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

2020 ◽  
Vol 74 ◽  
pp. 504-516
Author(s):  
Miriam Dawidowicz ◽  
Agnieszka Kula ◽  
Paweł Świętochowski ◽  
Zofia Ostrowska
Keyword(s):  
Enzymatic Activity ◽  
Inflammatory Diseases ◽  
Aspirin Resistance ◽  
Nucleotide Polymorphisms ◽  
Cyclooxygenase 1 ◽  
Genes Encoding ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
The Impact ◽  
Cox 1

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

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

2021 ◽  
Vol 28 ◽  
Author(s):  
Josiane Viana Cruz ◽  
Joaquín María Campos Rosa ◽  
Njogu Mark Kimani ◽  
Silvana Giuliatti ◽  
Cleydson Breno Rodrigues dos Santos
Keyword(s):  
Side Effects ◽  
Inflammatory Diseases ◽  
Structural Basis ◽  
Potential Inhibitor ◽  
Cyclooxygenase 1 ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 2 Inhibitors

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

scholarly journals ANTI-INFLAMMATORY ACTIVITY OF BACTERIA ASSOCIATED WITH MARINE SPONGE (HALICLONA AMBOINENSIS) VIA REDUCTING NO PRODUCTION AND INHIBITING CYCLOOXYGENASE-1, CYCLOOXYGENASE-2, AND SECRETORY PHOSPHOLIPASE A2 ACTIVITIES

2017 ◽  
Vol 10 (11) ◽  
pp. 95 ◽  
Author(s):  
Yosie Andriani ◽  
Leni Marlina ◽  
Habsah Mohamad ◽  
Hermansyah Amir ◽  
Siti Aisha M Radzi ◽  
...  
Keyword(s):  
Methanol Extract ◽  
Inflammatory Activity ◽  
No Production ◽  
Secretory Phospholipase A2 ◽  
Phytochemical Screening ◽  
Spla2 Activity ◽  
Cyclooxygenase 1 ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

  Objective: This study aimed to investigate the anti-inflammatory activity of methanol extract and fractions of bacteria associated with sponge (Haliclona amboinensis) and to evaluate their effect in reducing NO production and inhibiting cyclooxygenase-1 (COX-1), cyclooxgenase-2 (COX-2) and secretory phospholipase A2 (sPLA2) activity.Methods: All bacterial isolates were cultured and supernatants were collected for the extraction of secondary metabolites using diaion HP-20 to obtain methanol extracts. Evaluation of cytotoxicity property was carried out on macrophage cell lines (RAW264.7) by 3-(4,5-dimethylthiazol- 2-yl) 2,5-diphenyl tetrazoliumbromide assay. Anti-inflammatory screening was done by inducible nitric oxide assay on RAW264.7 cell lines with lipopolysaccharide (LPS) stimulation. Dianion HP-20 was used to remove salt content. A selected methanol extract was subjected to further fractionations by C-18 reverse phase and their anti-inflammatory potential was evaluated by COX-1 and COX-2, and sPLA2 enzymatic assay.Results: Seven methanol extracts showed no cytotoxic property against RAW 264.7 cell line (inhibitory concentration 50% > 30 μg/ml) and selected for anti-inflammatory screening assay. Result showed methanol extract HM 1.2 reduced NO production >80% and it has been selected for phytochemical screening, further fractionations and assay. Phytochemical screening showed alkaloids and terpenoids present in the HM 1.2. The HM 1.2 and its fractions (F1, F2, F1C1, F1C2, F1C3, and F1C4) were proven to inhibit COX-1, COX-2, and sPLA2 activity in the range of 60.516-116.886%, 20.554- 116.457%, and 70.2667-114.8148%, respectively.Conclusions: This study revealed that bacteria associated with H. amboinensis have produced anti-inflammatory activity via reducing NO production and inhibiting COX-1, COX-2, and sPLA2 activity. 

scholarly journals Evaluation of Anti-Inflammatory Components of Guizhi Fuling Capsule, an Ancient Chinese Herbal Formula, in Human Umbilical Vein Endothelial Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Yuzhong Zheng ◽  
Guizhong Xin ◽  
Guowei Gong ◽  
Tina TX Dong ◽  
Ping Li ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Active Components ◽  
Human Umbilical Vein ◽  
Cellular Inflammation ◽  
Cyclooxygenase 1 ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Umbilical Vein Endothelial Cells ◽  
Cox 1

Background. Guizhi Fuling capsule (GFC), a well-known formula composed of five medicinal herbs, is commonly prescribed to treat primary dysmenorrhea, as well as to achieve good clinical efficacy in China. However, the active components of GFC have not been identified. Here, the anti-inflammatory functions of GFC, as well as its major ingredients, were evaluated in human umbilical vein endothelial cells (HUVECs). Methods. Lipopolysaccharide (LPS) was used in HUVECs to imitate the cellular inflammation. Then, GFC-triggered mRNA expressions of cyclooxygenase-1 (COX-1) and COX-2 were determined by real-time PCR, while the expression of COX-2 protein was revealed by western blotting. Besides, nine components of GFC were evaluated for their contribution value in the anti-dysmenorrhea effects Results. The application of GFC downregulated the mRNA expressions of COX-1 and COX-2 mRNAs. Nine major components of GFC were tested in the inflammatory system, and three compounds, including paeoniflorin, benzoylpaeoniflorin, and amygdalin, exhibited robust activation in HUVECs. The combination of paeoniflorin, benzoylpaeoniflorin, and amygdalin showed over 80% of the anti-inflammatory activation. Conclusion. Our study supports that GFC plays a promising role in anti-dysmenorrhea function by decreasing COXs’ expression. Besides, paeoniflorin, benzoylpaeoniflorin, and amygdalin could be considered as major regulators for the anti-dysmenorrhea effects of GFC.

scholarly journals Structural Basis of Enantioselective Inhibition of Cyclooxygenase-1 by S-α-Substituted Indomethacin Ethanolamides

2007 ◽  
Vol 282 (38) ◽  
pp. 28096-28105 ◽  
Author(s):  
Christine A. Harman ◽  
Melissa V. Turman ◽  
Kevin R. Kozak ◽  
Lawrence J. Marnett ◽  
William L. Smith ◽  
...  
Keyword(s):  
Binding Pocket ◽  
Drug Binding ◽  
Structural Basis ◽  
Cyclooxygenase 1 ◽  
Cox 2 ◽  
The Impact ◽  
First Time ◽  
Side Pocket ◽  
Cox 1 ◽  
Equal Efficacy

The modification of the nonselective nonsteroidal anti-inflammatory drug, indomethacin, by amidation presents a promising strategy for designing novel cyclooxygenase (COX)-2-selective inhibitors. A series of α-substituted indomethacin ethanolamides, which exist as R/S-enantiomeric pairs, provides a means to study the impact of stereochemistry on COX inhibition. Comparative studies revealed that the R- and S-enantiomers of the α-substituted analogs inhibit COX-2 with almost equal efficacy, whereas COX-1 is selectively inhibited by the S-enantiomers. Mutagenesis studies have not been able to identify residues that manifest the enantioselectivity in COX-1. In an effort to understand the structural impact of chirality on COX-1 selectivity, the crystal structures of ovine COX-1 in complexes with an enantiomeric pair of these indomethacin ethanolamides were determined at resolutions between 2.75 and 2.85Å. These structures reveal unique, enantiomer-selective interactions within the COX-1 side pocket region that stabilize drug binding and account for the chiral selectivity observed with the (S)-α-substituted indomethacin ethanolamides. Kinetic analysis of binding demonstrates that both inhibitors bind quickly utilizing a two-step mechanism. However, the second binding step is readily reversible for the R-enantiomer, whereas for the S-enantiomer, it is not. These studies establish for the first time the structural and kinetic basis of high affinity binding of a neutral inhibitor to COX-1 and demonstrate that the side pocket of COX-1, previously thought to be sterically inaccessible, can serve as a binding pocket for inhibitor association.

scholarly journals Synthesis of Novel Benzodifuranyl; 1,3,5-Triazines; 1,3,5-Oxadiazepines; and Thiazolopyrimidines Derived from Visnaginone and Khellinone as Anti-Inflammatory and Analgesic Agents

Molecules ◽  
2020 ◽  
Vol 25 (1) ◽  
pp. 220 ◽  
Author(s):  
Ameen Ali Abu-Hashem ◽  
Sami A Al-Hussain ◽  
Magdi E. A. Zaki
Keyword(s):  
Sodium Ethoxide ◽  
Standard Drug ◽  
Chemical Structures ◽  
Cyclooxygenase 1 ◽  
Analgesic Agents ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
New Compounds ◽  
Cox 2 Inhibitors ◽  
Cox 1

Novel (4-methoxy or 4,8-dimethoxy)-3-methyl-N-(6-oxo-2-thioxo-1,2,3, 6-tetrahydro- pyrimidin-4-yl) benzo [1,2-b: 5, 4-b’] difuran-2-carboxamide (5a–b) has been synthesized by the reaction of visnagenone–ethylacetate (2a) or khellinone–ethylacetate (2b) with 6-aminothiouracil in dimethylformamide or refluxing of benzofuran-oxy-N-(2-thioxopyrimidine) acetamide (4a–b) in sodium ethoxide to give the same products (5a,b) in good yields. Thus, compounds 5a–b are used as an initiative to prepare many new heterocyclic compounds such as 2-(4-(3-methylbenzodifuran- 2-carbox-amido) pyrimidine) acetic acid (6a–b), N-(thiazolo[3, 2-a]pyrimidine)-3-methylbenzo- difuran-2-carboxamide (7a–b), N-(2-thioxopyrimidine)-methylbenzodifuran-2-carbimidoylchloride (8a–b), N-(2-(methyl-thio) pyrimidine)-3-methylbenzodifuran-2-carbimidoylchloride (9a–b), N-(2, 6 -di(piperazine or morpholine)pyrimidine)-1-(3-methylbenzodifuran)-1-(piperazine or morpholine) methanimine(10a–d), 8-(methylbenzodifuran)-thiazolopyrimido[1,6-a][1,3,5]triazine-3,5-dione (11a –b), 8-(3-methyl benzodifuran)-thiazolopyrimido[6,1-d][1,3,5]oxadiazepine-trione (12a–b), and 2,10 -di(sub-benzylidene)-8-(3-methylbenzodifuran)-thiazolopyrimido[6,1-d][1,3,5]oxadiazepine-3,5,11- trione (13a–f). All new chemical structures were illustrated on the basis of elemental and spectral analysis (IR, NMR, and MS). The new compounds were screened as cyclooxygenase-1/ cyclooxygenase-2 (COX-1/COX-2) inhibitors and had analgesic and anti-inflammatory activities. The compounds 10a–d and 13a–f had the highest inhibitory activity on COX-2 selectivity, with indices of 99–90, analgesic activity of 51–42% protection, and anti-inflammatory activity of 68%–59%. The inhibition of edema for the same compounds, 10a–d and 13a–f, was compared with sodium diclofenac as a standard drug.

scholarly journals Mechanisms Underlying the Antinociceptive, Antiedematogenic, and Anti-Inflammatory Activity of the Main Flavonoid fromKalanchoe pinnata

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Raquel Teixeira Ferreira ◽  
Marcela Araújo Soares Coutinho ◽  
David do Carmo Malvar ◽  
Elson Alves Costa ◽  
Iziara Ferreira Florentino ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Inflammatory Diseases ◽  
Subcutaneous Administration ◽  
Mechanisms Of Action ◽  
Selectivity Index ◽  
Kalanchoe Pinnata ◽  
Flavonoid Quercetin ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

Kalanchoe pinnata(KP) is popularly used for treating inflammatory diseases. This study investigated the antinociceptive, antiedematogenic, and anti-inflammatory potential of the subcutaneous administration of KP flower aqueous extract (KPFE), its ethyl acetate (EtOAcF) and butanol (BuOHF) fractions, and the main KP flavonoid [quercetin 3-O-α-L-arabinopyranosyl (1→2)α-L-rhamnopyranoside] (KPFV) in mice, as well as its possible mechanisms of action. KPFE (30–300 mg/kg) and KPFV (1–10 mg/kg) inhibited the acetic acid-induced writhing (ID50= 164.8 and 9.4 mg/kg, resp.). KPFE (300 mg/kg), EtOAcF (12 mg/kg), BuOHF (15 mg/kg), or KPFV (0.3–3.0 mg/kg) reduced leukocyte migration on carrageenan-induced pleurisy (ID50= 2.0 mg/kg for KPFV). KPFE (3–30 mg/kg) and KPFV (0.3–3.0 mg/kg) reduced the croton oil-induced ear edema (ID50= 4.3 and 0.76 mg/kg, resp.). KPFE and KPFV reduced the TNF-αconcentration in the pleural exudates on carrageenan-induced pleurisy test. Moreover, KPFV inhibited COX-1 (IC50= 22.1 μg/mL) and COX-2 (IC50> 50 μg/mL). The selectivity index (COX-1IC50/COX-2IC50) was <0.44. These results indicate that KPFE and KPFV produced antinociceptive, antiedematogenic, and anti-inflammatory activities through COX inhibition and TNF-αreduction, revealing that the main flavonoid in KP flowers and leaves plays an important role in the ethnomedicinal use of the plant.

Synthesis and evaluation of new benzimidazole-based COX inhibitors: a naproxen-like interaction detected by STD-NMR

RSC Advances ◽  
2015 ◽  
Vol 5 (61) ◽  
pp. 49098-49109 ◽  
Author(s):  
Luísa C. R. Carvalho ◽  
Daniela Ribeiro ◽  
Raquel S. G. R. Seixas ◽  
Artur M. S. Silva ◽  
Mariana Nave ◽  
...  
Keyword(s):  
Pharmacological Activity ◽  
Cox Inhibitors ◽  
Cyclooxygenase 1 ◽  
Inflammatory Drugs ◽  
Std Nmr ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

Non-steroidal anti-inflammatory drugs exert their pharmacological activity through inhibition of cyclooxygenase 1 and 2 (COX-1 and COX-2).

scholarly journals Mycophenolate suppresses inflammation by inhibiting prostaglandin synthases: a study of molecular and experimental drug repurposing

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11360
Author(s):  
Fahad Al-Hizab ◽  
Mahmoud Kandeel
Keyword(s):  
Root Mean Square ◽  
Inflammatory Diseases ◽  
Drug Repurposing ◽  
Inflammatory Cells ◽  
Acid Synthesis ◽  
Mean Square ◽  
Rat Paw Edema ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

Mycophenolate mofetil is an established anti-proliferative and immune-suppressive agent that minimizes the proliferation of inflammatory cells by interfering with nucleic acid synthesis. Herein, we report our discovery of the prostaglandin inhibiting properties of MMF, which offers new applications for the drug in the treatment of inflammatory diseases. The estimated values of IC50MMFCOX-1, IC50MMFCOX-2, and IC50MMF5-LOX were 5.53, 0.19, and 4.47 µM, respectively. In contrast, mycophenolic acid (MPA) showed slightly stronger inhibition: IC50MPACOX-1, IC50MPACOX-2, and IC50MPA5-LOX were 4.62, 0.14, and 4.49 µM, respectively. These results indicate that MMF and MPA are, respectively, 28.6 and 33 times more selective for cyclooxygenase-2 than for cyclooxygenase-1, which implies that MMF would have less impact on the gastric mucosa than most nonselective, nonsteroidal anti-inflammatory drugs. Furthermore, MMF provided dose-dependent relief of acute inflammation in the carrageenan-induced rat paw edema test, with results comparable to those of celecoxib and indomethacin. Molecular dynamics simulations indicated that the MMF bond with COX-2 was stable, as evidenced by a low root-mean-square deviation of atomic positions, complementary per-residue root-mean-square fluctuation, and 0–4 hydrogen bonds during the 50-ns simulation time. Therefore, MMF provides immune-suppressing, cyclooxygenase-inhibiting, and inflammation-relieving properties. Our results indicate that MMF can be 1) repositioned for inflammation treatment without the need for further expensive clinical trials, 2) used for local acute inflammations, and 3) used as a sparing agent for other steroid and non-steroid anti-inflammatory medications, especially in topical applications.

scholarly journals Anti- inflammatory effect of Prunus tomentosa Thunb total flavones in LPS-induced RAW264.7 cells

2019 ◽  
Vol 17 (1) ◽  
pp. 685-693
Author(s):  
Chen Xi ◽  
Liu Yuanyuan ◽  
Zhao Dongshuang ◽  
Fan Ziwei ◽  
Cao Shuang ◽  
...  
Keyword(s):  
Significant Inhibition ◽  
Raw264.7 Cells ◽  
Supernatant Fraction ◽  
Treatment Of Diabetes ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
The Impact ◽  
Cox 1 ◽  
Inflammatory Effect

AbstractIn this research, we investigated possible anti-inflammatory roles of Prunus tomentosa Thunb Total Flavones (PTTTF) in LPS-induced RAW264.7 cells. PTTTF (4μg/ml and 40μg/ml) was applied to RAW264.7 cells induced with 1μg/ml LPS to test the impact of these flavones on neutrophil phagocytosis in vitro. Levels of prostaglandin E2 (PGE2) and two pro-inflammatory interleukin cytokines (i.e. IL-6 and IL-1β) in the supernatant fraction were tested via Enzyme-linked immunosorbent assays (ELISA). Expression of cyclooxygenases COX-1 and COX-2 was detected via RT-PCR. Superoxide dismutase (SOD) content was determined with a spectrophotometric assay (Micromethod). The results revealed that PTTTF at doses higher than 4μg/ml reduces the content of IL-6, IL-1β and PGE2 (P < 0.05), and elevates the activity of SOD in LPS-induced RAW264.7 cells significantly (P < 0.05). PTTTF at 40μg/ml showed no significant effect on the expression of COX-1(P>0.05) but resulted in a significant inhibition of COX-2 in LPS-induced RAW264.7 cells (P<0.05). In summary, PTTTF had a substantial potential anti-inflammatory effect through the alteration of the synthesis of some cytokines and other mediators of the process of inflammation. Novelty statement - Prunus tomentosa Thunb Total Flavones (PTTTF) have known roles in the treatment of diabetes, but here we show that they are also potential anti-inflammatory agents. Our results show that PTTTF exhibited anti-inflammatory effects through altering the synthesis of some cytokines and other mediators of the inflammatory process.

scholarly journals The Biological Function Prediction of The 10-gingerol Compound of Ginger in Inhibiting Cyclooxygenase-2 Activity

2020 ◽  
Vol 9 (3) ◽  
pp. 222-232
Author(s):  
Gabriella Chandrakirana Krisnamurti ◽  
◽  
Fatchiyah Fatchiyah ◽  
◽  
◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Specific Binding ◽  
Membrane Binding ◽  
Binding Domain ◽  
Cyclooxygenase 2 ◽  
Cyclooxygenase 1 ◽  
Mechanism Of Inhibition ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

Anti-inflammatory agents inhibit prostaglandin synthesis by blocking cyclooxygenases (COXs). The compounds extracted from ginger, 10-gingerol and 10-shogaol can inhibit inflammation but the mechanism of inhibition remains unclear. Here we used molecular docking to predict the molecular interactions between COXs and the three inhibitors, acetaminophen (CID1983), 10-gingerol (CID168115) and 10-shogaol (CID6442612). By using that acetaminophen as a gold standard, the results demonstrated that acetaminophen, 10-gingerol, and 10-shogaol could bind catalytic domain and membrane binding domain of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The 10-shogaol did not show significantly different binding energy to bind to COX-1 and COX-2. The 10-gingerol posed a stronger and more specific binding to the membrane-binding domain of COX-2 than acetaminophen and 10-shogaol. The specific binding of the 10-gingerol to COX-2 could prevent the binding of the natural substrate, arachidonic acid. The results provide useful information to improving activities of anti-inflammatory.

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