In vitro COX-1, COX-2 and 5-LOX inhibitory activity of plant family Ranunculaceae

Interest in the anti-inflammatory effects of Ligustrum vulgare L., which has been used traditionally in China and Japan prompted us to determine anti-inflammatory effects of the plant's compounds in leukocytes. The leaves of L. vulgare were used to prepare a decoction which was successively extracted with organic solvents (dichloromethane (DCM), n-butanol, ethyl acetate) using liquid-liquid partition. Extracts were tested for inhibition of LTB4, resp. PGE2 biosynthesis. Each extract was evaluated for its in vitro cyclooxygenase-1/2 (COX-1/2) inhibitory activity using assays with purified COX-1 and COX-2 enzymes, as well as for their LTB4 formation inhibitory activity using an assay with activated human neutrophil granulocytes. All extracts reported inhibitory actions against COXs in comparison with the synthetic inhibitors NS-398 (IC50 = 2.6 μM) and indomethacin (IC50 = 0.9 μM). The dichloromethane extract of privet leaves showed a considerable inhibitory effect against COX-1 and COX-2 enzyme activity. The DCM extract revealed 2.7 times higher inhibitory activity against LTB4 formation in comparison with the known specific LT inhibitor zileuton (IC50 = 5.0 μM). Additionally, oleuropein and echinacoside were detected by HPLC-DAD and LC-MS in the Ligustrum vulgare leaves. Both compounds exhibited weak inhibitory activity on cyclooxygenases and leukotriene formation.

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Design, Synthesis and Pharmacological Evaluation of Gastro- Protective Anti-inflammatory Analgesic Agents based on Dual Oxidative Stress / Cyclooxygenase Inhibition

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry ◽

10.2174/1871523018666190325155244 ◽

2020 ◽

Vol 19 (3) ◽

pp. 268-290 ◽

Cited By ~ 1

Author(s):

Monika Gaba ◽

Sarbjot Singh ◽

Chander Mohan ◽

Richa Dhingra ◽

Monika Chauhan ◽

...

Keyword(s):

Antioxidant Activity ◽

Inhibitory Activity ◽

Frap Assay ◽

Anti Oxidant ◽

Cox 2 ◽

Anti Inflammatory ◽

Analgesic Activities ◽

Cox 1

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) derived local generation of reactive oxygen species (ROS) plays a crucial role in the formation of gastric ulceration. Objective: Therefore, anti-inflammatory analgesics with potent antioxidant activity could be a potential therapeutic strategy for the treatment of pain and inflammatory disorders without gastrointestinal (GI) side effects. Methods: In an effort to develop gastroprotective analgesic and anti-inflammatory agents, a series of 2-methylamino-substituted-1H-benzo[d] imidazol-1-yl) (phenyl) methanone derivatives were synthesized and evaluated in vitro for cyclooxygenase (COX) inhibition as well as anti-oxidant potential by the FRAP assay. The compounds with significant in vitro COX-1/COX-2 inhibitory activity and antioxidant activity were further screened in vivo for their anti-inflammatory and analgesic activities. Moreover, the ulcerogenic potential of test compounds was also studied. To gain insight into the plausible mode of interaction of compounds within the active sites of COX-1 and COX-2, molecular docking simulations were performed. Results: Among the various synthesized molecules, most of the compounds showed good cyclooxygenase inhibitory activity and efficient antioxidant activity in FRAP assay. After preliminary and indicative in vitro assays, three compounds exhibited most significant antiinflammatory and analgesic activity with better gastric tolerability during their in vivo evaluation. Ligand interaction studies indicated highest dock score -43.05 of 1,2- disubstituted benzimidazole derivatives in comparison to the reference ligand -30.70. Overall studies provided us (2-((4-methoxyphenylamino) methyl) -1h-benzo [d] imidazol- 1-yl) (phenyl) methanone as a lead with potent gastro-protective anti-inflammatory and analgesic activities that can be used for future research. Conclusion: From the above results, it can be concluded that designing of multifunctional molecules with COX-1/COX-2 inhibitory and anti-oxidant activities could hold a great promise for further development of GI-safer NSAIDs.

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Insilico and In Vitro Study: COX-2 Inhibition by Ethanol Extract of Dayak Onion Bulb (Eleutherine americana Merr) as Treatment Innovation of Benign Prostatic Hyperplasia (BPH)

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry ◽

10.2174/1871523019666200304121702 ◽

2020 ◽

Vol 19 ◽

Author(s):

Hendra Sutapa ◽

M Aris Widodo ◽

Basuki Bambang Purnomo ◽

Doddy M Soebadi ◽

Edvin Prawira Negara

Keyword(s):

Benign Prostatic Hyperplasia ◽

Experimental Research ◽

Inhibitory Activity ◽

Ethanol Extract ◽

Prostatic Hyperplasia ◽

Onion Bulb ◽

Cox 2 ◽

Eleutherine Americana ◽

Cox 1

Introduction: Benign Prostatic Hyperplasia (BPH) is benign tumor in male which is histopathologically known with an increase of epithelial cells and prostatic stroma. Androgens, estrogens, stroma-epithelial interactions, growth factors, and chronic inflammation play a role in the occurrence of BPH. Chronic inflammation in BPH is characterized by excessive expression of COX-2 which will trigger the expression of Bcl-2 anti-apoptotic protein. Dayak onion (Eleutherine americana Merr) is a typical Kalimantan plant that is believed as the treatment for prostate disease. This plant contains flavonoids which can inhibit the COX-2 enzyme. Thus, it causes a reduction in the production of prostaglandin E2. Method: this research was an experimental research computationally and in vitro laboratory experimental research to determine COX-2 inhibitory activity by ethanol extracts of dayak onion. Result and Discussion: In insilico flavonoid, it was strongly related to COX-2 receptor on the active side of TYR371. Thus, it had the potential to inhibit COX-2. COX-2 Inhibitor would cause bcl-2 to be inactive so that apoptosis occurred in BPH. In the in vitro research using human whole blood assay, the Dayak Onion bulb ethanol extract had IC50 COX-2 of 40.57 ng/ml and IC50 COX-1 of 364.89 ng/ml. Therefore, the ratio of IC50 COX-2 to IC50 COX-1 was 0.11. Conclusion: ethanol extract of Dayak onion bulb has inhibitory activity against COX-2. Thus, it has potential as innovation of BPH treatment. Patient Summary: male, age 25-35 years old, healthy (history taking, physical and laboratory examination), and not using NSAIDs for the past 2 weeks.

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New Ferrocene Compounds as Selective Cyclooxygenase (COX-2) Inhibitors: Design, Synthesis, Cytotoxicity and Enzyme-inhibitory Activity

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520617666171003145533 ◽

2018 ◽

Vol 18 (2) ◽

pp. 295-301 ◽

Cited By ~ 8

Author(s):

Shabnam Farzaneh ◽

Elnaz Zeinalzadeh ◽

Bahram Daraei ◽

Soraya Shahhosseini ◽

Afshin Zarghi

Keyword(s):

Cell Lines ◽

Inhibitory Activity ◽

Fibroblast Cell ◽

Breast Cancer Cell Lines ◽

Ferrocene Derivatives ◽

Cox 2 ◽

Cytotoxicity Effects ◽

Cox 2 Inhibitors ◽

Mcf 7

Background: Due to the astonishing properties of ferrocene and its derivatives, it has a broad application in diverse areas. Numerous ferrocene derivatives demonstrated anti-proliferative activity. Also COX-2, as a key isoenzyme for production of prostaglandins, is frequently overexpressed in various cancers. It is now recognized that COX-2 over expression promotes tumorigenic functions which can be suppressed by COX-2 inhibitors, a phenomenon useful for the preventing of tumor progression. The combination of COX-2 inhibitors with other anti-cancer or cancer prevention drugs may reduce their side effects in future cancer prevention and treatment. Objective: Owing to high anticancer potential of ferrocene derivatives and considerable COX-2 inhibitory and cytotoxicity effects of our previously synthesized chalcones, we decided to incorporate the ferrocenyl moiety into appropriate COX-2 inhibitor chalcone based scaffold, to evaluate COX-2 inhibitory activity as well as anticancer activities. Methods: Chalcones were synthesized via clasien-schmidt condensation of methylsulfonyl aldehyde and acetyl ferrocene. Further different amines with solvent free and ultra sound condition were reacted with chalcones to have different 1-ferrocenyl-3-amino carbonyl compounds. Docking study was carried out with Auto Dock vina software. All the newly-synthesized compounds were evaluated for their cyclooxygenase-2 (COX-2) inhibitory activity using chemiluminescent enzyme assays as well as cytotoxicity activity against MCF-7 and T47D and fibroblast cell lines by MTT assay. Results: In vitro COX-1/COX-2 inhibition studies demonstrated that all compounds were selective inhibitors of the COX-2 isozyme with IC50 values in the highly potent 0.05-0.12 µM range, and COX-2 selectivity indexes (SI) in the 148.3-313.7 range. These results indicated that either potency or selectivity of COX-2 inhibitory activity was affected by the nature and size of the substituents on C-3 of propane-1-one. Also anti-proliferative and toxicity activities of synthesized compounds against breast cancer cell lines MCF-7 and T47D and fibroblast cell lines showed that the synthesized compounds had mild to moderate cytotoxicity against MCT7 and T47D breast cancer cell lines at 10 µM concentration. In vitro COX-1/COX-2 inhibition studies and anticancer activity against MCF-7, identified 1-ferrocenyl-3-(4-methylsulfonylphenyl) propen-1-one as a potent compound (IC50 COX-2 = 0.05 µM, MCF-7: % inhibition (at concentration of 10 µM) = 32.7%), and also 1-ferrocenyl-3- (propan-1-amine)-3-(4-methylsulfonylphenyl) propan-1-one showed the most selectivity on COX-2 inhibition (selectivity index= 313.7). Conclusion: A novel group of ferrocene compounds, possessing a methyl sulfonyl COX-2 pharmacophore were synthesized to investigate the effect of different substituents on selectivity and potency of COX-2 inhibitory activity and their cytotoxicity effects. This study indicates that 1-ferrocenyl-3-amino carbonyl compounds having ferrocene motif and methyl sulfonyl COX-2 pharmacophore is a suitable scaffold to design COX-2 inhibitors and anti-cancer agents.

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Cyclooxygenase-2 plays a significant role in regulating the tone of the fetal lamb ductus arteriosus

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1999.276.3.r913 ◽

1999 ◽

Vol 276 (3) ◽

pp. R913-R921 ◽

Cited By ~ 13

Author(s):

Ronald I. Clyman ◽

Pierre Hardy ◽

Nahid Waleh ◽

Yao Qi Chen ◽

Françoise Mauray ◽

...

Keyword(s):

Significant Role ◽

Ductus Arteriosus ◽

Late Gestation ◽

Relative Contribution ◽

Cox Inhibitor ◽

Fetal Lamb ◽

Cox 2 ◽

Cox 2 Inhibitors ◽

Cox 1

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents but have adverse effects on the fetal ductus arteriosus. We hypothesized that COX-2 inhibitors may not affect the ductus if the predominant COX isoform is COX-1. To examine this hypothesis, we used ductus arteriosus obtained from late-gestation fetal lambs. In contrast to our hypothesis, fetal lamb ductus arteriosus expressed both COX-1- and COX-2-immunoreactive protein (by Western analysis). Although COX-1 was found in both endothelial and smooth muscle cells, COX-2 was found only in the endothelial cells lining the ductus lumen (by immunohistochemistry). The relative contribution of COX-1 and COX-2 to PGE2 synthesis was consistent with the immunohistochemical results: in the intact ductus, PGE2 formation was catalyzed by both COX-1 and COX-2 in equivalent proportions; in the endothelium-denuded ductus, COX-2 no longer played a significant role in PGE2 synthesis. NS-398, a selective inhibitor of COX-2, was 66% as effective as the selective COX-1 inhibitor valeryl salicylate and the nonselective COX inhibitor indomethacin in causing contraction of the ductus in vitro. At this time, caution should be used when recommending COX-2 inhibitors for use in pregnant women.

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Aktivitas Antiinflamasi Keladi Belau (Caladium bicolor (W. Ait) Vent.) Terhadap Enzim Siklooksigenase (COX) Secara In Vitro

Proceeding of Mulawarman Pharmaceuticals Conferences ◽

10.25026/mpc.v3i2.129 ◽

2016 ◽

Vol 3 ◽

pp. 331-334

Author(s):

Nisa Naspiah ◽

Yoppi Iskandar ◽

Moelyono M W Moelyono M W ◽

Febrina Mahmudah ◽

Lia Puspitasari

Keyword(s):

Cox 2 ◽

Cox 1

Penelitian mengenai aktivitas antiinflamasi keladi belau (Caladium bicolor (W. Ait) Vent.) terhadap enzim siklooksigenase (COX) secara in vitro telah dilakukan. Aktivitas antiinflamasi secara in vitro terhadap enzim COX ditentukan dengan menggunakan metode TMPD (N,N,N’,N’-tetrametil-p-fenilendiamin) secara spektrofotometri. Enzim COX yang diuji meliputi enzim COX-1 dan COX-2. Berdasarkan hasil pengujian diketahui ekstrak batang keladi belau mempunyai aktivitas antiinflamasi dengan nilai IC50 sebesar 250,66 ppm terhadap COX-1 dan 255,27 ppm terhadap COX-2. Hasil pengujian menunjukkan bahwa ekstrak tersebut lebih banyak menghambat enzim COX-1.

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Effects of phenacetin and its metabolite p-phenetidine on COX-1 and COX-2 activities and expression in vitro

Thrombosis Research ◽

10.1016/s0049-3848(03)00416-x ◽

2003 ◽

Vol 110 (5-6) ◽

pp. 299-303 ◽

Cited By ~ 6

Author(s):

Esko Kankuri ◽

Erkka Solatunturi ◽

Heikki Vapaatalo

Keyword(s):

Cox 2 ◽

Cox 1

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Cyclooxygenases Inhibitors Efficiently Induce Cardiomyogenesis in Human Pluripotent Stem Cells

Cells ◽

10.3390/cells9030554 ◽

2020 ◽

Vol 9 (3) ◽

pp. 554 ◽

Cited By ~ 1

Author(s):

Harshal Nemade ◽

Aviseka Acharya ◽

Umesh Chaudhari ◽

Erastus Nembo ◽

Filomain Nguemo ◽

...

Keyword(s):

Wnt Signaling Pathway ◽

Calcium Transient ◽

Cardiac Differentiation ◽

Cyclooxygenase Inhibitors ◽

Cox Inhibitors ◽

Screening Model ◽

Cox 2 ◽

Transient Measurements ◽

Cox 1

Application of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is limited by the challenges in their efficient differentiation. Recently, the Wingless (Wnt) signaling pathway has emerged as the key regulator of cardiomyogenesis. In this study, we evaluated the effects of cyclooxygenase inhibitors on cardiac differentiation of hPSCs. Cardiac differentiation was performed by adherent monolayer based method using 4 hPSC lines (HES3, H9, IMR90, and ES4SKIN). The efficiency of cardiac differentiation was evaluated by flow cytometry and RT-qPCR. Generated hPSC-CMs were characterised using immunocytochemistry, electrophysiology, electron microscopy, and calcium transient measurements. Our data show that the COX inhibitors Sulindac and Diclofenac in combination with CHIR99021 (GSK-3 inhibitor) efficiently induce cardiac differentiation of hPSCs. In addition, inhibition of COX using siRNAs targeted towards COX-1 and/or COX-2 showed that inhibition of COX-2 alone or COX-1 and COX-2 in combination induce cardiomyogenesis in hPSCs within 12 days. Using IMR90-Wnt reporter line, we showed that inhibition of COX-2 led to downregulation of Wnt signalling activity in hPSCs. In conclusion, this study demonstrates that COX inhibition efficiently induced cardiogenesis via modulation of COX and Wnt pathway and the generated cardiomyocytes express cardiac-specific structural markers as well as exhibit typical calcium transients and action potentials. These cardiomyocytes also responded to cardiotoxicants and can be relevant as an in vitro cardiotoxicity screening model.

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MESUAFERRIN A-BIOACTIVE FLAVONOID ISOLATED FROM THE BARK OF MESUA FERREA L. AGAINST PHOSPHOLIPASE A2, CYCLOOXYGENASE AND LIPOXYGENASE: AN IN VITRO, IN VIVO AND IN SILICO APPROACH

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2018v10i2.23576 ◽

2018 ◽

Vol 10 (2) ◽

pp. 102

Author(s):

Krishna Chaithanya K. ◽

Gopalakrishnan V. K. ◽

Zenebe Hagos ◽

Govinda Rao D.

Keyword(s):

Inhibitory Activity ◽

In Silico ◽

Late Phase ◽

Paw Edema ◽

Dual Inhibitor ◽

Metabolizing Enzymes ◽

In Silico Studies ◽

Cox 2

Objective: The main objective of the present study was to evaluate the anti-inflammatory activity of isolated bioactive flavonoid Mesuaferrin-A from the bark of Mesuaferrea L. by in vitro, in vivo and in silico approach.Methods: To evaluate the effect of isolated bioactive flavonoid Mesuaferrin-A on arachidonic acid metabolizing enzymes (PLA2, COX-2 and 5-LOX) using in vitro methods, followed by carrageenan-induced paw edema model by in vivo and to determine the binding orientation and interactions of Mesuaferrin-A onarachidonic acid metabolizing enzymes (PLA2, COX-2 and 5-LOX) crystal proteins using molecular docking (in silico) studies.Results: Mesuaferrin-A exhibited a dose-dependent significant 5-LOX inhibitory and considerable COX-2 inhibitory activity by in vitro, The inhibitory activities of 5-LOX and COX-2 at 100µg/ml were found to be 78.67%, 81.03% with IC50 values of 45.22µg/ml and 35.74µg/ml respectively. Whereas Mesuaferrin-A showed less PLA2 inhibitory activity. Mesuaferrin-A showed 68.34% inhibitory activity at 400 mg/kg body weight at the late phase of carrageenan-induced paw edema, and In silico studies demonstrated that Mesuaferrin-A strongly binds with 5-LOX and COX-2, these strong binding affinity of Mesuaferrin-A on active site amino acids of 5-LOX and COX-2 may be responsible for inhibition of enzyme activity. Mesuaferrin-A showeda comparable 5-LOX and COX-2 inhibition activity with (positive control).Conclusion: It was concluded that Mesuaferrin-A act as 5-LOX and COX dual inhibitor, from the results it was suggests that Mesuaferrin-A, may be an effective preventive and therapeutic approach for patients with inflammatory-related diseases.

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