects of LPS.

Effects of Almond- and Olive Oil-Based Docosahexaenoic- and Vitamin E-Enriched Beverage Dietary Supplementation on Inflammation Associated to Exercise and Age.

n-3-polyunsaturated fatty acids and polyphenols are potential key factors for the treatment and prevention of chronic inflammation associated to ageing and non-communicable diseases. The aim was to analyse effects of an almond and olive oil beverage enriched with α-tocopherol and docosahexaenoic, exercise and age on inflammatory plasma markers, and immune gene expression in peripheral blood mononuclear cells (PBMCs). Five young and five senior athletes who were supplemented for five weeks with a functional beverage performed a stress test under controlled conditions before and after beverage supplementation. Blood samples were taken immediately before and 1 h after each test. Plasma, erythrocytes and PBMCs were isolated. Beverage supplementation increased plasmatic Tumour Necrosis Factor α (TNFα) levels depending on age and exercise. Exercise increased plasma non esterified fatty acids (NEFAs), soluble Intercellular adhesion molecule 3 (sICAM3) and soluble L-selectin (sL-Selectin), and this increase was attenuated by the supplementation. Exercise increased PGE2 plasma levels in supplemented young and in senior placebo athletes. Exercise increased NFkβ-activated levels in PBMCs, which are primed to a pro-inflammatory response increasing pro-inflammatory genes expression after the exercise mainly in the young group after the supplementation. The functional beverage supplementation to young athletes enhances a pro-inflammatory circulating environment in response to the exercise that was less evident in the senior group.

Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization

Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently, N′-substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine-4-carbohydrazides were described as antiplatelet derivatives. In this work, we explore the properties of these antiplatelet agents through a series of pharmacological, biochemical and toxicological studies. The antiplatelet activity of each derivative was confirmed as 3a, 3b and 3 h significantly inhibited human platelet aggregation induced by arachidonic acid, with no detectable effect on clotting factors or healthy erythrocytes. Importantly, mice treated with derivative 3a showed a higher survival rate at an in vivo model of pulmonary thromboembolism with a lower bleeding risk in comparison to aspirin. The in silico studies pointed a series of structural parameters related to thromboxane synthase (TXS) inhibition by 3a, which was confirmed by tracking plasma levels of PGE2 and TXB2 through an in vitro enzyme immunoassay. Derivative 3a showed selective TXS inhibition allied with low bleeding risk and increased animal survival, revealing the derivative as a promising candidate for treatment of cardiovascular diseases.

Cyclooxygenase-2 and Prostaglandin E2 are Associated with Middle Cerebral Artery Occlusion and Hemorrhage in Patients with Moyamoya Disease.

Some inflammatory proteins, such as cyclooxygenase (COX)-2 and prostaglandin (PG) E2 are hypothesized to be implicated in the development of moyamoya disease (MMD). However, the functional roles of COX-2/PGE2 in the pathogenesis of MMD remain elusive. In this study, tiny pieces of middle cerebral artery (MCA) and superficial temporal artery (STA) were surgically harvested from 18 adult MMD patients and 5 surgical control patients. The expression levels of COX-2 and microsomal prostaglandin E2 synthase-1 (mPGES-1) in the vascular walls were immunohistochemically detected. With additional 10 healthy controls, the plasma levels of PGE2 were also measured by enzyme-linked immunosorbent assay (ELISA). Obvious intimal thickening was observed in both STA and MCA of MMD patients, but not in the controls. However, the MCA had a thicker intima than the STA (P < 0.01). Although plasma concentrations of PGE2 had no differences among the MMD patients, surgical controls and healthy controls, MCA of most MMD patients (15/18, 83.3%) were stained positively for COX-2 and all patients for mPGES-1. Staining of both COX-2 and mPGES-1 was more abundant in the MCA of hemorrhagic patients than those in their ischemic counterparts (P = 0.001 and 0.029, respectively). The expression levels of COX-2 were positively correlated with those of mPGES-1 (r = 0.647, P = 0.004). Positive COX-2 and mPGES-1 expressions were detected neither in the MCA samples from the surgical controls nor in all STA specimens. Our findings indicate that COX-2/PGE2 may be associated with the MCA occlusion and the hemorrhagic stroke in patients with MMD.

Effects of dietary Docosahexaenoic, training and acute exercise on lipid mediators.

BackgroundEicosanoids mediate initiation and resolution of inflammation. Our aim was evaluating the effects of training, exercise and docosahexaenoic (DHA) supplementation on plasma eicosanoids levels and peripheral blood mononuclear cells (PBMCs) eicosanoids production.MethodsFifteen male footballers were distributed to placebo and experimental groups. Experimental group consumed DHA-enriched beverage (1.16 g DHA/day) for 8 weeks, placebo group consumed a placebo beverage. Blood samples were taken before and after the nutritional intervention in basal conditions and 2 h after acute exercise.ResultsTraining increased basal Prostaglandin E1 (PGE1) plasma levels and PBMCs cyclooxygenase 2 (COX-2) protein levels in both groups, but COX-1 protein levels only in the experimental group. Acute exercise increased plasma PGE2 and PBMCs active NFκβ levels. Lipopolysaccharide (LPS)-stimulated PBMCs increases eicosanoids production (PGE1, PGE2, RvD1) in both groups and increased LPS-stimulated PBMCs active NFκβ. DHA supplementation increased COX-2 levels but decreased LPS-stimulated PBMCs PGE1 and PGE2 production. Neither DHA supplementation nor acute exercise altered the expression of NFκβ, COX-2, 15-LOX2, 5-LOX, or IL-1β genes in PBMCs.ConclusionsThe increase of PGE1 plasma levels after training promoted systemic anti-inflammatory and vasodilator environment. Exercise and DHA supplementation acted synergistically by increasing plasma PGE2 with anti-inflammatory effects. Exercise primed PBMCs to enhance PGE1, PGE2 and RvD1 production in response to LPS.Trial registrationThe project was registered at ClinicalTrial.gov (NCT02177383).

Inhibition of group IVA cytosolic phospholipase A2 by thiazolyl ketones in vitro, ex vivo, and in vivo.

Group IVA cytosolic phospholipase A2 (GIVA cPLA2) is the rate-limiting provider of pro-inflammatory mediators in many tissues and is thus an attractive target for the development of novel anti-inflammatory agents. In this work, we present the synthesis of new thiazolyl ketones and the study of their activities in vitro, in cells, and in vivo. Within this series of compounds, methyl 2-(2-(4-octylphenoxy)acetyl)thiazole-4-carboxylate (GK470) was found to be the most potent inhibitor of GIVA cPLA2, exhibiting an XI(50) value of 0.011 mole fraction in a mixed micelle assay and an IC50 of 300 nM in a vesicle assay. In a cellular assay using SW982 fibroblast-like synoviocytes, it suppressed the release of arachidonic acid with an IC50 value of 0.6 μM. In a prophylactic collagen-induced arthritis model, it exhibited an anti-inflammatory effect comparable to the reference drug methotrexate, whereas in a therapeutic model, it showed results comparable to those of the reference drug Enbrel. In both models, it significantly reduced plasma PGE2 levels.

Effect of electro-acupuncture stimulation of Ximen (PC4) and Neiguan (PC6) on remifentanil-induced breakthrough pain following thoracal esophagectomy.

The clinical analgesic effect of electro-acupuncture (EA) stimulation (EAS) on breakthrough pain induced by remifentanil in patients undergoing radical thoracic esophagectomy, and the mechanisms were assessed. Sixty patients (ASAIII) scheduled for elective radical esophagectomy were randomized into three groups: group A (control) receiving a general anesthesia only; group B (sham) given EA needles at PC4 (Ximen) and PC6 (Neiguan) but no stimulation; and group C (EAS) electrically given EAS of the ipsilateral PC4 and PC6 throughout the surgery. The EAS consisting of a disperse-dense wave with a low frequency of 2 Hz and a high frequency of 20 Hz, was performed 30 min prior to induction of general anesthesia and continued through the surgery. At the emergence, sufentanil infusion was given for postoperative analgesia with loading dose of 7.5 μg, followed by a continuous infusion of 2.25 μg/h. The patient self-administration of sufentanil was 0.75 μg with a lockout of 15 min as needed. Additional breakthrough pain was treated with dezocine (5 mg) intravenously at the patient's request. Blood samples were collected before (T1), 2 h (T2), 24 h (T3), and 48 h (T4) after operation to measure the plasma β-EP, PGE2, and 5-HT. The operative time, the total dose of sufentanil and the dose of self-administration, and the rescue doses of dezocine were recorded. Visual Analogue Scale (VAS) scores at 2, 12, 24 and 48 h postoperatively and the incidence of apnea and severe hypotension were recorded. The results showed that the gender, age, weight, operative time and remifentanil consumption were comparable among 3 groups. Patients in EAS group had the lowest VAS scores postoperatively among the three groups (P<0.05). The total dose of sufentanil was 115±6.0 μg in EAS group, significantly lower than that in control (134.3±5.9 μg) and sham (133.5±7.0 μg) groups. Similarly, the rescue dose of dezocine was the least in EAS group (P<0.05) among the three groups. Plasma β-EP levels in EAS group at T3 (176.90±45.73) and T4 (162.96±35.00 pg/mL) were significantly higher than those in control (132.33±36.75 and 128.79±41.24 pg/mL) and sham (136.56±45.80 and 129.85±36.14 pg/mL) groups, P<0.05 for all. EAS could decrease the release of PGE2. Plasma PGE2 levels in EAS group at T2 and T3 (41±5 and 40±5 pg/mL respectively) were significantly lower than those in control (64±5 and 62±7 pg/mL) and sham (66±6 and 62±6 pg/mL) groups. Plasma 5-HT levels in EAS group at T2 (133.66±40.85) and T3 (154.66±52.49 ng/mL) were significantly lower than those in control (168.33±56.94 and 225.28±82.03) and sham (164.54±47.53 and 217.74±76.45 ng/mL) groups. For intra-group comparison, plasma 5-HT and PGE2 levels in control and sham groups at T2 and T3, and β-EP in EAS group at T3 and T4 were significantly higher than those at T1 (P<0.05); PGE2 and 5-HT levels in EAS group showed no significant difference among the different time points (P>0.05). No apnea or severe hypotension was observed in any group. It was concluded that intraoperative ipsilateral EAS at PC4 and PC6 provides effective postoperative analgesia for patients undergoing radical esophagectomy with remifentanil anesthesia and significantly decrease requirement for parental narcotics. The underlying mechanism may be related to stimulation of the release of endogenous β-EP and inhibition of inflammatory mediators (5-HT and PGE2).

A new approach to an old hypothesis; phototherapy does not affect ductal patency via PGE2 and PGI2

Objective: Numerous investigations have demonstrated that phototherapy (PT) directly or indirectly causes ductal patency by photorelaxation effect. In this observational study, we aimed to assess the effect of PT on the incidence of patent ductus arteriosus (PDA) together with prostaglandins (PGE2) and (PGI2) levels in preterm infants.Methods: Preterm infants whose gestational age < 34 weeks and who required PT in the first 3 d of life were enrolled in this prospective study. The clinical signs of PDA, the data of detailed echocardiographic study were recorded and plasma PGE2 and PGI2 levels were measured before and after PT. The outcome measures were the status of ductus arteriosus and alterations of PGE2 and PGI2 levels under the effect of PT.Results: A total of 44 preterm infants were enrolled in the study, of these 21 (47.7%) were in Group 1 (Non-PDA Group) and 23 (52.3%) were in Group 2 (PDA Group). After PT, ductal reopening occurred in three infants (14.3%) in Group 1, while ductus closed in four infants in Group 2 (17.3%). PT does not seem to effect ductal patency for both groups (p = 0.250 and p = 0.125, respectively). PGE2 levels were not different before and after PT for both groups (p = 0.087, p = 0.408, respectively). However, PGI2 levels were significantly decreased after PT in both groups (p = 0.006, and p = 0.003, respectively).Conclusion: There was no effect of PT on ductal patency. We can conclude that PGs were eliminated simultaneously with ductal closure and photorelaxation effect did not influence PG levels.

Increased Prostaglandin E_2 Has a Positive Correlation with Plasma Calcium during Goldfish Reproduction

somatic index (r=0.81, p<0.001), plasma Ca and plasma PGE2 levels (r=0.635, p<0.05), and plasma Ca and plasma TRAP activities (r=0.584, p<0.05) from the analysis using samples of both reproductive and non- reproductive stages. Taking these data into consideration, we suggested that PGE2 acts on osteoclasts and increases plasma Ca as a result of osteoclastic bone resorption, and we concluded that PGE2 is an important hormone in Ca metabolism during fish reproduction.

Eicosapentaenoic acid suppression of systemic inflammatory responses and inverse up‐regulation of 15‐deoxyΔ12,14Prostaglandin J2 production

Eicosapentaenoic acid (EPA) has been shown to suppress immune cell responses, such as cytokine production and downstream PG production in vitro. Studies in vivo, however, have used EPA as a minor constituent of fish oil with variable results. We investigated the effects of EPA on systemic inflammatory responses as pure EPA has not been evaluated on immune/inflammatory responses in vivo. Rabbits were administered polyinosinic: polycytidylic acid (poly I:C) i.v. before and after oral treatment with EPA for 42 days (given daily). The responses to IL-1β and TNF-α were also studied. Immediately following administration of poly I:C, body temperature was continuously monitored and blood samples were taken. Plasma levels of IL-1β, PGE2 (PGE2), and 15-deoxy-Δ(12,14)-PGJ2 (15d-PGJ2) were measured by enzyme immunoassay. Following EPA treatment, the fever response to poly I:C was markedly suppressed compared with pretreatment responses. This was accompanied by a parallel reduction in the poly I:C-stimulated elevation in plasma levels of IL-1β and PGE2. Paradoxically, the levels of 15d-PGJ2 were higher following EPA treatment. EPA treatment did not significantly alter the fever response or plasma levels of PGE2 in response to either IL-1β or TNF-α. Oral treatment with EPA can suppress immune/inflammatory responses in vivo via a suppression of upstream cytokine production resulting in a decreased fever response and indirectly reducing circulating levels of PGE2. EPA also enhances the production of the cytoprotective prostanoid 15d-PGJ2 indicating the therapeutic benefit of EPA.

Selective COX-2 inhibition affects fatty acids, but not COX mRNA expression in patients with FAP.

Familial adenomatous polyposis (FAP) provides a model for sporadic colorectal cancer development. Cyclooxygenase (COX) inhibition may ameliorate polyp development, but rofecoxib was withdrawn due to cardiovascular side effects. Although this selective COX-2 inhibitor, like diet, may alter the fatty acid and eicosanoid pattern, data on the potential alteration in tissues after use, are scarce. The aims were to study if rofecoxib might influence the fatty acid distribution in serum phospholipids and duodenal lesions, mRNA for COX-1 and COX-2 in leucocytes and duodenal lesions, and finally plasma levels of PGE2 in a randomized, double-blind, placebo controlled study (n = 38). Significant reductions were found for essential fatty acid index both in serum phospholipids (P = 0.01, 95% CI = −0.9; −0.1), and in duodenal lesions (P = 0.04, 95 CI % = −0.9; −0.1) after treatment. No treatment effects were found on the COX mRNA expression, or in the plasma PGE2 levels. Dietary AA/EPA ratio was inversely associated with all the indicators of EFA status (all P < 0.01). These findings suggest that the effects of COX chemoprevention should be further investigated in FAP and that dietary needs should be included in the treatment of FAP.

Accelerated Blood Clearance Phenomenon Upon Repeated Injection of PEG-modified PLA-nanoparticles

We recently developed prostaglandin E(1) (PGE(1))-encapsulated nanoparticles, prepared with a poly(lactide) homopolymer (PLA, Mw = 17,500) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA) (NP-L20). In this study, we tested whether the accelerated blood clearance (ABC) phenomenon is observed with NP-L20 and other PEG-modified PLA-nanoparticles in rats. The plasma levels of PGE(1) and anti-PEG IgM antibody were determined by EIA and ELISA, respectively. Second injections of NP-L20 were cleared much more rapidly from the circulation than first injections, showing that the ABC phenomenon was induced. This ABC phenomenon, and the accompanying induction of anti-PEG IgM antibody production, was optimal at a time interval of 7 days between the first and second injections. Compared to NP-L20, NP-L33s that were prepared with PLA (Mw = 28,100) and have a smaller particle size induced production of anti-PEG IgM antibody to a lesser extent. NP-L20 but not NP-L33s gave rise to the ABC phenomenon with a time interval of 14 days. NP-L33s showed a better sustained-release profile of PGE(1) than NP-L20. This study revealed that the ABC phenomenon is induced by PEG-modified PLA-nanoparticles. We consider that NP-L33s may be useful clinically for the sustained-release and targeted delivery of PGE(1).