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Jyothi VGSS, Veerabomma H, Tryphena KP, Khatri DK, Singh SB, Madan J. Acute and sub-acute dermal toxicity of meloxicam emulgel: Analysis of biochemical, hematological, histopathological and immunohistochemical expression. Biochem Biophys Res Commun 2023; 660:88-95. [PMID: 37079955 DOI: 10.1016/j.bbrc.2023.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 03/22/2023] [Accepted: 04/02/2023] [Indexed: 04/22/2023]
Abstract
Meloxicam, a non-steroidal anti-inflammatory drug (NSAID) for the treatment of osteoarthritis. Despite being more effective against pain mediated by inflammation, it is associated with gastrointestinal, cardiovascular, and renal toxicity. In the current study, acute single-dose (2000 mg/kg) and subacute (500, 1000, and 2000 mg kg-1 for 28 days) dermal toxicity analyses of meloxicam emulgel were conducted in Wistar rats. Various biochemical, hematological, histopathological and immunohistochemical parameters were evaluated. The dermal LD50 (lethal dose) of meloxicam emulgel was found to be > 2000 mg/kg. No significant adverse effects of meloxicam emulgel following topical administration in subacute toxicity studies were noticed. IL-1β was not expressed post treatment with meloxicam emulgel. IL-1β is an influential pro-inflammatory cytokine that is decisive for host-defence consequence to injury and infection. Therefore, using data gleaned from the extant study, topical administration of meloxicam emulgel may be regarded as safe as the "no observed adverse effect level" (NOAEL) was >2000 mg/kg in experimental animals.
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Affiliation(s)
- Vaskuri G S Sainaga Jyothi
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Harithasree Veerabomma
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Kamatham Pushpa Tryphena
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Dharmendra Kumar Khatri
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India.
| | - Shashi Bala Singh
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Jitender Madan
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India.
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Rood KM, Patel N, DeVengencie IM, Quinn JP, Gowdy KM, Costantine MM, Kniss DA. Aspirin modulates production of pro-inflammatory and pro-resolving mediators in endothelial cells. PLoS One 2023; 18:e0283163. [PMID: 37098090 PMCID: PMC10128936 DOI: 10.1371/journal.pone.0283163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 03/02/2023] [Indexed: 04/26/2023] Open
Abstract
Endothelial cells synthesize biochemical signals to coordinate a response to insults, resolve inflammation and restore barrier integrity. Vascular cells release a variety of vasoactive bioactive lipid metabolites during the inflammatory response and produce pro-resolving mediators (e.g., Lipoxin A4, LXA4) in cooperation with leukocytes and platelets to bring a halt to inflammation. Aspirin, used in a variety of cardiovascular and pro-thrombotic disorders (e.g., atherosclerosis, angina, preeclampsia), potently inhibits proinflammatory eicosanoid formation. Moreover, aspirin stimulates the synthesis of pro-resolving lipid mediators (SPM), so-called Aspirin-Triggered Lipoxins (ATL). We demonstrate that cytokines stimulated a time- and dose-dependent increase in PGI2 (6-ketoPGF1α) and PGE2 formation that is blocked by aspirin. Eicosanoid production was caused by cytokine-induced expression of cyclooxygenase-2 (COX-2). We also detected increased production of pro-resolving LXA4 in cytokine-stimulated endothelial cells. The R-enantiomer of LXA4, 15-epi-LXA4, was enhanced by aspirin, but only in the presence of cytokine challenge, indicating dependence on COX-2 expression. In contrast to previous reports, we detected arachidonate 5-lipoxygenase (ALOX5) mRNA expression and its cognate protein (5-lipoxygenase, 5-LOX), suggesting that endothelial cells possess the enzymatic machinery necessary to synthesize both pro-inflammatory and pro-resolving lipid mediators independent of added leukocytes or platelets. Finally, we observed that, endothelial cells produced LTB4 in the absence of leukocytes. These results indicate that endothelial cells produce both pro-inflammatory and pro-resolving lipid mediators in the absence of other cell types and aspirin exerts pleiotropic actions influencing both COX and LOX pathways.
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Affiliation(s)
- Kara M Rood
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Niharika Patel
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Laboratory of Perinatal Research, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Ivana M DeVengencie
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Laboratory of Perinatal Research, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
| | - John P Quinn
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Laboratory of Perinatal Research, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Kymberly M Gowdy
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, College of Medicine and Wexner Medical Center, Columbus, Ohio, United States of America
- Dorothy Davis Heart and Lung Institute, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Maged M Costantine
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Douglas A Kniss
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Laboratory of Perinatal Research, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
- Department of Biomedical Engineering, College of Engineering, Fontana Labs, The Ohio State University, Columbus, Ohio, United States of America
- Infectious Disease Institute, The Ohio State University, Columbus, Ohio, United States of America
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3
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Aiolfi R, Sitia G, Iannacone M, Brunetta I, Guidotti LG, Ruggeri ZM. Arenaviral infection causes bleeding in mice due to reduced serotonin release from platelets. Sci Signal 2022; 15:eabb0384. [PMID: 35192415 PMCID: PMC11583808 DOI: 10.1126/scisignal.abb0384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Bleeding correlates with disease severity in viral hemorrhagic fevers. We found that the increase in type I interferon (IFN-I) in mice caused by infection with the Armstrong strain of lymphocytic choriomeningitis virus (LCMV; an arenavirus) reduced the megakaryocytic expression of genes encoding enzymes involved in lipid biosynthesis (cyclooxygenase 1 and thromboxane A synthase 1) and a thrombopoietic transcription factor (Nf-e2). The decreased expression of these genes was associated with reduced numbers of circulating platelets and defects in the arachidonic acid synthetic pathway, thereby suppressing serotonin release from δ-granules in platelets. Bleeding resulted when severe thrombocytopenia and altered platelet function reduced the amount of platelet-derived serotonin below a critical threshold. Bleeding was facilitated by the absence of the activity of the kinase Lyn or the administration of aspirin, an inhibitor of arachidonic acid synthesis. Mouse platelets were not directly affected by IFN-I because they lack the receptor for the cytokine (IFNAR1), suggesting that transfusion of normal platelets into LCMV-infected mice could increase the amount of platelet-released serotonin and help to control hemorrhage.
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Affiliation(s)
- Roberto Aiolfi
- Department of Molecular Medicine, MERU-Roon Research Center for Vascular Biology, Scripps Research, La Jolla, CA 92037, USA
- Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Giovanni Sitia
- Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Matteo Iannacone
- Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
- Vita-Salute San Raffaele University, Milan, Italy
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Ivan Brunetta
- Department of Molecular Medicine, MERU-Roon Research Center for Vascular Biology, Scripps Research, La Jolla, CA 92037, USA
| | - Luca G. Guidotti
- Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Zaverio M. Ruggeri
- Department of Molecular Medicine, MERU-Roon Research Center for Vascular Biology, Scripps Research, La Jolla, CA 92037, USA
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Krivoshey AV, Efremov AA, Matveishina EK, Panova VV, Vrzheshch PV. Simulation of the Level of Prostaglandins in Open Systems under the Action of Nonsteroidal Anti-Inflammatory Drugs. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2021. [DOI: 10.1134/s1068162021050289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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5
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Filimonov IS, Berzova AP, Barkhatov VI, Krivoshey AV, Trushkin NA, Vrzheshch PV. Negative Cooperativity in the Interaction of Prostaglandin H Synthase-1 with the Competitive Inhibitor Naproxen Can Be Described as the Interaction of a Non-competitive Inhibitor with Heterogeneous Enzyme Preparation. BIOCHEMISTRY (MOSCOW) 2018; 83:119-128. [PMID: 29618298 DOI: 10.1134/s0006297918020049] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The kinetic mechanism of the interaction of nonsteroidal anti-inflammatory drugs (NSAIDs) with their main pharmacological target, prostaglandin H synthase (PGHS), has not yet been established. We showed that inhibition of PGHS-1 from sheep vesicular glands by naproxen (a representative of NSAIDs) demonstrates a non-competitive character with respect to arachidonic acid and cannot be described within a framework of the commonly used kinetic schemes. However, it can be described by taking into account the negative cooperativity of naproxen binding to the cyclooxygenase active sites of the PGHS-1 homodimer (the first naproxen molecule forms a more stable complex (K1 = 0.1 µM) with the enzyme than the second naproxen molecule (K2 = 9.2 µM)). An apparent non-competitive interaction of PGHS-1 with naproxen is due to slow dissociation of the enzyme-inhibitor complexes. The same experimental data could also be described using commonly accepted kinetic schemes, assuming that naproxen interacts was a mixture of two enzyme species with the inhibition constants Kα = 0.05 µM and Kβ = 18.3 µM. Theoretical analysis and numerical calculations show that the phenomenon of kinetic convergence of these two models has a general nature: when K2 >> K1, the kinetic patterns (for transient kinetics and equilibrium state) generated by the cooperative model could be described by a scheme assuming the presence of two enzyme forms with the inhibition constants Kα = K1/2, Kβ = 2·K2. When K2 << K1, the cooperative model can be presented as a scheme with two inhibitor molecules simultaneously binding to the enzyme with the observed inhibition constant K (K = K1·K2). The assumption on the heterogeneity of the enzyme preparation in relation to its affinity to the inhibitor can be used instead of the assumption on the negative cooperativity of the enzyme-inhibitor interactions for convenient and easy practical description of such phenomena in enzymology, biotechnology, pharmacology, and other fields of science.
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Affiliation(s)
- I S Filimonov
- Lomonosov Moscow State University, International Biotechnological Center, Moscow, 119991, Russia
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6
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Pathogen–Host Interaction of Histoplasma capsulatum: an Update. CURRENT FUNGAL INFECTION REPORTS 2016. [DOI: 10.1007/s12281-016-0267-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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7
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Activation of Peroxisome Proliferator-Activated Receptor Alpha Improves Aged and UV-Irradiated Skin by Catalase Induction. PLoS One 2016; 11:e0162628. [PMID: 27611371 PMCID: PMC5017777 DOI: 10.1371/journal.pone.0162628] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 08/25/2016] [Indexed: 01/10/2023] Open
Abstract
Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear hormone receptor involved in the transcriptional regulation of lipid metabolism, fatty acid oxidation, and glucose homeostasis. Its activation stimulates antioxidant enzymes such as catalase, whose expression is decreased in aged human skin. Here we investigated the expression of PPARα in aged and ultraviolet (UV)-irradiated skin, and whether PPARα activation can modulate expressions of matrix metalloproteinase (MMP)-1 and procollagen through catalase regulation. We found that PPARα mRNA level was significantly decreased in intrinsically aged and photoaged human skin as well as in UV-irradiated skin. A PPARα activator, Wy14643, inhibited UV-induced increase of MMP-1 and decrease of procollagen expression and caused marked increase in catalase expression. Furthermore, production of reactive oxygen species (ROS) was suppressed by Wy14643 in UV-irradiated and aged dermal fibroblasts, suggesting that the PPARα activation-induced upregulation of catalase leads to scavenging of ROS produced due to UV irradiation or aging. PPARα knockdown decreased catalase expression and abolished the beneficial effects of Wy14643. Topical application of Wy14643 on hairless mice restored catalase activity and prevented MMP-13 and inflammatory responses in skin. Our findings indicate that PPARα activation triggers catalase expression and ROS scavenging, thereby protecting skin from UV-induced damage and intrinsic aging.
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Affiliation(s)
- Douglas A. Kniss
- Department of Obstetrics and Gynecology, Laboratory of Perinatal Research, The Ohio State University, College of Medicine and Public Health, Columbus, Ohio
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Balachandran C, Emi N, Arun Y, Yamamoto N, Duraipandiyan V, Inaguma Y, Okamoto A, Ignacimuthu S, Al-Dhabi NA, Perumal PT. In vitro antiproliferative activity of 2,3-dihydroxy-9,10-anthraquinone induced apoptosis against COLO320 cells through cytochrome c release caspase mediated pathway with PI3K/AKT and COX-2 inhibition. Chem Biol Interact 2016; 249:23-35. [PMID: 26915975 DOI: 10.1016/j.cbi.2016.02.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Revised: 01/30/2016] [Accepted: 02/19/2016] [Indexed: 12/22/2022]
Abstract
The present study investigated the anticancer activity of 2,3-dihydroxy-9,10-anthraquinone against different cancer cells such as MCF-7, COLO320, HepG-2, Skov-3, MOLM-14, NB-4, CEM, K562, Jurkat, HL-60, U937, IM-9 and Vero. 2,3-dihydroxy-9,10-anthraquinone showed good antiproliferative activity against COLO320 cells when compared to other tested cells. The cytotoxicity results showed 79.8% activity at the dose of 2.07 μM with IC50 value of 0.13 μM at 24 h in COLO320 cells. So we chose COLO320 cells for further anticancer studies. mRNA expression was confirmed by qPCR analysis using SYBR green method. Treatment with 2,3-dihydroxy-9,10-anthraquinone was found to trigger intrinsic apoptotic pathway as indicated by down regulation of Bcl-2, Bcl-xl; up regulation of Bim, Bax, Bad; release of cytochrome c and pro-caspases cleaving to caspases. Furthermore, 2,3-dihydroxy-9,10-anthraquinone stopped at G0/G1 phase with modulation in protein levels of cyclins. On the other hand PI3K/AKT signaling plays an important role in cell metabolism. We found that 2,3-dihydroxy-9,10-anthraquinone inhibits PI3K/AKT activity after treatment. Also, COX-2 enzyme plays a major role in colorectal cancer. Our results showed that the treatment significantly reduced COX-2 enzyme in COLO320 cells. These results indicated antiproliferative activity of 2,3-dihydroxy-9,10-anthraquinone involving apoptotic pathways, mitochondrial functions, cell cycle checkpoint and controlling the over expression genes during the colorectal cancer. Molecular docking studies showed that the compound bound stably to the active sites of Bcl-2, COX-2, PI3K and AKT. This is the first report of anticancer mechanism involving 2,3-dihydroxy-9,10-anthraquinone in COLO320 cells. The present results might provide helpful suggestions for the design of antitumor drugs toward colorectal cancer treatment.
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Affiliation(s)
- C Balachandran
- Department of Hematology, Fujita Health University, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan; Division of Cancer Biology, Entomology Research Institute, Loyola College, Chennai, 600 034, India.
| | - N Emi
- Department of Hematology, Fujita Health University, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Y Arun
- Organic & Bio-organic Chemistry Laboratory, CSIR-Central Leather Research Institute, Chennai, 600 020, India
| | - N Yamamoto
- Laboratory of Molecular Biology, Institute of Joint Research, Fujita Health University, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - V Duraipandiyan
- Division of Cancer Biology, Entomology Research Institute, Loyola College, Chennai, 600 034, India; Department of Botany and Microbiology, Addiriya Chair for Environmental Studies, College of Science, King Saud University, P.O.Box.2455, Riyadh, 11451, Saudi Arabia
| | - Yoko Inaguma
- Department of Hematology, Fujita Health University, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Akinao Okamoto
- Department of Hematology, Fujita Health University, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - S Ignacimuthu
- Division of Cancer Biology, Entomology Research Institute, Loyola College, Chennai, 600 034, India; Visiting Professor Program, Deanship of Scientific Research, College of Science, King Saud Univeristy, Saudi Arabia
| | - N A Al-Dhabi
- Department of Botany and Microbiology, Addiriya Chair for Environmental Studies, College of Science, King Saud University, P.O.Box.2455, Riyadh, 11451, Saudi Arabia
| | - P T Perumal
- Organic & Bio-organic Chemistry Laboratory, CSIR-Central Leather Research Institute, Chennai, 600 020, India
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Gutowska I, Baranowska-Bosiacka I, Goschorska M, Kolasa A, Łukomska A, Jakubczyk K, Dec K, Chlubek D. Fluoride as a factor initiating and potentiating inflammation in THP1 differentiated monocytes/macrophages. Toxicol In Vitro 2015; 29:1661-8. [PMID: 26119525 DOI: 10.1016/j.tiv.2015.06.024] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 06/23/2015] [Accepted: 06/25/2015] [Indexed: 02/08/2023]
Abstract
It is well known that exposure to fluorides lead to an increased ROS production and enhances the inflammatory reactions. Therefore we decided to examine whether cyclooxygenases (particular COX-2) activity and expression may be changed by fluoride in THP1 macrophages and in this way may change the prostanoids biosynthesis. In the present work we demonstrate that fluoride increased concentration of PGE2 and TXA2 in THP1 macrophages. Following exposure to 1-10 μM NaF, COX-2 protein and COX-2 transcript increased markedly. COX-2 protein up-regulation probably is mediated by ROS, produced during fluoride-induced inflammatory reactions. Additional fluoride activates the transcription factor, nuclear factor (NF)-kappaB, which is involved in the up-regulation of COX-2 gene expression. This study indicated that even in small concentrations fluoride changes the amounts and activity of COX-1 and COX-2 enzymes taking part in the initiating and development of inflammatory process.
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Affiliation(s)
- I Gutowska
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Broniewskiego 24 Str., Szczecin, Poland
| | - I Baranowska-Bosiacka
- Department of Biochemistry, Pomeranian Medical University, Powstańców Wlkp 72 Str., Szczecin, Poland.
| | - M Goschorska
- Department of Biochemistry, Pomeranian Medical University, Powstańców Wlkp 72 Str., Szczecin, Poland
| | - A Kolasa
- Department of Histology and Embryology, Pomeranian Medical University, Powstańców Wlkp 72 Str., Szczecin, Poland
| | - A Łukomska
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Broniewskiego 24 Str., Szczecin, Poland
| | - K Jakubczyk
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Broniewskiego 24 Str., Szczecin, Poland
| | - K Dec
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Broniewskiego 24 Str., Szczecin, Poland
| | - D Chlubek
- Department of Biochemistry, Pomeranian Medical University, Powstańców Wlkp 72 Str., Szczecin, Poland
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Zhang X, Sun J, Xin W, Li Y, Ni L, Ma X, Zhang D, Zhang D, Zhang T, Du G. Anti-inflammation effect of methyl salicylate 2-O-β-D-lactoside on adjuvant induced-arthritis rats and lipopolysaccharide (LPS)-treated murine macrophages RAW264.7 cells. Int Immunopharmacol 2015; 25:88-95. [PMID: 25637446 DOI: 10.1016/j.intimp.2015.01.024] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Revised: 01/23/2015] [Accepted: 01/23/2015] [Indexed: 01/12/2023]
Abstract
Methyl salicylate 2-O-β-D-lactoside (MSL) is a derivative of natural salicylate isolated from Gaultheria yunnanensis (Franch.) Rehder, which is widely used for treating rheumatoid arthritis (RA), swelling and pain. The aim of the present study was to investigate the effect of MSL on the progression of adjuvant-induced arthritis (AIA) in rat in vivo and explore the anti-inflammatory effects and mechanism of MSL in lipopolysaccharide (LPS)-treated murine macrophages RAW264.7 cells in vitro. Our results showed that MSL significantly inhibited the arthritis progression in AIA rats, decreasing the right hind paw swelling and ankle diameter, attenuating histopathological changes and suppressing the plasma levels of TNF-α and IL-1β in AIA rats. Besides, MSL had potent anti-inflammatory effects on the LPS-activated RAW264.7. MSL dose-dependently inhibited the activity of COX-1, and COX-2. Moreover, MSL prominently inhibited LPS-induced activation of MAPK in RAW264.7 cells by blocking phosphorylation of p38 and ERK. Our study suggests that MSL may be effective in the treatment of inflammatory diseases by inhibiting the pro-inflammatory cytokine production and regulating the MAPK signal pathway.
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Affiliation(s)
- Xue Zhang
- Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China.
| | - Jialin Sun
- Pharmacy Department of the Affiliated Hospital of Qingdao University, Qingdao 266003, China.
| | - Wenyu Xin
- Binzhou Medical University, Yantai 264003, China.
| | - Yongjie Li
- Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China.
| | - Lin Ni
- Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Xiaowei Ma
- Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Dan Zhang
- Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Dongming Zhang
- Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Tiantai Zhang
- Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China.
| | - Guanhua Du
- Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China.
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Park JB. Synthesis and characterization of norbelladine, a precursor of Amaryllidaceae alkaloid, as an anti-inflammatory/anti-COX compound. Bioorg Med Chem Lett 2014; 24:5381-4. [DOI: 10.1016/j.bmcl.2014.10.051] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 10/10/2014] [Accepted: 10/17/2014] [Indexed: 10/24/2022]
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13
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Shao Y, Sun K, Xu W, Li XL, Shen H, Sun WH. Helicobacter pylori infection, gastrin and cyclooxygenase-2 in gastric carcinogenesis. World J Gastroenterol 2014; 20:12860-12873. [PMID: 25278683 PMCID: PMC4177468 DOI: 10.3748/wjg.v20.i36.12860] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 03/12/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is one of the most frequent neoplasms and a main cause of death worldwide, especially in China and Japan. Numerous epidemiological, animal and experimental studies support a positive association between chronic Helicobacter pylori (H. pylori) infection and the development of gastric cancer. However, the exact mechanism whereby H. pylori causes gastric carcinogenesis remains unclear. It has been demonstrated that expression of cyclooxygenase-2 (COX-2) is elevated in gastric carcinomas and in their precursor lesions. In this review, we present the latest clinical and experimental evidence showing the role of gastrin and COX-2 in H. pylori-infected patients and their possible association with gastric cancer risk.
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Liu Y, Chen LY, Sokolowska M, Eberlein M, Alsaaty S, Martinez-Anton A, Logun C, Qi HY, Shelhamer JH. The fish oil ingredient, docosahexaenoic acid, activates cytosolic phospholipase A₂ via GPR120 receptor to produce prostaglandin E₂ and plays an anti-inflammatory role in macrophages. Immunology 2014; 143:81-95. [PMID: 24673159 DOI: 10.1111/imm.12296] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Revised: 03/11/2014] [Accepted: 03/21/2014] [Indexed: 12/13/2022] Open
Abstract
Docosahexaenoic acid (DHA) is one of the major ingredients of fish oil and has been reported to have anti-inflammatory properties mediated through the GPR120 receptor. Whether cytosolic phospholipase A2 (cPLA2 ) and lipid mediators produced from cPLA2 activation are involved in the anti-inflammatory role of DHA in macrophages has not been reported. We report here that DHA and the GPR120 agonist, GW9508, activate cPLA2 and cyclooxygenase 2 (COX-2), and cause prostaglandin E2 (PGE2) release in a murine macrophage cell line RAW264.7 and in human primary monocyte-derived macrophages. DHA and GW9508 activate cPLA2 via GPR120 receptor, G protein Gαq and scaffold protein β-arrestin 2. Extracellular signal-regulated kinase 1/2 activation is involved in DHA- and GW9508-induced cPLA2 activation, but not p38 mitogen-activated protein kinase. The anti-inflammatory role of DHA and GW9508 is in part via activation of cPLA2 , COX-2 and production of PGE2 as a cPLA2 inhibitor or a COX-2 inhibitor partially reverses the DHA- and GW9508-induced inhibition of lipopolysaccharide-induced interleukin-6 secretion. The cPLA2 product arachidonic acid and PGE2 also play an anti-inflammatory role. This effect of PGE2 is partially through inhibition of the nuclear factor-κB signalling pathway and through the EP4 receptor of PGE2 because an EP4 inhibitor or knock-down of EP4 partially reverses DHA inhibition of lipopolysaccharide-induced interleukin-6 secretion. Hence, DHA has an anti-inflammatory effect partially through induction of PGE2.
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Affiliation(s)
- Yueqin Liu
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
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Wan R, Liu Y, Li L, Zhu C, Jin L, Li S. Urocortin increased endothelial ICAM1 by cPLA2-dependent NF-κB and PKA pathways in HUVECs. J Mol Endocrinol 2014; 52:43-53. [PMID: 24363440 DOI: 10.1530/jme-13-0182] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Urocortin (Ucn1), a member of the corticotrophin-releasing hormone (CRH) family, has been reported to participate in inflammation. The increased expression of intercellular adhesion molecule 1 (ICAM1) plays important roles in inflammation and immune responses. Our previous results demonstrated that Ucn1 significantly enhanced the expression of ICAM1. However, the underlying mechanisms are still unknown. The purpose of this study is to investigate the detailed mechanisms of Ucn1-induced upregulation of ICAM1. Here, we characterized the mechanisms of Ucn1 usage to regulate ICAM1 expression in human umbilical vein endothelial cells (HUVECs). Our data revealed that Ucn1 increased ICAM1 and cyclooxygenase 2 (COX2) expressions in a time-dependent manner via CRH receptor 2 (CRHR2). In addition, COX2 was involved in ICAM1 upregulation. Furthermore, Ucn1 could increase the expression and phosphorylation of cytosolic phospholipases A2 (cPLA2) in a time-dependent manner via CRHR2 and CRHR1. Moreover, ablation of cPLA2 by the inhibitor pyrrophenone or siRNA attenuated the ICAM1 increase induced by Ucn1. In addition, nuclear factor κB (NF-κB) was activated, indicated by the increase in nuclear p65NF-κB expression and phosphorylation of p65NF-κB, depending on cPLA2 and CRHR2 activation. Pyrrolidinedithiocarbamic acid, an inhibitor of NF-κB, abolished the elevation of ICAM1 but not COX2. Also, Ucn1 increased the production of prostaglandin E2 (PGE2) which further activated protein kinase A (PKA)-CREB pathways dependent of cPLA2 via CRHR2. Moreover, the increase in NF-κB phosphorylation was not affected by the selective COX2 inhibitor NS-398 or the PKA inhibitor H89. In conclusion, these data indicate that Ucn1 increase the ICAM1 expression via cPLA2-NF-κB and cPLA2-COX2-PGE2-PKA-CREB pathways by means of CRHR2.
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Affiliation(s)
- Rong Wan
- Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Department of Pharmacology, Nanjing Medical University, Nanjing 210029, People's Republic of China The Key Laboratory of Molecular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China
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Habib MA, Salem SAM, Hakim SA, Shalan YAM. Comparative immunohistochemical assessment of cutaneous cyclooxygenase-2 enzyme expression in chronological aging and photoaging. PHOTODERMATOLOGY PHOTOIMMUNOLOGY & PHOTOMEDICINE 2013; 30:43-51. [DOI: 10.1111/phpp.12087] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/01/2013] [Indexed: 11/28/2022]
Affiliation(s)
| | | | - Sarah Adel Hakim
- Department of Pathology; Faculty of Medicine; Ain Shams University; Cairo Egypt
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Cyclooxygenase-1-dependent prostaglandins mediate susceptibility to systemic inflammation-induced acute cognitive dysfunction. J Neurosci 2013; 33:15248-58. [PMID: 24048854 DOI: 10.1523/jneurosci.6361-11.2013] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Systemic inflammatory events often precipitate acute cognitive dysfunction in elderly and demented populations. Delirium is a highly prevalent neuropsychiatric syndrome that is characterized by acute inattention and cognitive dysfunction, for which prior dementia is the major predisposing factor and systemic inflammation is a frequent trigger. Inflammatory mechanisms of delirium remain unclear. We have modeled aspects of delirium during dementia by exploiting progressive neurodegeneration in the ME7 mouse model of prion disease and by superimposing systemic inflammation induced by the bacterial endotoxin lipopolysaccharide (LPS). Here, we have used this model to demonstrate that the progression of underlying disease increases the incidence, severity, and duration of acute cognitive dysfunction. This increasing susceptibility is associated with increased CNS expression of cyclooxygenase (COX)-1 in microglia and perivascular macrophages. The COX-1-specific inhibitor SC-560 provided significant protection against LPS-induced cognitive deficits, and attenuated the disease-induced increase in hippocampal and thalamic prostaglandin E2, while the COX-2-specific inhibitor NS-398 was ineffective. SC-560 treatment did not alter levels of the proinflammatory cytokines interleukin (IL)-1β, tumor necrosis factor-α, IL-6, or C-X-C chemokine ligand 1 in blood or brain, but systemic IL-1RA blocked LPS-induced cognitive deficits, and systemic IL-1β was sufficient to induce similar deficits in the absence of LPS. Furthermore, the well tolerated COX inhibitor ibuprofen was protective against IL-1β-induced deficits. These data demonstrate that progressive microglial COX-1 expression and prostaglandin synthesis can underpin susceptibility to cognitive deficits, which can be triggered by systemic LPS-induced IL-1β. These data contribute to our understanding of how systemic inflammation and ongoing neurodegeneration interact to induce cognitive dysfunction and episodes of delirium.
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Sticht MA, Rock EM, Parker LA. 2-arachidonoylglycerol interferes with lithium-induced vomiting in the house musk shrew, Suncus murinus. Physiol Behav 2013; 120:228-32. [PMID: 23958470 DOI: 10.1016/j.physbeh.2013.08.015] [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: 05/06/2013] [Revised: 07/30/2013] [Accepted: 08/09/2013] [Indexed: 10/26/2022]
Abstract
The role of the endocannabinoid system in vomiting has been previously studied using several animal species. These investigations have clearly demonstrated an anti-emetic role for the eCB, anandamide, in these animal models; however, research concerning the role of 2-arhachidonoylglycerol (2AG) has been less clear. The aim of the present study was to assess the effects of exogenous 2AG administration in the house musk shrew, Suncus murinus. In Experiment 1, shrews were injected with vehicle or 2AG (1, 2, 5, 10 mg/kg) 15 min prior to behavioral testing in which the frequency of vomiting episodes was observed. In Experiment 2, shrews were pre-treated with 2AG (2, 5 mg/kg) prior to being administered the emetic drug, lithium chloride (LiCl). It was found that 2AG alone did not induce emesis, but interfered with vomiting in response to LiCl administration. The anti-emetic effects of 2AG in Suncus murinus do not appear to be mediated by CB1 receptors, as concomitant pretreatment with the CB1 receptor antagonist, SR141716, did not reverse the suppressive effects of 2AG. These results confirm that manipulations that increase levels of 2AG exert anti-emetic effects in the house musk shrew.
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Affiliation(s)
- M A Sticht
- Department of Psychology and Neuroscience Graduate Program, University of Guelph, Guelph, Ontario, Canada
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Shin MH, Park R, Nojima H, Kim HC, Kim YK, Chung JH. Atomic hydrogen surrounded by water molecules, H(H2O)m, modulates basal and UV-induced gene expressions in human skin in vivo. PLoS One 2013; 8:e61696. [PMID: 23637886 PMCID: PMC3634861 DOI: 10.1371/journal.pone.0061696] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Accepted: 03/12/2013] [Indexed: 01/16/2023] Open
Abstract
Recently, there has been much effort to find effective ingredients which can prevent or retard cutaneous skin aging after topical or systemic use. Here, we investigated the effects of the atomic hydrogen surrounded by water molecules, H(H2O)m, on acute UV-induced responses and as well as skin aging. Interestingly, we observed that H(H2O)m application to human skin prevented UV-induced erythema and DNA damage. And H(H2O)m significantly prevented UV-induced MMP-1, COX-2, IL-6 and IL-1β mRNA expressions in human skin in vivo. We found that H(H2O)m prevented UV-induced ROS generation and inhibited UV-induced MMP-1, COX-2 and IL-6 expressions, and UV-induced JNK and c-Jun phosphorylation in HaCaT cells. Next, we investigated the effects of H(H2O)m on intrinsically aged or photoaged skin of elderly subjects. In intrinsically aged skin, H(H2O)m application significantly reduced constitutive expressions of MMP-1, IL-6, and IL-1β mRNA. Additionally, H(H2O)m significantly increased procollagen mRNA and also decreased MMP-1 and IL-6 mRNA expressions in photoaged facial skin. These results demonstrated that local application of H(H2O)m may prevent UV-induced skin inflammation and can modulate intrinsic skin aging and photoaging processes. Therefore, we suggest that modifying the atmospheric gas environment within a room may be a new way to regulate skin functions or skin aging.
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Affiliation(s)
- Mi Hee Shin
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea
- Laboratory of Cutaneous Aging Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
- Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Korea
| | - Raeeun Park
- R&D Team, Samsung Electronics CO., LTD, Suwon, Korea
| | - Hideo Nojima
- R&D Team, Samsung Electronics CO., LTD, Suwon, Korea
| | | | - Yeon Kyung Kim
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea
- Laboratory of Cutaneous Aging Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
- Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Korea
| | - Jin Ho Chung
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea
- Laboratory of Cutaneous Aging Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
- Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Korea
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Celecoxib improves host defense through prostaglandin inhibition during Histoplasma capsulatum infection. Mediators Inflamm 2013; 2013:950981. [PMID: 23818746 PMCID: PMC3681213 DOI: 10.1155/2013/950981] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 02/22/2013] [Indexed: 11/18/2022] Open
Abstract
Prostaglandins act as mediators of inflammation and, similar to cytokines, function as immune modulators during innate and adaptive immune responses. Therefore, using a pharmacological inhibitor, celecoxib, we investigated the role of prostaglandins in host defense against Histoplasma capsulatum infection in C57BL/6 mice. Our results showed that treatment with celecoxib inhibited cyclooxygenase 2, reduced the total fungal burden, and reduced the concentration of PGE2, cytokines, lymphocytes, neutrophils, and mononuclear cells in the bronchoalveolar space and lung parenchyma. In addition, celecoxib treatment increased the synthesis of nitric oxide, IFN-γ, LTB4, and the phagocytic capacity of alveolar macrophages. Moreover, celecoxib treatment increased the survival of mice after infection with a lethal inoculum of H. capsulatum. These results suggest that prostaglandins alter the host immune response and play an important role in the pathogenesis of histoplasmosis. Thus, the inhibition of prostaglandins could be a valuable immunomodulatory strategy and antifungal therapy for histoplasmosis treatment.
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Kim SK, Kim H, Kim SA, Park HK, Kim W. Anti-inflammatory and anti-superbacterial activity of polyphenols isolated from black raspberry. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2013; 17:73-9. [PMID: 23440625 PMCID: PMC3579108 DOI: 10.4196/kjpp.2013.17.1.73] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Revised: 12/12/2012] [Accepted: 01/01/2013] [Indexed: 11/15/2022]
Abstract
The fruit of the black raspberry (Rubus coreanus Miquel) has been employed in traditional medicine, and recent studies have demonstrated its measureable biological activities. However, the root of the black raspberry has not been studied. Therefore, in this study, we evaluated the anti-inflammatory and antibacterial properties of the root and unripe fruit polyphenols of the black raspberry. Both polyphenols proved to have anti-inflammatory activity as evidenced by the decreased nitric oxide (NO), cytokines (IL-1β , IL-6, and IL-10) and prostaglandin E2 (PGE2) levels in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. However, root polyphenols showed stronger anti-inflammatory activity than fruit polyphenols. LPS-induced mRNA and protein expressions of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 levels were also decreased, confirming the anti-inflammatory activity. Root polyphenols showed lethal activity against methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Acinetobacter baumannii (CRAB), and Bacillus anthracis. In contrast, the black raspberry fruit did not demonstrate these properties. These data provide the first demonstration that black raspberry root has potential anti-inflammatory and anti-superbacterial properties that can be exploited as alternatives for use in the food and cosmetic industries and/or as pharmaceuticals.
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Affiliation(s)
- Seong Keun Kim
- Department of Microbiology, College of Medicine, Chung-Ang University, Seoul 156-756, Korea
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Park JB. Synthesis, biological activities and bioavailability of moschamine, a safflomide-type phenylpropenoic acid amide found inCentaurea cyanus. Nat Prod Res 2012; 26:1465-72. [DOI: 10.1080/14786419.2011.562207] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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Braden LM, Barker DE, Koop BF, Jones SR. Comparative defense-associated responses in salmon skin elicited by the ectoparasite Lepeophtheirus salmonis. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY D-GENOMICS & PROTEOMICS 2012; 7:100-9. [DOI: 10.1016/j.cbd.2011.12.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Revised: 12/15/2011] [Accepted: 12/20/2011] [Indexed: 01/29/2023]
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Veloso MP, Romeiro NC, Silva GMS, Alves HDM, Doriguetto AC, Ellena J, Miranda ALP, Barreiro EJ, Fraga CAM. Synthesis and characterization of the atropisomeric relationships of a substituted N-phenyl-bipyrazole derivative with anti-inflammatory properties. Chirality 2012; 24:463-70. [DOI: 10.1002/chir.22016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2011] [Revised: 01/15/2012] [Accepted: 01/18/2012] [Indexed: 11/10/2022]
Affiliation(s)
| | | | | | - Hélio De M. Alves
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Faculdade de Farmácia; Universidade Federal do Rio de Janeiro; Rio de Janeiro; RJ; Brazil
| | | | - Javier Ellena
- Instituto de Física de São Carlos; Universidade de São Paulo; São Carlos; SP; Brazil
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Bhagavat R, Saqib A, Karigar C. Molecular Docking Studies of Novel Palmitoyl-ligands for Cyclooxygenase-2. Chem Biol Drug Des 2012; 79:1043-8. [DOI: 10.1111/j.1747-0285.2012.01359.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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26
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Discovery of new orally effective analgesic and anti-inflammatory hybrid furoxanyl N-acylhydrazone derivatives. Bioorg Med Chem 2012; 20:2158-71. [DOI: 10.1016/j.bmc.2012.01.034] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2011] [Revised: 12/29/2011] [Accepted: 01/06/2012] [Indexed: 11/23/2022]
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Bynagari-Settipalli YS, Lakhani P, Jin J, Bhavaraju K, Rico MC, Kim S, Woulfe D, Kunapuli SP. Protein kinase C isoform ε negatively regulates ADP-induced calcium mobilization and thromboxane generation in platelets. Arterioscler Thromb Vasc Biol 2012; 32:1211-9. [PMID: 22362759 DOI: 10.1161/atvbaha.111.242388] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVE Members of the protein kinase C (PKC) family are shown to positively and negatively regulate platelet activation. Although positive regulatory roles are extensively studied, negative regulatory roles of PKCs are poorly understood. We investigated the mechanism and specific isoforms involved in PKC-mediated negative regulation of ADP-induced functional responses. METHODS AND RESULTS A pan-PKC inhibitor, GF109203X, potentiated ADP-induced cPLA(2) phosphorylation and thromboxane generation as well as ERK activation and intracellular calcium (Ca(2+)(i)) mobilization, 2 signaling molecules, upstream of cPLA(2) activation. Thus, PKCs inhibit cPLA(2) activation by inhibiting ERK and Ca(2+)(i) mobilization. Because the inhibitor of classic PKC isoforms, GO-6976, did not affect ADP-mediated thromboxane generation, we investigated the role of novel class of PKC isoforms. ADP-induced thromboxane generation, calcium mobilization, and ERK phosphorylation were potentiated in PKCε null murine platelets compared with platelets from wild-type littermates. Interestingly, when thromboxane release is blocked, ADP-induced aggregation in PKCε knockout and wild-type was similar, suggesting that PKCε does not affect ADP-induced aggregation directly. PKCε knockout mice exhibited shorter times to occlusion in an FeCl(3)-induced arterial injury model and shorter bleeding times in tail-bleeding experiments. CONCLUSIONS We conclude that PKCε negatively regulates ADP-induced thromboxane generation in platelets and offers protection against thrombosis.
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Abstract
A Mediterranean diet appears to have health benefits in many domains of human health, mediated perhaps by its anti-inflammatory effects. Metabolism of fatty acids and subsequent eicosanoid production is a key mechanism by which a Mediterranean diet can exert anti-inflammatory effects. Both dietary fatty acids and fatty acid metabolism determine fatty acid availability for cyclooxygenase- and lipoxygenase-dependent production of eicosanoids, namely prostaglandins and leukotrienes. In dietary intervention studies and in observational studies of the Mediterranean diet, blood levels of fatty acids do reflect dietary intakes but are attenuated. Small differences in fatty acid levels, however, appear to be important, especially when exposures occur over long periods of time. This review summarizes how fat intakes from a Greek-style Mediterranean diet can be expected to affect fatty acid metabolizing proteins, with an emphasis on the metabolic pathways that lead to the formation of proinflammatory eicosanoids. The proteins involved in these pathways are ripe for investigation using proteomic approaches and may be targets for colon cancer prevention.
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Affiliation(s)
- Zora Djuric
- Department of Family Medicine, University of Michigan, Ann Arbor, Michigan 48109-5930, USA.
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Protective Effect of Proanthocyanidin against Diabetic Oxidative Stress. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2011; 2012:623879. [PMID: 21912569 PMCID: PMC3168294 DOI: 10.1155/2012/623879] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Revised: 06/01/2011] [Accepted: 06/09/2011] [Indexed: 01/11/2023]
Abstract
We investigated the antidiabetic potential of proanthocyanidin and its oligomeric form in STZ-induced diabetic model rats and db/db type 2 diabetic mice. Proanthocyanidin ameliorated the diabetic condition by significant decreases of serum glucose, glycosylated protein, and serum urea nitrogen as well as decreases of urinary protein and renal-AGE in STZ-induced diabetic rats and decrease of serum glucose as well as significant decrease of glycosylated protein in db/db type 2 diabetic mice. The suppression of ROS generation and elevation of the GSH/GSSG ratio were also observed in the groups administered proanthocyanidin. Moreover, proanthocyanidin, especially its oligomeric form, affected the inflammatory process with the regulation of related protein expression, iNOS, COX-2 and upstream regulators, NF-κB, and the IκB-α. In addition, it had a marked effect on hyperlipidemia through lowering significant levels of triglycerides, total cholesterol, and NEFA. Moreover, expressions in the liver of SREBP-1 and SREBP-2 were downregulated by the administration of proanthocyanidins. The protective effect against hyperglycemia and hyperlipidemia in type 1 and 2 diabetic models was significantly strong in the groups administered the oligomeric rather than polymeric form. This suggests that oligomers act as a regulator in inflammatory reactions caused by oxidative stress in diabetes.
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Guerra C, Collado M, Navas C, Schuhmacher AJ, Hernández-Porras I, Cañamero M, Rodriguez-Justo M, Serrano M, Barbacid M. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 2011; 19:728-39. [PMID: 21665147 PMCID: PMC4890723 DOI: 10.1016/j.ccr.2011.05.011] [Citation(s) in RCA: 401] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2010] [Revised: 01/19/2011] [Accepted: 05/13/2011] [Indexed: 12/12/2022]
Abstract
Pancreatic acinar cells of adult mice (≥P60) are resistant to transformation by some of the most robust oncogenic insults including expression of K-Ras oncogenes and loss of p16Ink4a/p19Arf or Trp53 tumor suppressors. Yet, these acinar cells yield pancreatic intraepithelial neoplasias (mPanIN) and ductal adenocarcinomas (mPDAC) if exposed to limited bouts of non-acute pancreatitis, providing they harbor K-Ras oncogenes. Pancreatitis contributes to tumor progression by abrogating the senescence barrier characteristic of low-grade mPanINs. Attenuation of pancreatitis-induced inflammation also accelerates tissue repair and thwarts mPanIN expansion. Patients with chronic pancreatitis display senescent PanINs, providing they have received antiinflammatory drugs. These results support the concept that antiinflammatory treatment of people diagnosed with pancreatitis may reduce their risk of developing PDAC.
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Affiliation(s)
- Carmen Guerra
- Experimental Oncology, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
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Lee YM, Kang SM, Lee SR, Kong KH, Lee JY, Kim EJ, Chung JH. Inhibitory effects of TRPV1 blocker on UV-induced responses in the hairless mice. Arch Dermatol Res 2011; 303:727-36. [PMID: 21656169 DOI: 10.1007/s00403-011-1153-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2011] [Accepted: 05/17/2011] [Indexed: 11/21/2022]
Abstract
The transient receptor potential vanilloid 1 (TRPV1) channel can be activated by vanilloids, exposure to ultraviolet (UV) irradiation, heat, or protons, and conditions that occur during tissue injury. In the present study, we investigated whether or not TRPV1-specific blocker, 5'-iodoresiniferatoxin (I-RTX), can reduce UV-induced matrix metalloproteinases (MMPs), pro-inflammatory cytokines, cyclooxygenase (COX)-2, and p53 expression in the skin of hairless mice. Our results showed that I-RTX inhibited UV-induced skin thickening, as measured by a caliper, or in hematoxylin and eosin (H&E)-stained sections. UV-induced mRNA and protein expression of MMP-13, MMP-9, MMP-3, and MMP-2 was significantly reduced by I-RTX. We also observed the inhibitory effects of I-RTX on UV-induced mRNA expression of the pro-inflammatory cytokines, interleukin (IL)-1β, IL-2, IL-4, and tumor necrosis factor-α. UV-induced COX-2 and p53 protein expression was also significantly decreased by I-RTX. From the above results, we suggest that TRPV1-specific blocker, I-RTX, could prevent UV-induced skin responses, and provide new insight into development of effective therapeutic methods for photoaging.
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Affiliation(s)
- Young Mee Lee
- Department of Dermatology, Seoul National University Hospital,Yeongeon-Dong, Chongno-Gu, Korea
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Abstract
Prostaglandin D₂ (PGD₂) is a major prostanoid, produced mainly by mast cells, in allergic diseases, including bronchial asthma. PGD₂-induced vasodilatation and increased permeability are well-known classical effects that may be involved in allergic inflammation. Recently, novel functions of PGD₂ have been identified. To date, D prostanoid receptor (DP) and chemoattractant receptor homologous molecule expressed on T(H)2 cells (CRTH2) have been shown to be major PGD₂-related receptors. These two receptors have pivotal roles mediating allergic diseases by regulating the functions of various cell types, such as T(H)2 cells, eosinophils, basophils, mast cells, dendritic cells, and epithelial cells. This review will focus on the current understanding of the roles of PGD₂ and its metabolites in T(H)2 inflammation and the pathogenesis of bronchial asthma.
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Affiliation(s)
- Masafumi Arima
- Department of Developmental Genetics (H2), Chiba University Graduate School of Medicine, Chiba, Japan.
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Mangoni AA, Woodman RJ, Gaganis P, Gilbert AL, Knights KM. Use of non-steroidal anti-inflammatory drugs and risk of incident myocardial infarction and heart failure, and all-cause mortality in the Australian veteran community. Br J Clin Pharmacol 2010; 69:689-700. [PMID: 20565461 DOI: 10.1111/j.1365-2125.2010.03627.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
AIMS We studied the association between either non-selective NSAIDs (ns-NSAIDs), selective COX-2 inhibitors, or any NSAID and risk of incident myocardial infarction (MI) and heart failure (HF), and all-cause mortality in elderly subjects. METHODS We conducted a retrospective nested case-control study on Australian veterans using nationwide hospital admission and pharmacy dispensing data. We estimated adjusted odds ratios (OR) with 95% confidence intervals (CI) for the risk of events for three different measures of prescription supply exposure over the last 2 years: (i) supplied at least once, (ii) supply frequency: supplied more than twice within the last 30 days, once or twice within the last 30 days, and once or more 30 days to 2 years and (iii) total supplies. RESULTS We identified 83 623 cases and 1 662 099 matched controls (1:20) contributing 3 862 931 persons-years of observation. NSAID use at least once within the last 2 years did not significantly affect the risk of MI (OR 1.00, 95% CI 0.96, 1.04) but was associated with a mildly reduced risk of HF (OR 0.95, 95% CI 0.92, 0.98). There was a reduced all-cause mortality with at least one supply of either ns-NSAIDs (OR 0.94, 95% CI 0.90, 0.97), selective COX-2 inhibitors (OR 0.90, 95% CI 0.88, 0.93), or any NSAID (OR 0.87, 95% CI 0.85, 0.90). Risk of death was also inversely associated with the number of prescription supplies. CONCLUSIONS NSAID use is not associated with an increased risk of incident MI and HF but is associated with a reduction in all-cause mortality in Australian veterans.
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Affiliation(s)
- Arduino A Mangoni
- Department of Clinical Pharmacology, School of Medicine, Flinders University, Australia.
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Desai D, Kaushal N, Gandhi UH, Arner RJ, D’Souza C, Chen G, Vunta H, El-Bayoumy K, Amin S, Prabhu KS. Synthesis and evaluation of the anti-inflammatory properties of selenium-derivatives of celecoxib. Chem Biol Interact 2010; 188:446-56. [PMID: 20883674 PMCID: PMC3004533 DOI: 10.1016/j.cbi.2010.09.021] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2010] [Revised: 09/20/2010] [Accepted: 09/21/2010] [Indexed: 11/29/2022]
Abstract
Celecoxib is a selective cyclooxygenase (COX)-2 inhibitor used to treat inflammation, while selenium is known to down-regulate the transcription of COX-2 and other pro-inflammatory genes. To expand the anti-inflammatory property, wherein celecoxib could inhibit pro-inflammatory gene expression at extremely low doses, we incorporated selenium (Se) into two Se-derivatives of celecoxib, namely; selenocoxib-2 and selenocoxib-3. In vitro kinetic assays of the inhibition of purified human COX-2 activity by these compounds indicated that celecoxib and selenocoxib-3 had identical K(I) values of 2.3 and 2.4μM; while selenocoxib-2 had a lower K(I) of 0.72μM. Furthermore, selenocoxib-2 inhibited lipopolysaccharide-induced activation of NF-κB leading to the down-regulation of expression of COX-2, iNOS, and TNFα more effectively than selenocoxib-3 and celecoxib in RAW264.7 macrophages and murine bone marrow-derived macrophages. Studies with rat liver microsomes followed by UPLC-MS-MS analysis indicated the formation of selenenylsulfide conjugates of selenocoxib-2 with N-acetylcysteine. Selenocoxib-2 was found to release minor amounts of Se that was effectively inhibited by the CYP inhibitor, sulphaphenazole. While these studies suggest that selenocoxib-2, but not celecoxib and selenocoxib-3, targets upstream events in the NF-κB signaling axis, the ability to effectively suppress NF-κB activation independent of cellular selenoprotein synthesis opens possibilities for a new generation of COX-2 inhibitors with significant and broader anti-inflammatory potential.
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Affiliation(s)
- Dhimant Desai
- Department of Pharmacology and The Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033
| | - Naveen Kaushal
- Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis and Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802
| | - Ujjawal H. Gandhi
- Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis and Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802
| | - Ryan J. Arner
- Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis and Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802
| | | | - Gang Chen
- Department of Public Health Sciences, The Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033
| | - Hema Vunta
- Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis and Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802
| | - Karam El-Bayoumy
- Department of Biochemistry and Molecular Biology, The Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033
| | - Shantu Amin
- Department of Pharmacology and The Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033
| | - K. Sandeep Prabhu
- Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis and Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802
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Summ O, Andreou AP, Akerman S, Goadsby PJ. A potential nitrergic mechanism of action for indomethacin, but not of other COX inhibitors: relevance to indomethacin-sensitive headaches. J Headache Pain 2010; 11:477-83. [PMID: 20978816 PMCID: PMC2995862 DOI: 10.1007/s10194-010-0263-7] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2010] [Accepted: 09/01/2010] [Indexed: 11/29/2022] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) that act as cyclo-oxygenase (COX) inhibitors are commonly used in the treatment of a range of headache disorders, although their mechanism of action is unclear. Indomethacin is of particular interest given its very special effect in some primary headaches. Here the in vivo technique of intravital microscopy in rats has been utilised as a model of trigeminovascular nociception to study the potential mechanism of action of indomethacin. Dural vascular changes were produced using electrical (neurogenic) dural vasodilation (NDV), calcitonin gene-related peptide (CGRP) induced dural vasodilation and nitric oxide (NO) induced dural vasodilation using NO donors. In each of these settings the effect of intravenously administered indomethacin (5 mg kg(-1)), naproxen (30 mg kg(-1)) and ibuprofen (30 mg kg(-1)) was tested. All of the tested drugs significantly inhibited NDV (between 30 and 52%). Whilst none of them was able to inhibit CGRP-induced dural vasodilation, only indomethacin reduced NO induced dural vasodilation (35 ± 7%, 10 min post administration). We conclude NSAIDs inhibit release of CGRP after NDV without an effect on CGRP directly. Further we describe a differentiating effect of indomethacin inhibiting nitric oxide induced dural vasodilation that is potentially relevant to understanding its unique action in disorders such as paroxysmal hemicrania and hemicrania continua.
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Affiliation(s)
- Oliver Summ
- Headache Group, Department of Neurology, University of California, 1701 Divisadero St, Suite 480, San Francisco, CA 94115, USA
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36
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Yokozawa T, Cho EJ, Okamoto T, Sei Y. Effects of the Chinese prescription Kangen-karyu and its crude drug Tanjin on ageing process in rats. J Pharm Pharmacol 2010; 58:1591-9. [PMID: 17331322 DOI: 10.1211/jpp.58.12.0005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Abstract
The effects of the Chinese prescription Kangen-karyu and its crude drug Tanjin on the ageing process were investigated in rats. Diets supplemented with Kangen-karyu and Tanjin extracts decreased glycosylated protein levels in serum, a risk marker of ageing and ageing-related diseases. In addition, they inhibited the levels of thiobarbituric acid reactive substance in the serum and liver; Kangen-karyu in particular led to a strong decrease in hepatic mitochondrial thiobarbituric acid reactive substance. The decline in the reduced glutathione/oxidized glutathione ratio in the liver observed with ageing was ameliorated by Kangen-karyu and Tanjin, while these groups attenuated the increase in glutathione peroxidase activity of hepatic tissue against ageing. This suggests that Kangen-karyu and Tanjin regulate the glutathione redox cycle that maintains the cellular redox condition against age-related oxidative stress. Moreover, the overexpression of cytoplasmic cytochrome c observed with ageing was attenuated by Kangen-karyu and Tanjin. This provides new evidence that Kangen-karyu and Tanjin inhibit leakage of superoxide in mitochondria and attenuate cellular oxidative damage. Furthermore, Kangen-karyu and Tanjin would maintain mitochondrial function with ageing through the regulation of related protein expression such as bax and bcl-2 proteins. In addition, Kangen-karyu reduced the expression of nuclear factor kappa B; Kangen-karyu and Tanjin did not affect the expression of inhibitor kappa B. The present study demonstrated that Kangenkaryu prevented oxidative damage and mitochondrial dysfunction with ageing. Furthermore, Kangen-karyu showed a stronger protective effect against ageing by oxidative stress than Tanjin, probably through synergistic and/or additive effects.
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Affiliation(s)
- Takako Yokozawa
- Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
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37
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Mangoni AA, Woodman RJ, Gilbert AL, Knights KM. Use of non-steroidal anti-inflammatory drugs and risk of ischemic and hemorrhagic stroke in the Australian veteran community. Pharmacoepidemiol Drug Saf 2010; 19:490-8. [DOI: 10.1002/pds.1945] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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38
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Lakshmi BS, Kangueane P, Guo Y, Chen YZ, Gautam P. Molecular Basis for the Stereospecificity of Candida Rugosa Lipase (Crl) Towards Ibuprofen. BIOCATAL BIOTRANSFOR 2009. [DOI: 10.3109/10242420009003637] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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39
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Arúajo AMF, Mendez JC, Coelho AL, Sousa B, Barata F, Figueiredo A, Amaro T, Azevedo I, Soares M. Phase II study of celecoxib with cisplatin plus etoposide in extensive-stage small cell lung cancer. Cancer Invest 2009; 27:391-6. [PMID: 19266367 DOI: 10.1080/07357900802232756] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
We performed a phase II trial to test whether a cyclooxygenase (COX-2) inhibitor, celecoxib, added to standard first-line combination chemotherapy (CT) and as maintenance therapy would improve outcomes in extensive-stage (ES) small-cell lung cancer (SCLC). This was a multicenter trial in CT-naive patients with ES-SCLC. They received standard cisplatin and etoposide (EP) up to 6 cycles and celecoxib 400 mg PO bid continuously until disease progression. Primary end points were response rate (RR), time to progression (TTP), and toxicity. Secondary were overall survival (OS) and quality of life. Of 74 expected patients, only 24 were enrolled and the study stopped earlier because of the published safety concerns about celecoxib. The patients, all male, were between 38 and 74 years. A total of 130 cycles of CT were administered. Toxicity associated with celecoxib was minimal. The RR was 56.5%. Median TTP and OS were 8.6 and 11.3 months, respectively. These data suggest that celecoxib may safely be combined with EP for treatment of ES-SCLC. This combination showed a promising activity and, despite the safety concerns regarding celecoxib, it would be interesting to further evaluate this regimen.
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Affiliation(s)
- António M F Arúajo
- Department of Medical Oncology, Portuguese Institute of Oncology Francisco Gentil, Porto, Portugal.
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Abstract
Tolerance is maintained by central and peripheral regulatory mechanisms and is essential to prevent autoimmunity. In the setting of solid organ or haematopoietic transplantation, the indirect pathway of allorecognition is a significant driver of chronic rejection. Chronic rejection proceeds despite effective immunosuppressive therapy, therefore achieving immunological tolerance to control the indirect pathway is a desirable goal. Tolerance induction may be achieved by vaccination with modified antigen presenting cells (APCs). Mature dendritic cells (DCs) are potent APCs, but immature DCs have been shown to have a reduced allo-stimulatory capacity and can be tolerogenic. Drug treatment has been shown to decrease the allo-stimulatory capacity of DC compared to immature DC. Dexamethasone and vitamin D3 have been established as having potent effects on dendritic cell immunogenicity.The effects of aspirin, a non-steroidal anti-inflammatory, on DCs have not previously been so extensively studied and here we will review the work which has been carried out using aspirin to induce tolerogenic DCs.We have examined the mechanisms of tolerance induction using human DCs and T cells. It has been possible to demonstrate that in aspirin treated, human DCs there is inhibition of the nuclear factor K-B (NFKB) signalling pathway, modified cytokine production, reduced expression of co-stimulatory molecules (CD40, CD80, and CD86) and increased expression of immunoglobulin-like transcript-3 (ILT3). The decreased expression of co-stimulatory molecules is maintained following cytokine or lipopolysaccharide (LPS) challenge. Drug treatment of DCs increases the expression of immunoglobulin-like transcript 3 (ILT3) when compared with immature DCs (iDCs), and these high levels of expression are maintained when the cells are challenged with a maturational stimulus. Aspirin also reduces the allo-stimulatory capacity of human DCs, and induces hypo-responsiveness and regulatory activity in responder T cells. These regulatory T-cells were CD4(+) CD25(+) FOXP3(+) and by studying CD25(-) or CD45RA populations, it was possible to determine that these regulatory T cells were generated de novo rather than requiring the expansion of naturally occurring Tregs. Aspirin continues therefore to be of interest with regard its wider effects on immune regulation, other than that mediated by direct inhibition of cyclo-oxygenase, in particular its ability to induce tolerogenic DCs at therapeutic concentrations in humans.
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Affiliation(s)
- Matthew Buckland
- Immunoregulation Laboratory, Department of Nephrology, Thomas Guy House, Guys Hospital Campus, Kings College London School of Medicine, Guys, Kings College and St Thomas Hospitals, London SE1 9RT, UK.
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Tributino JLM, Duarte CD, Corrêa RS, Doriguetto AC, Ellena J, Romeiro NC, Castro NG, Miranda ALP, Barreiro EJ, Fraga CAM. Novel 6-methanesulfonamide-3,4-methylenedioxyphenyl-N-acylhydrazones: orally effective anti-inflammatory drug candidates. Bioorg Med Chem 2008; 17:1125-31. [PMID: 19135376 DOI: 10.1016/j.bmc.2008.12.045] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2008] [Revised: 12/13/2008] [Accepted: 12/17/2008] [Indexed: 10/21/2022]
Abstract
We described herein the molecular design of novel in vivo anti-inflammatory 6-methanesulfonamide-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives (1) planned by applying the molecular hybridization approach. This work also points out to the discovery of LASSBio-930 (1c) as a novel anti-inflammatory and anti-hyperalgesic prototype, which was able to reduce carrageenan-induced rat paw edema with an ED(50) of 97.8 micromol/kg, acting mainly as a non-selective COX inhibitor.
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Affiliation(s)
- Jorge L M Tributino
- LASSBio-Laboratório de Avaliação e Síntese de Substâncias Bioativas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, PO Box 68023, 21941-902 Rio de Janeiro, RJ, Brazil
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Sun WH, Chen GS, Ou XL, Yang Y, Luo C, Zhang Y, Shao Y, Xu HC, Xiao B, Xue YP, Zhou SM, Zhao QS, Ding GX. Inhibition of COX-2 and activation of peroxisome proliferator-activated receptor gamma synergistically inhibits proliferation and induces apoptosis of human pancreatic carcinoma cells. Cancer Lett 2008; 275:247-55. [PMID: 19056168 DOI: 10.1016/j.canlet.2008.10.023] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2008] [Revised: 10/05/2008] [Accepted: 10/17/2008] [Indexed: 01/03/2023]
Abstract
Although inhibition of cyclooxygenase-2 (COX-2) or activation of peroxisome proliferators-activated receptor gamma (PPAR-gamma) leads to growth inhibition in malignancies, the synergistic anti-tumor effects of combination of COX-2 inhibitor (NS-398) and PPAR-gamma agonist (rosiglitazone) on the human pancreatic cancer cells remains unknown. Here, we evaluated the effects of NS-398 and/or rosiglitazone on the cell proliferation and apoptosis in a pancreatic cancer cell line, SW1990. NS-398 and rosiglitazone decreased cell proliferation in a dose- and time-dependent manner. Proliferating cell nuclear antigen (PCNA) labeling index significantly decreased in the cells treated with either NS-398 or rosiglitazone. Both NS-398 and rosiglitazone alone induced apoptotic cell death of SW1990. The combination of NS-398 and rosiglitazone exerted synergistic effects on proliferation inhibition, and apoptosis induction in SW1990 cells, with down-regulation of Bcl-2 and up-regulation of Bax expression. Our results indicate that simultaneous targeting of COX-2 and PPAR-gamma inhibits pancreatic cancer development more effectively than targeting each molecule alone.
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Affiliation(s)
- Wei-Hao Sun
- Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, PR China.
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Papich MG. An Update on Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in Small Animals. Vet Clin North Am Small Anim Pract 2008; 38:1243-66, vi. [DOI: 10.1016/j.cvsm.2008.09.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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44
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Celecoxib potently inhibits TNFα-induced nuclear translocation and activation of NF-κB. Biochem Pharmacol 2008; 76:662-71. [DOI: 10.1016/j.bcp.2008.06.015] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2008] [Revised: 06/22/2008] [Accepted: 06/24/2008] [Indexed: 11/22/2022]
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Yang HM, Oh SM, Lim SS, Shin HK, Oh YS, Kim JK. Antiinflammatory activities of Rubus coreanus depend on the degree of fruit ripening. Phytother Res 2008; 22:102-7. [PMID: 17724764 DOI: 10.1002/ptr.2274] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The dried unripe fruit of Rubus coreanus, which is well-known in Korea and referred to as 'Bok-bun-ja', has been employed as a traditional medicine for centuries. This crude drug is utilized in Korea for the management of impotence, spermatorrhea, enuresis, asthma and allergic diseases. The principal objective of the present study was to conduct a comparison of the antiinflammatory effects of ethanol extracts of the unripe (URCE), half-ripened (HRCE) and ripe fruits (RCE) of Rubus coreanus. URCE and HRCE were found to reduce the production of nitric oxide (NO) and prostaglandin E2 (PGE2) as well as pro-inflammatory cytokines, in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages. However, RCE exerted no inhibitory effects against the production of NO and IL-6. The results of the study show that the degree of fruit ripening of Rubus coreanus affects the production of inflammatory mediators such as NO, PGE2 and inflammatory cytokines.
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Affiliation(s)
- Hyun Mo Yang
- Center for Efficacy Assessment and Development of Functional Foods and Drugs, Hallym University, Gangwon-do 200-702, Korea
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Zacher J, Altman R, Bellamy N, Brühlmann P, Da Silva J, Huskisson E, Taylor RS. Topical diclofenac and its role in pain and inflammation: an evidence-based review. Curr Med Res Opin 2008; 24:925-50. [PMID: 18279583 DOI: 10.1185/030079908x273066] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVE Topical diclofenac is widely used in the treatment of pain and inflammation. This comprehensive review assesses the safety and efficacy of topical diclofenac in a range of painful and inflammatory disorders. METHODS Double-blind, randomized, placebo- or active-controlled trials (RCT) evaluating topical diclofenac in soft-tissue injuries, soft-tissue rheumatic disorders and osteoarthritis were identified through detailed literature searches. In addition, non-RCT evidence from publications evaluating the pharmacologic characteristics of topical diclofenac were also included in this review to obtain a more complete picture of the drug's profile, its efficacy and safety. RESULTS Studies demonstrate that the drug preferentially distributes to the target tissues in sufficient concentrations to produce a therapeutic effect. A total of 19 double-blind RCTs in more than 3000 patients, supported by single-blind or open trials, consistently show that topical diclofenac significantly reduces pain and inflammation in acute and chronic conditions compared with placebo and is comparable to other topical non-steroidal anti-inflammatory drugs (NSAIDs) and some oral NSAIDs (diclofenac, ibuprofen, naproxen). Improvements have also been observed in patients' functional capacity and mobility. Topical diclofenac is well tolerated, resulting mostly in mild, easily resolved local skin irritation, and is associated with fewer side-effects than other topical NSAIDs and a lower rate of gastrointestinal complications than oral NSAIDs (diclofenac, ibuprofen, naproxen). CONCLUSION This evidence-based review shows topical diclofenac to be an effective and well tolerated treatment in painful and inflammatory conditions, at least in the short-term. However, only published RCT studies have been included in this analysis, which may exclude some interesting data from non-RCT studies. Future trials of topical diclofenac need to be of longer duration, be better reported and consider a broader spectrum of acute and chronic pain indications.
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Affiliation(s)
- J Zacher
- Department of Orthopedic Surgery and Orthopedic Rheumatology, HELIOS Hospital Group, Berlin, Germany
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Han S, Kim K, Kim H, Kwon J, Lee YH, Lee CK, Song Y, Lee SJ, Ha N, Kim K. Auranofin inhibits overproduction of pro-inflammatory cytokines, cyclooxygenase expression and PGE2 production in macrophages. Arch Pharm Res 2008; 31:67-74. [PMID: 18277610 DOI: 10.1007/s12272-008-1122-9] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Auranofin (AF), a gold compound, is an orally active therapeutic agent used to treat rheumatoid arthritis (RA), a self-perpetuating inflammatory disease. RA is characterized by autoimmune-mediated proliferation of synovial cells that leads to inflammation, pain, and swelling in most major joints: However, the mechanism as to how AF relieves RA symptoms has not been fully elucidated. The object of this study was to examine the ability of AF to immunomodulate macrophages as antigen presenting cells (APCs). Macrophages are recognized as playing an important role in the pathogenesis of RA, in that there is a relative abundance of macrophage-derived cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) in rheumatoid synovium. In this work, we tested whether AF (2.5-20 mM) could inhibit inflammatory activity in the macrophage cell line RAW 264.7. AF decreased production of nitric oxide (NO) and the pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6 in macrophages. Furthermore, AF inhibited cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production in a concentration-dependent manner. In conclusion, these findings may provide an explanation for the clinical effects of AF in patients with RA.
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Affiliation(s)
- Shinha Han
- Department of Pharmacy, Sahmyook University, Nowon-gu, Seoul 139-743, Korea
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Brune K. Persistence of NSAIDs at effect sites and rapid disappearance from side-effect compartments contributes to tolerability. Curr Med Res Opin 2007; 23:2985-95. [PMID: 17949535 DOI: 10.1185/030079907x242584] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND Non-steroidal, anti-inflammatory drugs (NSAIDs) are still the most widely used drugs worldwide. The introduction of selective cyclooxygenase (COX)-2 inhibitors has led to compounds which appear less damaging to the gastrointestinal tract, but possibly more risky to the cardiovascular system than older drugs. None has as yet reached OTC-status. OBJECTIVE This situation necessitates an analysis of the characteristics of those older ones which - due to their relative safety - have achieved over-the-counter (OTC) status. DESIGN The pharmacodynamic and pharmacokinetic characteristics of non-selective COX inhibitors in OTC use were obtained from the literature by systematic search, examined and used to construct a coherent hypothesis why they achieved OTC status, i.e. effectiveness and relative safety at low doses. RESULTS Pharmacodynamic (COX-2 preferential, but not selective inhibition) and, more importantly, pharmacokinetic characteristics of some of the older compounds may make them particularly safe drugs if used at low (OTC) doses with treatment limited to a few days of intake. The reason why some NSAIDs are particularly active while being relatively free from side-effects may be due to their specific biodistribution and metabolism, leading to drug accumulation and persistence in inflamed tissue (effect compartment) together with fast clearance from the central compartment, including blood, vascular wall, heart and kidney, i.e., possible sideeffect compartments. CONCLUSION This specific pharmacokinetic behavior of some non-selective COX inhibitors, such as diclofenac and ibuprofen, may explain why these widely used, non-steroidal, anti-inflammatory compounds are relatively well suited for OTC use and why some are more appropriate for the therapy of certain pain conditions than others.
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Affiliation(s)
- Kay Brune
- Department of Experimental and Clinical Pharmacology and Toxicology, FAU Erlangen-Nuremberg, Germany.
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Lee YA, Kim YJ, Cho EJ, Yokozawa T. Ameliorative effects of proanthocyanidin on oxidative stress and inflammation in streptozotocin-induced diabetic rats. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2007; 55:9395-9400. [PMID: 17939733 DOI: 10.1021/jf071523u] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Recent evidence strongly suggests that oxidative stress due to redox imbalance is causally associated with inflammatory processes and various diseases including diabetes. We examined the effects of proanthocyanidin from persimmon peel, using both oligomers and polymers, against oxidative stress with elucidation of the underlying mechanisms in streptozotocin-induced diabetic rats. The elevation of lipid peroxidation in the kidney and serum under the diabetic condition was decreased by the administration of proanthocyanidin. The suppression of reactive oxygen species generation and elevation of the reduced glutathione/oxidized glutathione ratio were observed in the groups administered proanthocyanidin. These results support the protective role of proanthocyanidin from oxidative stress induced by diabetes. Moreover, proanthocyanidin, especially its oligomeric form, affected the inflammatory process with regulation of related protein expression, inducible nitric oxide synthase, cyclooxygenase-2, and upstream regulators, nuclear factor kappaB, and inhibitor-binding protein kappaB-alpha. Proanthocyanidin ameliorated the diabetic condition by decreases of serum glucose, glycosylated protein, serum urea nitrogen, urinary protein, and renal advanced glycation endproducts. In particular, oligomeric proanthocyanidin exerted a stronger protective activity than the polymeric form. This suggests that the polymerization of proanthocyanidin has an effect on its protective effect against diabetes. The present study supports the beneficial effect of proanthocyanidin against diabetes and oxidative stress-related inflammatory processes.
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Affiliation(s)
- Young A Lee
- Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
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Duarte CD, Tributino JLM, Lacerda DI, Martins MV, Alexandre-Moreira MS, Dutra F, Bechara EJH, De-Paula FS, Goulart MOF, Ferreira J, Calixto JB, Nunes MP, Bertho AL, Miranda ALP, Barreiro EJ, Fraga CAM. Synthesis, pharmacological evaluation and electrochemical studies of novel 6-nitro-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives: Discovery of LASSBio-881, a new ligand of cannabinoid receptors. Bioorg Med Chem 2007; 15:2421-33. [PMID: 17275312 DOI: 10.1016/j.bmc.2007.01.013] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2006] [Accepted: 01/11/2007] [Indexed: 10/23/2022]
Abstract
We describe herein the discovery of LASSBio-881 (3c) as a novel in vivo antinociceptive, anti-inflammatory, and in vitro antiproliferative and antioxidant compound, with a cannabinoid ligand profile. We observed that LASSBio-881 (3c) was able to bind to CB1 receptors (71% at 100microM) and also to inhibit T-cell proliferation (66% at 10microM) probably by binding to CB2 receptors, in a non-proapoptotic manner, different from anandamide (1). It was also demonstrated that LASSBio-881 (3c) had an important antioxidant profile toward free radicals (DPPH and hydroxyl), probably due to its particular redox behavior, which reflects the presence of both nitro and 3,5-di-tert-butyl-4-hydroxyphenyl sub-units, as demonstrated by cyclic voltammetry studies. In addition, we showed that these structural sub-units are essential for the observed pharmacological activity.
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MESH Headings
- Analgesics/chemical synthesis
- Analgesics/chemistry
- Analgesics/pharmacology
- Animals
- Anti-Inflammatory Agents/chemical synthesis
- Anti-Inflammatory Agents/chemistry
- Anti-Inflammatory Agents/pharmacology
- Antioxidants/chemical synthesis
- Antioxidants/chemistry
- Antioxidants/pharmacology
- Arachidonic Acid/toxicity
- Arachidonic Acids/pharmacology
- Biphenyl Compounds/metabolism
- Brain/drug effects
- Cannabinoid Receptor Modulators/pharmacology
- Carrageenan/toxicity
- Cell Proliferation/drug effects
- Edema/chemically induced
- Edema/prevention & control
- Endocannabinoids
- Female
- Formaldehyde/toxicity
- Free Radical Scavengers/chemical synthesis
- Free Radical Scavengers/chemistry
- Free Radical Scavengers/pharmacology
- Hydrazines/chemical synthesis
- Hydrazines/chemistry
- Hydrazines/metabolism
- Hydrazines/pharmacology
- Hydrazones/chemical synthesis
- Hydrazones/chemistry
- Hydrazones/pharmacology
- Ligands
- Male
- Mice
- Models, Molecular
- Pain/drug therapy
- Picrates
- Polyunsaturated Alkamides/pharmacology
- Pyridines/toxicity
- Rats
- Rats, Wistar
- Receptor, Cannabinoid, CB1/agonists
- Receptor, Cannabinoid, CB1/metabolism
- Receptor, Cannabinoid, CB2/agonists
- Receptor, Cannabinoid, CB2/metabolism
- Structure-Activity Relationship
- Superoxides/metabolism
- T-Lymphocytes/drug effects
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Affiliation(s)
- Carolina D Duarte
- LASSBio--Laboratório de Avaliação e Síntese de Substâncias Bioativas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, PO Box 68006, 21944-971, Rio de Janeiro, RJ, Brazil
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