High Levels Of Prostaglandins Research Articles

Efficacy of Cannabidiol Versus Ibuprofen in the Relief of Menstrual Pain in Females Living with Primary Dysmenorrhea A phase II, Non-Inferiority trial

Introduction: Pain is the cardinal symptom in women living with primary dysmenorrhea (PDM), resulting in a relentless negative effect on their quality of life.  Women with PDM have higher levels of prostaglandin in their endometrial fluid, which correlates with the degree of pain. The standard of care treatment for pain associated with PDM starts with nonsteroidal anti-inflammatory drugs (NSAIDs) that block prostaglandin-triggering enzymes. Although NSAIDs present as a feasible option, they are also associated with a significant risk of side effects. Around 20 to 25% of patients will experience pain refractory to NSAIDs and will then seek alternative therapies. Cannabidiol (CBD) is a well-tolerated potential therapy for several chronic diseases, including pain, and acts by blocking prostaglandin-triggering enzymes, similarly to NSAIDs. The safety of CBD is well established, with the advantage of it acting via central and peripheral mechanisms. To date, no previous trials assessing CBD alone for dysmenorrhea have been conducted. Objective: To evaluate the effect of CBD alone in the reduction of acute menstrual pain compared to ibuprofen, as assessed by the total pain relief (TOTPAR) scale. Design: Randomized (with random block sizes), triple-blinded, multicenter, parallel-group, non-inferiority clinical trial. Setting: St. George, Scarborough, and Mississauga campuses at the University of Toronto, Ontario, Canada. Participants: PDM patients aged 18 to 40 years, regular menstrual cycles (ranging from 21 to 35 days), and a visual analog scale (VAS) score of ≥ 5. Intervention: 108 patients will be randomized with an allocation ratio of 1:1 to either CBD 200 mg/day or ibuprofen 800mg/day. The sample size is based on a mean expected pain relief for ibuprofen of 16.49 and CBD of 14.02, as assessed by the TOTPAR scale and on a 30% estimated dropout rate. Main Outcome Measures: The primary outcome will be the mean difference in the TOTPAR scale (range, 0-4) after taking the study drugs over four menstrual cycles. TOTPAR will be assessed after 1, 2, 3, 4, 5, and 6 hours after taking the study drugs. Secondary outcomes include pain VAS, adverse events, the need for breakthrough medications, and quality of life (QoL). Discussion: NSAIDs may cause troubling side effects, and CBD is well tolerated in clinical trials, with acceptable adverse event profiles. Numerous randomized clinical trials have demonstrated the safety and efficacy of CBD in alleviating central and peripheral pain of other disorders. The results of this trial aim to provide much-needed evidence that oral CBD alone is an alternative for the treatment of menstrual pain in women with PDM. CBD presents as an important promise for women with PDM who do not respond or who have contraindications to NSAIDs. Keywords: Cannabidiol, CBD, menstrual pain, ibuprofen, pain relief, non-inferiority, dysmenorrhea

Tumor-Induced T Cell Polarization by Schwann Cells.

Nerve-cancer crosstalk resulting in either tumor neurogenesis or intratumoral neurodegeneration is critically controlled by Schwann cells, the principal glial cells of the peripheral nervous system. Though the direct stimulating effect of Schwann cells on malignant cell proliferation, motility, epithelial-mesenchymal transition, and the formation of metastases have been intensively investigated, the ability of Schwann cells to affect the effector and regulatory immune cells in the tumor environment is significantly less studied. Here, we demonstrated that tumor cells could stimulate Schwann cells to produce high levels of prostaglandin E, which could be blocked by COX-2 inhibitors. This effect was mediated by tumor-derived TGF-β as neutralization of this cytokine in the tumor-conditioned medium completely blocked the inducible prostaglandin E production by Schwann cells. Similar protective effects were also induced by the Schwann cell pretreatment with TGF-βR1/ALK4/5/7 and MAPK/ERK kinase inhibitors of the canonical and non-canonical TGF-β signaling pathways, respectively. Furthermore, prostaglandin E derived from tumor-activated Schwann cells blocked the proliferation of CD3/CD28-activated T cells and upregulated the expression of CD73 and PD-1 on both CD4+ and CD8+ T cells, suggesting T cell polarization to the exhausted phenotype. This new pathway of tumor-induced T cell inhibition via the activation of neuroglial cells represents new evidence of the importance of nerve-cancer crosstalk in controlling tumor development and progression. A better understanding of the tumor-neuro-immune axis supports the development of efficient targets for harnessing this axis and improving the efficacy of cancer therapy.

Nifedipine for primary dysmenorrhoea.

Dysmenorrhoea (period pain) is a common condition with a substantial impact on the well-being and productivity of women. Primary dysmenorrhoea is defined as recurrent, cramping pelvic pain that occurs with periods, in the presence of a normal uterus, ovaries and fallopian tubes. It is thought to be caused by uterine contractions (cramps) associated with a high level of production of local chemicals such as prostaglandins. The muscle of the uterus (the myometrium) responds to these high levels of prostaglandins by contracting forcefully, causing low oxygen levels and consequently pain. Nifedipine is a calcium channel blocker in widespread clinical use for preterm labour due to its ability to inhibit uterine contractions in that setting. This review addresses whether this effect of nifedipine also helps with relief of the uterine contractions during menstruation OBJECTIVES: To assess the effectiveness and safety of nifedipine for primary dysmenorrhoea. We searched for all published and unpublished randomised controlled trials (RCTs) of nifedipine for dysmenorrhoea, without language restriction and in consultation with the Cochrane Gynaecology and Fertility Group (CGF) Information Specialist. The following databases were searched to 25 November 2021: the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL. Also searched were the international trial registers: ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal, the Web of Science, OpenGrey, LILACS database, PubMed and Google Scholar. We checked the reference lists of relevant articles. We included RCTs comparing nifedipine with placebo for the treatment of primary dysmenorrhoea. The primary outcomes to be assessed were pain, and health-related quality of life. Secondary outcomes were adverse effects, satisfaction, and need for additional medication. The two review authors independently assessed the included trials. There were insufficient data to allow meaningful meta-analysis. The evidence assessed was of very low quality overall. We examined three small RCTs, with a total of 106 participants. Data for analysis could be extracted from only two of these trials (with a total of 66 participants); two trials were published in the 1980s, and the third in 1993. Nifedipine may be effective for "any pain relief" compared to placebo in women with primary dysmenorrhoea (odds ratio (OR) 9.04, 95% confidence interval (CI) 2.61 to 31.31; 2 studies, 66 participants; very low-quality evidence). The evidence suggests that if the rate of pain relief using placebo is 40%, the rate using nifedipine would be between 64% and 95%. For the outcome of "good" or "excellent" pain relief, nifedipine may be more effective than placebo; the confidence interval was very wide (OR 43.78, 95% CI 5.34 to 259.01; 2 studies, 66 participants; very low-quality evidence). We are uncertain if the use of nifedipine was associated with less requirement for additional analgesia use than placebo (OR 0.54, 95% CI 0.07 to 4.20, 1 study, 42 participants; very low-quality evidence). Participants indicated that they would choose to use nifedipine over their previous analgesic if the option was available. There were similar levels of adverseeffects and menstruation-related symptoms in the placebo and intervention groups (OR 0.94, 95% CI 0.08 to 10.90; 1 study, 24 participants; very low-quality evidence); if the chance of adverseeffects with placebo is 80%, the rate using nifedipine would be between 24% and 98%. There were no results regarding formal assessment of health-related quality of life. The evidence is insufficient to confirm whether nifedipine is a possible medical treatment for primary dysmenorrhoea. The trials included in this review had very low numbers and were of low quality. Notably, there was a large imbalance in numbers randomised between placebo and treatment groups in one of the two trials with data available for analysis. While there was no evidence of a difference noted in adverse effects between groups, more data from larger participant numbers are needed for this outcome. Larger, more well-conducted trials are required to elucidate the potential role of nifedipine in the treatment of this common condition, as it could be a useful addition to the therapeutic options available if shown to be well tolerated and effective. The safety of nifedipine in women of reproductive age is well established from trials of its use in preterm labour, and clinicians are accustomed to off-label use for this indication. The drug is inexpensive and readily available. Other options for relief of primary dysmenorrhoea are not suitable for all women; NSAIDs and the oral contraceptive pill (OCP) are contraindicated for some women, and the OCP is not suitable for women who are trying to conceive. In addition, the trials examined suggest there may be a participant preference for nifedipine.

Polychaete consumption increased prostaglandin biosynthesis in female Penaeus monodon.

The polychaete Perinereis nuntia is preferred over commercial feed pellets for boosting ovarian maturation of the female black tiger shrimp Penaeus monodon. High levels of prostaglandins in polychaetes are believed to enhance shrimp ovarian development. However, the impact of polychaete feeding on shrimp prostaglandin biosynthesis and fatty acid regulatory pathways have yet to be investigated. As polychaetes contain higher levels of arachidonic acid (ARA), eicosapentaenoic acid (EPA), prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) than feed pellets, we examined the effects of polychaete feeding alone and in combination with eyestalk ablation on shrimp hepatopancreases and ovaries. Shrimp fed with polychaetes contained higher levels of EPA, PGE2 and PGF2α in hepatopancreases than those of pellet-fed shrimp. Similarly, higher levels of ARA and higher transcription levels of cyclooxygenase (COX) and prostaglandin F synthase (PGFS) were detected in ovaries of polychaete-fed shrimp compared to those of pellet-fed shrimp. The combination of polychaete-feeding and eyestalk ablation, commonly practiced to induce ovarian development, increased levels of ARA and EPA and transcription levels of COX in hepatopancreases and ovaries of polychaete-fed shrimp compared to those of pellet-fed shrimp. In ovaries, prostaglandin biosynthesis gene transcripts were induced by polychaete feeding while transcriptional levels of fatty acid regulatory genes were regulated by shrimp feed and eyestalk ablation. Our findings not only elucidate the effects of polychaete consumption on shrimp prostaglandin biosynthesis and fatty acid regulatory pathways during larvae production, but also suggests that high levels of dietary ARA, EPA and prostaglandins are essential during P. monodon ovarian development.

Molecular and Mechanical Mechanisms Regulating Ductus Arteriosus Closure in Preterm Infants.

Failure of ductus arteriosus closure after preterm birth is associated with significant morbidities. Ductal closure requires and is regulated by a complex interplay of molecular and mechanical mechanisms with underlying genetic factors. In utero patency of the ductus is maintained by low oxygen tension, high levels of prostaglandins, nitric oxide and carbon monoxide. After birth, ductal closure occurs first by functional closure, followed by anatomical remodeling. High oxygen tension and decreased prostaglandin levels mediated by numerous factors including potassium channels, endothelin-1, isoprostanes lead to the contraction of the ductus. Bradykinin and corticosteroids also induce ductal constriction by attenuating the sensitivity of the ductus to PGE2. Smooth muscle cells of the ductus can sense oxygen through a mitochondrial network by the role of Rho-kinase pathway which ends up with increased intracellular calcium levels and contraction of myosin light chains. Anatomical closure of the ductus is also complex with various mechanisms such as migration and proliferation of smooth muscle cells, extracellular matrix production, endothelial cell proliferation which mediate cushion formation with the interaction of blood cells. Regulation of vessel walls is affected by retinoic acid, TGF-β1, notch signaling, hyaluronan, fibronectin, chondroitin sulfate, elastin, and vascular endothelial cell growth factor (VEGF). Formation of the platelet plug facilitates luminal remodeling by the obstruction of the constricted ductal lumen. Vasa vasorum are more pronounced in the term ductus but are less active in the preterm ductus. More than 100 genes are effective in the prostaglandin pathway or in vascular smooth muscle development and structure may affect the patency of ductus. Hemodynamic changes after birth including fluid load and flow characteristics as well as shear forces within the ductus also stimulate closure. Current pharmacological treatment for the closure of a patent ductus is based on the blockage of the prostaglandin pathway mainly through COX or POX inhibition, albeit with some limitations and side effects. Further research for new agents aiming ductal closure should focus on a clear understanding of vascular biology of the ductus.

Bartter's syndrome: clinical findings, genetic causes and therapeutic approach.

Bartter's syndrome (BS) is a rare group of salt losing tubulopathies due to the impairment of transport mechanisms at the thick ascending limb of the Henle's loop. Literature reviews and original research articles were collected from database, including PubMed and Scopus. According to the time of onset and symptoms, BS can be classified into antenatal and classic BS. Molecular studies have identified different subtypes of BS. BS types I, II and III are caused by mutations on genes encoding the luminal Na+-K+-2Cl- co-transporter, the luminal K+ channel ROMK, and the basolateral chloride channel ClC-Kb (CLCNKB), respectively. Loss-of-function mutations of Barttin CLCNK type accessory beta subunit cause BS type IVa. Simultaneous mutations of CLCNKB and CLCNKA cause BS type IVb. BS type V consists in a novel transient form characterized by antenatal presentation due to mutations in the MAGE family member D2. Severe gain-of-function mutations of the extracellular calcium sensing receptor gene can result in an autosomal dominant condition of BS. Main clinical and biochemical alterations in BS include polyuria, dehydration, hypokalemia, hypochloremic metabolic alkalosis, hyperreninemia, high levels of prostaglandins, normal or low blood pressure, hypercalciuria and failure to thrive. Treatment focuses mainly at correcting dehydration and electrolyte disturbances and in measures to reduce polyuria, including the use of nonsteroidal anti-inflammatory medications to control excessive renal prostaglandin E2 production. Early diagnosis and treatment of BS may prevent long-term consequences such as growth failure, nephrocalcinosis and end-stage renal disease.

Mesenchymal COX2-Derived PGD2 Activates an ILC2-Treg Axis to Promote Proliferation of Normal and Malignant HSPCs

Cyclooxygenase (COX)-dependent production of prostaglandins (PGs) is known to play important roles in tumorigenesis. PGD2 has recently emerged as a key regulator of tumor- and inflammation-associated functions. We previously reported that mesenchymal stromal cells (MSCs) from patients with acute myeloid leukemia (AML) overexpressed COX-2 and secreted high levels of PGs including PGD2. Since little is known about the role of PGD2 in normal and malignant hematopoiesis, we prioritized this mesenchymal source of PG for further investigation. We observed that AML MSCs or normal MSCs overexpressing COX-2 promotes proliferation of co-cultured hematopoietic stem and progenitor cells (HSPCs), which can be prevented by treatment with COX-2 knockdown or TM30089, a specific antagonist of the PGD2 receptor CRTH2. Mechanistically, we demonstrate that PGD2-CRTH2 signaling acts directly on type 2 innate lymphoid cells (ILC2s), potentiating their expansion and driving them to produce Interleukin-5 (IL-5) and IL-13. We further show that IL-5 but not IL-13 expands CD25+Foxp3+ IL5Ra+ T regulatory cells (Tregs) and promotes HSCP proliferation. Disruption of the PGD2-activated ILC2-Treg axis by specifically blocking the PGD2 receptor CRTH2 or IL-5 impedes proliferation of normal and malignant HSPCs. Conversely, co-transfer of Lin-CD127+CRTH2+ ILC2s and CD4+CD25+IL5Ra+ Tregs promotes malignant HSCP proliferation and accelerates leukemia development in xenotransplanted mice. Collectively, these results indicate that the mesenchymal source of PGD2 promotes proliferation of normal and malignant HSPCs through activation of the ILC2-Treg axis. These findings also suggest that this PGD2-activated ILC2-Treg axis may be a valuable therapeutic target for cancer and inflammation-associated diseases. Disclosures No relevant conflicts of interest to declare.

Reducing primary dysmenorrhea among adolescent girls with mung bean extract drinks and stretching

<p>Primary dysmenorrhea is pain during menstruation period due to high levels of prostaglandins, especially prostaglandin F2α in epithelial cells. MungBean Extract Drinks contain several nutrients including vitamin C, calcium, carbohydrates and flavonoids as anti-depressants and anti-inflammatory agent. Stretching is a relaxation technique that can helps relieve menstrual pain in the abdominal part by increasing the production of endorphins which function as neurotransmitters. To determine the effect of Mung Bean ExtractDrinks and Stretching on primary dysmenorrhea (primary menstrual pain) in adolescent girls stressed. This type of open-label non-randomized controlled trial used 87female adolescents who experienced primary menstrual pain with moderate and severe stress levels from two Islamic boarding schools in Mataram City, West Nusa Tenggara, Indonesia, which were divided into 3 groups, one group as the control and two groups as the experiment. The experiment of 29people with pre and post-test. Mung bean extract drinks were given 250ml/day, otherwise stretching was given 1x/day for 7days before menstruation. Control and experimental group was observed for 1 month. Measurement of menstrual pain scale using the Numeric Rating Scale (NRS) assessment sheet. Data analysis uses T-test. The mean primary menstrual pain in adolescents for MungBean Extract Drinks with moderate stress levels was 1.31±1.32 and the difference before and after mung bean extract drinks experience is significant at p=0.004 while at severe stress levels was 1.69±1.54 and the difference between before and after mung bean extract drinks experience is significant at p=0.001. The mean primary menstrual pain in adolescents for stretching experience with moderate stress levels was 2.50±1.93 and the difference before and after stretching experience is significant at p=0.008 while the severe stress level was 2.05±1.80 and the difference before and after stretching experience is significant at p≤0.001. The multivariate test with linear regression revealed that mung bean extract drinks contributed y= (-)138X1+4.897(p=0.001) and related stretching contributed y= (-)2.517X1+6.276(p=0.001). MungBean ExtractDrinks and Stretching will affect to the reduction of primary dysmenorrhea in adolescent girls both at moderate and severe stress levels</p>

Smoking alters hydroxyprostaglandin dehydrogenase expression in fetal membranes

IntroductionThe way in which tobacco smoking increases the risk of preterm labor remains uncertain. Altered prostaglandin metabolism is one potential mechanism. MethodsProteins in fetal membrane samples (amniochoriodecidua) from 20 women were relatively quantified using Tandem Mass Tagging nano-liquid chromatography mass spectrometry. ResultsProstaglandin synthases and two enzymes involved in prostaglandin degradation, hydroxyprostaglandin dehydrogenase (HPGD) and CBR1, were detected by the mass spectrometer. The expression of HPGD was significantly lower in smokers relative to non-smokers (0.43 fold, p = 0.016). There was no effect of labor, inflammatory status or gestational age on the HPGD levels. DiscussionWe describe for the first time an association between maternal smoking and HPGD expression. We propose that reduced expression of HPGD is one mechanism through which smoking may contribute to preterm labor. Lower levels of this enzyme, key to metabolising prostaglandins, may result in higher levels of prostaglandins and therefore precipitate labor prematurely.

Pengaruh Konsumsi Susu Sapi Terhadap Penurunan Intensitas Nyeri Dismenore Primer Pada Siswi Jurusan Keperawatan Di SMKN 2 Malang

Primary dysmenorrhea is a common gynecological disorder among adolescents females without pathological abnormalities. Primary dysmenorrhea usually begins two days before menstruation or during menstruation and lasts up to 48-72 hours. This is due to high levels of prostaglandins that cause contraction in the myometrium. The incidence of dysmenorrhea in Indonesia is 64.25%, which 54.89% has primary dysmenorrhea while 9.36% has secondary dysmenorrhea. In principle there are two therapies for treatment of primary dysmenorrhea that is pharmacological and non-pharmacological. Cow milk is a food that containing high calcium and can be used as one of the non-pharmacological therapy to reduce pain intensity of primary dysmenorrhea. This study aims to determine the influence of cow milk consumption to decrease the pain intensity of primary dysmenorrhea in students of nursing department at SMKN 2 Malang. The research design used was true experiment with pre test-post test with control group design. The sample in this study were 21 people and divided into three groups taken by simple random sampling . The results showed that there was a difference of decrease pain intensity in three groups using One Way Anova test with p value 0.000 (p <0.005). The optimal dose can decrease pain intensity of primary dysmenorrhea is cow milk with 1000 mg calcium which has the highest pain delta value of 4.57 compared with experimental group II and control group. So it can be concluded that the higher value of the delta pain then the greater the dose effect given to decreased pain intensity of primary dysmenorrhea.

Aldo-keto reductase activity after diethylhexyl phthalate exposure in eutopic and ectopic endometrial cells

ObjectiveEndometriosis is a multifactorial gynaecological disease in reproductive-age women. Endometriotic tissue is characterized by high prostaglandin levels and progesterone resistance. Human aldo-keto reductases (AKRs) convert progesterone to a less potent metabolite and cause progesterone resistance. Therefore, in this study, we evaluated whether diethylhexyl phthalate (DEHP) alters AKR expression in human ectopic and eutopic endometrium. Study designWe used microarrays and western blotting to study the effects of DEHP, and checked the presence of AKR in endometriosis patients by enzyme-linked immunosorbent assay (ELISA). ResultsCultured human endometrial cells from normal endometrium of women without endometriosis (NE), eutopic endometrium from endometriosis patients (EE), and ectopic endometrium from endometriosis patients (EC) differed in genetic expression changes after DEHP treatment. DEHP upregulated AKR1C1, AKR1C2, AKR1C3, and AKR1B10 expression in EE, while EC showed continuously increased AKR1C3 expression before and after DEHP exposure. In western blot analysis, before and after DEHP exposure, the AKR1B10 protein band was detected in NE, EE, and EC, whereas the AKR1C3 band was detected only in EC. AKR1B10 and AKR1C3 expression levels in the blood of the enrolled patients were evaluated using ELISA. AKR1B10 expression did not differ between groups (without endometriosis [N=13], 0.10 vs. with endometriosis [N=20], 0.11; P=0.27). AKR1C3 expression was significantly higher in the blood of endometriosis patients than in that of patients without endometriosis (without endometriosis, 9.1 vs. with endometriosis, 10.1; P=0.02). Analysis according to menstrual period showed significantly increased AKR1C3 levels in patients with endometriosis only during the secretory phase and not the proliferative phase (P<0.05). ConclusionDEHP induces AKR activity in the endometrium of endometriosis patients, and AKR1C3 might influence the development of endometriosis.

Primary hypertrophic osteoarthropathy due to a novel SLCO2A1 mutation masquerading as acromegaly

SummaryA 20-year-old man with an 8-year history of progressive enlargement of his hands and feet, coarsening facial features, painful joints and thickened, oily skin was referred for investigation of acromegaly. On examination, the subject was of normal height and weight. He had markedly increased skin thickness around the forehead, eyelids and scalp with redundant skin folds. Bilateral painful knee swelling was accompanied by enlargement of the extremities, and his fingers were markedly clubbed. Routine hematological, biochemical and hormonal blood tests, including GH and IGF-1 were normal. The clinical picture suggested primary hypertrophic osteoarthropathy (PHOA) rather than acromegaly and radiological studies were supportive of this, demonstrating increased subperiosteal bone formation and increased bone density and cortical thickening. There was widespread joint disease, with narrowing of joint spaces, whereas the knees demonstrated effusions and calcification. A skull X-ray revealed calvarial hyperostosis and a normal sellar outline. Family history was negative. Genetic studies were performed on peripheral blood leukocyte DNA for mutations in the two genes associated with PHOA, 15-hydroxyprostaglandin dehydrogenase (HPGD; OMIM: 601688) and solute carrier organic anion transporter family member 2A1 (SLCO2A1; OMIM: 601460). The sequence of HPGD was normal, whereas the subject was homozygous for a novel pathological variant in SLCO2A1, c.830delT, that predicted a frameshift and early protein truncation (p.Phe277Serfs*8). PHOA, also known as pachydermoperiostosis, is a rare entity caused by abnormal prostaglandin E2 metabolism, and both HPGD and SLCO2A1 are necessary for normal prostaglandin E2 handling. High prostaglandin levels lead to bone formation and resorption and connective tissue inflammation causing arthropathy, in addition to soft tissue swelling.Learning points:The differential diagnosis of enlarged extremities, coarsened facial features, skin changes and increased sweating in suspected acromegaly is quite limited and primary hypertrophic osteoarthropathy (PHOA) is one of the few conditions that can mimic acromegaly at presentation.PHOA is not associated with abnormalities in GH and IGF-1 secretion and can be readily differentiated from acromegaly by hormonal testing.Clubbing in the setting of diffuse enlargement of joints and extremities in addition to skin changes should alert the physician to the possibility of PHOA, as clubbing is not a usual feature of acromegaly. Underlying causes of secondary hypertrophic osteoarthroapthy (e.g. bronchial neoplasia) should be considered.PHOA is a very rare condition caused by abnormalities in prostaglandin metabolism and has two known genetic causes (HPGD and SLCO2A1 mutations). SLCO2A1 gene mutations lead usually to autosomal recessive PHOA; fewer than 50 SLCO2A1 mutations have been described to date and the current case is only the second in a Hispanic patient.Treatment of primary hypertrophic osteoarthropathy is focused on the management of joint pain usually in the form of non-steroidal anti-inflammatory drug therapy.

Induction of Cyclooxygenase 2 by Streptococcus pyogenes Is Mediated by Cytolysins

Prostaglandin E₂ (PGE₂), an arachidonic acid metabolite regulating a broad range of physiological activities, is an important modulator of the severity of infection caused by Streptococcus pyogenes. Here, we investigated the role of streptococcal cytolysin S (SLS) and streptococcal cytolysin O (SLO) in the induction of cyclooxygenase-2 (COX-2), the rate-limiting enzyme in the synthesis of prostaglandins, in in vitro cultured macrophages and during in vivo infection. Macrophages were infected with S. pyogenes wild type or with the isogenic mutant strains deficient in SLS (ΔSLS), SLO (ΔSLO), or both (ΔSLS/ΔSLO), and the expression of COX-2 was determined at the transcriptional and the protein level. The results indicated that S. pyogenes induced expression of COX-2 and concomitant synthesis of PGE₂ in macrophages mediated by the synergistic activity of both SLS and SLO, and involved calcium and the PKC/JNK signaling pathway. These results were validated using recombinant cytolysins. In a murine skin infection model, COX-2-positive cells were found more abundant at the site of S. pyogenes wild-type infection than at the site of infection with ΔSLS/ΔSLO mutant strain. These findings suggest that inhibitory targeting of SLS and SLO could ameliorate the adverse effects of high levels of prostaglandins during S. pyogenes infection.

Nonsteroidal anti-inflammatory drugs for dysmenorrhoea.

Dysmenorrhoea is a common gynaecological problem consisting of painful cramps accompanying menstruation, which in the absence of any underlying abnormality is known as primary dysmenorrhoea. Research has shown that women with dysmenorrhoea have high levels of prostaglandins, hormones known to cause cramping abdominal pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are drugs that act by blocking prostaglandin production. They inhibit the action of cyclooxygenase (COX), an enzyme responsible for the formation of prostaglandins. The COX enzyme exists in two forms, COX-1 and COX-2. Traditional NSAIDs are considered 'non-selective' because they inhibit both COX-1 and COX-2 enzymes. More selective NSAIDs that solely target COX-2 enzymes (COX-2-specific inhibitors) were launched in 1999 with the aim of reducing side effects commonly reported in association with NSAIDs, such as indigestion, headaches and drowsiness. To determine the effectiveness and safety of NSAIDs in the treatment of primary dysmenorrhoea. We searched the following databases in January 2015: Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, November 2014 issue), MEDLINE, EMBASE and Web of Science. We also searched clinical trials registers (ClinicalTrials.gov and ICTRP). We checked the abstracts of major scientific meetings and the reference lists of relevant articles. All randomised controlled trial (RCT) comparisons of NSAIDs versus placebo, other NSAIDs or paracetamol, when used to treat primary dysmenorrhoea. Two review authors independently selected the studies, assessed their risk of bias and extracted data, calculating odds ratios (ORs) for dichotomous outcomes and mean differences for continuous outcomes, with 95% confidence intervals (CIs). We used inverse variance methods to combine data. We assessed the overall quality of the evidence using GRADE methods. We included 80 randomised controlled trials (5820 women). They compared 20 different NSAIDs (18 non-selective and two COX-2-specific) versus placebo, paracetamol or each other. NSAIDs versus placeboAmong women with primary dysmenorrhoea, NSAIDs were more effective for pain relief than placebo (OR 4.37, 95% CI 3.76 to 5.09; 35 RCTs, I(2) = 53%, low quality evidence). This suggests that if 18% of women taking placebo achieve moderate or excellent pain relief, between 45% and 53% taking NSAIDs will do so.However, NSAIDs were associated with more adverse effects (overall adverse effects: OR 1.29, 95% CI 1.11 to 1.51, 25 RCTs, I(2) = 0%, low quality evidence; gastrointestinal adverse effects: OR 1.58, 95% CI 1.12 to 2.23, 14 RCTs, I(2) = 30%; neurological adverse effects: OR 2.74, 95% CI 1.66 to 4.53, seven RCTs, I(2) = 0%, low quality evidence). The evidence suggests that if 10% of women taking placebo experience side effects, between 11% and 14% of women taking NSAIDs will do so. NSAIDs versus other NSAIDsWhen NSAIDs were compared with each other there was little evidence of the superiority of any individual NSAID for either pain relief or safety. However, the available evidence had little power to detect such differences, as most individual comparisons were based on very few small trials. Non-selective NSAIDs versus COX-2-specific selectorsOnly two of the included studies utilised COX-2-specific inhibitors (etoricoxib and celecoxib). There was no evidence that COX-2-specific inhibitors were more effective or tolerable for the treatment of dysmenorrhoea than traditional NSAIDs; however data were very scanty. NSAIDs versus paracetamolNSAIDs appeared to be more effective for pain relief than paracetamol (OR 1.89, 95% CI 1.05 to 3.43, three RCTs, I(2) = 0%, low quality evidence). There was no evidence of a difference with regard to adverse effects, though data were very scanty.Most of the studies were commercially funded (59%); a further 31% failed to state their source of funding. NSAIDs appear to be a very effective treatment for dysmenorrhoea, though women using them need to be aware of the substantial risk of adverse effects. There is insufficient evidence to determine which (if any) individual NSAID is the safest and most effective for the treatment of dysmenorrhoea. We rated the quality of the evidence as low for most comparisons, mainly due to poor reporting of study methods.

Atf3 negatively regulates Ptgs2/Cox2 expression during acute inflammation

By generating prostaglandins, cyclooxygenase-2 (Cox-2/Ptgs2) plays a critical role in regulating inflammatory responses. While several inflammatory stimuli have been shown to increase Ptgs2 expression, less is known about how the transcription of this gene is terminated. Here we show that stimulation of macrophages with yeast zymosan, a TLR2/6 and dectin-1 agonist, causes a transient increase in the expression of Ptgs2 accompanied by a simultaneous increase in the expression of the transcriptional repressor, activating transcription factor-3 (Atf3). The expression of Ptgs2 was significantly higher in resident peritoneal macrophages isolated from Atf3−/− mice than that from Atf3+/+ mice and was associated with higher prostaglandin production upon stimulation with zymosan. In activated macrophages, Atf3 accumulated in the nucleus and chromatin-immunoprecipitation analysis showed that Atf3 is recruited to the Ptgs2 promoter region. In acute peritonitis and in cutaneous wounds, there was increased leukocyte accumulation and higher levels of prostaglandins (PGE2/PGD2) in inflammatory exudates of Atf3−/− mice compared with WT mice. Collectively, these results demonstrate that during acute inflammation Atf3 negatively regulates Ptgs2 and therefore dysregulation of this axis could potentially contribute to aberrant Ptgs2 expression in chronic inflammatory diseases. Moreover, this axis could be a new therapeutic target for suppressing Ptgs2 expression and the resultant inflammatory responses.

Effect of Diethylcarbamazine (DEC) on prostaglandin levels in Wuchereria bancrofti infected microfilaraemics

Diethylcarbamazine (DEC) interferes with arachidonic acid metabolism for the clearance of microfilariae in Wuchereria bancrofti infected individuals. In this study, we have quantified the plasma concentrations of prostaglandin E2 (PGE2) and 6-keto-PGF1α, the end products of arachidonic acid metabolic pathway in microfilaraemics (DEC treated and untreated), and normal healthy individuals at pre- and 3,9,12,36, and 72h of post-DEC treatment. We have also determined the microfilariae counts at pre and post day 2 (36h) and day 3 (72h) of DEC treatment by membrane filtration technique. Significant reduction in PGE2 and 6-keto-PGF1α concentrations was found at 12h of DEC treatment. Rapid reduction in microfilarial counts was observed at 36h of post-DEC treatment. Higher levels of prostaglandins were found at pre-treatment hours in microfilaraemics compared to normal healthy individuals (P < 0.05). Our findings indicate that DEC inhibits prostaglandins for the clearance of microfilariae, and increased levels of prostaglandins in microfilaraemics may be contributed by the parasite or host upon stimulation.

Effect of combined chemotherapy and anti-inflammatory drugs on murine schistosomiasis.

Hepatic granulomas resulting from Schistosoma mansoni infection contain high levels of prostaglandins (PG) and leukotrienes. The present experimental study was conducted to show the effect of murine S. mansoni infection on PGE2 level in the liver granuloma homogenate and to explore the possibility of using non-steroidal anti-inflammatory drugs (NSAIDs) namely, ibuprofen (CAS 15687-27-1) and naproxen (CAS 22204-53-1), either alone or in combination with praziquantel (CAS 55268-74-1) to induce regression of hepatic morbidity or to ameliorate the biochemical and histopathological consequences and intensity of infection. Infection with S. mansoni increased the level of alanine amino-transaminase (ALT), gamma glutamyl transferase (GGT), PGE2, hepatic collagen deposition, antibody titre and circulating schistosomal antigen. The last parameter was reduced significantly by progression of infection in the 11th and 16th weeks. Treatment with praziquantel was found to reduce the number of worms (97%), with complete absence of immature ova and increase in the number of dead ova. Also it reduced all the elevated parameters except PGE2. NSAIDs were found to reduce significantly the level of PGE2 at 9 weeks but not at 11 and 16 weeks post-infection. ALT and GGT were not significantly decreased compared to their corresponding controls. Treatment with ibuprofen or naproxen either alone or in combination with praziquantel or praziquantel alone reduced significantly the granuloma diameters. Collagen deposition and percentage of fibrotic area were significantly decreased compared to infected control but the antibody titre or circulating antigen levels were not affected. Combined therapy of praziquantel with ibuprofen or naproxen improved most of the parameters estimated and maintained the reducing effect on PGE2 at 11 and 16 weeks post-infection. So it can be concluded that in S. mansoni infection treatment with ibuprofen or naproxen is not preferable without treatment of schistosomiasis by using praziquantel.

Evaluation of the use of sumatriptan–naproxen sodium for menstrual migraine and dysmenorrhea

Evaluation of: Cady RK, Diamond ML, Diamond MP et al. Sumatriptan–naproxen sodium for menstrual migraine and dysmenorrhea: satisfaction, productivity, and functional disability outcomes. Headache 51(5), 664–673 (2011).Menstrual migraine (MM) is a form of headache that tends to occur with prolonged, intense and extremely disabling attacks in a short period around the menstrual cycle (usually 2 days before to 3 days after the onset of the menstrual flow). At least 50% of the female migraine population suffers from this subtype of migraine. The possible presence of other perimenstrual pain, such as dysmenorrhea, can make the attacks even more disabling. Since both of these conditions have a common pathological background consisting of a secretion of abnormally high levels of prostaglandins, it can be particularly useful to use a combination of sumatriptan, the progenitor of the triptans and the drug of choice in the treatment of migraine attack, and naproxen sodium, a potent inhibitor of prostaglandin biosynthesis. The combination of sumatriptan 85 mg and naproxen sodium 500 mg has been tested in women suffering from MM and dysmenorrhea, and this combination has been shown to achieve greater satisfaction when compared with placebo. Moreover, sumatriptan–naproxen was also better than placebo in reducing functional disability and improving productivity. The study is discussed in the context of the current state of knowledge about MM treatment.

Lubiprostone Suppresses Growth of Colon Cancer Cells in vitro and in vivo

Purpose: Colon and other tumors show low levels of expression of 15-hydroxy-prostaglandin dehydrogenase [NAD+] (HPGD), also known as 15-PGDH, a prostone synthetase, which converts prostaglandins to their metabolites, prostones. 15-PGDH, a tumor suppressor, is low in HT-29 colon cancer cells. Deficiency in 15-PGDH results in high prostaglandin levels (and perhaps low prostone levels), which in turn may lead to stimulation of tumor growth. Lubiprostone is a prostone derivative that activates ClC-2 Cl- channels and is used for the treatment of chronic idiopathic constipation in adults and irritable bowel syndrome with constipation in adult women. Cellular effects of lubiprostone include activation of ion channels, subsequent membrane hyperpolarization, reduced intracellular free calcium ([Ca2+]i), and no effect on [cAMP]i. In contrast, PGE1 and PGE2 cause membrane depolarization and increased [Ca2+]i and [cAMP]i by binding to EP receptors (Prostaglandin and Other Lipid Mediators 86: 56-60, 2008). The effect of lubiprostone on tumor growth rate was investigated using wild-type, mock-transfected and 15-PGDH-transfected HT-29 colon cancer cells and HT-29-derived tumors orthotopically implanted on the cecum mucosa of nude mice. Methods: For in vitro studies, HT-29 cells were plated in 60-mm Petri dishes in triplicate and counted in a 1 mm2 area using a microscope grid in a randomly chosen field. Lubiprostone or vehicle (0.1% DMSO) was added after 48 h of plating and cells were then counted 24, 48, 72 and 96 h later. For the animal study, HT-29 tumors were surgically implanted on the cecum mucosa in nude mice and tumor sizes were measured once/week. Lubiprostone and vehicle were given daily orally at day 15 after tumor implantation and monitored at day 22 and day 29 after implantation. Results: Growth of HT-29 cells was significantly inhibited even at 24 h by 100 nM lubiprostone in vitro and inhibited up to about 73% by 72 h. Lubiprostone inhibition of HT-29 cell growth was dose dependent with IC50=1.8±0.3 nM. In PGDH-transfected-HT-29 cells, the inhibitory effect of lubiprostone was lost compared to mock-transfected or non-transfected cells. Lubiprostone (1, 3, 5 mg/kg) also significantly suppressed growth of HT-29 orthotopically implanted tumors by 40-50%. Conclusion: Lubiprostone suppresses growth of HT-29 colon cancer cells in vitro and HT-29 tumor growth in vivo. The mechanism might involve interference with the growth effects caused by high prostaglandin levels in tumor cells with low 15-PGDH (low prostone synthetase activity). These results suggest that lubiprostone might be useful for treatment and/or prevention of colon and potentially other cancers. Supported by Sucampo Pharmaceuticals, Inc. Disclosure: John Cuppoletti is a consultant to, holds stock options in, and has a research grant from Sucampo Pharmaceuticals Inc. Danuta H. Malinowska and Jayati Chakrabarti are supported by the grant from Sucampo Pharmaceuticals Inc. Takashi Sekida is an employee of Sucampo Pharmaceuticals, Inc. Ryuji Ueno is CEO and Chief Scientific Officer, Chairman of the Board and Founder of Sucampo Pharmaceuticals, Inc. This research was supported by an industry grant from Sucampo Pharmaceuticals Inc.

Prostaglandin D2 inhibits C2C12 myogenesis

Muscle repair following injury is preceded by a rapid inflammatory response with myoblasts being exposed to high levels of prostaglandin D(2) (PGD(2)) from invading leukocytes. We demonstrate that PGD(2) strongly inhibits C2C12 myogenesis as measured by cell fusion, creatine kinase activity and MyoD, myogenin and alpha-actin expression. Inhibition of myogenesis required micromolar PGD(2) concentrations and was independent of the known PGD(2) receptors DP1 and DP2. Unlike its cyclopentenone derivative 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)), PGD(2) did not generate toxic mitochondrial superoxide indicating that the inhibition of myogenesis is not mediated by generation of high concentrations of PGD(2)-derived 15d-PGJ(2). Thus our observations provide evidence for a novel PGD(2) signalling mechanism during muscle repair exclusively mediated by high inflammatory associated PGD(2) concentrations. These findings indicate a complex interplay between myoblasts and inflammatory cells during the repair process and have implications for the use of non-steroidal anti-inflammatory drugs in the treatment of muscle injuries.