PGF2α Levels Research Articles

LH-stimulated periodic lincRNA HEOE regulates follicular dynamics and influences estrous cycle and fertility via miR-16-ZMAT3 and PGF2α in pigs

Disruption of the estrous cycle affects fertility and reproductive health. Follicular dynamics are key to the regularity of the estrous cycle. We identified a novel lincRNA, HEOE, showing significant upregulation in the ovaries during the estrus phase across various pig breeds. Functional analysis revealed that HEOE is responsive to luteinizing hormone (LH) stimulation, modulating transcriptional suppression and alternative splicing in ovarian granulosa cells (GCs). This leads to increased GC apoptosis and inhibition of proliferation. Mechanistically, HEOE inhibits miR-16 maturation in the nucleus, and sequesters miR-16 in the cytoplasm, thereby collectively reducing miR-16's inhibition on ZMAT3, enhancing the expression of ZMAT3, a key factor in the p53 pathway and alternative splicing, thereby regulating follicular development. This effect was validated in both mice and pig follicles. Persistent overexpression or suppression of HEOE throughout the estrous cycle impairs cycle regularity and reduces litter size. These outcomes are associated with HEOE reduced follicular PGF2α levels and modulation of the cAMP signaling pathway. Our data, combined with public databases, indicate that the high expression of HEOE during the estrus phase is crucial for maintaining the estrous cycle. HEOE is a potential therapeutic target for regulating fertility and ensuring estrous cycle regularity in pigs.

Therapeutic Efficacy of Wet Cupping on Uterine Inflammation in Primary Dysmenorrhea: An In Vivo Investigation Targeting Bilateral L4/L5 Vertebrae

Primary dysmenorrhea (PD) is a prevalent problem in gynecology affecting the quality of life for young women. This medical condition is often responsible for the absence of young women from school or work, increasing the risk of developing hyperemesis gravidarum in the future. Furthermore, PD causes pain due to the activation of the local PGF2α pathway in the endometrium, which triggers oxidative stress processes, uterine ischemia and spasmodic uterine contractions. The first-line therapies for PD, Nonsteroid anti-inflammatory drugs (NSAIDs) and oral contraceptives, can cause side effects such as headache, nausea, intestinal ulcers and platelet abnormalities. To overcome the impact of PD, cupping has been proven effective as an alternative pain therapy with minimal side effects. Therefore, this study aimed to evaluate the effects of cupping on writing latency threshold time, PGF2α levels and FP receptor expression in PD model rats. The experiment was conducted using female Sprague Dawley rats to analyze the effects of wet cupping therapy (WCT) on inflammatory repair in the uterus. The method used was a pre- and post-test control group design, with 35 female rats randomly divided into 5 groups. These consisted of normal control (NC), negative control (C−), positive control (C+) + ibuprofen 7.2 mg, as well as treatment groups, comprising dry cupping (DC) and WCT. The results showed that writhing time threshold of WCT was the same as C+ (p = 0.368), while PGF2α decreased in DC (43.43 pg/mL, p = 0.008) and WCT (189.25 pg/mL, p = 0.0154). Similar to C+, WCT significantly decreased serum PGF2α levels compared to C−. WCT also influenced the expression of PTGFR subunit similarly to NC, showing the capacity to control the inflammatory pathway. The study suggested that WCT was a promising therapeutic strategy for PD by decreasing PGF2α and PTGFR expression. HIGHLIGHTS Previous investigations conducted on experimental animals using wet cupping therapy (WCT) have shown histopathological results associated with primary dysmenorrhea (PD) caused by estradiol benzoate and oxytocin. Moreover, this study shows the potential of WCT in reducing inflammation-induced PD pain by inhibiting the expression of PGF2α and PTGFR in the cyclooxygenase pathway, potentially increasing the pain threshold. The results show that WCT offers a potential alternative therapy for PD caused by estradiol benzoate and oxytocin. GRAPHICAL ABSTRACT

Fu's subcutaneous needling combined with monkshood cake-separated moxibustion for primary dysmenorrhea with cold congealing and blood stasis: a randomized controlled trial

To observe the clinical efficacy of Fu's subcutaneous needling combined with monkshood cake-separated moxibustion for primary dysmenorrhea with cold congealing and blood stasis. Sixty patients with primary dysmenorrhea of cold congealing and blood stasis were randomly divided into an observation group (30 cases, 1 case dropped out) and a control group (30 cases, 2 cases dropped out). The control group received monkshood cake-separated moxibustion at Shenque (CV 8) and bilateral Zigong (EX-CA 1), while the observation group received Fu's subcutaneous needling based on the control group. The muscles were palpated and the affected muscles were determined. Needles were inserted 5-10 cm away from the affected muscles and reperfusion activity was performed simultaneously. All the treatment started on the first day of menstrual cycle pain, once a day, for 3 days, totaling for 3 menstrual cycles. The visual analogue scale (VAS) score, Cox menstrual symptom scale (CMSS) score, and traditional Chinese medicine (TCM) syndrome score in the two groups were observed before treatment, after 2 treatment courses and after 3 treatment courses. The serum prostaglandin F2α(PGF2α) levels before and after 3 treatment courses were measured, and the clinical efficacy of the two groups was evaluated. After 2 and 3 treatment courses, the VAS scores, CMSS scores, and TCM syndrome scores in the two groups were lower than those before treatment (P<0.05), and the scores in the observation group were lower than those in the control group (P<0.05). After 3 treatment courses, the PGF2α level in the observation group was decreased (P<0.05), and were lower than that in the control group (P<0.05). The total effective rate was 96.6% (28/29) in the observation group, which was higher than 64.3% (18/28) in the control group (P<0.05). Fu's subcutaneous needling combined with monkshood cake-separated moxibustion could effectively reduce the pain intensity, improve clinical symptoms of dysmenorrhea, and lower PGF2α level in patients with primary dysmenorrhea of cold congealing and blood stasis.

Association of oxidative stress and inflammatory metabolites with Alzheimer’s disease cerebrospinal fluid biomarkers in mild cognitive impairment

BackgroundIsoprostanes and prostaglandins are biomarkers for oxidative stress and inflammation. Their role in Alzheimer's disease (AD) pathophysiology is yet unknown. In the current study, we aim to identify the association of isoprostanes and prostaglandins with the Amyloid, Tau, Neurodegeneration (ATN) biomarkers (Aβ-42, p-tau, and t-tau) of AD pathophysiology in mild cognitive impairment (MCI) subjects.MethodsTargeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LCMS) in 147 paired plasma-CSF samples from the Ace Alzheimer Center Barcelona and 58 CSF samples of MCI patients from the Mannheim/Heidelberg cohort. Linear regression was used to evaluate the association of metabolites with CSF levels of ATN biomarkers in the overall sample and stratified by Aβ-42 pathology and APOE genotype. We further evaluated the role of metabolites in MCI to AD dementia progression.ResultsIncreased CSF levels of PGF2α, 8,12-iso-iPF2α VI, and 5-iPF2α VI were significantly associated (False discovery rate (FDR) < 0.05) with higher p-tau levels. Additionally, 8,12-iso-iPF2α VI was associated with increased total tau levels in CSF. In MCI due to AD, PGF2α was associated with both p-tau and total tau, whereases 8,12-iso-iPF2α VI was specifically associated with p-tau levels. In APOE stratified analysis, association of PGF2α with p-tau and t-tau was observed in only APOE ε4 carriers while 5-iPF2α VI showed association with both p-tau and t-tau in APOE ε33 carriers. CSF levels of 8,12- iso-iPF2α VI showed association with p-tau and t-tau in APOE ε33/APOE ε4 carriers and with t-tau in APOE ε3 carriers. None of the metabolites showed evidence of association with MCI to AD progression.ConclusionsOxidative stress (8,12-iso-iPF2α VI) and inflammatory (PGF2α) biomarkers are correlated with biomarkers of AD pathology during the prodromal stage of AD and relation of PGF2α with tau pathology markers may be influenced by APOE genotype.

Pregnane X receptor (PXR) deficiency promotes hepatocarcinogenesis via induction of Akr1c18 expression and prostaglandin F2α (PGF2α) levels

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, plays a critical role in the metabolism of endogenous and exogenous substances in the liver. Here, we investigate whether PXR plays a role in pathogenesis of HCC. We show that liver tumors were developed in diethylnitrosamine (DEN)-treated in PXR knockout (KO) mice. Hepatic levels of prostaglandin F2α (PGF2α) and aldo–keto reductase family 1 member C18 (Akr1c18), a prostaglandin synthase of catalyzing reduction of PGH2 to PGF2α, were significantly elevated in DEN-treated PXR KO mice. Hepatic mRNA levels of alpha fetoprotein (AFP), cyclin D1 (Ccnd1), fibroblast growth factor 21 (FGF21), and inflammatory cytokine interleukin 6 (IL-6) were significantly increased in DEN-treated PXR KO mice. Other members of Akr1c family, liver metabolizing enzymes including Cyp1a2, Cyp2b10 and Cyp3a11, and bile acid synthesis enzyme Cyp7a1 mRNA levels were significantly decreased in DEN-treated PXR KO mice. Our findings revealed that PXR deficiency promoted DEN-induced HCC in mice via induction of Akr1c18 expression and PGF2α levels and the increased PGF2α levels synthetized by Akr1c18 enhanced hepatocytes proliferation and induced inflammatory cytokine production, which accelerated liver tumor development after DEN treatment, suggesting that PXR deficiency may create a microenvironment that is more prone to DEN-induced liver tumors and targeting PXR and Akr1c18 to reduce PGF2α biosynthesis may be a potential and novel therapeutic strategy for HCC.

Ge-gen decoction alleviates primary dysmenorrhoea symptoms in a rat model

Background Existing treatments for primary dysmenorrhoea (PD), such as NSAIDs, impart side effects. Ge-Gen decoction (GGD), a traditional Chinese medicine, has shown promise in treating PD, but its exact mechanisms remain unclear. Here, we aimed to investigate the efficiency of GGD in alleviating PD using a rat model to understand its precise mechanism of action. Methods We established a rat model of dysmenorrhoea induced by oestradiol and oxytocin. The PD rats were administered GGD or Ibuprofen (positive control) intragastrically once daily for seven consecutive days. Serum levels of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2α), β-endorphin (β-EP), thromboxane B2 (TXB2), 6-keto-prostaglandin F1α (6-keto-PGF1α) were determined using an enzyme-linked immunosorbent assay (ELISA). The expression levels of oestrogen receptor alpha (ERα) and cyclooxygenase-2 (COX-2) in uterine tissue were measured using immunohistochemical assays, and those of phosphorylated and total extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) were assessed using western blot analysis. Results Treatment with GGD significantly reduced writhing behaviour, histopathological scores, and levels of COX-2, PGE2, and PGF2α in the serum of PD rats. Additionally, GGD increased β-EP content and inhibited ERK1/2 activation and ERα expression in uterine tissues. Conclusions The results of this study suggest that GGD alleviates PD in rats by suppressing the COX-2-mediated release of PGE2 and PGF2α, modulating the ERα/ERK1/2/COX-2 pathway, and increasing β-EP content. These results provide insights into the potential mechanisms of GGD in treating PD and support its further investigation as an alternative therapy for this condition.

The influence of physical activity, body mass index and urinary levels of prostaglandin (PGF2α) with the incidence of primary dysmenorrhea in adolescents.

This study aims to investigate the effect of physical activity, body mass index (BMI), and levels of prostaglandins (PGF2α) urine on the occurrence of dysmenorrhea in adolescents. A total of 128 female students included in the study. The study was conducted from January to March 2023 using a cross-sectional design. This study utilized the Menstrual Symptom Questionnaire (MSQ) and gynecological examination with ultrasonography. The urinary prostaglandin (PGF2α) was measured using the enzyme linked immuno sorbent assay (ELISA). Data were analyzed using the chi-square test and logistic regression test. The age range of the participants included in the study was 14-17, with a mean age of 15.85 ± 0.65. There was an correlation between physical activity, BMI, and urinary prostaglandin (PGF2α) levels with the incidence of dysmenorrhea in adolescents (p < 0.001). In multivariate analysis, it revealed that underweight, and had a high urinary prostaglandin significant correlated to primary dysmenorrhea with odds ratio 4.78 (95% confidence interval [CI] 1.98-11.54) and 4.88 (95% CI 1.98-12.08), respectively. High physical activity and overweight was not associated with incidence of dysmenorrhea in adolescents. This study provides valuable insights into the correlation between physical activity, BMI, and levels of prostaglandins (PGF2α) in urine. A high level of urinary prostaglandin was found to be the most influential factor in the incidence of primary dysmenorrhea in adolescents. By addressing factors associated with dysmenorrhea in adolescents, healthcare professionals can potentially enhance well-being by reducing menstrual pain and encouraging a healthy lifestyle to prevent dysmenorrhea.

Prostaglandin F2α Affects the Cycle of Clock Gene Expression and Mouse Behavior.

Prostaglandins are bioactive compounds, and the activation of their receptors affects the expression of clock genes. However, the prostaglandin F receptor (Ptgfr) has no known relationship with biological rhythms. Here, we first measured the locomotor period lengths of Ptgfr-KO (B6.129-Ptgfrtm1Sna) mice and found that they were longer under constant dark conditions (DD) than those of wild-type (C57BL/6J) mice. We then investigated the clock gene patterns within the suprachiasmatic nucleus in Ptgfr-KO mice under DD and observed a decrease in the expression of the clock gene cryptochrome 1 (Cry1), which is related to the circadian cycle. Moreover, the expression of Cry1, Cry2, and Period2 (Per2) mRNA were significantly altered in the mouse liver in Ptgfr-KO mice under DD. In the wild-type mouse, the plasma prostaglandin F2α (PGF2α) levels showed a circadian rhythm under a 12 h cycle of light-dark conditions. In addition, in vitro experiments showed that the addition of PTGFR agonists altered the amplitude of Per2::luc activity, and this alteration differed with the timing of the agonist addition. These results lead us to hypothesize that the plasma rhythm of PGF2α is important for driving clock genes, thus suggesting the involvement of PGF2α- and Ptgfr-targeting drugs in the biological clock cycle.

Nicotinic acetylcholine receptor-mediated effects of varenicline on LPS-elevated prostaglandin and cyclooxygenase levels in RAW 264.7 macrophages.

Introduction: The purpose of this study is to delineate anti-inflammatory and antioxidant potential of varenicline, a cigarette smoking cessation aid, on decreasing lipopolysaccharide (LPS)-elevated proinflammatory cytokines in RAW 264.7 murine macrophage cultures which we showed earlier to occur via cholinergic anti-inflammatory pathway (CAP) activation. To this end, we investigated the possible suppressive capacity of varenicline on LPS-regulated cyclooxygenase (COX-1 and COX-2) via α7 nicotinic acetylcholine receptor (α7nAChR) activation using the same in vitro model. Materials and Methods: In order to test anti-inflammatory effectiveness of varenicline, the levels of COX isoforms and products (PGE2, 6-keto PGF1α, a stable analog of PGI2, and TXA2) altered after LPS administration were determined by Enzyme Linked Immunosorbent Assay (ELISA). The antioxidant effects of varenicline were assessed by measuring reductions in reactive oxygen species (ROS) using a fluorometric intracellular ROS assay kit. We further investigated the contribution of nAChR subtypes by using non-selective and/or selective α7nAChR antagonists. The results were compared with that of conventional anti-inflammatory medications, such as ibuprofen, celecoxib and dexamethasone. Results: Varenicline significantly reduced LPS-induced COX-1, COX-2 and prostaglandin levels and ROS to an extent similar to that observed with anti-inflammatory agents used. Discussion: Significant downregulation in LPS-induced COX isoforms and associated decreases in PGE2, 6-keto PGF1α, and TXA2 levels along with reduction in ROS may be partly mediated via varenicline-activated α7nAChRs.

Peony Pollen Protects against Primary Dysmenorrhea in Mice by Inhibiting Inflammatory Response and Regulating the COX2/PGE2 Pathway.

Peony pollen contains multiple nutrients and components and has been used as a traditional Chinese medicine with a long history, but the effect of the treatment of primary dysmenorrhea remains to be clarified. The aim of this study is to investigate the therapeutic effect of peony pollen on primary dysmenorrhea mice and the potential mechanism. A uterus contraction model in vitro and primary dysmenorrhea mice were used to evaluate the treatment effect of peony pollen on primary dysmenorrhea. The primary dysmenorrhea mice were treated with 62.5 mg/kg, 125 mg/kg, or 250 mg/kg of peony pollen, and the writhing response, latency period, histopathological changes in the uterus, prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) levels, and infiltration of neutrophils and macrophages were investigated. Protein expression of interleukin 1 β (IL-1β), interleukin 6 (IL-6), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), cyclooxygenase-2 (COX-2), microsomal prostaglandin-E synthase 1 (mPGEs-1), BCL2-Associated X (Bax), B-cell lymphoma-2 (BCL-2), caspase-3, and cleaved caspase-3 were detected by Western blot, and the oxidative stress related marker malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and reactive oxygen species (ROS) were evaluated. Peony pollen could attenuate spontaneous or oxytocin-induced uterus contractions in vitro. Moreover, peony pollen decreased the writhing times, prolonged the writhing latency, and reduced the pathological damage of uterine tissues. Furthermore, the inflammatory cell infiltration and the protein expression of IL-1β, IL-6, and NLRP3 were decreased. The COX-2/PGE2 pathway was inhibited; oxidative stress and apoptosis in the uterus also improved in the uterus of primary dysmenorrhea mice. Peony pollen exerts a positive effect on primary dysmenorrhea by inhibiting the inflammatory response and modulating oxidative stress and apoptosis by regulating the COX-2/PGE2 pathway.

The Association of Reproductive Hormones During the Menstrual Period with Primary Dysmenorrhea.

This study aimed to investigate the association of reproductive hormones with primary dysmenorrhea in Chinese women. A case-control study was conducted and patients with primary dysmenorrhea and non-dysmenorrhea participants were recruited. Oxytocin, PGF2α, vasopressin, estriol and estradiol were respectively measured in plasma collected three to five days after menstruation. Restricted cubic spline and multiple logistic regression models were adopted to analyze the association between hormones and primary dysmenorrhea. There were 604 participants enrolled in our study including 300 patients with primary dysmenorrhea. After adjustment for the potential confounders, oxytocin levels (Q3: OR (95% CI) = 0.50 (0.27~0.95) (p=0.035); Q4: 0.34 (0.17~0.66) (p=0.001)) and PGF2α levels (Q3: 0.45 (0.24~0.87) (p=0.017); Q4: 0.43 (0.22~0.84) (p=0.013)) were respectively associated with an decreased risk of primary dysmenorrhea, but estradiol (Q2: 2.18 (1.13~4.19) (p=0.020); Q3: 2.17 (1.12~4.19) (p=0.022)) and vasopressin (Q3: 2.88 (1.48~5.63) (p=0.002); Q4: 3.20 (1.65~6.22) (p<0.001)) with an increased risk of primary dysmenorrhea, respectively. Among patients with primary dysmenorrhea, the higher estriol level was associated with higher frequent dysmenorrhea (Q2: 3.12 (1.32~7.34) (p=0.009); Q3: 4.97 (2.08~11.85) (p<0.001)) and always dysmenorrhea (Q2: 2.51 (1.03~6.11) (p=0.041); Q3: 3.10 (1.25~7.73) (p=0.015)). Similarly, high estriol levels were associated with the higher degree of pain significantly only when hormone levels were at a high level (Q3: 2.06 (1.03~4.18) (p=0.043)). Higher serum vasopressin and estradiol concentrations as well as lower oxytocin and PGF2α levels were associated with higher risk of primary dysmenorrhea. Estrogen showed a reverse U-shape association on the frequency and degree of pain among patients with primary dysmenorrhea.

Co-exposure to particulate matter and humidity increases blood pressure in hypertensive mice via the TRPV4-cPLA2-COX2 pathway

Epidemiological studies have demonstrated that particulate matter (PM) can induce or exacerbate hypertension. High relative humidity has been associated with elevated blood pressure in certain regions. However, the coupling effect of humidity and PM on elevated blood pressure and the underlying mechanisms remain unknown. Herein, we aimed to explore the effects of exposure to PM and/or high relative humidity on hypertension, as well as elucidate underlying mechanisms. Male C57/BL6 mice were intraperitoneally administered NG-nitro-L-arginine methyl ester (L-NAME) to establish a hypertensive mouse model. The hypertensive mice were exposed to PM (0.15 mg/kg/day) and/or different relative humidities (45/90%) for eight weeks. Histopathological changes, systolic blood pressure (SBP), endothelial-derived contracting factors (thromboxane B2 [TXB2], Prostaglandin F2α [PGF2α], endothelin-1 [ET-1], and angiotensin II [Ang II]), and relaxing factors (prostaglandin I2 [PGI2] and nitric oxide [NO]) were measured to assess the effects of PM exposure and humidity on hypertension in mice. Levels of transient receptor potential vanilloid 4 (TRPV4), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase 2 (COX2) were measured to explore their potential mechanisms. Herein, exposure to 90% relative humidity or PM alone had a slight but insignificant effect on hypertension. However, pathological changes and elevated blood pressure were markedly exacerbated following exposure to PM and 90% relative humidity. Levels of PGF2α, TXB2, and ET-1 were significantly increased, whereas the PGI2 level was substantially decreased. HC-067047-mediated blockade of TRPV4 suppressed TRPV4, cPLA2, and COX2 expression and effectively alleviated the increased blood pressure induced by exposure to PM and 90% relative humidity. These results indicate that 90% relative humidity and PM can activate the TRPV4-cPLA2-COX2 ion channel in the aorta, altering the endothelial-derived contracting and relaxing factors and enhancing blood pressure in hypertensive mice.

Polyunsaturated and Saturated Oxylipin Plasma Levels Allow Monitoring the Non-Alcoholic Fatty Liver Disease Progression to Severe Stages.

Hepatic fat accumulation is the hallmark of non-alcoholic fatty liver disease (NAFLD). Our aim was to determine the plasma levels of oxylipins, free polyunsaturated fatty acids (PUFA) and markers of lipid peroxidation in patients with NAFLD in progressive stages of the pathology. Ninety 40-60-year-old adults diagnosed with metabolic syndrome were distributed in without, mild, moderate or severe NAFLD stages. The free PUFA and oxylipin plasma levels were determined by the UHPLC-MS/MS system. The plasma levels of oxylipins produced by cyclooxygenases, lipoxygenases and cytochrome P450, such as prostaglandin 2α (PGF2α), lipoxinB4 and maresin-1, were higher in severe NAFLD patients, pointing to the coexistence of both inflammation and resolution processes. The plasma levels of the saturated oxylipins 16-hydroxyl-palmitate and 3-hydroxyl-myristate were also higher in the severe NAFLD patients, suggesting a dysregulation of oxidation of fatty acids. The plasma 12-hydroxyl-estearate (12HEST) levels in severe NAFLD were higher than in the other stages, indicating that the hydroxylation of saturated fatty acid produced by reactive oxygen species is more present in this severe stage of NAFLD. The plasma levels of 12HEST and PGF2α are potential candidate biomarkers for diagnosing NAFLD vs. non-NAFLD. In conclusion, the NAFLD progression can be monitored by measuring the plasma levels of free PUFA and oxylipins characterizing the different NAFLD stages or the absence of this disease in metabolic syndrome patients.

Effects of electroacupuncture on NLRP3 inflammasome and pyroptosis protein GSDMD in uterine tissue in rats with primary dysmenorrhea

To observe the effects of electroacupuncture (EA) on NLRP3 inflammasome and its downstream protein gastermin D (GSDMD) in rats with primary dysmenorrhea (PDM), and to explore the potential mechanism of EA on the treatment of PDM. Forty healthy female SD rats without pregnancy were randomly divided into a control group, a model group, an EA group and an ibuprofen group, 10 rats in each group. PDM model was prepared by injection of estradiol benzoate and oxytocin. Except the control group, the rats in each group were subcutaneously injected with estradiol benzoate for 10 days, and oxytocin was injected on the 11th day. The rats in the EA group were intervened with EA (dense wave, frequency of 50 Hz) at "Guanyuan" (CV 4) and "Sanyinjiao" (SP 6) at the same time of modeling, once a day, 20 min each time, for 10 consecutive days. The rats in the ibuprofen group were treated with 0.8 mL of ibuprofen by gavage (concentration of ibuprofen solution was 1.25 mg/mL) for 10 consecutive days. After modeling, the writhing reaction was observed. After intervention, the HE staining method was used to observe the histological morphology of uterus and evaluate the pathological damage score of uterus; ELISA method was used to detect the serum levels of prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α); Western blot method was used to detect the protein expression of NLRP3, apoptosis related spot like protein (ASC), caspase-1, GSDMD, GSDMD-N and inflammatory factors (interleukin [IL]-1β, IL-18) in uterine tissue. In the model group, a large number of vacuolar degeneration and death of endometrial epithelial cells, spiral arterioles congestion in lamina propria and neutrophil infiltration were observed. In the EA group, there was a small amount of vacuolar degeneration and death of endometrial epithelial cells, a small amount of spiral arterioles congestion in the lamina propria, and a small amount of neutrophils infiltration. In the ibuprofen group, there was very small number of degeneration and death of endometrial epithelial cells, and no obvious arterial congestion was found in lamina propria, and neutrophil infiltration was occasionally seen. Compared with the control group, in the model group the number of writhing was increased (P<0.01), the writhing reaction score and serum level of PGF2α and PGF2α/PGE2 value were increased (P<0.01), the level of PGE2 was decreased (P<0.01). Compared with the model group, in the EA group and the ibuprofen group the number of writhing were decreased (P<0.05), the latency of writhing was prolonged (P<0.01), the writhing reaction scores and serum levels of PGF2α and PGF2α/PGE2 values were decreased (P<0.05, P<0.01), the levels of PGE2 were increased (P<0.01). Compared with the control group, the protein expression of NLRP3, ASC, caspase-1, GSDMD, GSDMD-N, IL-1β and IL-18 in the uterine tissues of rats was increased in the model group (P<0.01). Compared with the model group, the protein expression of NLRP3, ASC, caspase-1, GSDMD, GSDMD-N, IL-1β and IL-18 in the uterine tissues of rats was decreased in the EA group and the ibuprofen group (P<0.01, P<0.05). There was no significant difference between the EA group and the ibuprofen group in the above indexes (P>0.05). EA could alleviate pain and uterine tissue injury in rats with PDM. The mechanism may be related to the inhibition of the activation of NLRP3 inflammasome in rat uterine tissues, thereby inhibiting pyroptosis and its inflammatory factors release.

Protective role of CoQ10 in reducing the side effects resulting from the use of Tramadol on some immunological variables in the endemic female rabbits

The aim of study to determine out the role of CoQ10 in reducing the side effects from the use of Tramadol on the level of Interlukin IL-6, IL-10 and PGF2α the study included 30 endemic female rabbits, where each group included 5 animals. The results showed increase with a highly significant with (P≤0.01) in the concentration of IL-10 in sera of treated group with tramadol (initial dose) and group treated tramadol (double dose) group treated tramadol (initial dose + CoQ10) and group treated with tramadol (double dose + CoQ10) compare with control.&#x0D; The results showed no significant differences in the concentration of IL-10 in sera of treated group with Co Q10 compare with control. The results revealed high significant increase (P≤0.01) in the concentration of IL-6 in the sera of the treated group with tramadol (double dose) group treated with tramadol (initial dose + COQ10) as compared with the control and the results showed the presence of high significant decrease (P≤0.01) in the concentration of IL-6 in the sera of the group treated with tramadol (initial dose) and treated with group tramadol (double dose + COQ10) compare with control. the results showed there were no significant differences in the concentration of IL-6 in serum of group treated with CoQ10 as compare with control. Results indicated occurrence of high significant increase (P≤0.01) in a concentration of PGF 2α in serum of the group treated with tramadol (initial dose) and group treated with tramadol (double dose)and group treated with tramadol (initial dose + CoQ10) and group treated with tramadol (double dose +CoQ10) compare with control. The results showed presence of a highly significant decrease (P≤0.01) in the concentration of P G F 2α in sera of group treated with CoQ10 as compare with control.

Effect of omega-3 polyunsaturated fatty acid supplementation on oxidative stress parameters and sex hormone levels of modern genotype sows.

Sows are exposed to severe stress and hormonal challenges during their whole productive life. As polyunsaturated fatty acids play an important role in immune and reproductive functions, with a better understanding of their role in breeding sows' nutrition, improved performance and more sustainable pig production can be achieved. In this study, we investigated the effects of omega-6 and omega-3 fatty acid supplementation on the antioxidant status and hormone levels of sows. A total of 48 Danish Large white × Danish Landrace sows were supplemented either with sunflower oil (SO) as a control group or with fish oil (FO) as experimental group at the same dose of 10g/kg feed. Blood samples were collected on day 14 of lactation, 5 days after weaning (insemination), and 30 days after insemination. To estimate antioxidant and reproductive effects, the amounts of reduced glutathione (GSH), thiobarbituric acid reactive substance, the activity of glutathione peroxidase (GPx), serum 17β oestradiol (E2), progesterone (P4), and 6-keto prostaglandin F1α (6-keto PGF1α) levels were investigated. FO-based supplementation increased GPx activity on day 14 of lactation. Five days after weaning, the concentration of GSH in FO-fed sows was significantly higher than that in SO-fed sows. The E2 content of blood was significantly lower in the experimental group than in the control group for two of the three examined periods (day 14 of lactation and 30 days after insemination), whereas P4 levels were significantly higher in the experimental group 5 days after weaning. We found that 6-keto PGF1α levels were systematically lower in the experimental group throughout the trial. This study provides evidence of the major impact of omega-6 and -3 fatty acids on the tested hormone levels, which serve as precursors for the production of E2 and P4 but have an opposite effect on PGF2α production.

Inhibition of P2X7 receptors by Lu AF27139 diminishes colonic hypersensitivity and CNS prostanoid levels in a rat model of visceral pain.

Visceral pain is a prominent feature of various gastrointestinal diseases. The P2X7 receptor is expressed by multiple cell types including dorsal root ganglion satellite glial cells, macrophages, and spinal microglia, all of which have been implicated in nociceptive sensitization. We have used the selective and CNS penetrant P2X7 receptor antagonist Lu AF27139 to explore this receptor's role in distinct rat models of inflammatory and visceral hypersensitivity. Rats injected with CFA in the hindpaw displayed a marked reduction in hindpaw mechanical threshold, which was dose-dependently reversed by Lu AF27139 (3-30mg/kg, p.o.). In rats injected with TNBS in the proximal colon, the colorectal distension threshold measured distally was significantly lower than sham treated rats at 7days post-injection (P < 0.001), indicative of a marked central sensitization. Colonic hypersensitivity was also reversed by Lu AF27139 (10-100mg/kg) and by the κ-opioid receptor agonist U-50,488H (3mg/kg, s.c.). Moreover, both Lu AF27139 and U-50,488H prevented a TNBS-induced increase in spinal and brain levels of PGE2 and LTB4, as well as an increase in brain levels of PGF2α and TXB2. Lu AF27139 was well tolerated as revealed by a lack of significant effect on rotarod motor function and coordination at all doses tested up to 300mg/kg. Thus, P2X7 receptor antagonism is efficacious in a rat model of visceral pain, via a mechanism which potentially involves attenuation of microglial function within spinal and/or supraspinal pain circuits, albeit a peripheral site of action cannot be excluded.

Flexible Ureteroscopy and Nephroscopy for Stone Removal in Patients with Multiple Renal Calculi.

Objective Renal calculi are a common type of urological calculi and are associated with morbidity. This study was aimed at exploring the effect of flexible ureteroscopy and nephroscopy on stone removal in patients with multiple renal calculi. Method This randomized controlled trial included a total of 78 cases with multiple renal calculi in our hospital. The patients were randomly divided into the study and control groups and treated with flexible ureteroscopy and percutaneous nephrolithotomy with pneumatic ballistics, respectively. The surgery condition, levels of prostaglandin F2α (PGF2α), prostaglandin E2 (PGE2), keratocyte growth factor (KGF), renal function indices, and the incidence of complications were analyzed before and after surgery in the two groups. Result The operation time, the postoperative analgesia pump application time, one-time stone removal rate, the intraoperative blood loss, and hospital stay of the study group were significantly lower than those of the control group. Postsurgery, the levels of PGE2, PGF2α, and KGF in the study group were significantly lower than those in the control group. The serum levels of SCR, BUN, and NGAL in the study group were significantly lower than those in the control group. In addition, the incidence complications in the study group were significantly lower. Conclusion Flexible ureteroscopy and laser lithotripsy under nephroscopy were equally effective against multiple renal calculi. Flexible ureteroscopy reduced surgical trauma without affecting renal function and had a low incidence of complications.

Cytokines and Lipid Mediators of Inflammation in Lungs of SARS-CoV-2 Infected Mice.

Coronavirus disease 19 (COVID-19) is the clinical manifestation of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection. A hallmark of COVID-19 is a lung inflammation characterized by an abundant leukocyte infiltrate, elevated levels of cytokines/chemokines, lipid mediators of inflammation (LMI) and microthrombotic events. Animal models are useful for understanding the pathophysiological events leading to COVID-19. One such animal model is the K18-ACE2 transgenic mice. Despite their importance in inflammation, the study of LMI in lung of SARS-CoV-2 infected K18-ACE2 mice has yet to be studied to our knowledge. Using tandem mass spectrometry, the lung lipidome at different time points of infection was analyzed. Significantly increased LMI included N-oleoyl-serine, N-linoleoyl-glycine, N-oleoyl-alanine, 1/2-linoleoyl-glycerol, 1/2-docosahexaenoyl-glycerol and 12-hydroxy-eicosapenatenoic acid. The levels of prostaglandin (PG) E1, PGF2α, stearoyl-ethanolamide and linoleoyl-ethanolamide were found to be significantly reduced relative to mock-infected mice. Other LMI were present at similar levels (or undetected) in both uninfected and infected mouse lungs. In parallel to LMI measures, transcriptomic and cytokine/chemokine profiling were performed. Viral replication was robust with maximal lung viral loads detected on days 2-3 post-infection. Lung histology revealed leukocyte infiltration starting on day 3 post-infection, which correlated with the presence of high concentrations of several chemokines/cytokines. At early times post-infection, the plasma of infected mice contained highly elevated concentration of D-dimers suggestive of blood clot formation/dissolution. In support, the presence of blood clots in the lung vasculature was observed during infection. RNA-Seq analysis of lung tissues indicate that SARS-CoV-2 infection results in the progressive modulation of several hundred genes, including several inflammatory mediators and genes related to the interferons. Analysis of the lung lipidome indicated modest, yet significant modulation of a minority of lipids. In summary, our study suggests that SARS-CoV-2 infection in humans and mice share common features, such as elevated levels of chemokines in lungs, leukocyte infiltration and increased levels of circulating D-dimers. However, the K18-ACE2 mouse model highlight major differences in terms of LMI being produced in response to SARS-CoV-2 infection. The potential reasons and impact of these differences on the pathology and therapeutic strategies to be employed to treat severe COVID-19 are discussed.

Assessment of prostaglandin F2-alpha (PGF2α) in lesional and nonlesional skin of vitiligo patients.

F2-isoprostane is one of the members of biologically active prostaglandins. It is considered a reliable marker of oxidative stress. This study aimed at investigating and studying the hypothesis of the possible role of prostaglandin F2-alpha (PGF2α) in the pathogenesis of vitiligo and to know if there is a possibility of using it in therapy. This case-control study involved 30 patients with nonsegmental vitiligo and 30 healthy sex- and age-matched controls over a period of 7 months. Skin biopsies were taken from lesional and nonlesional vitiliginous skin of patients and from normal skin of controls for measurement of PGF2α in tissue by ELISA. The tissue levels of PGF2α in vitiligo patients were significantly higher in both lesional and nonlesional skin than in healthy controls (P < 0.001). The tissue levels of PGF2α in lesional skin were significantly higher than in nonlesional skin (P < 0.001). Based on the fact that PGF2α is a reliable biomarker of oxidative stress, in addition to our results that revealed higher tissue levels of PGF2α in vitiliginous skin than in healthy skin, we can conclude that PGF2α may be incriminated in the pathogenesis of vitiligo. This finding could help in the treatment of this disease by using anti-PGF2α drugs.