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Pham L, Jiang R, Liu Z, Nguyen M, Nguyen Y, Gong Y, Bi Y, Kim HR, Kim YR, Kim G. Synthesis of 9-Cinnamyl-9 H-purine Derivatives as Novel TLR4/MyD88/NF-κB Pathway Inhibitors for Anti-inflammatory Effects. ACS Med Chem Lett 2023; 14:1839-1847. [PMID: 38116448 PMCID: PMC10726439 DOI: 10.1021/acsmedchemlett.3c00437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/28/2023] [Accepted: 11/20/2023] [Indexed: 12/21/2023] Open
Abstract
The novel 9-cinnamyl-9H-purine skeleton, inspired by resveratrol and curcumin, was developed to avoid a pan-assay interference compound (PAINS) related to invalid metabolic pancreas activity (IMPS). It replaced the phenol group with purine analogues, the building blocks of DNA and RNA. Alterations to the hydroxyl group in the cinnamyl group, such as H, Me, or F substitutions, were made to impede its oxidation to a PAINS-associated quinone. Among the compounds tested, 5e significantly inhibited nitric oxide production in LPS-induced macrophages (IC50: 6.4 vs 26.4 μM for resveratrol). 5e also reduced pro-inflammatory cytokine levels (IL-6, TNF-α, IL-1β) and lowered iNOS and COX-2 protein levels. Mechanistically, 5e disrupted the TLR4-MyD88 protein interaction, leading to the suppression of the NF-κB signaling pathway suppression. In an atopic dermatitis mouse model, 5e reduced ear edema and inflammation. These findings indicate that the novel 9-cinnamyl-9H-purine skeleton provides therapeutic insight into treating various human diseases by regulating inflammation.
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Affiliation(s)
- Linh Pham
- College
of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Korea
| | - Rui Jiang
- College
of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Korea
| | - Zijing Liu
- College
of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Korea
| | - Mai Nguyen
- College
of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Korea
| | - Yen Nguyen
- College
of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Korea
| | - Yue Gong
- College
of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Korea
| | - Yanran Bi
- College
of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Korea
| | - Hong-Rae Kim
- Department
of Biomedical Sciences, College of Medicine, Korea University, Seoul 02708, Korea
| | - Young Ran Kim
- College
of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Korea
| | - Gyudong Kim
- College
of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Korea
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2
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Feng L, A L, Li H, Mu X, Ta N, Bai L, Fu M, Chen Y. Pharmacological Mechanism of Aucklandiae Radix against Gastric Ulcer Based on Network Pharmacology and In Vivo Experiment. Medicina (B Aires) 2023; 59:medicina59040666. [PMID: 37109624 PMCID: PMC10140907 DOI: 10.3390/medicina59040666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/13/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023] Open
Abstract
Background and Objectives: Aucklandiae Radix is a well-known medicinal herb that is often used to treat gastric ulcer, but its molecular mechanism of anti-ulcer action is poorly understood. This research aimed to reveal the potential active components, core targets, and mechanisms of Aucklandiae Radix in treating gastric ulcer by combining network pharmacology and animal experimentation. Materials and Methods: First, a network pharmacology strategy was used to predict the main components, candidate targets, and potential signaling pathways. Molecular docking was then used to confirm the binding affinity between the main components and primary targets. Finally, rats were treated with indomethacin 30 mg/kg to establish a gastric ulcer model. Aucklandiae Radix extract (0.15, 0.3, and 0.6 g/kg) was pre-treated in rats by oral gavage for 14 days, and the protective effect and candidate targets of network pharmacology were validated through morphological observation, pathological staining, and biochemical index detection. Results: A total of eight potential active components and 331 predicted targets were screened from Aucklandiae Radix, 37 of which were common targets with gastric ulcer. According to the component–target network and protein-protein interaction (PPI) network, stigmasterol, mairin, sitosterol, and dehydrocostus lactone were identified as the key components, and RAC-alpha serine/threonine-protein kinase (AKT1), prostaglandin-endoperoxide synthase 2 (PTGS2), interleukin 1 beta (IL1B), caspase-3 (CASP3), and CASP8 were selected as the core targets. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment results revealed the pharmacological mechanism of Aucklandiae Radix against gastric ulcer related to many biological processes and pathways, including antibacterial, anti-inflammatory, prostaglandin receptor response, and apoptosis. Molecular docking verification showed that the key components and core targets had good binding affinities. In the in vivo experiments, Aucklandiae Radix notably relieved the gastric ulcer by reducing the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and myeloperoxidase (MPO) while improving the gastric histopathological features. Conclusion: The overall findings suggest that Aucklandiae Radix treats gastric ulcer with a multi-component, multi-target, and multi-mechanism model.
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Affiliation(s)
- Lan Feng
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou 571199, China
| | - Lisha A
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou 571199, China
| | - Huifang Li
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China
| | - Xiyele Mu
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China
| | - Na Ta
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China
| | - Laxinamujila Bai
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China
| | - Minghai Fu
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou 571199, China
- Correspondence: (M.F.); (Y.C.)
| | - Yongsheng Chen
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China
- Correspondence: (M.F.); (Y.C.)
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3
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Stopschinski BE, Weideman RA, McMahan D, Jacob DA, Little BB, Chiang HS, Saez Calveras N, Stuve O. Microglia as a cellular target of diclofenac therapy in Alzheimer's disease. Ther Adv Neurol Disord 2023; 16:17562864231156674. [PMID: 36875711 PMCID: PMC9974624 DOI: 10.1177/17562864231156674] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 01/26/2023] [Indexed: 03/07/2023] Open
Abstract
Alzheimer's disease (AD) is an untreatable cause of dementia, and new therapeutic approaches are urgently needed. AD pathology is defined by extracellular amyloid plaques and intracellular neurofibrillary tangles. Research of the past decades has suggested that neuroinflammation plays a critical role in the pathophysiology of AD. This has led to the idea that anti-inflammatory treatments might be beneficial. Early studies investigated non-steroidal anti-inflammatory drugs (NSAIDS) such as indomethacin, celecoxib, ibuprofen, and naproxen, which had no benefit. More recently, protective effects of diclofenac and NSAIDs in the fenamate group have been reported. Diclofenac decreased the frequency of AD significantly compared to other NSAIDs in a large retrospective cohort study. Diclofenac and fenamates share similar chemical structures, and evidence from cell and mouse models suggests that they inhibit the release of pro-inflammatory mediators from microglia with leads to the reduction of AD pathology. Here, we review the potential role of diclofenac and NSAIDs in the fenamate group for targeting AD pathology with a focus on its potential effects on microglia.
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Affiliation(s)
- Barbara E Stopschinski
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | | - Danni McMahan
- Pharmacy Service, Dallas VA Medical Center, Dallas, TX, USA
| | - David A Jacob
- Veterans Integrated Service Network 17, Arlington, TX, USA
| | - Bertis B Little
- School of Public Health and Information Sciences, University of Louisville, Louisville, KY, USA
| | - Hsueh-Sheng Chiang
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Nil Saez Calveras
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Olaf Stuve
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Neurology Section, Dallas VA Medical Center, 4500 South Lancaster Road, Dallas, TX 75216, USA
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Barranco R, Bonsignore A, Ventura F. Immunohistochemistry in postmortem diagnosis of acute cerebral hypoxia and ischemia: A systematic review. Medicine (Baltimore) 2021; 100:e26486. [PMID: 34160462 PMCID: PMC8238305 DOI: 10.1097/md.0000000000026486] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 05/28/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND : Discovery of evidence of acute brain ischemia or hypoxia and its differentiation from agonal hypoxia represents a task of interest but extremely difficult in forensic neuropathology. Generally, more than 50% of forensic autopsies indicate evidence of brain induced functional arrest of the organ system, which can be the result of a hypoxic/ischemic brain event. Even if the brain is the target organ of hypoxic/ischemic damage, at present, there are no specific neuropathological (macroscopic and histological) findings of hypoxic damage (such as in drowning, hanging, intoxication with carbon monoxide) or acute ischemia. In fact, the first histological signs appear after at least 4 to 6 hours. Numerous authors have pointed out how an immunohistochemical analysis could help diagnose acute cerebral hypoxia/ischemia.Data sources: This review was based on articles published in PubMed and Scopus databases in the past 25 years, with the following keywords "immunohistochemical markers," "acute cerebral ischemia," "ischemic or hypoxic brain damage," and "acute cerebral hypoxia". OBJECTIVES : Original articles and reviews on this topic were selected. The purpose of this review is to analyze and summarize the markers studied so far and to consider the limits of immunohistochemistry that exist to date in this specific field of forensic pathology. RESULTS : We identified 13 markers that had been examined (in previous studies) for this purpose. In our opinion, it is difficult to identify reliable and confirmed biomarkers from multiple studies in order to support a postmortem diagnosis of acute cerebral hypoxia/ischemia. Microtubule-associated protein 2 (MAP2) is the most researched marker in the literature and the results obtained have proven to be quite useful. CONCLUSION Immunohistochemistry has provided interesting and promising results, but further studies are needed in order to confirm and apply them in standard forensic practice.
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Kumari P, Singh P, Kaur J, Bhatti R. Design, Synthesis, and Activity Evaluation of Stereoconfigured Tartarate Derivatives as Potential Anti-inflammatory Agents In Vitro and In Vivo. J Med Chem 2021; 64:9550-9566. [PMID: 34137625 DOI: 10.1021/acs.jmedchem.1c00880] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Preclinical and clinical data reveal that inflammation is strongly correlated with the pathogenesis of a number of diseases including those of cancer, Alzheimer, and diabetes. The inflammatory cascade involves a multitude of cytokines ending ultimately with the activation of COX-2/LOX for the production of prostaglandins and leukotrienes. While the available inhibitors for these enzymes suffer from nonoptimal selectivity, in particular for COX-2, we present here the results of purposely designed tartarate derivatives that exhibit favorable selectivity and significant effectiveness against COX-2 and LOX. Integrated approaches of molecular simulation, organic synthesis, and biochemical/physical experiments identified 15 inhibiting COX-2 and LOX with respective IC50 4 and 7 nM. At a dose of 5 mg kg-1 to Swiss albino mice, 15 reversed algesia by 65% and inflammation by 33% in 2-3 h. We find good agreement between experiments and simulations and use the simulations to rationalize our observations.
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Hajhashemi V, Ghanadian M, Palizaban A, Mahnam K, Eshaghi H, Gheisari B, Sadeghi-Aliabadi H. Cycloarta-23-ene-3beta,25-diol a pentacyclic steroid from Euphorbia spinidens, as COX inhibitor with molecular docking, and in vivo study of its analgesic and anti-inflammatory activities in male swiss mice and wistar rats. Prostaglandins Other Lipid Mediat 2020; 150:106473. [PMID: 32634574 DOI: 10.1016/j.prostaglandins.2020.106473] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 06/03/2020] [Accepted: 07/01/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND AND AIMS Euphorbia is a large genus of flowering plants. In Iran, some plants of this family have been used in the treatment of inflammatory disorders and also to relieve back pain. Euphorbia spinidens is a rich source of Cycloarta-23-ene-3beta,25-diol. Cycloartane structures are the starting material for the synthesis of plant steroids, and the aim of this study is to demonstrate COX inhibitory activity, molecular docking and in vivo approach of anti-inflammatory activity of cycloartane compound isolated from Euphorbia spinidens. MATERIAL AND METHODS Plant material was extracted with acetone-chloroform and submitted to column chromatography for fractionation. Based on preliminary 1H-NMR spectra, cycloartane fraction was selected and purified by repeated recycle HPLC system. The structure and purity of compound were determined by 1H and 13C-NMR, HPTLC, and mass spectra. Inhibitory activities of the tested compounds on COX-1 and COX-2 were evaluated by a colorimetric COX (ovine) inhibitor screening method. Vero cells were used to assess the toxicity against the normal cells, and calculate the selectivity index. COX inhibitory activity results were evaluated and confirmed by molecular docking experiments. In the in vivo approach, analgesic activity was assessed by acetic acid-induced abdominal writhing and formalin tests. Croton oil-induced ear edema in mice and carrageenan-induced rat paw edema in rats were used to evaluate anti-inflammatory activity. Pain tests were carried out on male Swiss mice (25-35 g). Male Wistar rats (160-200 g) were used for the carrageenan test. RESULTS Cycloart-23-ene-3β,25-diol showedin vitro cyclooxygenase 1 and 2 inhibitory activities with more selectivity for COX-2. Molecular docking by predicting binding energies in COX protein receptors confirmed in vitro COX inhibitory results, and determined the best position for ligand in COX receptors along with its residue interactions in receptor pockets, which must be considered for designing of their inhibitors. In the in vivo studies, cycloartane inhibited significantly acetic acid-induced abdominal contractions and formalin-induced licking behavior at a dose of 200 mg/kg. The same dose reduced croton oil ear edema in mice and carrageenan-induced paw edema in rats. CONCLUSION Therefore, according to these findings, cycloart-23-ene-3beta,25-diol showed promising analgesic and anti-inflammatory effects with low toxicity against normal cells and can be suggested as a template lead for designing anti-inflammatory compounds with good selectivity index, and potency for COX-2 inhibitory activity.
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Affiliation(s)
- Valiollah Hajhashemi
- Pharmacology department, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Mustafa Ghanadian
- Pharmacognosy department, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran; Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Abbasali Palizaban
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Karim Mahnam
- Biology Department, Faculty of Science, Shahrekord University, Shahrekord, Iran.
| | - Hamed Eshaghi
- Pharmacognosy department, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Bahareh Gheisari
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Hojjat Sadeghi-Aliabadi
- Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
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The quest for effective pharmacological suppression of neointimal hyperplasia. Curr Probl Surg 2020; 57:100807. [PMID: 32771085 DOI: 10.1016/j.cpsurg.2020.100807] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 04/22/2020] [Indexed: 12/15/2022]
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Morgan A, Kondev V, Bedse G, Baldi R, Marcus D, Patel S. Cyclooxygenase-2 inhibition reduces anxiety-like behavior and normalizes enhanced amygdala glutamatergic transmission following chronic oral corticosterone treatment. Neurobiol Stress 2019; 11:100190. [PMID: 31467944 PMCID: PMC6710559 DOI: 10.1016/j.ynstr.2019.100190] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/27/2019] [Accepted: 08/05/2019] [Indexed: 12/16/2022] Open
Abstract
Chronic stress increases the probability of receiving an anxiety, depression, or chronic illness diagnosis. Pharmacological interventions that reduce the behavioral and physiological effects of chronic stress in animal models may represent novel approaches for the treatment of stress-related psychiatric disorders. Here, we examined the effects of cyclooxygenase-2 (COX-2) inhibition on anxiety-like behaviors and amygdala glutamatergic signaling after chronic non-invasive oral corticosterone (CORT) administration in mice. Treatment with the highly selective COX-2 inhibitor Lumiracoxib (LMX) reversed anxiety-like behavior induced by chronic CORT. Specifically, acute and repeated administration of LMX 5 mg kg−1 reduced chronic CORT-induced anxiety-like behavior measured using the elevated-plus maze, elevated-zero maze, and light-dark box tests. In contrast, LMX did not affect anxiety-like behaviors in naïve mice. Ex vivo electrophysiology studies revealed that repeated LMX treatment normalized chronic CORT-induced increases in spontaneous excitatory glutamatergic currents recorded from anterior, but not posterior, basolateral amygdala neurons. These data indicate COX-2 inhibition can reverse chronic CORT-induced increases in anxiety-like behaviors and amygdala glutamatergic signaling, and support further clinical investigation of selective COX-2 inhibitors for the treatment of affective and stress-related psychiatric disorders.
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Affiliation(s)
- Amanda Morgan
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Veronika Kondev
- The Vanderbilt Brain Institute, Vanderbilt University School of Medicine, TN, 37232, USA
| | - Gaurav Bedse
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Rita Baldi
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - David Marcus
- The Vanderbilt Brain Institute, Vanderbilt University School of Medicine, TN, 37232, USA
| | - Sachin Patel
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.,Department of Molecular Physiology & Biophysics and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.,The Vanderbilt Brain Institute, Vanderbilt University School of Medicine, TN, 37232, USA
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Li Y, Zou L, Li T, Lai D, Wu Y, Qin S. Mogroside V inhibits LPS-induced COX-2 expression/ROS production and overexpression of HO-1 by blocking phosphorylation of AKT1 in RAW264.7 cells. Acta Biochim Biophys Sin (Shanghai) 2019; 51:365-374. [PMID: 30877761 DOI: 10.1093/abbs/gmz014] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 01/28/2019] [Accepted: 01/30/2019] [Indexed: 11/14/2022] Open
Abstract
Momordica grosvenori is a valuable edible plant with medicinal purposes, and it is widely used in medicated diets and traditional Chinese medicine in Asia. Mogroside V (MV), the main bioactive component from M. grosvenori, is commonly used as a natural sweetener. M. grosvenori extracts have been reported to exert potent anti-inflammatory property, however the underlying molecular mechanism still remains unknown. In the present study, the biological effect of MV in inflammation was investigated in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The ELISA and western blot analysis results showed that MV significantly inhibited LPS-induced prostaglandin E2 (PGE2) production and cyclooxygenase-2 (COX-2) expression. MV markedly decreased the phosphorylation of IκB-α, increased IκB-α, and reduced nuclear p-65 and C/EBPδ. Furthermore, MV attenuated LPS-induced phosphorylation of MAPKs and AKT1, and only the phosphorylation status of AKT1 was found to be consistent with the expression trend of COX-2. Moreover, MV reduced ROS level and restored overexpressed HO-1 and AP-1 to basal level, which can be markedly reversed by AKT1 inhibitor LY294002. These results revealed that AKT1 plays a key role in LPS-induced COX-2 expression, and acts as a mediator to keep the redox balance in LPS-stimulated RAW264.7 cells. MV exerts anti-inflammatory property by blocking AKT1-mediated NF-κB and C/EBPδ activation, ROS generation and AP-1/ HO-1 expression. Therefore, the present study indicated that MV has a significant chemopreventive effect on the inflammatory lesions and suggested that AKT1 is a potential specific target of MV for relieving inflammation.
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Affiliation(s)
- Yong Li
- Core Research Program 1515, Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha, China
| | - Luyan Zou
- Core Research Program 1515, Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha, China
| | - Tao Li
- Core Research Program 1515, Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha, China
| | - Dengni Lai
- Core Research Program 1515, Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha, China
| | - Yanyang Wu
- Core Research Program 1515, Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha, China
| | - Si Qin
- Core Research Program 1515, Key Laboratory for Food Science and Biotechnology of Hunan Province, College of Food Science and Technology, Hunan Agricultural University, Changsha, China
- The United Graduate School of Agricultural Sciences, Faculty of Agriculture, Kagoshima University, Korimoto 1-21-24, Kagoshima, Japan
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Meurer M, Ebert K, Schweda F, Höcherl K. The renal vasodilatory effect of prostaglandins is ameliorated in isolated-perfused kidneys of endotoxemic mice. Pflugers Arch 2018; 470:1691-1703. [DOI: 10.1007/s00424-018-2183-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 07/09/2018] [Accepted: 07/10/2018] [Indexed: 12/29/2022]
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Hernández-Castellano LE, Özçelik R, Hernandez LL, Bruckmaier RM. Short communication: Supplementation of colostrum and milk with 5-hydroxy-l-tryptophan affects immune factors but not growth performance in newborn calves. J Dairy Sci 2018; 101:794-800. [DOI: 10.3168/jds.2017-13501] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 08/31/2017] [Indexed: 01/15/2023]
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Liu S, Wang F, Liu J, Jin P, Wang X, Yang L, Xi S. ATF2 partly mediated the expressions of proliferative factors and inhibited pro-inflammatory factors' secretion in arsenite-treated human uroepithelial cells. Toxicol Res (Camb) 2017; 6:468-476. [PMID: 30090515 PMCID: PMC6062379 DOI: 10.1039/c6tx00407e] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 03/28/2017] [Indexed: 11/21/2022] Open
Abstract
Inorganic arsenic (iAs) could induce the expression of activating transcription factor-2 (ATF2) in the human urinary bladder epithelial cell line (SV-HUC-1 cells). ATF2, as a member of the bZIP transcription factor family, has been implicated in a transcriptional response leading to cell growth, migration and malignant tumor progression. However, little is known about the effects of ATF2 on proliferative factors in iAs treated human urothelial cells. In this study, ATF2 siRNA was employed to investigate the relationship between ATF2 activation and the expressions of proliferative factors, such as BCL2, cyclin D1, COX-2, MMP1 and PCNA, and pro-inflammatory factors (TNFα, TGFα and IL-8) in SV-HUC-1 cells. The results showed that low concentration arsenite increased the expressions of proliferative factors BCL2, cyclin D1, COX-2, MMP1 and PCNA in SV-HUC-1 cells, and ATF2 siRNA partly decreased the expressions of BCL2, cyclin D1, and COX-2. A neutralizing antibody of IL-8 was used for attenuating the levels of IL-8 and neutralizing antibody of IL-8 did not relieve the expressions of ATF2 and proliferative factors induced by arsenite in SV-HUC-1 cells. In addition, ATF2 knockdown did not decrease the expressions of pro-inflammatory cytokines induced by arsenite in SV-HUC-1 cells, but dramatically increased mRNA expressions of TNFα, TGFα and IL-8 under arsenite and non-arsenite conditions. In conclusion, our present study indicated that ATF2, but not IL-8, played a partial role in the expressions of proliferative factors induced by arsenite in human uroepithelial cells.
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Affiliation(s)
- Shengnan Liu
- Department of Environmental and Occupational Health , School of Public Health , China Medical University , No. 77 Puhe Road , Shenyang North New Area , Shenyang , Liaoning Province 110122 , People's Republic of China .
| | - Fei Wang
- Department of Environmental and Occupational Health , School of Public Health , China Medical University , No. 77 Puhe Road , Shenyang North New Area , Shenyang , Liaoning Province 110122 , People's Republic of China .
| | - Jieyu Liu
- Department of Environmental and Occupational Health , School of Public Health , China Medical University , No. 77 Puhe Road , Shenyang North New Area , Shenyang , Liaoning Province 110122 , People's Republic of China .
| | - Peiyu Jin
- Department of Environmental and Occupational Health , School of Public Health , China Medical University , No. 77 Puhe Road , Shenyang North New Area , Shenyang , Liaoning Province 110122 , People's Republic of China .
| | - Xiaoyan Wang
- Department of Environmental and Occupational Health , School of Public Health , China Medical University , No. 77 Puhe Road , Shenyang North New Area , Shenyang , Liaoning Province 110122 , People's Republic of China .
| | - Li Yang
- Department of Environmental and Occupational Health , School of Public Health , China Medical University , No. 77 Puhe Road , Shenyang North New Area , Shenyang , Liaoning Province 110122 , People's Republic of China .
| | - Shuhua Xi
- Department of Environmental and Occupational Health , School of Public Health , China Medical University , No. 77 Puhe Road , Shenyang North New Area , Shenyang , Liaoning Province 110122 , People's Republic of China .
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Moghaddasi M, Taati M, Asadian P, Khalatbary AR, Asaei R, Pajouhi N. The effects of two-stage carotid occlusion on spatial memory and pro-inflammatory markers in the hippocampus of rats. J Physiol Sci 2017; 67:415-423. [PMID: 27470129 PMCID: PMC10717598 DOI: 10.1007/s12576-016-0474-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2015] [Accepted: 07/13/2016] [Indexed: 02/07/2023]
Abstract
The purpose of this study was to evaluate the effects of cerebral hypoperfusion on cognitive ability, TNFα, IL1β and PGE2 levels in both hippocampi in a modified two-vessel occlusion model. Both common carotid arteries of adult male Wistar rats were permanently occluded with an interval of 1 week between occlusions. Learning and memory were significantly decreased after 1 month. This reduction was not significant after 2 months, which may be attributed to blood flow compensation. The TNFα level was significantly increased after 3 h and 1 day. IL1β was significantly increased after 1 day. After a week there was no significant difference in pro-inflammatory levels. Furthermore, there was no difference between right and left hippocampi. It is possible that TNFα and IL1β elevation initiates pathologic processes that contribute to memory impairment.
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Affiliation(s)
- Mehrnoush Moghaddasi
- Department of Physiology, Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran.
| | - Majid Taati
- Department of Pathobiology, Faculty of Veterinary Medicine, Lorestan University, Khorramabad, Iran
| | - Payman Asadian
- Ontario Veterinary College, University of Guelph, Guelph, Canada
| | - Ali Reza Khalatbary
- Department of Anatomy, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Raheleh Asaei
- Department of Physiology, Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Naser Pajouhi
- Department of Physiology, Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
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Seo MJ, Oh DK. Prostaglandin synthases: Molecular characterization and involvement in prostaglandin biosynthesis. Prog Lipid Res 2017; 66:50-68. [DOI: 10.1016/j.plipres.2017.04.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Revised: 03/30/2017] [Accepted: 04/01/2017] [Indexed: 01/30/2023]
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Guevara-Balcazar G, Ramirez-Sanchez I, Mera-Jimenez E, Rubio-Gayosso I, Aguilar-Najera ME, Castillo-Hernandez MC. Participation of COX-1 and COX-2 in the contractile effect of phenylephrine in prepubescent and old rats. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY 2017; 21:407-413. [PMID: 28706454 PMCID: PMC5507779 DOI: 10.4196/kjpp.2017.21.4.407] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 03/08/2017] [Accepted: 04/04/2017] [Indexed: 12/01/2022]
Abstract
Vascular reactivity can be influenced by the vascular region, animal age, and pathologies present. Prostaglandins (produced by COX-1 and COX-2) play an important role in the contractile response to phenylephrine in the abdominal aorta of young rats. Although these COXs are found in many tissues, their distribution and role in vascular reactivity are not clear. At a vascular level, they take part in the homeostasis functions involved in many physiological and pathologic processes (e.g., arterial pressure and inflammatory processes). The aim of this study was to analyze changes in the contractile response to phenylephrine of thoracic/abdominal aorta and the coronary artery during aging in rats. Three groups of rats were formed and sacrificed at three distinct ages: prepubescent, young and old adult. The results suggest that there is a higher participation of prostanoids in the contractile effect of phenylephrine in pre-pubescent rats, and a lower participation of the same in old rats. Contrarily, there seems to be a higher participation of prostanoids in the contractile response of the coronary artery of older than pre-pubescent rats. Considering that the changes in the expression of COX-2 were similar for the three age groups and the two tissues tested, and that expression of COX-1 is apparently greater in older rats, COX-1 and COX-2 may lose functionality in relation to their corresponding receptors during aging in rats.
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Affiliation(s)
- Gustavo Guevara-Balcazar
- Cardiovascular Pharmacology and Hyperbaric Experimental Medicine, Escuela Superior de Medicina, Instituto Politecnico Nacional, 11340 Mexico City, Mexico
| | - Israel Ramirez-Sanchez
- Cardiovascular Pharmacology and Hyperbaric Experimental Medicine, Escuela Superior de Medicina, Instituto Politecnico Nacional, 11340 Mexico City, Mexico
| | - Elvia Mera-Jimenez
- Cardiovascular Pharmacology and Hyperbaric Experimental Medicine, Escuela Superior de Medicina, Instituto Politecnico Nacional, 11340 Mexico City, Mexico
| | - Ivan Rubio-Gayosso
- Cardiovascular Pharmacology and Hyperbaric Experimental Medicine, Escuela Superior de Medicina, Instituto Politecnico Nacional, 11340 Mexico City, Mexico
| | - Maria Eugenia Aguilar-Najera
- Cardiovascular Pharmacology and Hyperbaric Experimental Medicine, Escuela Superior de Medicina, Instituto Politecnico Nacional, 11340 Mexico City, Mexico
| | - Maria C. Castillo-Hernandez
- Cardiovascular Pharmacology and Hyperbaric Experimental Medicine, Escuela Superior de Medicina, Instituto Politecnico Nacional, 11340 Mexico City, Mexico
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Ogorodnikov A, Kargapolova Y, Danckwardt S. Processing and transcriptome expansion at the mRNA 3' end in health and disease: finding the right end. Pflugers Arch 2016; 468:993-1012. [PMID: 27220521 PMCID: PMC4893057 DOI: 10.1007/s00424-016-1828-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 04/19/2016] [Indexed: 01/09/2023]
Abstract
The human transcriptome is highly dynamic, with each cell type, tissue, and organ system expressing an ensemble of transcript isoforms that give rise to considerable diversity. Apart from alternative splicing affecting the "body" of the transcripts, extensive transcriptome diversification occurs at the 3' end. Transcripts differing at the 3' end can have profound physiological effects by encoding proteins with distinct functions or regulatory properties or by affecting the mRNA fate via the inclusion or exclusion of regulatory elements (such as miRNA or protein binding sites). Importantly, the dynamic regulation at the 3' end is associated with various (patho)physiological processes, including the immune regulation but also tumorigenesis. Here, we recapitulate the mechanisms of constitutive mRNA 3' end processing and review the current understanding of the dynamically regulated diversity at the transcriptome 3' end. We illustrate the medical importance by presenting examples that are associated with perturbations of this process and indicate resulting implications for molecular diagnostics as well as potentially arising novel therapeutic strategies.
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Affiliation(s)
- Anton Ogorodnikov
- Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Langenbeckstr 1, 55131, Mainz, Germany
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr 1, 55131, Mainz, Germany
| | - Yulia Kargapolova
- Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Langenbeckstr 1, 55131, Mainz, Germany
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr 1, 55131, Mainz, Germany
| | - Sven Danckwardt
- Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Langenbeckstr 1, 55131, Mainz, Germany.
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr 1, 55131, Mainz, Germany.
- German Center for Cardiovascular Research (DZHK), Langenbeckstr 1, 55131, Mainz, Germany.
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Pathophysiological Roles of Cyclooxygenases and Prostaglandins in the Central Nervous System. Mol Neurobiol 2015; 53:4754-71. [PMID: 26328537 DOI: 10.1007/s12035-015-9355-3] [Citation(s) in RCA: 135] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 07/07/2015] [Indexed: 01/01/2023]
Abstract
Cyclooxygenases (COXs) oxidize arachidonic acid to prostaglandin (PG) G2 and H2 followed by PG synthases that generates PGs and thromboxane (TX) A2. COXs are divided into COX-1 and COX-2. In the central nervous system, COX-1 is constitutively expressed in neurons, astrocytes, and microglial cells. COX-2 is upregulated in these cells under pathophysiological conditions. In hippocampal long-term potentiation, COX-2, PGE synthase, and PGE2 are induced in post-synaptic neurons. PGE2 acts pre-synaptic EP2 receptor, generates cAMP, stimulates protein kinase A, modulates voltage-dependent calcium channel, facilitates glutamatergic synaptic transmission, and potentiates long-term plasticity. PGD2, PGE2, and PGI2 exhibit neuroprotective effects via Gs-coupled DP1, EP2/EP4, and IP receptors, respectively. COX-2, PGD2, PGE2, PGF2α, and TXA2 are elevated in stroke. COX-2 inhibitors exhibit neuroprotective effects in vivo and in vitro models of stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, and schizophrenia, suggesting neurotoxicities of COX products. PGE2, PGF2α, and TXA2 can contribute to the neurodegeneration via EP1, FP, and TP receptors, respectively, which are coupled with Gq, stimulate phospholipase C and cleave phosphatidylinositol diphosphate to produce inositol triphosphate and diacylglycerol. Inositol triphosphate binds to inositol triphosphate receptor in endoplasmic reticulum, releases calcium, and results in increasing intracellular calcium concentrations. Diacylglycerol activates calcium-dependent protein kinases. PGE2 disrupts Ca(2+) homeostasis by impairing Na(+)-Ca(2+) exchange via EP1, resulting in the excess Ca(2+) accumulation. Neither PGE2, PGF2α, nor TXA2 causes neuronal cell death by itself, suggesting that they might enhance the ischemia-induced neurodegeneration. Alternatively, PGE2 is non-enzymatically dehydrated to a cyclopentenone PGA2, which induces neuronal cell death. Although PGD2 induces neuronal apoptosis after a lag time, neither DP1 nor DP2 is involved in the neurotoxicity. As well as PGE2, PGD2 is non-enzymatically dehydrated to a cyclopentenone 15-deoxy-Δ(12,14)-PGJ2, which induces neuronal apoptosis without a lag time. However, neurotoxicities of these cyclopentenones are independent of their receptors. The COX-2 inhibitor inhibits both the anchorage-dependent and anchorage-independent growth of glioma cell lines regardless of COX-2 expression, suggesting that some COX-2-independent mechanisms underlie the antineoplastic effect of the inhibitor. PGE2 attenuates this antineoplastic effect, suggesting that the predominant mechanism is COX-dependent. COX-2 or EP1 inhibitors show anti-neoplastic effects. Thus, our review presents evidences for pathophysiological roles of cyclooxygenases and prostaglandins in the central nervous system.
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Al-Kofahi M, Becker F, Gavins FNE, Woolard MD, Tsunoda I, Wang Y, Ostanin D, Zawieja DC, Muthuchamy M, von der Weid PY, Alexander JS. IL-1β reduces tonic contraction of mesenteric lymphatic muscle cells, with the involvement of cycloxygenase-2 and prostaglandin E2. Br J Pharmacol 2015; 172:4038-4051. [PMID: 25989136 PMCID: PMC4543611 DOI: 10.1111/bph.13194] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Revised: 04/02/2015] [Accepted: 04/28/2015] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND AND PURPOSE The lymphatic system maintains tissue homeostasis by unidirectional lymph flow, maintained by tonic and phasic contractions within subunits, 'lymphangions'. Here we have studied the effects of the inflammatory cytokine IL-1β on tonic contraction of rat mesenteric lymphatic muscle cells (RMLMC). EXPERIMENTAL APPROACH We measured IL-1β in colon-conditioned media (CM) from acute (AC-CM, dextran sodium sulfate) and chronic (CC-CM, T-cell transfer) colitis-induced mice and corresponding controls (Con-AC/CC-CM). We examined tonic contractility of RMLMC in response to CM, the cytokines h-IL-1β or h-TNF-α (5, 10, 20 ng·mL(-1) ), with or without COX inhibitors [TFAP (10(-5) M), diclofenac (0.2 × 10(-5) M)], PGE2 (10(-5) M)], IL-1-receptor antagonist, Anakinra (5 μg·mL(-1) ), or a selective prostanoid EP4 receptor antagonist, GW627368X (10(-6) and 10(-7) M). KEY RESULTS Tonic contractility of RMLMC was reduced by AC- and CC-CM compared with corresponding control culture media, Con-AC/CC-CM. IL-1β or TNF-α was not found in Con-AC/CC-CM, but detected in AC- and CC-CM. h-IL-1β concentration-dependently decreased RMLMC contractility, whereas h-TNF-α showed no effect. Anakinra blocked h-IL-1β-induced RMLMC relaxation, and with AC-CM, restored contractility to RMLMC. IL-1β increased COX-2 protein and PGE2 production in RMLMC.. PGE2 induced relaxations in RMLMC, comparable to h-IL-1β. Conversely, COX-2 and EP4 receptor inhibition reversed relaxation induced by IL-1β. CONCLUSIONS AND IMPLICATIONS The IL-1β-induced decrease in RMLMC tonic contraction was COX-2 dependent, and mediated by PGE2 . In experimental colitis, IL-1β and tonic lymphatic contractility were causally related, as this cytokine was critical for the relaxation induced by AC-CM and pharmacological blockade of IL-1β restored tonic contraction.
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Affiliation(s)
- M Al-Kofahi
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center – ShreveportShreveport, LA, USA
| | - F Becker
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center – ShreveportShreveport, LA, USA
- Department for General and Visceral Surgery, University Hospital MuensterMuenster, Germany
| | - F N E Gavins
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center – ShreveportShreveport, LA, USA
| | - M D Woolard
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center – ShreveportShreveport, LA, USA
| | - I Tsunoda
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center – ShreveportShreveport, LA, USA
| | - Y Wang
- Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center – ShreveportShreveport, LA, USA
| | - D Ostanin
- Department of Medicine, Division of Rheumatology, Louisiana State University Health Sciences Center – ShreveportShreveport, LA, USA
| | - D C Zawieja
- Department of Medicine, Cardiovascular Research Institute, Texas A&M Health Science CenterCollege Station, TX, USA
| | - M Muthuchamy
- Department of Medicine, Cardiovascular Research Institute, Texas A&M Health Science CenterCollege Station, TX, USA
| | - P Y von der Weid
- Department of Physiology and Pharmacology, University of CalgaryCalgary, Alberta, Canada
| | - J S Alexander
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center – ShreveportShreveport, LA, USA
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Turcotte C, Chouinard F, Lefebvre JS, Flamand N. Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites. J Leukoc Biol 2015; 97:1049-70. [PMID: 25877930 DOI: 10.1189/jlb.3ru0115-021r] [Citation(s) in RCA: 167] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 02/28/2015] [Indexed: 12/26/2022] Open
Abstract
2-Arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA) are endocannabinoids that have been implicated in many physiologic disorders, including obesity, metabolic syndromes, hepatic diseases, pain, neurologic disorders, and inflammation. Their immunomodulatory effects are numerous and are not always mediated by cannabinoid receptors, reflecting the presence of an arachidonic acid (AA) molecule in their structure, the latter being the precursor of numerous bioactive lipids that are pro- or anti-inflammatory. 2-AG and AEA can thus serve as a source of AA but can also be metabolized by most eicosanoid biosynthetic enzymes, yielding additional lipids. In this regard, enhancing endocannabinoid levels by using endocannabinoid hydrolysis inhibitors is likely to augment the levels of these lipids that could regulate inflammatory cell functions. This review summarizes the metabolic pathways involved in the biosynthesis and metabolism of AEA and 2-AG, as well as the biologic effects of the 2-AG and AEA lipidomes in the regulation of inflammation.
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Affiliation(s)
- Caroline Turcotte
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Département de Médecine, Faculté de Médecine, Université Laval, Québec City, QC, Canada
| | - François Chouinard
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Département de Médecine, Faculté de Médecine, Université Laval, Québec City, QC, Canada
| | - Julie S Lefebvre
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Département de Médecine, Faculté de Médecine, Université Laval, Québec City, QC, Canada
| | - Nicolas Flamand
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Département de Médecine, Faculté de Médecine, Université Laval, Québec City, QC, Canada
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20
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Amagase K, Izumi N, Takahira Y, Wada T, Takeuchi K. Importance of cyclooxygenase-1/prostacyclin in modulating gastric mucosal integrity under stress conditions. J Gastroenterol Hepatol 2014; 29 Suppl 4:3-10. [PMID: 25521725 DOI: 10.1111/jgh.12767] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM We investigated the roles of cyclooxygenase (COX) isozymes and prostaglandins (PGs) and their receptors in mucosal defense against cold-restraint stress (CRS)-induced gastric lesions. METHODS Male C57BL/6 wild-type (WT) mice and those lacking COX-1 or COX-2 as well as those lacking EP1, EP3, or IP receptors were used after 18 h fasting. Animals were restrained in Bollman cages and kept in a cold room at 10°C for 90 min. RESULTS CRS induced multiple hemorrhagic lesions in WT mouse stomachs. The severity of these lesions was significantly worsened by pretreatment with the nonselective COX inhibitors (indomethacin, loxoprofen) or selective COX-1 inhibitor (SC-560), while neither of the selective COX-2 inhibitors (rofecoxib and celecoxib) had any effect. These lesions were also aggravated in animals lacking COX-1, but not COX-2. The expression of COX-2 mRNA was not detected in the stomach after CRS, while COX-1 expression was observed under normal and stressed conditions. The gastric ulcerogenic response to CRS was similar between EP1 or EP3 knockout mice and WT mice, but was markedly worsened in animals lacking IP receptors. Pretreating WT mice with iloprost (the PGI2 analog) significantly prevented CRS-induced gastric lesions in the presence of indomethacin. PGE2 also reduced the severity of these lesions, and the effect was mimicked by the EP4 agonist, AE1-329. CONCLUSIONS These results suggest that endogenous PGs derived from COX-1 play a crucial role in gastric mucosal defense during CRS, and this action is mainly mediated by PGI2 /IP receptors and partly by PGE2 /EP4 receptors.
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Affiliation(s)
- Kikuko Amagase
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan
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21
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HONG HUA, JANG BYEONGCHURL. Prednisone inhibits the IL-1β-induced expression of COX-2 in HEI-OC1 murine auditory cells through the inhibition of ERK-1/2, JNK-1 and AP-1 activity. Int J Mol Med 2014; 34:1640-6. [DOI: 10.3892/ijmm.2014.1967] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Accepted: 10/01/2014] [Indexed: 11/05/2022] Open
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22
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Stepensky D, Rimon G. Competition between low-dose aspirin and other NSAIDs for COX-1 binding and its clinical consequences for the drugs’ antiplatelet effects. Expert Opin Drug Metab Toxicol 2014; 11:41-52. [DOI: 10.1517/17425255.2014.971010] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- David Stepensky
- Ben-Gurion University of the Negev, Department of Clinical Biochemistry and Pharmacology, The Faculty of Health Sciences, P.O.Box 653, Beer Sheva 84105, Israel
| | - Gilad Rimon
- Ben-Gurion University of the Negev, Department of Clinical Biochemistry and Pharmacology, The Faculty of Health Sciences, P.O.Box 653, Beer Sheva 84105, Israel
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23
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Cheng Y, Li Y, Liu D, Zhang R, Zhang J. miR-137 effects on gastric carcinogenesis are mediated by targeting Cox-2-activated PI3K/AKT signaling pathway. FEBS Lett 2014; 588:3274-81. [PMID: 25064845 DOI: 10.1016/j.febslet.2014.07.012] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 07/11/2014] [Accepted: 07/15/2014] [Indexed: 12/15/2022]
Abstract
The discovery of microRNAs (miRNAs) provided a new avenue for early diagnosis and treatment of GC. MiR-137 has been reported to be under-expressed and involved in various cell processes. However, the role of miR-137 in GC is less known. In this study, we show that miR-137 is under-expressed in GC and functions as a tumor suppressor through targeting Cyclooxygenase-2 (Cox-2), which subsequently suppresses the activation of PI3K/AKT signaling pathway both in vitro and in vivo. Moreover, restored Cox-2 expression partially abolished the tumor suppressive effects of miR-137 in GC cells, suggesting miR-137 may suppress GC carcinogenesis by targeting Cox-2.
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Affiliation(s)
- Yan Cheng
- Department of Digestive Diseases, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, PR China
| | - Yang Li
- Department of Otolaryngology-head and neck surgery, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China
| | - Dong Liu
- Department of Digestive Diseases, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, PR China
| | - Rong Zhang
- Department of Digestive Diseases, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, PR China
| | - Jun Zhang
- Department of Digestive Diseases, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, PR China.
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Stone AJ, Copp SW, Kaufman MP. Role of prostaglandins in spinal transmission of the exercise pressor reflex in decerebrated rats. Neuroscience 2014; 277:26-35. [PMID: 25003710 DOI: 10.1016/j.neuroscience.2014.06.061] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Revised: 06/24/2014] [Accepted: 06/26/2014] [Indexed: 11/29/2022]
Abstract
Previous studies found that prostaglandins in skeletal muscle play a role in evoking the exercise pressor reflex; however the role played by prostaglandins in the spinal transmission of the reflex is not known. We determined, therefore, whether or not spinal blockade of cyclooxygenase (COX) activity and/or spinal blockade of endoperoxide (EP) 2 or 4 receptors attenuated the exercise pressor reflex in decerebrated rats. We first established that intrathecal doses of a non-specific COX inhibitor Ketorolac (100 μg in 10 μl), a COX-2-specific inhibitor Celecoxib (100 μg in 10 μl), an EP2 antagonist PF-04418948 (10 μg in 10 μl), and an EP4 antagonist L-161,982 (4 μg in 10 μl) effectively attenuated the pressor responses to intrathecal injections of arachidonic acid (100 μg in 10 μl), EP2 agonist Butaprost (4 ng in 10 μl), and EP4 agonist TCS 2510 (6.25 μg in 2.5 μl), respectively. Once effective doses were established, we statically contracted the hind limb before and after intrathecal injections of Ketorolac, Celecoxib, the EP2 antagonist and the EP4 antagonist. We found that Ketorolac significantly attenuated the pressor response to static contraction (before Ketorolac: 23 ± 5 mmHg, after Ketorolac 14 ± 5 mmHg; p<0.05) whereas Celecoxib had no effect. We also found that 8 μg of L-161,982, but not 4 μg of L-161,982, significantly attenuated the pressor response to static contraction (before L-161,982: 21 ± 4 mmHg, after L-161,982 12 ± 3 mmHg; p<0.05), whereas PF-04418948 (10 μg) had no effect. We conclude that spinal COX-1, but not COX-2, plays a role in evoking the exercise pressor reflex, and that the spinal prostaglandins produced by this enzyme are most likely activating spinal EP4 receptors, but not EP2 receptors.
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Affiliation(s)
- A J Stone
- Heart and Vascular Institute, Penn State College of Medicine, Hershey, PA 17033, USA.
| | - S W Copp
- Heart and Vascular Institute, Penn State College of Medicine, Hershey, PA 17033, USA
| | - M P Kaufman
- Heart and Vascular Institute, Penn State College of Medicine, Hershey, PA 17033, USA
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25
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Lin Z, Shengnan L, Fei W, Yingli S, Qingshan S, Wei S, Shuhua X, Guifan S. Dimethylarsinic acid (DMA(V) ) changed the expressions of proliferative related factors and secretion of inflammatory cytokines in rat bladder. J Appl Toxicol 2014; 35:133-41. [PMID: 24832369 DOI: 10.1002/jat.3001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2013] [Revised: 02/02/2014] [Accepted: 02/08/2014] [Indexed: 12/11/2022]
Abstract
Dimethylarsinic acid (DMA(V) ), the major urinary metabolite of inorganic arsenic, is a urinary bladder carcinogen and bladder tumor promoter in adult rats. Increased urothelial cellular proliferation has been considered as an earlier phenotype in DMA(V) -induced bladder carcinogenesis. The present study examined the ultrastructural changes of bladder epithelial cells and expressions of proliferation factors, as well as the secretion of inflammatory cytokines in rats exposed to DMA(V) for 10 weeks by transmission electron microscopy (TEM), qRT-PCR, immunohistochemical staining and ELISA methods. The results showed that DMA(V) administered in the drinking water produced urothelial cytotoxicity and ultrastructural changes in rats. PCNA, cyclin D1 and COX-2 mRNA expressions and immunoreactivities were elevated in bladder urothelium. In addition, 200 ppm DMA(V) treatment increased the transforming growth factor-beta 1 (TGF-β1) secretion and decreased tumor necrosis factor-alpha (TNF)-α level in the urine of rats. These data suggest that chronic inflammation, bladder epithelium lesions and proliferation might be the basic process of the chronic toxicity effects in DMA(V) -treated rats.
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Affiliation(s)
- Zhang Lin
- Department of Occupational and Environmental Health, Liaoning Provincial Key Lab of Arsenic Biological Effect and Poisoning, School of Public Health, China Medical University, No. 92 Bei Er Road, Heping District, Shenyang, 110001, China
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Alexandre-Pires G, Martins C, Galvão AM, Correia M, Ramilo D, Quaresma M, Ligeiro D, Nunes T, Caldeira RM, Ferreira-Dias G. Morphological aspects and expression of estrogen and progesterone receptors in the interdigital sinus in cyclic ewes. Microsc Res Tech 2014; 77:313-25. [PMID: 24779038 DOI: 10.1002/jemt.22345] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Many species that belong to Artiodactyls order show an interdigital sinus (IS), as it occurs in sheep, in all four extremities. These are considered to be scent glands responsible for sexual communication having strong attractiveness to mature males at the peak of the breeding season. The aim of this study was to evaluate, in IS in cyclic ewes, the microscopic and ultrastructure (scanning and transmission electron microscopy) anatomy, secretion composition, and mRNA and protein expression of estrogen receptors a and b and progesterone receptors. Glandular sebaceous structures occupy a superficial area of the pouch. The other glands present in the IS show a coiled tubular structure and tall and polyhedral secretory cells with irregular luminal surface resulting from the secretory process. Protein and mRNA gene transcription studies were performed to determine the presence of ER (a and b) and P4r in IS. At the follicular phase, IS cell populations analyzed using flow cytometry expressed higher levels of ERb compared with ERa (P<0.05), whereas no difference was observed between them in the luteal phase. The IS amount of secretion was the highest in the follicular phase compared with luteal phase (P<0.05) or pregnancy (P<0.001).To the best of our knowledge, for the first time, the presence of ER (a and b) within the IS was demonstrated. As estrogen action is mediated by specific receptors in target cells, the presence of these receptors in IS might be needed to trigger signaling pathways involved in conspecific chemical (sexual) communication attributed to this area.
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Low-level laser therapy (LLLT) reduces the COX-2 mRNA expression in both subplantar and total brain tissues in the model of peripheral inflammation induced by administration of carrageenan. Lasers Med Sci 2014; 29:1397-403. [DOI: 10.1007/s10103-014-1543-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2013] [Accepted: 02/04/2014] [Indexed: 12/19/2022]
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De Oliveira F, Maifrino LBM, De Jesus GPP, Carvalho JG, Marchon C, Ribeiro DA. The role of cyclooxygenase-2 on endurance exercise training in female LDL-receptor knockout ovariectomized mice. AN ACAD BRAS CIENC 2014; 85:1157-64. [PMID: 23969853 DOI: 10.1590/s0001-37652013005000046] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Accepted: 03/12/2013] [Indexed: 11/22/2022] Open
Abstract
Estrogen deprivation in postmenopausal women increases cardiovascular risk. Cardiovascular risk as a result of atherosclerosis is able to induce an inflammatory disease as far as cyclooxygenase-2 ( COX-2) expression. The purpose of the study was to investigate the role of COX-2 on exercise training in female mice low-density lipoprotein receptor knockout ( LDL-KO) with or without ovariectomy. A total of 15 female C57BL/6 mice and 15 female LDL-KO mice were distributed into 6 groups: sedentary control, sedentary control ovariectomized, trained control ovariectomized, LDL-KO sedentary, LDL-KO sedentary ovariectomized and LDL-KO trained ovariectomized. The ascending part of the aorta was stained with H&E and COX-2 expression was assessed by immunohistochemistry. Results revealed that ovariectomy as well as exercise training were not able to induce histopathological changes in mouse aorta for all groups investigated. LDL-KO mice demonstrated plaque containing cholesterol clefts, foamy histiocytes and mild inflammatory process for all groups indistinctly. Ovariectomy induced a strong immunoexpression in atherosclerosis lesion of LDL-KO mice. Nevertheless, a down-regulation of COX-2 expression was detected in LDL-KO trained ovariectomized when compared to LDL-KO sedentary. Our results are consistent with the notion that exercise training is able to modulate COX-2 expression in LDL-KO mice as a result of COX-2 down-regulation.
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Affiliation(s)
- Flavia De Oliveira
- Departamento de Biociências, Universidade Federal de São Paulo, Campus Baixada Santista, 11060-001 Santos SP, Brasil.
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Wang F, Liu S, Xi S, Yan L, Wang H, Song Y, Sun G. Arsenic induces the expressions of angiogenesis-related factors through PI3K and MAPK pathways in SV-HUC-1 human uroepithelial cells. Toxicol Lett 2013; 222:303-11. [DOI: 10.1016/j.toxlet.2013.08.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Revised: 08/07/2013] [Accepted: 08/09/2013] [Indexed: 11/26/2022]
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Hashimoto Y, Yamada K, Tsushima H, Miyazawa D, Mori M, Nishio K, Ohkubo T, Hibino H, Ohara N, Okuyama H. Three dissimilar high fat diets differentially regulate lipid and glucose metabolism in obesity-resistant Slc:Wistar/ST rats. Lipids 2013; 48:803-15. [PMID: 23807365 DOI: 10.1007/s11745-013-3805-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2012] [Accepted: 05/15/2013] [Indexed: 12/25/2022]
Abstract
Epidemiologic and ecologic studies suggest that dietary fat plays an important role in the development of obesity. Certain Wistar rat strains do not become obese when fed high-fat diets unlike others. In a preliminary study, we confirmed that Slc:Wistar/ST rats did not become obese when fed high-fat diets. The mechanisms governing the response of hepatic lipid-metabolizing enzymes to large quantities of dietary lipids consumed by obesity-resistant animals are unknown. The aim of the present study is to examine how obesity-resistant animals metabolize various types of high-fat diets and why they do not become obese. For this purpose, male Slc:Wistar/ST rats were fed a control low-fat diet (LS) or a high-fat diet containing fish oil (HF), soybean oil (HS), or lard (HL) for 4 weeks. We observed their phenotypes and determined lipid profiles in plasma and liver as well as mRNA expression levels in liver of genes related to lipid and glucose metabolism using DNA microarray and quantitative reverse transcriptase polymerase chain analyses. The body weights of all dietary groups were similar due to isocaloric intakes, whereas the weight of white adipose tissues in the LS group was significantly lower. The HF diet lowered plasma lipid levels by accelerated lipolysis in the peroxisomes and suppressed levels of very-low-density lipoprotein (VLDL) secretion. The HS diet promoted hepatic lipid accumulation by suppressed lipolysis in the peroxisomes and normal levels of VLDL secretion. The lipid profiles of rats fed the LS or HL diet were similar. The HL diet accelerated lipid and glucose metabolism.
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Affiliation(s)
- Yoko Hashimoto
- Department of Biochemistry, School of Dentistry, Aichi-Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan.
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Knudsen CS, Williams A, Brearley MJ, Demetriou JL. COX-2 expression in canine anal sac adenocarcinomas and in non-neoplastic canine anal sacs. Vet J 2013; 197:782-7. [PMID: 23778258 DOI: 10.1016/j.tvjl.2013.05.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2012] [Revised: 03/08/2013] [Accepted: 05/06/2013] [Indexed: 01/06/2023]
Abstract
Anal sac adenocarcinoma (ASAC) is a clinically significant canine neoplasm characterized by early lymphatic invasion. Up-regulation of cyclooxygenase isoform 2 (COX-2) has been confirmed in several animal and human neoplastic tissues. The aim of the current study was primarily to evaluate COX-2 expression in canine ASAC and compare it to COX-2 expression in non-neoplastic canine anal sac tissue using immunohistochemistry with scoring for percentage positivity and intensity. Twenty-five ASAC samples and 22 normal anal sacs were available for evaluation. All canine ASAC samples and the normal anal sac tissues stained positively for COX-2. However, while normal anal sac tissue showed strong staining of the ductal epithelial cells, ASAC samples showed staining of the neoplastic glandular epithelial cells, with varying percentage positivity and intensity between ASAC samples. COX-2 immunoreactivity of ASAC samples was of low intensity in 52% and high in 12% of the cases; the remaining samples were of intermediate intensity. Seventy-six per cent of the ASAC had over 50% of the neoplastic glandular cells staining positive. These results confirm that COX-2 is expressed in the neoplastic glandular epithelial cells in canine ASAC and suggest a potential role for COX-2 inhibitors in the management of ASAC. Furthermore, the results indicate that COX-2 is expressed in ductal epithelial cells of the normal anal sac.
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Affiliation(s)
- C S Knudsen
- The Queen's Veterinary School Hospital, Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
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Wang H, Xi S, Xu Y, Wang F, Zheng Y, Li B, Li X, Zheng Q, Sun G. Sodium arsenite induces cyclooxygenase-2 expression in human uroepithelial cells through MAPK pathway activation and reactive oxygen species induction. Toxicol In Vitro 2013; 27:1043-8. [PMID: 23376440 DOI: 10.1016/j.tiv.2013.01.012] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Revised: 10/22/2012] [Accepted: 01/07/2013] [Indexed: 10/27/2022]
Abstract
Arsenic can induce reactive oxygen species (ROS) leading to oxidative stress and carcinogenesis. Bladder is one of the major target organs of arsenic, and cyclooxygenase-2 (COX-2) may play an important role in arsenic-induced bladder cancer. However, the mechanism by which arsenic induces COX-2 in bladder cells remains unclear. This study aimed at investigating arsenic-mediated intracellular redox status and signaling cascades leading to COX-2 induction in human uroepithelial cells (SV-HUC-1). SV-HUC-1 cells were exposed to sodium arsenite and COX-2 expression, mitogen-activated protein kinase (MAPK) phosphorylation, glutathione (GSH) levels, ROS induction and Nrf2 expression were quantified. Our results demonstrate that arsenite (1-10 μM) elevates COX-2 expression, GSH levels, ROS and Nrf2 expression. Arsenite treatment for 24h stimulates phosphorylation of ERK and p38, but not JNK in SV-HUC-1 cells. Induction of Cox-2 mRNA levels by arsenite was attenuated by inhibitors of ERK, p38 and JNK. Arsenite-induced ROS generation and COX-2 expression were significantly attenuated by treatment with melatonin (a ROS scavenger), but enhanced by DL-buthionine-(S, R)-sulfoximine (BSO, an inhibitor of gamma-glutamylcysteine synthetase (γ-GCS) resulting in lower GSH and increased ROS levels). These data indicate that arsenite promotes an induction of ROS, which results in an induction of COX-2 expression through activation of the MAPK pathway.
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Affiliation(s)
- Huihui Wang
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, PR China
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Takeuchi K, Amagase K. Evaluation of gastric ulcerogenic and healing impairment effects of bisphosphonates: adverse gastric reactions of bisphosphonate. ACTA ACUST UNITED AC 2013; Chapter 21:Unit 21.10.1-29. [PMID: 22896009 DOI: 10.1002/0471140856.tx2110s53] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Bisphosphonates (BPPs) were developed as antiresorptive drugs capable of treating diseases related to bone remodeling; however, they have untoward effects including ulceration in the upper gastrointestinal tract and worsen the healing-impairment action of nonsteroidal anti-inflammatory drugs, prescribed in patients with arthritis or osteoporosis. We produced ulcers in the antrum by administering BPPs to fasted rats, followed by refeeding, and confirmed their healing-impairment action on pre-existing gastric ulcers; the ulcerogenic effect is due to direct mucosal irritation and decrease in the mucosal anti-oxidative system, while the latter effect is due to dysregulation of growth factor expression, such as vascular endothelial growth factor and basic fibroblast growth factor, and angiogenesis in the ulcerated mucosa. In this article, we describe these two animal models for investigating BPP-related adverse reactions, including methods for the induction of antral ulcers and healing impairment of gastric ulcers, as well as measurement of pathogenic functional and biochemical changes.
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Affiliation(s)
- Koji Takeuchi
- Department of Pharmacology and Experimental Therapeutics, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
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Galvão A, Valente L, Skarzynski DJ, Szóstek A, Piotrowska-Tomala K, Rebordão MR, Mateus L, Ferreira-Dias G. Effect of cytokines and ovarian steroids on equine endometrial function: an in vitro study. Reprod Fertil Dev 2013; 25:985-97. [DOI: 10.1071/rd12153] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 09/05/2012] [Indexed: 11/23/2022] Open
Abstract
Regulation of immune–endocrine interactions in the equine endometrium is not fully understood. The aims of the present study were to: (1) investigate the presence of tumour necrosis factor alpha (TNF), interferon gamma (IFNG), Fas ligand (FASLG) and their receptors in the mare endometrium throughout the oestrous cycle; and (2) assess endometrial secretory function (prostaglandins), angiogenic activity and cell viability in response to TNF, oestradiol (E2), progesterone (P4) and oxytocin (OXT). Transcription of TNF and FASLG mRNA increased during the early and late luteal phase (LP), whereas IFNG mRNA increased in late LP. Transcription of the mRNA of both TNF receptors was highest in the mid-LP. All cytokines and receptors were expressed in surface and glandular epithelium, as well as in the stroma. Expression of TNF and its receptor TNFRSF1A increased during the follicular phase (FP) and mid-LP. IFNG was expressed in the mid-LP, whereas its receptor IFNR1 was expressed in the in mid- and late LP. The highest expression of FASLG and FAS occurred during the late LP. OXT increased the secretion of prostaglandin (PG) E2 and PGF2α in the FP and mid-LP. In the mid-LP, E2 and P4+E2 stimulated PGF2α secretion, whereas TNF and P4 increased cell viability. All treatments, with the exception of P4, increased nitric oxide and angiogenic activity in both phases. The coordinated action of cytokines and ovarian hormones may regulate secretory, angiogenic and proliferative functions in the equine endometrium.
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Cui JH, Ju J, Yoon MH. Pharmacology of Cannabinoid Receptor Agonists and a Cyclooxygenase-2 Inhibitor in Rat Bone Tumor Pain. Pharmacology 2013; 92:150-7. [DOI: 10.1159/000354296] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Accepted: 07/11/2013] [Indexed: 11/19/2022]
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Hirz T, Khalaf A, El-Hachem N, Mrad MF, Abdallah H, Créminon C, Grée R, Merhi RA, Habib A, Hachem A, Hamade E. New analogues of 13-hydroxyocatdecadienoic acid and 12-hydroxyeicosatetraenoic acid block human blood platelet aggregation and cyclooxygenase-1 activity. Chem Cent J 2012; 6:152. [PMID: 23228056 PMCID: PMC3582601 DOI: 10.1186/1752-153x-6-152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Accepted: 12/03/2012] [Indexed: 12/05/2022] Open
Abstract
Background Thromboxane A2 is derived from arachidonic acid through the action of cyclooxygenases and thromboxane synthase. It is mainly formed in blood platelets upon activation and plays an important role in aggregation. Aspirin is effective in reducing the incidence of complications following acute coronary syndrome and stroke. The anti-thrombotic effect of aspirin is obtained through the irreversible inhibition of cyclooxygenases. Analogues of 12-hydroxyeicosatetraenoic acid and 13-hydroxyocatdecadienoic acid were shown previously to modulate platelet activation and to block thromboxane receptors. Results and discussion We synthesized 10 compounds based on the structures of analogues of 12-hydroxyeicosatetraenoic acid and 13-hydroxyocatdecadienoic acid and evaluated their effect on platelet aggregation triggered by arachidonic acid. The structure activity relationship was evaluated. Five compounds showed a significant inhibition of platelet aggregation and highlighted the importance of the lipidic hydrophobic hydrocarbon chain and the phenol group. Their IC50 ranged from 7.5 ± 0.8 to 14.2 ± 5.7 μM (Mean ± S.E.M.). All five compounds decreased platelet aggregation and thromboxane synthesis in response to collagen whereas no modification of platelet aggregation in response to thromboxane receptor agonist, U46619, was observed. Using COS-7 cells overexpressing human cyclooxygenase-1, we showed that these compounds are specific inhibitors of cyclooxygenase-1 with IC50 ranging from 1.3 to 12 μM. Docking observation of human recombinant cyclooxygenase-1 supported a role of the phenol group in the fitting of cyclooxygenase-1, most likely related to hydrogen bonding with the Tyr 355 of cyclooxygenase-1. Conclusions In conclusion, the compounds we synthesized at first based on the structures of analogues of 12 lipoxygenase metabolites showed a role of the phenol group in the anti-platelet and anti-cyclooxygenase-1 activities. These compounds mediate their effects via blockade of cyclooxygenase-1.
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Affiliation(s)
- Taghreed Hirz
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, AUB, Beirut, POBox 11-236, Lebanon.
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Li H, Edin ML, Gruzdev A, Cheng J, Bradbury JA, Graves JP, DeGraff LM, Zeldin DC. Regulation of T helper cell subsets by cyclooxygenases and their metabolites. Prostaglandins Other Lipid Mediat 2012. [PMID: 23201570 DOI: 10.1016/j.prostaglandins.2012.11.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Cyclooxygenases and their metabolites are important regulators of inflammatory responses and play critical roles in regulating the differentiation of T helper cell subsets in inflammatory diseases. In this review, we highlight new information on regulation of T helper cell subsets by cyclooxygenases and their metabolites. Prostanoids influence cytokine production by both antigen presenting cells and T cells to regulate the differentiation of naïve CD4(+) T cells to Th1, Th2 and Th17 cell phenotypes. Cyclooxygenases and PGE2 generally exacerbate Th2 and Th17 phenotypes, while suppressing Th1 differentiation. Thus, cycloxygenases may play a critical role in diseases that involve immune cell dysfunction. Targeting of cyclooxygenases and their eicosanoid products may represent a new approach for treatment of inflammatory diseases, tumors and autoimmune disorders.
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Affiliation(s)
- Hong Li
- Laboratory of Respiratory Biology, Division of Intramural Research, NIEHS/NIH, Research Triangle Park, NC 27709, USA
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Di Nisio C, Zara S, Cataldi A, di Giacomo V. 2-Hydroxyethyl methacrylate inflammatory effects in human gingival fibroblasts. Int Endod J 2012; 46:466-76. [PMID: 23137186 DOI: 10.1111/iej.12012] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Accepted: 09/10/2012] [Indexed: 01/24/2023]
Abstract
AIM To investigate the inflammatory response in human gingival fibroblasts (HGFs) treated with a relatively low 2-hydroxyethyl methacrylate (HEMA) concentration by studying reactive oxygen species (ROS) production, cyclooxygenase-2 (COX-2) and tumour necrosis factor-alpha (TNF-α) gene expression, and prostaglandin E2 (PGE₂) release. METHODOLOGY Cultured HGFs were exposed to 3 mmol L⁻¹ HEMA for 0, 24 or 96 h. ROS production was investigated by flow cytometry; TNF-α and COX-2 gene expression was determined by RT-PCR, and prostaglandin E2 production was detected by an enzyme immunoassay. RESULTS After 24- or 96-h HEMA incubation, ROS levels were approximately eightfold and elevenfold higher than controls, whilst COX-2 gene expression was approximately twofold or fourfold higher than controls, respectively. Twenty-four-hour exposure enhanced TNF-α mRNA levels by approximately 66%, whilst after 96-h incubation, TNF-α gene expression was fivefold higher than controls. Ninety-six-hour HEMA treatment increased PGE₂ concentration in the culture medium by around 17% compared with controls. CONCLUSIONS 2-Hydroxyethyl methacrylate treatment (3 mmol L⁻¹) induced an inflammatory response in HGFs modulated by ROS production, as well as by the increase in TNF-α and COX-2 gene expression and by PGE₂ release.
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Affiliation(s)
- C Di Nisio
- Dipartimento di Farmacia, Università G. d'Annunzio, Chieti-Pescara, Italy
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Cytotoxicity of functionalized carbon nanotubes in J774A macrophages. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2012; 8:853-9. [DOI: 10.1016/j.nano.2011.10.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Revised: 08/31/2011] [Accepted: 10/02/2011] [Indexed: 01/09/2023]
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Egydio F, Ribeiro DA, Noguti J, Tufik S, Andersen ML. Influence of sleep deprivation and morphine on the expression of inducible nitric oxide synthase and cyclooxygenase-2 in skin of hairless mice. Toxicol Mech Methods 2012; 22:577-83. [PMID: 22694732 DOI: 10.3109/15376516.2012.702797] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Skin performs a host of primordial functions that keep the body alive. Morphine is a drug with immunosuppressant properties whose chronic use may lead to increased infection and delayed wound healing. Sleep is a fundamental biological phenomenon that promotes the integrity of several bodily functions. Sleep deprivation adversely affects several systems, particularly the immune system. The aim of this study was to perform an immunohistochemical evaluation on the expression of inducible nitric oxide synthase and cyclooxygenase-2 in skin of sleep-deprived mice and mice chronically treated with morphine. Adult hairless male mice were distributed into the following groups: Control, morphine, sleep-deprived, and morphine + SD. Morphine (10 mg/kg, subcutaneous) was injected every 12 h for 9 days. Morphine induced immunoexpression of cyclooxygenase-2 and nitric oxide synthase. Sleep deprivation did not modulate outcomes induced by morphine. Morphine, not sleep loss, induces cyclooxygenase-2 and nitric oxide synthase immunoexpression in the skin of hairless mice.
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Affiliation(s)
- Flavia Egydio
- Departamento de Psicobiologia, Universidade Federal de São Paulo (UNIFESP), Rua Napoleão de Barros, São Paulo, Brazil
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Inflammation modulates expression of laminin in the central nervous system following ischemic injury. J Neuroinflammation 2012; 9:159. [PMID: 22759265 PMCID: PMC3414761 DOI: 10.1186/1742-2094-9-159] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2012] [Accepted: 07/03/2012] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Ischemic stroke induces neuronal death in the core of the infarct within a few hours and the secondary damage in the surrounding regions over a long period of time. Reduction of inflammation using pharmacological reagents has become a target of research for the treatment of stroke. Cyclooxygenase 2 (COX-2), a marker of inflammation, is induced during stroke and enhances inflammatory reactions through the release of enzymatic products, such as prostaglandin (PG) E2. METHODS Wild-type (WT) and COX-2 knockout (COX-2KO) mice were subjected to middle cerebral artery occlusion (MCAO). Additionally, brain slices derived from these mice or brain microvascular endothelial cells (BMECs) were exposed to oxygen-glucose deprivation (OGD) conditions. The expression levels of extracellular matrix (ECM) proteins were assessed and correlated with the state of inflammation. RESULTS We found that components of the ECM, and specifically laminin, are transiently highly upregulated on endothelial cells after MCAO or OGD. This upregulation is not observed in COX-2KO mice or WT mice treated with COX-2 inhibitor, celecoxib, suggesting that COX-2 is associated with changes in the levels of laminins. CONCLUSIONS Taken together, we report that transient ECM remodeling takes place early after stroke and suggest that this increase in ECM protein expression may constitute an effort to revascularize and oxygenate the tissue.
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Chang HH, Chang MC, Huang GF, Wang YL, Chan CP, Wang TM, Lin PS, Jeng JH. Effect of triethylene glycol dimethacrylate on the cytotoxicity, cyclooxygenase-2 expression and prostanoids production in human dental pulp cells. Int Endod J 2012; 45:848-58. [DOI: 10.1111/j.1365-2591.2012.02042.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Paiotti APR, Ribeiro DA, Silva RM, Marchi P, Oshima CTF, Neto RA, Miszputen SJ, Franco M. Effect of COX-2 inhibitor lumiracoxib and the TNF-α antagonist etanercept on TNBS-induced colitis in Wistar rats. J Mol Histol 2012; 43:307-17. [PMID: 22426941 DOI: 10.1007/s10735-012-9400-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2011] [Accepted: 03/05/2012] [Indexed: 12/18/2022]
Abstract
Crohn's disease (CD) is associated with gut barrier dysfunction. Besides the baseline barrier defect, a subgroup of patients also expresses an intestinal barrier hyperresponsiveness to nonsteroidal anti-inflammatory drugs. On the other hand, the anti-tumour necrosis factor alpha (TNF-α) treatment has brought benefits to these patients. Thus, this study aimed to evaluate the effect of lumiracoxib, a selective-cyclooxygenase-2 (COX-2) inhibitor, and Etanercept (ETC), a TNF-α antagonist on the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis. A total of 47 Wistar rats were randomized into seven groups, as follows: (1) Sham: sham induced-colitis; (2) TNBS: nontreated induced-colitis; (3) Lumiracoxib control; (4) Lumiracoxib-treated induced-colitis; (5) ETC control; (6) ETC-treated induced-colitis; (7) Lumiracoxib-ETC-treated induced-colitis. Rats from groups 6 and 7 presented significant improvement of macroscopic and histopathological damages in the distal colon. The gene expression of COX-2 mRNA, as well of TNF-α mRNA, decreased significantly in groups 6 and 7 compared to the TNBS nontreated and lumiracoxib-treated groups. The treatment only with lumiracoxib did not reduce the inflammation on TNBS-induced experimental colitis. ETC attenuated the damage seen in the colon and reduced the inflammation caused by TNBS. Our results suggest that down-regulation of TNF-α and COX-2 resulted in a decrease in inflammation caused by TNBS and thus provided some protection from the colonic damage caused by TNBS.
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Affiliation(s)
- Ana Paula Ribeiro Paiotti
- Department of Pathology, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, UNIFESP, Sao Paulo, SP, Brazil
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Expression of cyclooxygenase-1 and cyclooxygenase-2 in normal and pathological human oral mucosa. Folia Histochem Cytobiol 2011; 48:555-63. [PMID: 21478098 DOI: 10.2478/v10042-010-0066-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Cyclooxigenase (COX) is the rate-limiting enzyme for the conversion of arachidonic acid (AA) to prostaglandins (PGs). Two isoforms of COX have been identified: COX-1 is constitutively expressed in many cells and is involved in cell homeostasis, angiogenesis and cell-cell signalling; COX-2 is not expressed in normal condition however it is strongly expressed in inflammation. The oral cavity is constantly exposed to physical and chemical trauma that could lead to mucosal reactions such as hyperplasia, dysplasia and cancer. Early diagnosis is the most important issue to address for a positive outcome of oral cancer; therefore it would be useful to identify molecular markers whose expression is associated with the various stages of oral cancer progression. Since COX enzyme has been involved, with different mechanisms, in the development and progression of malignancies we decided to investigate the expression and localization of COX-1 and COX-2 in normal human oral mucosa and three different pathologies (hyperplasia, dysplasia and carcinoma) by immunohistochemistry and RT-PCR. COX-1 mRNA and protein have been detected already in normal oral mucosa and their expression progressively increases from normal samples towards hyperplasia, dysplasia and finally carcinoma. On the contrary, COX-2 is not expressed in the normal tissue, starts to be expressed in hyperplasia, reaches the maximum activation in dysplasia and then starts to be downregulated in carcinoma.
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Atikuzzaman M, Koo OJ, Kang JT, Kwon DK, Park SJ, Kim SJ, Gomez MNL, Oh HJ, Hong SG, Jang G, Lee BC. The 9-cis retinoic acid signaling pathway and its regulation of prostaglandin-endoperoxide synthase 2 during in vitro maturation of pig cumulus cell-oocyte complexes and effects on parthenogenetic embryo production. Biol Reprod 2011; 84:1272-81. [PMID: 21368300 DOI: 10.1095/biolreprod.110.086595] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
The addition of 9-cis retinoic acid to the oocyte maturation culture medium has a beneficial effect on in vitro fertilized embryos. However, the mechanism of this activity is not known. Therefore, this study was done to elucidate the effect of 9-cis retinoic acid on parthenogenetic embryo production and its signaling pathway and molecular function during in vitro maturation of porcine cumulus cell-oocyte complexes (COCs). Concentrations of 0, 5, 50, and 500 nM 9-cis retinoic acid were added to the in vitro maturation medium, and the embryos were assessed after parthenogenetic activation. Cumulus cells and oocytes from the in vitro matured COCs were separated and subjected to RT-PCR and real-time RT-PCR for detecting retinoic acid receptors and measuring expression of prostaglandin-endoperoxide synthase1 and 2. The addition of 5 nM 9-cis retinoic acid to the maturation medium was beneficial for parthenogenetic embryo production. The effect of 9-cis retinoic acid was exerted directly through the oocytes via the retinoic acid receptor alpha and retinoid X receptor gamma signaling pathways and indirectly through the cumulus cells by the retinoic acid receptor beta and gamma and retinoid X receptor alpha and beta signaling pathways. The addition of 5 nM 9-cis retinoic acid-stimulated cumulus cells reaches full expansion by suppressing their excessive expression of prostaglandin-endoperoxide synthase 2. This study shows that 9-cis retinoic acid can exert its beneficial effect on parthenogenetic embryo production in pigs by multidimensional pathways affecting oocyte maturation.
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Affiliation(s)
- Mohammad Atikuzzaman
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Seoul National University, Korea
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Takeuchi K, Satoh H. Measurement of small intestinal damage. CURRENT PROTOCOLS IN TOXICOLOGY 2011; Chapter 21:Unit 21.7. [PMID: 20967749 DOI: 10.1002/0471140856.tx2107s45] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Many animal models have been devised for investigating the pathogenesis of intestinal lesions and for screening drugs for the treatment of intestinal ulcers in humans. Recently, particular attention has been focused on NSAID-induced intestinal lesions as a result of the development of the capsule endoscope and double-balloon endoscope. Ischemic enteritis, one of the most dramatic abdominal emergencies, is known to cause severe damage to the small intestine by a significant decrease of arterial blood flow in the small intestine. In this unit, two animal models for small intestinal damage induced by NSAIDs or intestinal ischemia are described. Also included are methods for lesion induction and evaluation of the damage as well as the measurement of pathogenic functional and biochemical changes.
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Galvao AM, Ramilo DW, Skarzynski DJ, Lukasik K, Tramontano A, Mollo A, Mateus LM, Ferreira-Dias GML. Is FAS/Fas Ligand System Involved in Equine Corpus Luteum Functional Regression?1. Biol Reprod 2010; 83:901-8. [DOI: 10.1095/biolreprod.110.084699] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
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Yagami T. Cerebral arachidonate cascade in dementia: Alzheimer's disease and vascular dementia. Curr Neuropharmacol 2010; 4:87-100. [PMID: 18615138 DOI: 10.2174/157015906775203011] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2005] [Revised: 08/17/2005] [Accepted: 09/30/2005] [Indexed: 11/22/2022] Open
Abstract
Phospholipase A(2) (PLA(2)), cyclooxygenase (COX) and prostaglandin (PG) synthase are enzymes involved in arachidonate cascade. PLA(2) liberates arachidonic acid (AA) from cell membrane lipids. COX oxidizes AA to PGG(2) followed by an endoperoxidase reaction that converts PGG(2) into PGH(2). PGs are generated from astrocytes, microglial cells and neurons in the central nervous system, and are altered in the brain of demented patients. Dementia is principally diagnosed into Alzheimer's disease (AD) and vascular dementia (VaD). In older patients, the brain lesions associated with each pathological process often occur together. Regional brain microvascular abnormalities appear before cognitive decline and neurodegeneration. The coexistence of AD and VaD pathology is often termed mixed dementia. AD and VaD brain lesions interact in important ways to decline cognition, suggesting common pathways of the two neurological diseases. Arachidonate cascade is one of the converged intracellular signal transductions between AD and VaD. PLA(2) from mammalian sources are classified as secreted (sPLA(2)), Ca(2+)-dependent, cytosolic (cPLA(2)) and Ca(2+)-independent cytosolic PLA(2) (iPLA(2)). PLA(2) activity can be regulated by calcium, by phosphorylation, and by agonists binding to G-protein-coupled receptors. cPLA(2) is upregulalted in AD, but iPLA(2) is downregulated. On the other hand, sPLA(2) is increased in animal models for VaD. COX-2 is induced and PGD(2) are elevated in both AD and VaD. This review presents evidences for central roles of PLA(2)s, COXs and PGs in the dementia.
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Affiliation(s)
- Tatsurou Yagami
- Faculty of Health Care Sciences, Himeji Dokkyo University, 2-1, Kami-ohno 7-Chome, Himeji, Hyogo, 670-8524, Japan.
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Takeuchi K, Tanigami M, Amagase K, Ochi A, Okuda S, Hatazawa R. Endogenous prostaglandin E2 accelerates healing of indomethacin-induced small intestinal lesions through upregulation of vascular endothelial growth factor expression by activation of EP4 receptors. J Gastroenterol Hepatol 2010; 25 Suppl 1:S67-74. [PMID: 20586869 DOI: 10.1111/j.1440-1746.2010.06222.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIMS The effects of an EP4 agonist/antagonist on the healing of lesions produced by indomethacin in the small intestine were examined in rats, especially in relation to the expression of vascular endothelial growth factor (VEGF) and angiogenesis. METHODS Animals were given indomethacin (10 mg/kg s.c.) and killed at various time points. To impair the healing of these lesions, a small dose of indomethacin (2 mg/kg p.o.) or AE3-208 (EP4 antagonist: 3 mg/kg i.p.) was given once daily for 6 days after the ulceration was induced, with or without the co-administration of AE1-329 (EP4 agonist: 0.1 mg/kg i.p.). RESULTS Indomethacin (10 mg/kg) caused severe damage in the small intestine, but the lesions healed rapidly decreasing to approximately one-fifth of their initial size within 7 days. The healing process was significantly impaired by indomethacin (2 mg/kg) given once daily for 6 days after the ulceration. This effect of indomethacin was mimicked by the EP4 antagonist and reversed by co-administration of the EP4 agonist. Mucosal VEGF expression was upregulated after the ulceration, reaching a peak on day 3 followed by a decrease. The changes in VEGF expression paralleled those in mucosal cyclooxygenase-2 expression, as well as prostaglandin E(2) (PGE(2)) content. Indomethacin (2 mg/kg) downregulated both VEGF expression and angiogenesis in the mucosa during the healing process, and these effects were significantly reversed by co-treatment with the EP4 agonist. CONCLUSION The results suggest that endogenous PGE(2) promotes the healing of small intestinal lesions by stimulating angiogenesis through the upregulation of VEGF expression mediated by the activation of EP4 receptors.
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Affiliation(s)
- Koji Takeuchi
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
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