Dynamics of Cyclooxygenase-1 Positive Microglia/Macrophage in the Retina of Pathological Model Mice as a Biomarker of the Retinal Inflammatory Diseases

In an intraocular inflammatory state, microglia residing in the retina become active and migrate inside the retina. In this study, we investigated whether cyclooxygenase-1 (COX-1) expressed by retinal microglia/macrophage can be a biomarker for the diagnosis of retinal diseases. COX-1 was immunopositive in microglia/macrophage and neutrophils, while COX-2 was immunopositive in astrocytes and neurons in the inner layer of normal retina. The number of COX-1 positive cells per section of the retinal tissue was 14 ± 2.8 (mean ± standard deviation) in normal mice, which showed significant increase in the lipopolysaccharide (LPS)-administrated model (62 ± 5.0, p = 8.7 × 10−9). In addition to microglia, we found neutrophils that were positive for COX-1. In the early stage of inflammation in the experimental autoimmune uveoretinitis (EAU), COX-1 positive cells, infiltrating from the ciliary body into the retinal outer nuclear layer, were observed. The number of infiltrating COX-1 positive cells correlated with the severity of EAU. Taken together, the increased number of COX-1 positive microglia/macrophage with morphological changes were observed in the retinas of retinal inflammatory disease models. This suggests that COX-1 can be a marker of disease-related activities of microglia/macrophage, which should be useful for the diagnosis of retinal diseases.

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Dynamic Alterations in the Expression of P2Y12 Receptor but Not COX-1 in Platelets from Streptozocin-Induced Diabetic Rats.

Blood ◽

10.1182/blood.v106.11.2638.2638 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2638-2638

Author(s):

Chi Chen ◽

Zili He ◽

Candice Ruby ◽

Waqas Arslan ◽

Madhumati Kalavar ◽

...

Keyword(s):

Mrna Expression ◽

Messenger Rna ◽

Early Stage ◽

Diabetic Rats ◽

Dense Granule ◽

Receptor Expression ◽

P2y12 Receptor ◽

Mrna Levels ◽

Cyclooxygenase 1 ◽

Cox 1

Abstract In patients or animals with established diabetes mellitus, platelets have been shown to be hyperreactive to ADP. This alteration of the platelet function occurs independent of activation of the arachidonate pathway or release of dense granule contents. In the present study, we examined the expression of the platelet ADP-binding receptor, P2Y12, in early stage of streptozocin(STZ)-induced diabetes in rats. Platelet messenger RNA (mRNA) levels for P2Y12 and cyclooxygenase-1 (COX-1) were determined by comparative RT-PCR in 7 control rats on day 0, 6 diabetic rats each on days 2, 3, 4, and 4 diabetic rats on day 7 after intraperitoneal injection of streptozocin (50 mg/kg). The plasma glucose level was 406 ± 10 mg/dl in diabetic rats, significantly greater than 151 ± 12 mg/dl in control rats. After induction of diabetes, the expression of P2Y12 mRNA significantly decreased to 76 ± 9% of the level of control on day 2, 54 ± 6% of control on day 3, reached a nadir of 28 ± 6% of control on day 4, and rose to 43 ± 10% of control on day 7. These dynamic changes of P2Y12 mRNA in platelets reflected the expression of P2Y12 mRNA in megakaryocytes isolated to a high state of purity (>96 %) from rat bone marrow. Specifically, the megakaryocytic P2Y12 mRNA expression in the diabetic rats on days 1, 2 and 3 were 74 ± 8 %, 93 ± 1%, and 117 ± 6% of those in control rats, respectively. Treatment of diabetic rats with insulin reduced the trend of decline in the platelet P2Y12 expression. By contrast, the platelet COX-1 mRNA expression measured on days 2, 3, 4 and 7 after the induction of diabetes was similar to that in the control rats. These results in diabetic rats demonstrate dynamic alterations of the mRNA expression of megakaryocyte-platelet P2Y12, but not of COX-1. The decrease in the P2Y12 receptor expression in early stage of STZ-induced diabetes may serve to attenuate the hyperaggregability of platelets and reduce the risk of vascular thrombosis.

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Assessment of the impact of PTGS1, PTGS2 and CYP2C9 polymorphisms on pain, effectiveness and safety of NSAID therapies

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0014.5497 ◽

2020 ◽

Vol 74 ◽

pp. 504-516

Author(s):

Miriam Dawidowicz ◽

Agnieszka Kula ◽

Paweł Świętochowski ◽

Zofia Ostrowska

Keyword(s):

Enzymatic Activity ◽

Inflammatory Diseases ◽

Aspirin Resistance ◽

Nucleotide Polymorphisms ◽

Cyclooxygenase 1 ◽

Genes Encoding ◽

Cox 2 ◽

Anti Inflammatory ◽

The Impact ◽

Cox 1

Cyclooxygenase 1 and 2 (COX-1, COX-2) are enzymes that catalyze the first reaction in the arachidonic acid pathway. COXs are the therapeutic target for non-steroidal anti-inflammatory drugs. Inhibition of COX enzymatic activity has an analgesic, anti-inflammatory and sometimes antiplatelet effect. Single-nucleotide polymorphisms (SNPs) within genes encoding COX-1 and COX-2 (PTGS1, PTGS2) influence the risk of pain and their intensity in some diseases. They also affect the effectiveness of NSAID therapy in rheumatoid diseases. Moreover, the relationship between certain polymorphisms of PTGS2 and a higher risk of migraine and the development of aspirin resistance in the prophylaxis of cardiovascular diseases was demonstrated. The isoform of cytochrome P450, CYP2C9 has a significant influence on the efficacy and safety of NSAID use. It is responsible for the metabolism and speed of removal of these drugs. The occurrence of some of its polymorphic forms is associated with a decrease in CYP2C9 enzymatic activity, leading to changes in the pharmacokinetics and pharmacodynamics of NSAIDs. The prolonged half-life and decrease in clearance of these drugs lead to serious side effects such as hepatotoxicity, nephrotoxicity, anaphylactic reactions, cardiovascular or gastrointestinal incidents. Studies on polymorphisms of cyclooxygenases and CYP2C9 may improve the safety and efficacy of NSAIDs therapy by adjusting the dose to individual polymorphic variants, as well as expanding knowledge about the pathomechanism of inflammatory diseases.

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Connection of discontinuous segments in early functional recovery from thoracic ossification of the posterior longitudinal ligament treated with posterior instrumented surgery

Journal of Neurosurgery Spine ◽

10.3171/2019.8.spine19604 ◽

2020 ◽

Vol 32 (2) ◽

pp. 200-206

Author(s):

Kei Ando ◽

Kazuyoshi Kobayashi ◽

Masaaki Machino ◽

Kyotaro Ota ◽

Satoshi Tanaka ◽

...

Keyword(s):

Early Stage ◽

Morphological Changes ◽

Japanese Orthopaedic Association ◽

Multislice Ct ◽

Posterior Longitudinal Ligament ◽

Ct Images ◽

Rigid Fixation ◽

Disc Space ◽

Fusion Surgery ◽

Estimated Blood Loss

OBJECTIVEThe objective of this study was to investigate the relationship between morphological changes in thoracic ossification of the posterior longitudinal ligament (T-OPLL) and postoperative neurological recovery after thoracic posterior fusion surgery. Changes of OPLL morphology and postoperative recovery in cases with T-OPLL have not been examined.METHODSIn this prospective study, the authors evaluated data from 44 patients (23 male and 21 female) who underwent posterior decompression and fusion surgery with instrumentation for the treatment of T-OPLL at our hospital. The patients’ mean age at surgery was 50.7 years (range 38–68 years). The minimum duration of follow-up was 2 years. The location of thoracic ossification of the ligamentum flavum (T-OLF), T-OLF at the OPLL level, OPLL morphology, fusion range, estimated blood loss, operative time, pre- and postoperative Japanese Orthopaedic Association (JOA) scores, and JOA recovery rate were investigated. Reconstructed sagittal multislice CT images were obtained before and at 3 and 6 months and 1 and 2 years after surgery. The basic fusion area was 3 vertebrae above and below the OPLL lesion. All parameters were compared between patients with and without continuity across the disc space at the OPLL at 3 and 6 months after surgery.RESULTSThe preoperative morphology of OPLL was discontinuous across the disc space between the rostral and caudal ossification regions on sagittal CT images in all but one of the patients. Postoperatively, these segments became continuous in 42 patients (97.7%; occurring by 6.6 months on average) without progression of OPLL thickness. Patients with continuity at 3 months had significantly lower rates of diabetes mellitus (p < 0.05) and motor palsy in the lower extremities (p < 0.01). The group with continuity also had significantly higher mean postoperative JOA scores at 3 (p < 0.01) and 6 (p < 0.05) months and mean JOA recovery rates at 3 and 6 months (both p < 0.01) after surgery.CONCLUSIONSPreoperatively, discontinuity of rostral and caudal ossified lesions was found on CT in all patients but one of this group of 44 patients who needed surgery for T-OPLL. Rigid fixation with instrumentation may have allowed these segments to connect at the OPLL. Such OPLL continuity at an early stage after surgery may accelerate spinal cord recovery.

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The Ability of Metabolomics to Discriminate Non-Small-Cell Lung Cancer Subtypes Depends on the Stage of the Disease and the Type of Material Studied

Cancers ◽

10.3390/cancers13133314 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3314

Author(s):

Tomasz Kowalczyk ◽

Joanna Kisluk ◽

Karolina Pietrowska ◽

Joanna Godzien ◽

Miroslaw Kozlowski ◽

...

Keyword(s):

Metabolic Pathways ◽

Early Stage ◽

Chronic Obstructive ◽

Liquid Chromatography Mass Spectrometry ◽

Obstructive Pulmonary Disease ◽

Cell Lung Carcinoma ◽

Cancer Subtypes ◽

Inflammatory State ◽

Nsclc Patients

Identification of the NSCLC subtype at an early stage is still quite sophisticated. Metabolomics analysis of tissue and plasma of NSCLC patients may indicate new, and yet unknown, metabolic pathways active in the NSCLC. Our research characterized the metabolomics profile of tissue and plasma of patients with early and advanced NSCLC stage. Samples were subjected to thorough metabolomics analyses using liquid chromatography-mass spectrometry (LC-MS) technique. Tissue and/or plasma samples from 137 NSCLC patients were analyzed. Based on the early stage tissue analysis, more than 200 metabolites differentiating adenocarcinoma (ADC) and squamous cell lung carcinoma (SCC) subtypes as well as normal tissue, were identified. Most of the identified metabolites were amino acids, fatty acids, carnitines, lysoglycerophospholipids, sphingomyelins, plasmalogens and glycerophospholipids. Moreover, metabolites related to N-acyl ethanolamine (NAE) biosynthesis, namely glycerophospho (N-acyl) ethanolamines (GP-NAE), which discriminated early-stage SCC from ADC, have also been identified. On the other hand, the analysis of plasma of chronic obstructive pulmonary disease (COPD) and NSCLC patients allowed exclusion of the metabolites related to the inflammatory state in lungs and the identification of compounds (lysoglycerophospholipids, glycerophospholipids and sphingomyelins) truly characteristic to cancer. Our results, among already known, showed novel, thus far not described, metabolites discriminating NSCLC subtypes, especially in the early stage of cancer. Moreover, the presented results also indicated the activity of new metabolic pathways in NSCLC. Further investigations on the role of NAE biosynthesis pathways in the early stage of NSCLC may reveal new prognostic and diagnostic targets.

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Sustained Systemic Levels of IL-6 Impinge Early Muscle Growth and Induce Muscle Atrophy and Wasting in Adulthood

Cells ◽

10.3390/cells10071816 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1816

Author(s):

Laura Pelosi ◽

Maria Grazia Berardinelli ◽

Laura Forcina ◽

Francesca Ascenzi ◽

Emanuele Rizzuto ◽

...

Keyword(s):

Plasma Levels ◽

Muscle Wasting ◽

Inflammatory Diseases ◽

Early Stage ◽

Muscle Growth ◽

Postnatal Life ◽

Stunted Growth ◽

Skeletal Muscle Wasting ◽

Potential Biomarker ◽

Muscle Homeostasis

IL-6 is a pleiotropic cytokine that can exert different and opposite effects. The muscle-induced and transient expression of IL-6 can act in an autocrine or paracrine manner, stimulating anabolic pathways associated with muscle growth, myogenesis, and with regulation of energy metabolism. In contrast, under pathologic conditions, including muscular dystrophy, cancer associated cachexia, aging, chronic inflammatory diseases, and other pathologies, the plasma levels of IL-6 significantly increase, promoting muscle wasting. Nevertheless, the specific physio-pathological role exerted by IL-6 in the maintenance of differentiated phenotype remains to be addressed. The purpose of this study was to define the role of increased plasma levels of IL-6 on muscle homeostasis and the mechanisms contributing to muscle loss. Here, we reported that increased plasma levels of IL-6 promote alteration in muscle growth at early stage of postnatal life and induce muscle wasting by triggering a shift of the slow-twitch fibers toward a more sensitive fast fiber phenotype. These findings unveil a role for IL-6 as a potential biomarker of stunted growth and skeletal muscle wasting.

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Interactions of gallic acid, resveratrol, quercetin and aspirin at the platelet cyclooxygenase-1 level Functional and modelling studies

Thrombosis and Haemostasis ◽

10.1160/th09-01-0057 ◽

2009 ◽

Vol 102 (08) ◽

pp. 336-346 ◽

Cited By ~ 35

Author(s):

Marilena Crescente ◽

Gisela Jessen ◽

Stefania Momi ◽

Hans-Dieter Höltje ◽

Paolo Gresele ◽

...

Keyword(s):

Salicylic Acid ◽

Platelet Aggregation ◽

Gallic Acid ◽

Molecular Modelling ◽

In Silico Docking ◽

Cyclooxygenase 1 ◽

Modelling Studies ◽

Cox 1

SummaryWhile resveratrol and quercetin possess antiplatelet activity, little is known on the effect of gallic acid on platelets.We studied the interactions of these three different polyphenols among themselves and with aspirin, at the level of platelet cyclooxygenase-1 (COX-1). Both functional (in vitro and in vivo) and molecular modelling approaches were used. All three polyphenols showed comparable antioxidant activity (arachidonic acid [AA]-induced intraplatelet ROS production); however, resveratrol and quercetin, but not gallic acid, inhibited AA-induced platelet aggregation. Gallic acid, similarly to salicylic acid, the major aspirin metabolite, prevented inhibition of AA-induced platelet function by aspirin but, at variance with salicylic acid, also prevented inhibition by the other two polyphenols. Molecular modelling studies, performed by in silico docking the polyphenols into the crystal structure of COX-1, suggested that all compounds form stable complexes into the COX-1 channel, with slightly different but functionally relevant interaction geometries. Experiments in mice showed that gallic acid administered before aspirin, resveratrol or quercetin fully prevented their inhibitory effect on serum TxB2. Finally, a mixture of resveratrol, quercetin and gallic acid, at relative concentrations similar to those contained in most red wines, did not inhibit platelet aggregation, but potentiated sub-inhibitory concentrations of aspirin. Gallic acid interactions with other polyphenols or aspirin at the level of platelet COX-1 might partly explain the complex,and possibly contrasting, effects of wine and other components of the Mediterranean diet on platelets and on the pharmacologic effect of lowdose aspirin.

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Differential expression of cyclooxygenase 1 and cyclooxygenase 2 in the bovine oviduct

Journal of Endocrinology ◽

10.1677/joe.1.06761 ◽

2006 ◽

Vol 191 (1) ◽

pp. 263-274 ◽

Cited By ~ 29

Author(s):

Simone Odau ◽

Christoph Gabler ◽

Christoph Holder ◽

Ralf Einspanier

Keyword(s):

Mrna Expression ◽

Estrous Cycle ◽

Luteal Phase ◽

Cellular Level ◽

Differential Distribution ◽

Cyclooxygenase 1 ◽

Epithelial Cell Layer ◽

Cox 2 ◽

Cycle Dependent ◽

Cox 1

The aim of the present study was to investigate the enzymes for the local prostaglandin (PG) biosynthesis present in the bovine oviduct during the estrous cycle to influence early reproductive events. Bovine oviducts were classified into four phases: pre-ovulatory, post-ovulatory, early-to-mid luteal, and late luteal phase, subdivided further into ipsi- or contralateral site and separated into ampulla or isthmus. Oviductal cells were gained by flushing the oviductal regions. Quantitative real-time reverse transcriptase-PCR was performed for the secretory and cytosolic phospholipases A2 (sPLA2IB, cPLA2α, and cPLA2β) and cyclooxygenases (COX-1 and COX-2) as the first step enzymes of PG synthesis. COX-1 and cPLA2β showed significant highest mRNA expression around and before ovulation compared with the luteal phase respectively. sPLA2IB and cPLA2α mRNA expression was unregulated during the estrous cycle. Regional differences in mRNA content were found for sPLA2IB with higher mRNA expression in the ampulla than in the isthmus. Western blot analysis revealed the highest COX-1 protein content in the early-to-mid luteal phase. Immunohistochemistry demonstrated that COX-1 was localized in epithelial and smooth muscle cells, whereas COX-2 was only localized in epithelial cells. COX-2 showed a differential distribution within the epithelial cell layer suggesting a regulation on a cellular level, although the COX-2 mRNA and protein amounts did not vary throughout the estrous cycle. A COX activity assay of oviductal cells revealed that COX activity originated predominantly from COX-1 than from COX-2. Treatment of primary oviductal cells with 10 pg/ml 17β-estradiol or 10 ng/ml progesterone resulted in a higher expression of COX-2 and cPLA2α, but not of the other enzymes. The expression pattern of these enzymes suggests that an estrous-cycle dependent and region-specific PG synthesis in the bovine oviduct may be required for a successful reproduction.

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The C50T polymorphism of the cyclooxygenase-1 gene and the risk of thrombotic events during low-dose therapy with acetyl salicylic acid

Thrombosis and Haemostasis ◽

10.1160/th08-03-0172 ◽

2008 ◽

Vol 100 (07) ◽

pp. 70-75 ◽

Cited By ~ 22

Author(s):

Martijn G. H. van Oijen ◽

Santosh Sundaresan ◽

Marc A. Brouwer ◽

Rene H. M. te Morsche ◽

Wessel Keuper ◽

...

Keyword(s):

Myocardial Infarction ◽

Platelet Aggregation ◽

Primary Endpoint ◽

Low Dose ◽

Cardiovascular Death ◽

Hazard Ratio ◽

Cyclooxygenase 1 ◽

Thromboxane Production ◽

The Common ◽

Cox 1

SummaryAspirin prevents thrombotic events by inhibiting platelet cyclooxygenase-1 (COX-1), thus reducing thromboxane A2 formation and platelet aggregation. The C50T polymorphism of COX-1 is associated with an impaired inhibition of both thromboxane production and in-vitro platelet aggregation by aspirin. We studied whether this polymorphism is also associated with the risk of clinical thrombotic events in patients using aspirin. We included 496 patients admitted to our Coronary Care Unit for various indications treated with aspirin 80 mg daily. Genotyping for the C50T polymorphism demonstrated that 86.7% of the patients had the common genotype, and 13.3% had the variant (12.5% heterozygous, 0.8% homozygous). Baseline variables were well balanced, except that patients with the common genotype more frequently used aspirin prior to admission compared to those patients with the variant genotype. The composite primary endpoint of myocardial infarction, stroke, and/or cardiovascular death occurred in 98 patients (19.8%). Myocardial infarction occurred in 9.6% of patients, stroke in 1.6%, and cardiovascular death in 12.1%.The unadjusted hazard ratio (95% CI) for the primary endpoint for patients with the variant versus the common genotype was 1.07 (0.62–1.85), p=0.8.The adjusted hazard ratio was 0.86 (0.49–1.50), p=0.6. In prior laboratory studies the COX-1 C50T polymorphism was associated with an impaired inhibitory effect of aspirin on thromboxane production and platelet function. However, in this cohort of patients using low-dose aspirin for secondary prevention the polymorphism was not associated with a higher risk of atherothrombotic events.

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Staphylococcal infection and pathomurfological characteristic of the pituitary-adrenal-thyroid system

NATURE AND SCIENCE ◽

10.36719/2707-1146/04/69-73 ◽

2020 ◽

Vol 03 (04) ◽

pp. 69-73

Author(s):

Samira Mammadhasan Yagubova ◽

◽

Elchin Chingiz Akbarov ◽

Tarana Nadir Mirzayeva ◽

◽

...

Keyword(s):

Structural Changes ◽

Adrenal Glands ◽

Early Stage ◽

Morphological Changes ◽

Endocrine System ◽

Staphylococcal Infection ◽

The Body ◽

Glandular Cells ◽

Exogenous Factors ◽

Specific Symptoms

During the staphylococcal infection, changes in the interaction of glandular cells, dystrophic and disorganizing pathologies in tissues, especially acute structural and hemodynamic changes in the stroma of the glands in the pituitary-adrenal-thyroid system, develop from the first day of the experiment. At the end of the experiment, on the background of a decrease in exudative processes, fibroplastic reactions are significantly activated, resulting in signs of incomplete regeneration – mainly sclerotic processes and cystic-atrophic changes in the parenchyma. Structural changes in tissues in the early stages of staphylococcal infection and the dynamics of development are characterized by specific symptoms in each of the glands. Since the pituitary gland is exposed to endogenous and exogenous factors earlier and more often than the adrenal glands, and the adrenal glands are earlier than the thyroid gland, dystrophic and destructive changes in the pituitary and adrenal glands are more pronounced at the early stage of the experiment. These morphological changes can change the hormonal status of the body and lead to dysfunction of the endocrine system as a whole – a decrease in the functional activity of the glands to some extent, and even inhibition of adenohypophyseal cells. Key words: staphylococcal infection, peritonitis, pituitary, adrenal and thyroid glands

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The role of celecoxib as a potential inhibitor in the treatment of inflammatory diseases - a review

Current Medicinal Chemistry ◽

10.2174/0929867328666210910125229 ◽

2021 ◽

Vol 28 ◽

Author(s):

Josiane Viana Cruz ◽

Joaquín María Campos Rosa ◽

Njogu Mark Kimani ◽

Silvana Giuliatti ◽

Cleydson Breno Rodrigues dos Santos

Keyword(s):

Side Effects ◽

Inflammatory Diseases ◽

Structural Basis ◽

Potential Inhibitor ◽

Cyclooxygenase 1 ◽

Inflammatory Drugs ◽

Cox 2 ◽

Anti Inflammatory ◽

Cox 2 Inhibitors

: This article presents a simplified view of celecoxib as a potential inhibitor in the treatment of inflammatory diseases. The enzyme cyclooxygenase (COX) has, predominantly, two isoforms called cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). The former plays a constitutive role that is related to homeostatic effects in renal and platelets, while the latter is mainly responsible for induction of inflammatory effects. Since COX-2 plays an important role in the pathogenesis of inflammatory diseases, it has been signaled as a target for the planning of anti-inflammatory intermediates. Many inhibitors developed and planned for COX-2 inhibition have presented side effects to humans, mainly in the gastrointestinal and/or cardiovascular tract. Therefore, it is necessary to design new potential COX-2 inhibitors, which are relatively safe and without side effects. To this end, of the generation of non-steroidal anti-inflammatory drugs from “coxibs”, celecoxib is the only potent selective COX-2 inhibitor that is still commercially available. Thus, the compound celecoxib became a commercial prototype inhibitor for the development of anti-inflammatory agents for COX-2 enzyme. In this review, we provide highlights where such inhibition should provide a structural basis for the design of promising new non-steroidal anti-inflammatory drugs (NSAIDs) which act as COX-2 inhibitors with lesser side effects on the human body.

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