Prostaglandin E2/Leukotriene B4 balance and viral load in distinct clinical stages of COVID-19: A cross-sectional study.

BACKGROUND: Prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) are eicosanoids involved in modulation of the antiviral immune response. Recent studies have identified increased levels of several eicosanoids in the plasma and bronchoalveolar lavage of patients with coronavirus disease (COVID-19). This study investigated correlations between plasma levels of PGE2 and LTB4 and clinical severity of COVID-19. METHODS: This cross-sectional study involved non-infected (n = 10) individuals and COVID-19 patients classified as cured (n = 13), oligosymptomatic (n = 29), severe (n = 15) or deceased (n = 11). Levels of D-dimer a, known COVID-19 severity marker, PGE2 and LTB4 were measured by ELISAs and data were analysed with respect to viral load. RESULTS: PGE2 plasma levels were decreased in COVID-19 patients compared to the non-infected group. Changes in PGE2 and LTB4 levels did not correlate with any particular clinical presentations of COVID-19. However, LTB4 was related to decreased SARS-CoV-2 burden in patients, suggesting that only LTB4 is associated with control of viral load. CONCLUSIONS: Our data indicate that PGE2/LTB4 plasma levels are not associated with COVID-19 clinical severity. Hospitalized patients with COVID-19 are treated with corticosteroids, which may influence the observed eicosanoid imbalance. Additional analyses are required to fully understand the participation of PGE2 receptors in the pathophysiology of COVID-19.

[Transurethral resection of the prostate versus transurethral columnar balloon dilatation of the prostate in the treatment of benign prostatic hyperplasia].

OBJECTIVE: To compare the effects of transurethral resection of the prostate (TURP) and transurethral columnar balloon dilatation of the prostate (TUCBDP) in the treatment of BPH. METHODS: This study included 218 BPH patients treated in Qinhuangdao Workers' Hospital from July 2021 to November 2022, 109 by TURP and the other 109 by TUCBDP. We followed up the patients for 12 months, observed their postoperative recovery, complications, serum pain, inflammatory index, cytokine level, urodynamic index, symptom improvement and quality of life (QOL) and compared the data obtained between the two groups of patients. RESULTS: At 12 months after surgery, the total effectiveness rate was significantly higher in the TUCBDP than in the TURP group (93.58% vs 84.40%, P< 0.05), and the postoperative recovery was better in the former than in the latter (P< 0.05). Compared with the baseline, the levels of serum prostaglandin E2 (PGE2), substance P, tumor necrosis factor-alpha (TNF-α) and high sensitive C-reactive protein (hs-CRP) were remarkably increased in both of the groups on the first day after surgery (P< 0.05), more significantly in the TURP than in the TUCBDP group (P< 0.05), while the levels of serum PSA and E2 decreased and the T level elevated in all the patients at 3 months postoperatively (P< 0.05), more significantly in the TUCBDP than in the TURP group (P< 0.05). Before and at 3 and 12 months after operation, the postvoid residual urine volume (PVR) and NIH-CPSI, IPSS and QOL scores showed a decreasing trend, while the maximum urinary flow rate (Qmax), maximum cystometric capacity (MCC) and maximum urethral closure pressure (MUCP) exhibited an increasing trend in both of the two groups, even more significantly in the TUCBDP than in the TURP group (P< 0.05). CONCLUSION: TUCBDP is advantageous over TURP in promoting postoperative recovery, improving QOL, reducing postoperative pain, inflammation and complications, regulating the levels of serum cytokines, and improving urodynamics and clinical symptoms in BPH patients. However, with the extension of postoperative time, the two strategies are basically comparable in improving the urodynamics, symptoms and QOL of the patients.

[Dental gel Cholisal at the stage of conservative treatment of inflammatory periodontal diseases]. / Klinicheskaya effektivnost' konservativnogo lecheniya patsientov s khronicheskim generalizovannym parodontitom s primeneniem gelya Kholisal.

PURPOSE OF THE STUDY: To study the effectiveness of the drug Cholisal as part of the conservative treatment of chronic periodontitis. MATERIAL AND METHODS: We selected 100 patients aged 35 to 65 years of both sexes with a diagnosis of moderate chronic periodontitis in the acute stage with a periodontal pocket depth of 3.5-5 mm. Depending on the tactics of conservative treatment of periodontitis, patients were divided into two groups of 50 people. In the main group, Cholisal dental gel was used as part of complex conservative treatment, and in the control group, Metrogil-denta gel was used. To assess the effectiveness of treatment, a dental examination of patients was carried out with an index assessment of the condition of periodontal tissues and a biochemical analysis of the content of arachidonic acid and prostaglandin E2 in gingival blood, comparing the indicators before treatment and 14 days after the start of treatment. RESULTS: When the drug Cholisal was included in complex treatment, 14 days from the start of treatment, patients experienced a statistically significant decrease in the depth of periodontal pockets from 4.7±0.32 mm to 3.6±0.19, and the Green-Vermillion hygiene index by 60.7%, Silness-Loe plaque index by 73.1%, PMA index by 68.8%, Muhlemann-Cowell bleeding index by 68.0% (p<0.001 compared to baseline). When Metrogil-denta gel was used in complex therapy, the effectiveness of treatment was lower: the depth of periodontal pockets did not change significantly (from 4.5±0.22 mm to 4.2±0.17 mm, p>0.05), reduction in the hygiene index Green-Vermillion was 51.9%, Silness-Loe plaque index - 64.0%, PMA index - 43.7%, Muhlemann-Cowell bleeding index - 45.8% (p<0.001 compared to baseline, p<0.001 compared to the main group). A laboratory study showed that in patients of the main group, after completing a course of conservative treatment, the content of biomarkers of inflammation significantly decreased compared to the initial level (p<0.05), while in patients of the control group the content of arachidonic acid and prostaglandin E2 in the gingival blood during the study period did not change significantly (p>0.05 compared to the initial level). CONCLUSIONS: The use of the drug Cholisal in the conservative treatment of chronic periodontitis has demonstrated more pronounced positive dynamics of clinical and biochemical parameters compared to traditional therapy, which suggests its high effectiveness.

Identification of potential serum metabolic biomarkers for patient with keratoconus using untargeted metabolomics approach.

This study aimed to investigate the metabolite differences between patients with keratoconus and control subjects and identify potential serum biomarkers for keratoconus using a non-targeted metabolomics approach. Venous blood samples were obtained from patients with keratoconus (n = 20) as well as from age-, gender- and race-matched control subjects (n = 20). Metabolites extracted from serum were separated and analyzed by liquid chromatography/quadrupole time-of-flight mass spectrometer. Processing of raw data and analysis of the data files was performed using Agilent Mass Hunter Qualitative software. The identified metabolites were subjected to a principal component and hierarchical cluster analysis. Appropriate statistical tests were used to analyze the metabolomic profiling data. Together, the analysis revealed that the dehydroepiandrosterone sulfate from the steroidal hormone synthesis pathway was significantly upregulated in patients with keratoconus (p < 0.05). Also, a combination of eicosanoids from the arachidonic acid pathway, mainly prostaglandin F2α, prostaglandin A2, 16,16-dimethyl prostaglandin E2, and 5-hydroxyeicosatetraenoic acid were collectively up-regulated as a group in keratoconus patients (p < 0.05). On the other hand, glycerophospholipid PS(17:2(9Z,12Z)/20:4(5Z,8Z,11Z,14Z)) was found to be significantly upregulated in the metabolomics profiles of control subjects (p < 0.05). The differently regulated metabolites provide insights into the pathophysiology of keratoconus and could potentially be used as biomarkers for keratoconus to aid in screening for individuals at risk hence, enabling early diagnosis and timely monitoring of disease.

Synthesis and biological evaluation of new nicotinate derivatives as potential anti-inflammatory agents targeting COX-2 enzyme.

Two novel series derived from nicotinic acid were synthesized and evaluated for their inhibitory activity against cyclooxygenases COX-1 and COX-2, and their selectivity indices were determined. Celecoxib, diclofenac and indomethacin were used as reference drugs. All compounds showed highly potent COX-2 inhibitory activity and higher selectivity towards COX-2 inhibition compared to indomethacin. In addition, these compounds except 3a showed clear preferential COX-2 over COX-1 inhibition compared to diclofenac. Compounds 3b, 3e, 4c and 4f showed COX-2 inhibitory activity equipotent to celecoxib. Compounds 4c and 4f demonstrated selectivity indices 1.8-1.9 fold higher than celecoxib. These two most potent and COX-2 selective compounds were further tested in vivo for anti-inflammatory activity by means of carrageenan induced rat paw edema method. Ulcerogenic activity with histopathological studies were performed. The results showed no ulceration, which implies their safe gastric profile. Compound 4f exhibited the most potent in vivo anti-inflammatory activity comparable to all reference drugs. Further, compounds 4c and 4f were investigated for their influence on certain inflammatory cytokines TNF-α and IL-1ß in addition to PEG2. The findings revealed that these candidates could be identified as promising potent anti-inflammatory agents. Molecular docking of 4c and 4f in the COX-2 active site was performed to rationalize their COX-2 inhibitory potency. The results were found to be in line with the biological findings as they exerted more favorable interactions compared to that of celecoxib, explaining their remarkable COX-2 inhibitory activity.

Possible protective effect of TNF-α inhibition and triad NO/cGMP/VEGF activation on gastric ulcer in rats.

Peptic ulcers are one of the world's major gastrointestinal disorders, embracing both gastric and duodenal ulcers, and affecting 10% of the world population. The current study aimed to investigate the possible protective effect of tadalafil and pentoxifylline (PTX) on indomethacin-induced peptic ulcers. Male albino rats were divided into five groups: control group; ulcerated group; Indomethacin + Tadalafil, in which animals were pretreated with tadalafil orally before indomethacin; Indomethacin+ PTX, in which animals were pretreated with PTX orally before indomethacin; and Indomethacin + Tadafil + PTX. Indomethacin treatment revealed histopathological changes and ulcer scoring and ulcer index were markedly increased. Serum levels of prostaglandin and heme oxygenase-1 were significantly decreased. The ulcerogenic also induced marked oxidative stress as evident from the increased malondialdehyde, decreased in gastric glutathione content and superoxide dismutase activity, while the gastric myeloperoxidase was increased. Gastric nitric oxide content was decreased and the expression of vascular endothelial growth factor was downregulated while the tumor necrosis factor α (TNF-α) level was dramatically increased. Pretreatment of the ulcerative group by either tadalafil or PTX or their combination improved all these pathological changes. Tadalafil or PTX may have a role in protecting gastric mucosa damage caused by indomethacin which may be useful in the future for the treatment of gastric ulceration.

Therapeutic appraisal of ephedrine against rheumatoid arthritis: A new indication.

Ephedra, natural flora has been used traditionally to treat rheumatism since decades. The scientific evidence of anti-rheumatic effect of this plant has also been reported. But the anti-rheumatic activity of major constituent of this plant (ephedrine) has not been evaluated. Based on this, the current study was aimed to assess anti-arthritic activity of ephedrine by using in vitro and in vivo approaches. Correspondingly, enzyme linked immunosorbent assay was performed for the estimation of prostaglandins E2 (PGE2) and tumor necrosis factor-α (TNF-α) in serum of formaldehyde-induced arthritic animals. The results elaborated significant reduction in albumin denaturation and remarkable progress on stabilization of red blood cells outer membrane at higher concentration during in vitro experiments. The ephedrine (40mg/kg) revealed noteworthy (p<0.001) inhibition in paw swelling in animals intoxicated with albumin as well as formaldehyde as compared to animals of control group by in vivo results. In this assay, ephedrine (20 & 40 mg/kg orally) significantly suppressed the level of these inflammatory markers (PGE2 & TNF-α). Ephedrine exhibited anti-arthritic effect by decreasing pro-inflammatory cytokines (PGE2 & TNF-α). This experimental work pharmacologically supports the use of ephedrine as anti-rheumatic drug but limited to evaluate in immunological arthritic model.

PGE2 ameliorated viral myocarditis development and promoted IL-10-producing regulatory B cell expansion via MAPKs/AKT-AP1 axis or AhR signaling.

B10 cells, a specific subset of regulatory B cells, are capable of regulating immune response and restricting inflammation and autoimmune disease progression by producing IL-10. B10 cells frequently change significantly during inflammation and autoimmunity. However, how B10 cell populations change in viral myocarditis (VMC) remains unclear. Therefore, this work was conducted to clarify the changes in B10 cells and their potential mechanisms. Our results showed that the B10 cell frequency significantly changed in the VMC model. Changes in prostaglandin E2 (PGE2) levels in VMC model hearts were consistent with B10 expansion. PGE2 induced B10 cell expansion via the MAPKs/AKT-AP1 axis or AhR signaling. Additionally, PGE2-pretreated B10 cells inhibited naïve CD4+ T cell differentiation into Th17 cells. In vivo, PGE2 treatment or adoptive B10 cell transfer significantly restricted VMC development. Our results provide sufficient evidence that PGE2-induced B10 cell expansion may become a promising therapeutic approach for VMC and acute inflammatory injury.

The relationship between inflammatory markers and spirometric parameters in ACOS, Asthma, and COPD.

Objective: The inflammatory mechanisms underpinning asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) have not been fully elucidated. Here, we examined the levels of cysteinyl leukotrienes (cys-LTs), prostaglandin D2 (PG-D2), prostaglandin E2 (PG-E2), interleukin 5 (IL-5), and a disintegrin and metalloprotease domain (ADAM 33) in ACOS patients to determine the relationship between levels of these inflammatory markers and pulmonary functions.Methods: Blood samples were obtained from asthma, COPD, and ACOS patients who received combined therapy and were stable for the last month to measure cys-LTs, PG-D2, PG-E2, IL-5, and ADAM33 levels. Differences between groups and their correlations with pulmonary function tests were evaluated.Results: In total, 24 ACOS, 27 asthma, and 35 COPD patients were included. . PG-D2 levels were higher in ACOS (120.9 ± 117.2 ng/L) and asthma (119.6 ± 111.7 ng/L) patients than in COPD (82.6 ± 46.7 ng/L) patients (p = 0.036 and p = 0.038, respectively). In ACOS patients, PG-D2, cys-LTs, and ADAM33 levels were negatively correlated with FEV1/FVC% values (p = 0.021, p = 0.008, and p = 0.028, respectively). In COPD patients, a negative correlation was detected between PG-E2 and FEV1/FVC% (p = 0.007), whereas positive correlations were detected between IL-5 and pulmonary function tests, including FVC, FVC%, FEV1, FEV1%, FEF25-75, and FEF25-75% (p = 0.047, p = 0.005, p = 0.002, p = 0.002, p = 0.010, and p = 0.005, respectively). In asthma patients, cys-LTs levels were negatively correlated with FEV1 and FEF25-75 values (p = 0.045 and p = 0.037, respectively).Conclusions: PG-D2 levels may be a valuable biomarker to differentiate COPD in asthma and ACOS patients.

Fibroblast Growth Factor (FGF) Signaling Protects Against Acute Pancreatitis-Induced Damage by Modulating Inflammatory Responses.

BACKGROUND Acute pancreatitis (AP) is a symptom of sudden pancreas inflammation, which causes patients severe suffering. In general, fibroblast growth factor (FGF) levels are increased and amylase and lipase activities are elevated during AP pathogenesis, but protein concentration are low. However, the mechanism through which FGF signaling regulates AP pathogenesis remains elusive. MATERIAL AND METHODS The concentrations of PGE2, TNF-alpha, sCRP, FGF1, and FGF2 in the serum samples of the AP group and healthy control group were detected by enzyme-linked immunosorbent assay. In addition, IkappaBalpha and p-IkappaBalpha levels were analyzed in the serum samples. Subsequently, the AP rat model was established, and FGF1, FGF2, anti-FGF1, and anti-FGF2 antibodies and Bay11-7082 were injected into AP rats. TNF-alpha, PAI-1 JNK, p-JNK, IkappaBalpha, and p-IkappaBalpha levels were also examined. RESULTS Results showed that levels of PGE2, TNF-alpha, sCRP, p-IkappaBalpha, FGF1, and FGF2, as well as amylase and lipase activity were increased in patients with AP compared with those in healthy people. In addition, protein concentrations were lower in patients with AP than in the healthy group. Activation of FGF signaling by injecting FGF1 or FGF2 also inhibited AP-induced inflammation response in the pancreas and increased amylase and lipase activities, as well as protein concentration. However, the injection of FGF1 and FGF2 antibodies accelerated AP-mediated inflammation responses in the serum. In addition, Bay11-7082 injection inhibited AP activation of inflammation response and amylase and lipase activities. Protein concentration were also increased in AP rats. CONCLUSIONS FGF signaling protects against AP-mediated damage by inhibition of AP-activating inflammatory responses.

Design, synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX-2/5-LOX inhibitors.

A new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through 1 H nuclear magnetic resonance (NMR), 13 C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone-privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5-LOX inhibitory activity and COX-2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising anti-inflammatory activity. Compound 3j was found to be the most promising derivative, with IC50 values of 667 and 47 nM against COX-1 and COX-2, respectively, which are superior to that of celecoxib (IC50 value against COX-2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX-1 inhibition, with IC50 values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5-LOX, with IC50 values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC50 values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC50 = 0.8 µM). These promising derivatives, 3f, 3h, and 3j, were further investigated in vivo for anti-inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX-2 and 5-LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX-2 and 5-LOX as dual inhibitors, as a new avenue in anti-inflammatory therapy.

Eicosanoids in Nonalcoholic Fatty Liver Disease (NAFLD) Progression. Do Serum Eicosanoids Profile Correspond with Liver Eicosanoids Content during NAFLD Development and Progression?

Nonalcoholic fatty liver disease (NAFLD) is becoming a major public health problem worldwide. The study aimed to evaluate the concentration of eicosanoids in serum and liver tissue during steatosis progression and to assess whether eicosanoid change scores may predict liver tissue remodeling. Thirty six eight-week-old male Sprague Dawley rats were enrolled and sacrificed at different stages of NAFLD. Eicosanoid concentrations, namely lipoxin A4, hydroxyeicosatetraenoic acids (HETE), hydroxyloctadecadienoic acids (HODE), protectin DX, Maresine1, leucotriene B4, prostaglandin E2, and resolvin D1 measurement in serum and liver tissue with Agilent Technologies 1260 liquid chromatography were evaluated. For the liver and serum concentrations of 9-HODE and 13-HODE, the correlations were found to be strong and positive (r > 0.7, p < 0.05). Along with NAFLD progression, HODE concentration significantly increased, and change scores were more abundant in the liver. The moderate positive correlation between liver and serum (r = 0.52, p < 0.05) was also observed for resolvin E1. The eicosanoid concentration decreased during NAFLD progression, but mostly in serum. There were significant correlations between HETE concentrations in liver and serum, but their associations were relatively low and changes the most in liver tissue. Eicosanoids profile, predominantly 9-HODE and 13-HODE, may serve as a potential biomarker for NAFLD development.

Anti-Obesity and Gut Microbiota Modulation Effect of Secoiridoid-Enriched Extract from Fraxinus mandshurica Seeds on High-Fat Diet-Fed Mice.

Previously we conducted a phytochemical study on the seeds of Fraxinus excelsior and isolated nine secoiridoid compounds with adipocyte differentiation inhibitory activity and peroxisome proliferator activated receptor alpha (PPARα) activation effects. However, the bioactive constituents and functions of Fraxinus mandshurica seeds have not been studied. In the present study, we investigated the secoiridoid compounds in F. mandshurica seed extract (FM) using column chromatography, 1H-NMR, 13C-NMR and HPLC-DAD methods. The pancreatic lipase inhibitory activities of isolated compounds were evaluated in vitro. Additionally, the anti-obesity and gut microbiota modulation effect of FM on high-fat diet-induced obesity in C57BL/6 mice were also studied in vivo. The results showed that 19 secoiridoids were isolated from FM and identified. The total content of secoiridoids in FM reached 181.35 mg/g and the highest content was nuzhenide (88.21 mg/g). All these secoiridoid compounds exhibited good pancreatic lipase inhibitory activity with inhibition rate ranged from 33.77% to 70.25% at the concentration of 100 µM. After obese mice were administrated with FM at 400 mg/kg.bw for 8 weeks, body weight was decreased by 15.81%. Moreover, FM could attenuate the lipid accumulation in serum and liver, relieve the damage in liver and kidney, and extenuate oxidative stress injury and inflammation caused by obesity in mice. FM could also modulate the structural alteration of gut microbiota in obese mice, increasing the proportion of anti-obesity gut microbiota (Bacteroidetes, Bacteroidia, S24-7 and Allobaculum), and reducing the proportion of obesogenic gut microbiota (Firmicutes and Dorea). This study suggests that F. mandshurica seeds or their secoiridoids may have potential for use as a dietary supplement for obesity management.

Inflammation increases MMP levels via PGE2 in human vascular wall and plasma of obese women.

BACKGROUND AND OBJECTIVES: Matrix metalloproteinases (MMPs) are involved in several inflammatory processes including obesity-related vascular diseases and graft failure of coronary artery (CA) bypass grafts [internal mammary artery (IMA), saphenous vein (SV)]. In these inflammatory conditions, the release of prostaglandin E2 (PGE2) is increased via the activity of inducible microsomal PGE synthase-1 (mPGES-1). Our aim was to investigate whether MMPs and their endogenous inhibitor (TIMPs) may be regulated by PGE2 under inflammatory conditions in human vasculature and perivascular adipose tissue (PVAT), as well as in plasma of obese patients. METHODS: MMP-1,-2 and TIMP-1,-2 densities were measured in human plasma (n = 68) as well as in supernatants of human vascular wall (IMA n = 16, SV n = 14, CA n = 13) and their PVAT. The effects of inflammation and mPGES-1 inhibitor (Compound III, 10 µM) on MMPs regulation were evaluated. The correlations between PGE2 and several parameters were calculated in plasma from patients with or without obesity. RESULTS: The vascular wall and PVAT from SV exhibited the greatest MMP-1,-2 release. An increase of MMP-1,-2 and/or a decrease of TIMP-1 quantities have been detected under inflammation only in vascular wall not in PVAT. These changes under inflammation were completely reversed by inhibition of mPGES-1. In obesity, C-reactive protein (CRP), biomarker of inflammation, and PGE2 levels were increased. PGE2 contents were positively correlated with some anthropometric parameters and plasmatic CRP in both genders, while the correlation with the plasmatic MMP-1 density was significant only in women. CONCLUSIONS: The greater MMP activity observed in SV may contribute to the increased prevalence of graft failure. Under inflammation, the greater mPGES-1 and PGE2 levels lead to enhanced MMP activity in human vascular walls. The positive association between PGE2 and MMP-1 or CRP has been observed in plasma of women. We suggest that mPGES-1 inhibitors could prevent graft failure and obesity-related vascular remodeling mostly in women.

Regulatory Control of Microglial Phagocytosis by Estradiol and Prostaglandin E2 in the Developing Rat Cerebellum.

Microglia are essential to sculpting the developing brain, and they achieve this in part through the process of phagocytosis which is regulated by microenvironmental signals associated with cell death and synaptic connectivity. In the rat cerebellum, microglial phagocytosis reaches its highest activity during the third postnatal week of development but the factors regulating this activity are unknown. A signaling pathway, involving prostaglandin E2 (PGE2) stimulation of the estrogen synthetic enzyme aromatase, peaks during the 2nd postnatal week and is a critical regulator of Purkinje cell maturation. We explored the relationship between the PGE2-estradiol pathway and microglia in the maturing cerebellum. Toward that end, we treated developing rat pups with pharmacological inhibitors of estradiol and PGE2 synthesis and then stained microglia with the universal marker Iba1 and quantified microglia engaged in phagocytosis as well as phagocytic cups in the vermis and cerebellar hemispheres. Inhibition of aromatase reduced the number of phagocytic cups in the vermis, but not in the cerebellar hemisphere at postnatal day 17. Similar results were found after treatment with nimesulide and indomethacin, inhibitors of the PGE2-producing enzymes cyclooxygenase 1 and 2. In contrast, treatment with estradiol or PGE2 had little effect on microglial phagocytosis in the developing cerebellum. Thus, endogenous estrogens and prostaglandins upregulate the phagocytic activity of microglia during a select window of postnatal cerebellar development, but exogenous treatment with these same signaling molecules does not further increase the already high levels of phagocytosis. This may be due to an upper threshold or evidence of resistance to exogenous perturbation.

The Adjuvant Effect of Squalene, an Active Ingredient of Functional Foods, on Doxorubicin-Treated Allograft Mice.

Many functional foods or physiologically active ingredients derived from plants and animals are actively being investigated for their role in chronic disease prevention. Squalene (SQ) is found as active ingredient in the functional foods predominantly present in olive oil and shark liver oil. It is known that during chemotherapy anticancer drugs induce inflammation. SQ has been thought to prevent and suppress inflammation; however, there is little direct evidence available. We examined the adjuvant effect of SQ on tumor-transplanted mice along with anticancer drug doxorubicin (DOX). SQ significantly suppressed the DOX-induced increase in prostaglandin E2 (PGE2) concentration (P < 0.05) in plasma of tumor-bearing mice. SQ inhibited the numbers of writhing response (P < 0.05), formalin-induced pain and decreased COX-2 and substance P expression in the tumor tissue compared to control mice and also enhanced the antitumor efficacy of DOX in allograft mice. Thus, SQ reduces inflammation through modulation of PGE2 production indicating its potential as an adjuvant during chemotherapy in tumor-bearing mice.

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, 17ß-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.

The effectiveness of marine based fatty acid compound (PCSO-524) and firocoxib in the treatment of canine osteoarthritis.

BACKGROUND: NSAIDs are accepted as the most predictably efficacious medical treatment of the clinical signs of osteoarthritis (OA). The marine-based fatty-acid compound PCSO-524 has been proposed as an adjunctive treatment for canine OA, however benefits of this agent is still controversial. The purpose of this study was to evaluate and compare the effectiveness of PCSO-524 combined with the NSAID firocoxib using force plate gait analysis, orthopedic assessment score (OAS) and canine brief pain inventory score (CBPI) in dogs with OA. A prospective, randomized, double-blinded study was conducted. Seventy-nine dogs that had hip and/or stifle OA were assigned randomly into three treatment groups: firocoxib, PCSO-524 and combination of firocoxib and PCSO-524, orally for 4 weeks. Peak vertical force (PVF, expressed as a percentage of bodyweight), OAS, CBPI, serum prostaglandin E2 concentration, hematology and blood chemistry values were evaluated before treatment (Day0), as well as at the second (Day14) and fourth week (Day28) during treatment. RESULTS: Within group analysis revealed significant increases in PVF over the 4-week treatment period for firocoxib, PCSO-524 and the combination (p < 0.05). Mean increases in PVF were 3.25 ± 4.13, 2.01 ± 3.86, 4.11 ± 4.69%BW (mean ± SD) respectively. The OAS showed non-significant change in all treatment groups. There were significant decreases in CBPI pain severity score (PSS) and CBPI pain interference scores (PIS) within some groups over time, however no significant differences were found between the groups. Significantly decreased serum PGE2 concentration (p < 0.05) was found in the combination group. Significant increases in BUN and creatinine (p < 0.05) compared to pre-treatment values were found in the firocoxib and combination groups but not in the PCSO-524 group at day28, but all values in all dogs remained within the normal ranges. CONCLUSIONS: The results of this study suggested combination of both PCSO-524 and firocoxib is more effective in alleviation of inflammation and improvement of weight bearing ability when compared to the uses of either PCSO-524 or firocoxib alone. Further clinical studies are needed to confirm this, and to determine if there is any benefit of PCSO-524 over placebo.

PBMT and topical diclofenac as single and combined treatment on skeletal muscle injury in diabetic rats: effects on biochemical and functional aspects.

Physical exercise generates several benefits in a short time in patients with diabetes mellitus. However, it can increase the chances of muscle damage, a serious problem for diabetic patients. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat these injuries, despite the serious adverse effects. In this way, photobiomodulation therapy (PBMT) with low-level laser therapy (LLLT) and/or light emitting diode therapy (LEDT) can be used as an alternative in this case. However, its efficacy in tissue repair of trauma injuries in diabetes mellitus until now is unknown, as well as the combination between PBMT and NSAIDs. The objective of the present study was to evaluate the effects of NSAIDs and PBMT applied alone or combined on functional and biochemical aspects, in an experimental model of muscle injury through controlled trauma in diabetic rats. Muscle injury was induced by means of a single trauma to the animals' anterior tibialis muscle. After 1 h, the rats were treated with PBMT (830 nm; continuous mode, with a power output of 100 mW; 3.57 W/cm2; 3 J; 107.1 J/cm2, 30 s), diclofenac sodium for topical use (1 g), or combination of them. Our results demonstrated that PBMT + diclofenac, and PBMT alone reduced the gene expression of cyclooxygenase-2 (COX-2) at all assessed times as compared to the injury and diclofenac groups (p < 0.05 and p < 0.01 respectively). The diclofenac alone showed reduced levels of COX-2 only in relation to the injury group (p < 0.05). Prostaglandin E2 levels in blood plasma demonstrated similar results to COX2. In addition, we observed that PBMT + diclofenac and PBMT alone showed significant improvement compared with injury and diclofenac groups in functional analysis at all time points. The results indicate that PBMT alone or in combination with diclofenac reduces levels of inflammatory markers and improves gait of diabetic rats in the acute phase of muscle injury.

Impacts of a Specific Cyclooxygenase-2 Inhibitor on Pressure Overload-Induced Myocardial Hypertrophy in Rats.

OBJECTIVE: The aim of this study was to observe the impacts of the specific cyclooxygenase-2 inhibitor celecoxib on cardiac structures, functions, and inflammatory factors during the process of pressure overload-induced myocardial hypertrophy. METHODS: Twenty-four male Sprague Dawley rats were randomly divided into 3 groups: the sham operation group, the surgery group, and the celecoxib group. The model was established according to the abdominal aortic coarctation method. RESULTS: At 16 weeks, rats in the celecoxib group were fed a celecoxib-mixed diet (10 mg/kg) for 8 consecutive weeks. At week 24 after model establishment, the cardiac structures and functions were observed; changes in the levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß, prostaglandin E2 (PGE2), C-reactive protein (CRP), and uric acid (UA) were detected; and the contents of Smad1/2/3 proteins (Smad1, Smad2, and Smad3)  were determined. Left ventricular mass index, the heart weight/body weight ratio, and TNF-α, TGF-ß, PGE2, CRP, and UA levels of the celecoxib group were all significantly decreased relative to those of the surgery group (P < .05); moreover, the cardiac functions were significantly improved compared to those of the surgery group (P < .05). CONCLUSIONS: These results show that inflammatory factors are involved in the myocardial hypertrophy process and that celecoxib may reverse myocardial hypertrophy through a variety of pathways.