Design and Synthesis of Novel Ibuprofen Derivatives as Selective COX-2 inhibitors and potential anti-inflammatory agents: Evaluation of PGE2, TNF-α, IL-6 and histopathological study

2021 ◽  
Vol 17 ◽  
Author(s):  
Peter Amir Halim ◽  
Hala Bakr El-Nassan ◽  
Yara Sayed El-Dash
Keyword(s):  
Carboxylic Acid ◽  
Gastric Mucosa ◽  
Docking Simulation ◽  
Histopathological Study ◽  
Acid Moiety ◽  
Rat Serum ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory

Background: The reported binding mode of ibuprofen in the COX-2 binding site indicated that the carboxylic group binds with Arg-120 and Tyr-355 at the entrance of the cyclooxygenase channel and does not extend into the pocket. This accounted for the non-selectivity of ibuprofen. Based on this fact, we assumed that extending the length of the carboxylic acid moiety in ibuprofen and adding more bulky rigid groups as well as bulky groups carrying H-bonding functions might increase the selectivity and reduce the side effects of ibuprofen while maintaining its analgesic and anti-inflammatory activities. Objective: In this work, four series of ibuprofen derivatives were designed and prepared. The compounds were designed by increasing the length of the carboxylate group along with the incorporation of large hydrophobic groups. Method: Four series of ibuprofen derivatives were synthesized starting from ibuprofen. Their chemical structure was confirmed by spectral data. All the compounds were tested for their COX inhibitory activity. Results : The best COX-2 activity and selectivity were obtained with compounds 5c and 5d, which were subjected to further in vivo testing (carrageenan-induced paw edema, rat serum PGE2, TNF- α and IL-6, hot plate latency test) to investigate their anti-inflammatory and analgesic activities as well as their effects on the gastric mucosa. The anti-inflammatory activity of both compounds was comparable to that of ibuprofen, diclofenac, and indomethacin. Both compounds suppressed the production of PGE2 as well as the rat serum concentrations of both TNF-α and IL-6. This potent anti-inflammatory and analgesic behavior was not accompanied by any effect on the gastric mucosa. Docking simulation studies of the two compounds explained the higher selectivity for the COX-2 enzyme. Conclusion: Potent and selective ibuprofen derivatives can be successively obtained by extending the length of the carboxylic acid moiety in ibuprofen and adding more bulky rigid groups as well as bulky groups with H-bonding functions.

scholarly journals Nerolidol Mitigates Colonic Inflammation: An Experimental Study Using both In Vivo and In Vitro Models

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 2032
Author(s):  
Vishnu Raj ◽  
Balaji Venkataraman ◽  
Saeeda Almarzooqi ◽  
Sanjana Chandran ◽  
Shreesh K. Ojha ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
In Vitro Models ◽  
Mrna Levels ◽  
Colonic Inflammation ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Ht 29

Nerolidol (NED) is a naturally occurring sesquiterpene alcohol present in various plants with potent anti-inflammatory effects. In the current study, we investigated NED as a putative anti-inflammatory compound in an experimental model of colonic inflammation. C57BL/6J male black mice (C57BL/6J) were administered 3% dextran sodium sulfate (DSS) in drinking water for 7 days to induce colitis. Six groups received either vehicle alone or DSS alone or DSS with oral NED (50, 100, and 150 mg/kg body weight/day by oral gavage) or DSS with sulfasalazine. Disease activity index (DAI), colonic histology, and biochemical parameters were measured. TNF-α-treated HT-29 cells were used as in vitro model of colonic inflammation to study NED (25 µM and 50 µM). NED significantly decreased the DAI and reduced the inflammation-associated changes in colon length as well as macroscopic and microscopic architecture of the colon. Changes in tissue Myeloperoxidase (MPO) concentrations, neutrophil and macrophage mRNA expression (CXCL2 and CCL2), and proinflammatory cytokine content (IL-1β, IL-6, and TNF-α) both at the protein and mRNA level were significantly reduced by NED. The increase in content of the proinflammatory enzymes, COX-2 and iNOS induced by DSS were also significantly inhibited by NED along with tissue nitrate levels. NED promoted Nrf2 nuclear translocation dose dependently. NED significantly increased antioxidant enzymes activity (Superoxide dismutase (SOD) and Catalase (CAT)), Hemeoxygenase-1 (HO-1), and SOD3 mRNA levels. NED treatment in TNF-α-challenged HT-29 cells significantly decreased proinflammatory chemokines (CXCL1, IL-8, CCL2) and COX-2 mRNA levels. NED supplementation attenuates colon inflammation through its potent antioxidant and anti-inflammatory activity both in in vivo and in vitro models of colonic inflammation.

Anti-Oxidative and Anti-Inflammatory Effects of Lobelia chinensis In Vitro and In Vivo

2015 ◽  
Vol 43 (02) ◽  
pp. 269-287 ◽  
Author(s):  
Kun-Cheng Li ◽  
Yu-Ling Ho ◽  
Guan-Jhong Huang ◽  
Yuan-Shiun Chang
Keyword(s):  
Nitric Oxide ◽  
Folk Medicine ◽  
Ethyl Acetate Fraction ◽  
Raw264.7 Macrophages ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Factor Α

Lobelia chinensis Lour (LcL) is a popular herb that has been widely used as folk medicine in China for the treatment of fever, lung cancer, and inflammation for hundreds of years. Recently, several studies have shown that the anti-inflammatory properties were correlated with the inhibition of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) from the NF-κB pathway. The aim of this study was to evaluate the anti-oxidative and anti-inflammatory activities of L. chinensis. Both suppressive activities on LPS-induced nitric oxide production in RAW264.7 macrophages in vitro and the acute rat lung injury model in vivo were studied. The results showed that the methanol extract of LcL and its fractions within the range of 62.5–250 μg/mL did not induce cytotoxicity (p < 0.001). The ethyl acetate fraction of LcL showed better NO inhibition activity than other fractions. On the other hand, the Lc-EA (62.5, 125, 250 mg/kg) pretreated rats showed a decrease in the pro-inflammatory cytokines (TNF-α, IL-β, IL-6) and inhibited iNOS, COX-2 expression through the NF-κB pathway. These results suggested that L. chinensis exhibited an anti-inflammatory effect through the NF-κB pathways.

scholarly journals Fucoxanthin-Containing Cream Prevents Epidermal Hyperplasia and UVB-Induced Skin Erythema in Mice

Marine Drugs ◽  
2018 ◽  
Vol 16 (10) ◽  
pp. 378 ◽  
Author(s):  
Azahara Rodríguez-Luna ◽  
Javier Ávila-Román ◽  
María González-Rodríguez ◽  
María Cózar ◽  
Antonio Rabasco ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Antioxidant Properties ◽  
Epidermal Hyperplasia ◽  
Topical Formulation ◽  
Tnf Α ◽  
Skin Erythema ◽  
Cox 2 ◽  
Anti Inflammatory

Microalgae represent a source of bio-active compounds such as carotenoids with potent anti-inflammatory and antioxidant properties. We aimed to investigate the effects of fucoxanthin (FX) in both in vitro and in vivo skin models. Firstly, its anti-inflammatory activity was evaluated in LPS-stimulated THP-1 macrophages and TNF-α-stimulated HaCaT keratinocytes, and its antioxidant activity in UVB-irradiated HaCaT cells. Next, in vitro and ex vivo permeation studies were developed to determine the most suitable formulation for in vivo FX topical application. Then, we evaluated the effects of a FX-containing cream on TPA-induced epidermal hyperplasia in mice, as well as on UVB-induced acute erythema in hairless mice. Our results confirmed the in vitro reduction of TNF-α, IL-6, ROS and LDH production. Since the permeation results showed that cream was the most favourable vehicle, FX-cream was elaborated. This formulation effectively ameliorated TPA-induced hyperplasia, by reducing skin edema, epidermal thickness, MPO activity and COX-2 expression. Moreover, FX-cream reduced UVB-induced erythema through down-regulation of COX-2 and iNOS as well as up-regulation of HO-1 protein via Nrf-2 pathway. In conclusion, FX, administered in a topical formulation, could be a novel natural adjuvant for preventing exacerbations associated with skin inflammatory pathologies as well as protecting skin against UV radiation.

scholarly journals Anti-Arthritic and Anti-Inflammatory Potential of Spondias mangifera Extract Fractions: An In Silico, In Vitro and In Vivo Approach

Plants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 825
Author(s):  
Mohammad Khalid ◽  
Mohammed H. Alqarni ◽  
Ambreen Shoaib ◽  
Muhammad Arif ◽  
Ahmed I. Foudah ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Arthritis Score ◽  
Beneficial Effects ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

The fruits of Spondias mangifera (S. mangifera) have traditionally been used for the management of rheumatism in the northeast region of India. The present study explores the probable anti-arthritis and anti-inflammatory potential of S. mangifera fruit extract’s ethanolic fraction (EtoH-F). To support this study, we first approached the parameters in silico by means of the active constituents of the plant (beta amyrin, beta sitosterol, oleonolic acid and co-crystallised ligands, i.e., SPD-304) via molecular docking on COX-1, COX-2 and TNF-α. Thereafter, the absorption, distribution, metabolism, excretion and toxicity properties were also determined, and finally experimental activity was performed in vitro and in vivo. The in vitro activities of the plant extract fractions were evaluated by means of parameters like 1,1-Diphenyl-2- picrylhydrazyl (DPPH), free radical-reducing potential, albumin denaturation, and protease inhibitory activity. The in vivo activity was evaluated using parameters like COX, TNF-α and IL-6 inhibition assay and arthritis score in Freund Adjuvant (CFA) models at a dose of 400 mg/kg b.w. per day of different fractions (hexane, chloroform, alcoholic). The molecular docking assay was performed on COX-1, COX-2 and TNF-α. The results of in vitro studies showed concentration-dependent reduction in albumin denaturation, protease inhibitors and scavenging activity at 500 µg/mL. Administration of the S. mangifera alcoholic fraction at the abovementioned dose resulted in a significant reduction (p < 0.01) in arthritis score, paw diameters, TNF-α, IL-6 as compared to diseased animals. The docking results showed that residues show a critical binding affinity with TNF-α and act as the TNF-α antagonist. The alcoholic fraction of S. mangifera extract possesses beneficial effects on rheumatoid arthritis as well as anti-inflammatory potential, and can further can be used as a possible agent for novel target-based therapies for the management of arthritis.

scholarly journals Validating potent anti-inflammatory and anti-rheumatoid properties of Drynaria quercifolia rhizome methanolic extract through in vitro, in vivo, in silico and GC-MS-based profiling

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Debabrata Modak ◽  
Subhashis Paul ◽  
Sourav Sarkar ◽  
Subarna Thakur ◽  
Soumen Bhattacharjee
Keyword(s):  
Rheumatoid Arthritis ◽  
In Silico ◽  
Methanolic Extract ◽  
Paw Edema ◽  
Active Components ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory

Abstract Background The fronds of Drynaria quercifolia have traditionally been used in rheumatic pain management. The goal of the present study was to validate the potent anti-inflammatory and anti-rheumatoid properties of the methanolic-extract of its rhizome using in vitro, in vivo and in silico strategies. Methods The plant was collected and the methanolic extract was prepared from its rhizome. Protein denaturation test, hypotonicity and heat-induced haemolysis assays were performed in vitro. The in vivo anti-rheumatoid potential was assessed in Freund’s complete adjuvant (FCA)-induced Wistar rat model through inflammatory paw-edema, haematological, biochemical, radiological and histopathological measurements. Moreover, metabolites of methanolic extract were screened by gas chromatography-mass spectrometry (GC-MS) and 3D molecular structures of active components were utilized for in silico docking study using AutoDock. Results In vitro results evinced a significant (p < 0.05) anti-inflammatory activity of the rhizome methanolic extract in a dose-linear response. Further, Drynaria quercifolia rhizome methanolic extract (DME) significantly ameliorated rheumatoid arthritis as indicated by the inhibition of arthritic paw-edema (in millimeter) in the rat rheumatoid arthritis models in both the low (57.71 ± 0.99, p < 0.01) and high dose groups (54.45 ± 1.30, p < 0.001) when compared to arthritic control. Treatment with DME also normalized the haematological (RBC, WBC, platelet counts and hemoglobin contents) and biochemical parameters (total protein, albumin, creatinine and ceruloplasmin) significantly (p < 0.05), which were further supported by histopathological and radiological analyses. Furthermore, GC-MS analysis of DME demonstrated the presence of 47 phytochemical compounds. Compounds like Squalene, Gamma Tocopherol, n-Hexadecanoic acid showed potent inhibition of cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF-α), and interleukin (IL-6) in the docking analysis. Conclusion Results from in vivo and in vitro studies indicated that DME possesses a potent anti-inflammatory and anti-arthritic activity. In silico studies delineated the emergent potent inhibitory effects of several bio-active components on the target inflammatory markers (COX-2, TNF-α and IL-6).

scholarly journals Activation of Nrf2/HO-1 by Peptide YD1 Attenuates Inflammatory Symptoms through Suppression of TLR4/MYyD88/NF-κB Signaling Cascade

2021 ◽  
Vol 22 (10) ◽  
pp. 5161
Author(s):  
Md Saifur Rahman ◽  
Md Badrul Alam ◽  
Young Kyun Kim ◽  
Mst Hur Madina ◽  
Ismail Fliss ◽  
...  
Keyword(s):  
Therapeutic Agent ◽  
Signaling Cascade ◽  
Immunomodulatory Effects ◽  
In Vivo Models ◽  
Nrf2 Pathway ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory

In this study, we investigate the immunomodulatory effects of a novel antimicrobial peptide, YD1, isolated from Kimchi, in both in vitro and in vivo models. We establish that YD1 exerts its anti-inflammatory effects via up-regulation of the Nrf2 pathway, resulting in the production of HO-1, which suppresses activation of the NF-κB pathway, including the subsequent proinflammatory cytokines IL-1β, IL-6, and TNF-α. We also found that YD1 robustly suppresses nitric oxide (NO) and prostaglandin E2 (PGE2) production by down-regulating the expression of the upstream genes, iNOS and COX-2, acting as a strong antioxidant. Collectively, YD1 exhibits vigorous anti-inflammatory and antioxidant activity, presenting it as an interesting potential therapeutic agent.

scholarly journals Targeting Mammalian 5-Lipoxygenase by Dietary Phenolics as an Anti-Inflammatory Mechanism: A Systematic Review

2021 ◽  
Vol 22 (15) ◽  
pp. 7937
Author(s):  
Juan Antonio Giménez-Bastida ◽  
Antonio González-Sarrías ◽  
José Moisés Laparra-Llopis ◽  
Claus Schneider ◽  
Juan Carlos Espín
Keyword(s):  
Systematic Review ◽  
Nordihydroguaiaretic Acid ◽  
Current Evidence ◽  
Inflammatory Mechanism ◽  
Tnf Α ◽  
Beneficial Impact ◽  
Cox 2 ◽  
Anti Inflammatory

5-Lipoxygenase (5-LOX) plays a key role in inflammation through the biosynthesis of leukotrienes and other lipid mediators. Current evidence suggests that dietary (poly)phenols exert a beneficial impact on human health through anti-inflammatory activities. Their mechanisms of action have mostly been associated with the modulation of pro-inflammatory cytokines (TNF-α, IL-1β), prostaglandins (PGE2), and the interaction with NF-κB and cyclooxygenase 2 (COX-2) pathways. Much less is known about the 5-lipoxygenase (5-LOX) pathway as a target of dietary (poly)phenols. This systematic review aimed to summarize how dietary (poly)phenols target the 5-LOX pathway in preclinical and human studies. The number of studies identified is low (5, 24, and 127 human, animal, and cellular studies, respectively) compared to the thousands of studies focusing on the COX-2 pathway. Some (poly)phenolics such as caffeic acid, hydroxytyrosol, resveratrol, curcumin, nordihydroguaiaretic acid (NDGA), and quercetin have been reported to reduce the formation of 5-LOX eicosanoids in vitro. However, the in vivo evidence is inconclusive because of the low number of studies and the difficulty of attributing effects to (poly)phenols. Therefore, increasing the number of studies targeting the 5-LOX pathway would largely expand our knowledge on the anti-inflammatory mechanisms of (poly)phenols.

Anti-inflammatory effect of an Ayurveda polyherbal topical application and exploration of its mechanism of action

2017 ◽  
Vol 2 (06) ◽  
Author(s):  
Sitaram Ahalya ◽  
B. A. Venkatesh ◽  
R. Vijayasarathi ◽  
Tirumalapura Vijayanna Shalini
Keyword(s):  
Topical Application ◽  
Inflammatory Activity ◽  
Polyherbal Formulation ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Ear Oedema ◽  
Inflammatory Effect

Background: Topical application of herbs is one of the recommended treatment modalities for Osteoarthritis (OA) in Ayurveda (Indian system of medicine). The current study intended to evaluate the anti-inflammatory effect of a polyherbal powder used as Upanaha (poultice) for OA by in vitro and in vivo techniques. Materials and Methods: The polyherbal formulation Upanaha Choornam (UC) was sourced from Vaidyaratnam Oushadhasala (P) Ltd., Thrissur, India. Changes in the secretion of TNF-α and NO and expression of Cox-2 genes were evaluated by semi quantitative PCR activity to establish anti-inflammatory action in vitro. Macrophages and connective tissue of mice were used as media for the former two experiments and only macrophages for the latter. In vivo anti–inflammatory activity was evaluated by TPA induced ear oedema in Swiss Albino mice (n=24), divided into 4 groups as Group I - saline treatment, Group II - Indomethacin treatment, and Groups III and IV treated with 30% and 60% of UC respectively. Results: In the in vitro study, UC at 1000 µg/ml and 500 µg/ml upregulated the COX-2 level by 0.08 and 0.03 folds respectively as compared to control. Release of TNF-α, and NO in LPS-induced RAW cells were significantly inhibited in a dose dependent manner. The TPA induced ear oedema significantly reduced in Groups III and IV (F=1250, p less than 0.001) Conclusion: The current study demonstrates the safety and anti-inflammatory activity of a polyherbal formulation Upanaha Choornam as a topical application. This indicates the potential of select herbs in managing degenerative conditions like OA.

scholarly journals In vivo anti-inflammatory activity of Liquidambar formosana Hance infructescence extract

2017 ◽  
Vol 16 (10) ◽  
pp. 2403-2410
Author(s):  
Haoran Ma ◽  
Fuqian Wang ◽  
Jie Jiang ◽  
Lu Cheng ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Inflammatory Activity ◽  
Enzyme Linked Immunosorbent Assay ◽  
Paw Edema ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Underlying Mechanisms ◽  
Anti Inflammatory Cytokine ◽  
Inflammatory Effect

Purpose: To evaluate the anti-inflammatory activity of Liquidambar formosana  Hance infructescence (Liquidambaris fructus, ELF) in vivo, and clarify its underlying mechanisms. Methods: The in vivo anti-inflammatory activity of ELF was examined by xylene-induced ear swelling test in mice as well as carrageenan-induced paw edema method in rats. The levels of inflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-10) in serum were measured by enzyme-linked immunosorbent assay (ELISA), while the expressions of COX-2, iNOS and NF-κB p65 in paw tissue of rats were evaluated by western blot.Results: After ELF treatment, the levels of TNF-α (p < 0.001), IL-1β (p < 0.001) and IL-6 (p < 0.001) in serum decreased and the levels of anti-inflammatory cytokine IL-10 increased (p < 0.01). In addition, ELF treatment resulted in decrease of COX-2 (p < 0.01), iNOS (p < 0.01) and NF-κB p65 (p < 0.01) expressions in Wistar rats.Conclusion: The results reveal that ELF possesses significant anti-inflammatory effect in vivo. The anti-inflammatory activity is associated with the levels of TNF-α, IL-1β, IL-6 and IL-10 in serum. Furthermore, the suppression of NF-κB p65, iNOS and COX-2 is linked to its anti-inflammatory effect. These results provide a rationale for the use of Liquidambaris fructus in inflammatory disease in traditional medicine.Keywords: Anti-inflammatory activity, Liquidambaris fructus, Cytokines, Ear swelling test, Paw edema

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