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Attenuation of CFA-induced chronic inflammation by a bicyclic monoterpene fenchone targeting inducible nitric oxide, prostaglandins, C-reactive protein and urea

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Abstract

Fenchone (a bicyclic monoterpene) is present in the essential oils of plant species like Foeniculum vulgare and Peumus boldus and is used to treat GIT disorders. Research reports have indicated its strong anti-inflammatory, antioxidant, and anti-nociceptive properties. The present study was designed to investigate fenchone’s anti-arthritic effects in a rat model of chronic joint inflammation (Complete Freud’s Adjuvant-mediated inflammation [CFA]). Molecular docking analysis revealed a high binding interaction of fenchone with inducible nitric oxide synthase (iNOS), Interleukin-17, Prostaglandin E Receptor EP4, and Cycloxygenase-2 (COX-2), indicating its anti-inflammatory efficacy using computational tests. Fenchone treatment at 100 mg/kg, 200 mg/kg, and 400 mg/kg significantly enhanced the tail-flick latency when compared with the solvent-treated group. Correspondingly, the raised mRNA values of iNOS, IL-17, IL-1β, IL-6, TNF-α, and COX-2 in solvent-treated group were significantly reduced following treatment with fenchone. Moreover, fenchone significantly lowered spleen and thymus indices, Nitric oxide (NO) and PGE2 values as compared to solvent-treated group. Hence, the results of the present study indicated that fenchone has a potent anti-inflammatory effect by inhibiting pro-inflammatory markers and thus may have therapeutic potential for chronic joint inflammation as well as chronic inflammatory disorders.

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The data mentioned in this study is transparent.

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References

  • Ahmed EA, Ahmed OM, Fahim HI, Ali TM, Elesawy BH, Ashour MB (2021) Potency of bone marrow-derived mesenchymal stem cells and indomethacin in complete Freund’s adjuvant-induced arthritic rats: roles of TNF-α, IL-10, iNOS, MMP-9, and TGF-β1. Stem Cells Int 2011:1–11

  • Akhter S, Irfan HM, Ullah A, Jahan S, Roman M, Latif MB, Mustafa Z, Almutairi FM, Althobaiti YS (2022a) Noscapine hydrochloride (benzyl-isoquinoline alkaloid) effectively prevents protein denaturation through reduction of IL-6, NF-kB, COX-2, Prostaglandin-E2 in rheumatic rats. Saudi Pharmaceut J 30(12):1791–1801

  • Akhter S, Irfan HM, Yuchi A, Jahan S, Shahzad M, Latif MB (2022b) Nerolidol: a potential approach in rheumatoid arthritis through reduction of TNF-α, IL-1β, IL-6, NF-Kβ, COX-2 and anti-oxidant effect in CFA-induced arthritic model. Inflammopharmacology 30:537–548

    Article  CAS  PubMed  Google Scholar 

  • Al-Ghani R, Nirwani WP, Novianti TN, Sari AGP (2022) In silico anti-inflammatory activity evaluation from usnea misaminensis through molecular docking approach. Chem Mater 1:77–82

    Article  Google Scholar 

  • Aslam S, Younis W, Malik MN, Jahan S, Alamgeer, Uttra AM, Munir MU, Roman M (2022) Pharmacological evaluation of anti-arthritic potential of terpinen-4-ol using in vitro and in vivo assays. Inflammopharmacology 30(3):945–959

  • Azam SS, Abbasi SW (2013) Molecular docking studies for the identification of novel melatoninergic inhibitors for acetylserotonin-O-methyltransferase using different docking routines. Theor Biol Med Model. https://doi.org/10.1186/1742-4682-10-63

    Article  PubMed  PubMed Central  Google Scholar 

  • de Souza Pessoa ML, Silva LM, Araruna ME, de Lima Serafim CA Jr, Júnior EB, Silva AO, Pessoa MM, Neto HD, de Oliveira LE, Batista LM (2020) Antifungal activity and antidiarrheal activity via antimotility mechanisms of (-)-fenchone in experimental models. World J Gastroenterol 26:6795

    Article  Google Scholar 

  • Emamuzo ED, Miniakiri SI, Tedwin EJO, Ufouma O, Lucky M (2010) Analgesic and anti-inflammatory activities of the ethanol extract of the leaves of Helianthus Annus in Wistar rats. Asian Pac J Trop Med 3:341–347

    Article  Google Scholar 

  • Ganesh VS, Reddy KS, Balaraju JB (2019) Neuroprotective effect of fenchone on chronic unpredictable mild stress (CUMS) induced neuroinflammation. Int J Indi Herbs Drugs 30:1–7

  • Gao Q, Qin H, Zhu L, Li D, Hao X (2020) Celastrol attenuates collagen-induced arthritis via inhibiting oxidative stress in rats. Int Immunopharmacol 84:106527

    Article  CAS  PubMed  Google Scholar 

  • Gohil P, Patel V, Deshpande S, Chorawala M, Shah G (2018) Anti-arthritic activity of cell wall content of Lactobacillus plantarum in Freund’s adjuvant-induced arthritic rats: involvement of cellular inflammatory mediators and other biomarkers. Inflammopharmacology 26:171–181

    Article  CAS  PubMed  Google Scholar 

  • Hari S (2019) In silico molecular docking and ADME/T analysis of plant compounds against IL17A and IL18 targets in gouty arthritis. J Appl Pharm Sci 9:018–026

    Article  CAS  Google Scholar 

  • Hasan UH, Uttra AM, Rasool S (2015) Evaluation of in vitro and in vivo anti-arthritic potential of Berberis calliobotrys. Bangladesh J Pharmacol 10:807–819

    Article  Google Scholar 

  • Herawati H, Oktanella Y, Anisa A (2021) Molecular docking analysis of curcuminoids from curcuma longa extract on inos as an immunomodulator candidate in broilers. Adv Anim Vet Sci 9:519–524

    Article  Google Scholar 

  • Him A, Ozbek H, Turel I, Oner AC (2008) Antinociceptive activity of alpha-pinene and fenchone. Pharmacologyonline 3:363–369

    Google Scholar 

  • Hsia CH, Jayakumar T, Lu WJ, Sheu JR, Hsia CW, Saravana Bhavan P, Manubolu M, Huang WC, Chang Y (2021) Auraptene, a monoterpene coumarin, inhibits LTA-induced inflammatory mediators via modulating NF-κB/MAPKs signaling pathways. Evid Based Complementary Altern Med 2021:1–11

  • Hwang J, Yadav D, Lee PC, Jin JO (2022) Immunomodulatory effects of polysaccharides from marine algae for treating cancer, infectious disease, and inflammation. Phytother Res 36:761–777

    Article  CAS  PubMed  Google Scholar 

  • Iftikhar F, Khan MBN, Musharraf SG (2021) Monoterpenes as therapeutic candidates to induce fetal hemoglobin synthesis and up-regulation of gamma-globin gene: an in vitro and in vivo investigation. Eur J Pharmacol 891:173700

    Article  CAS  PubMed  Google Scholar 

  • Iqbal M, Verpoorte R, Korthout HA, Mustafa NR (2013) Phytochemicals as a potential source for TNF-α inhibitors. Phytochem Rev 12:65–93

    Article  CAS  Google Scholar 

  • Iraji A, Yazdanpanah S, Alizadeh F, Mirzamohammadi S, Ghasemi Y, Pakshir K, Yang Y, Zomorodian K (2020) Screening the antifungal activities of monoterpenes and their isomers against Candida species. J Appl Microbiol 129:1541–1551

    Article  CAS  PubMed  Google Scholar 

  • Kelly V, Genovese M (2013) Novel small molecule therapeutics in rheumatoid arthritis. Rheumatology 52:1155–1162

    Article  CAS  PubMed  Google Scholar 

  • Keskin I, Gunal Y, Ayla S, Kolbasi B, Sakul A, Kilic U, Gok O, Koroglu K, Ozbek H (2017) Effects of Foeniculum vulgare essential oil compounds, fenchone and limonene, on experimental wound healing. Biotech Histochem 92:274–282

    Article  CAS  PubMed  Google Scholar 

  • Krieger E, Vriend G (2014) YASARA View—molecular graphics for all devices—from smartphones to workstations. Bioinformatics 30:2981–2982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kugyelka R, Kohl Z, Olasz K, Mikecz K, Rauch TA, Glant TT, Boldizsar F (2016) Enigma of IL-17 and Th17 cells in rheumatoid arthritis and in autoimmune animal models of arthritis. Mediators Inflamm 2016:1–12

  • Liu S, Ma H, Zhang H, Deng C, Xin P (2021) Recent advances on signaling pathways and their inhibitors in rheumatoid arthritis. Clin Immunol 230:108793

    Article  CAS  PubMed  Google Scholar 

  • Mahnashi MH, Jabbar Z, Alamgeer, Irfan HM, Asim MH, Akram M, Saif A, Alshahrani MA, Alshehri MA, Asiri SA (2021) Venlafaxine demonstrated anti-arthritic activity possibly through down regulation of TNF-α, IL-6, IL-1β, and COX-2. Inflammopharmacology 29:1413–1425

  • Manan M, Saleem U, Akash MSH, Qasim M, Hayat M, Raza Z, Ahmad B (2020) Antiarthritic potential of comprehensively standardized extract of Alternanthera bettzickiana: in vitro and in vivo studies. ACS Omega 5:19478–19496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marius M, Gonzal TE, Gilbert A, William NY, Francis Désiré BT, Stephanie Flore DN, Sorelle MN, Marius Tresor WK (2018) Analgesic, anti-inflammatory and anti-arthritic properties of aqueous and methanolic stem bark extracts from Nauclea pobeguinii (Rubiacee) in rats. J Complement Integr Med 15(4):2017–0140

  • Mobashar A, Shabbir A, Shahzad M, Gobe G (2022) Preclinical rodent models of arthritis and acute inflammation indicate immunomodulatory and anti-inflammatory properties of juglans regia extracts. Evid Based Complementary Altern Med 2022:1–10

  • Negi V, Mariaselvam C, Misra D, Muralidharan N, Fortier C, Charron D, Krishnamoorthy R, Tamouza R (2017) Polymorphisms in the promoter region of iNOS predispose to rheumatoid arthritis in south Indian Tamils. Int J Immunogenet 44:114–121

    Article  CAS  PubMed  Google Scholar 

  • Obese E, Biney RP, Henneh IT, Anokwah D, Adakudugu EA, Woode E, Ameyaw EO (2021) Antinociceptive effect of the hydroethanolic leaf extract of Calotropis procera (Ait) R. Br. (Apocynaceae): possible involvement of glutamatergic, cytokines, opioidergic and adenosinergic pathways. J Ethnopharmacol 278:114261

    Article  CAS  PubMed  Google Scholar 

  • Özbek H (2007) Investigation of lethal dose levels and anti-lnflammatory effect of fenchone. Turkish Bull Hygiene Experiment Biol 64:22–25

    Google Scholar 

  • Peng X, Zhu L, Guo J, Sun Z, Zhao M, Zhan X (2020) Enhancing biocompatibility and neuronal anti-inflammatory activity of polymyxin B through conjugation with gellan gum. Int J Biol Macromol 147:734–740

    Article  CAS  PubMed  Google Scholar 

  • Pina LT, Ferro JN, Rabelo TK, Oliveira MA, Scotti L, Scotti MT, Walker CIB, Barreto EO, Quintans Júnior LJ, Guimarães AG (2019) Alcoholic monoterpenes found in essential oil of aromatic spices reduce allergic inflammation by the modulation of inflammatory cytokines. Nat Prod Res 33:1773–1777

    Article  CAS  PubMed  Google Scholar 

  • Qadri M, Jay GD, Zhang LX, Schmidt TA, Totonchy J, Elsaid KA (2021) Proteoglycan-4 is an essential regulator of synovial macrophage polarization and inflammatory macrophage joint infiltration. Arthritis Res Ther 23:1–16

    Google Scholar 

  • Qasim S, Alamgeer, Kalsoom S, Shahzad M, Irfan HM, Zafar MS, Bukhari IA, Vohra F, Afzal (2020) Appraisal of disease-modifying potential of amlodipine as an anti-arthritic agent: new indication for an old drug. Inflammopharmacology. 28:1121–1136

  • Qasim S, Saleem M, Alotaibi NH, Bukhari SNA, Alharbi KS, Irfan HM, Anwar R (2021) Appraisal of the antiarthritic potential of prazosin via inhibition of proinflammatory cytokine TNF-α: a key player in rheumatoid arthritis. ACS Omega 6:2379–2388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rehman MFU, Akhter S, Batool AI, Selamoglu Z, Sevindik M, Eman R, Mustaqeem M, Akram MS, Kanwal F, Lu C (2021) Effectiveness of natural antioxidants against SARS-CoV-2? Insights from the in-silico world. Antibiotics 10:1011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robert M, Miossec P (2019) IL-17 in rheumatoid arthritis and precision medicine: from synovitis expression to circulating bioactive levels. Front Med 5:364

    Article  Google Scholar 

  • Schinocca C, Rizzo C, Fasano S, Grasso G, La Barbera L, Ciccia F, Guggino G (2021) Role of the IL-23/IL-17 pathway in rheumatic diseases: an overview. Front Immunol 12:637829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Van Hoovels L, Studenic P, Sieghart D, Steiner G, Bossuyt X, Rönnelid J (2022) Impact of autoimmune serology test results on RA classification and diagnosis. J Transl Autoimmun 5:100142

    Article  PubMed  PubMed Central  Google Scholar 

  • Venkatesha SH, Dudics S, Acharya B, Moudgil KD (2015) Cytokine-modulating strategies and newer cytokine targets for arthritis therapy. Int J Mol Sci 16:887–906

    Article  CAS  Google Scholar 

  • Xin P, Wang S, Xu X, Liu Q, Zhang C (2023) Natural fulvic acids inhibit non-small-cell lung cancer through the COX-2/PGE2/EP4 axis: In silico and in vivo assessments. Heliyon. https://doi.org/10.1016/j.heliyon.2023.e17080

    Article  PubMed  PubMed Central  Google Scholar 

  • Yuniwati Y, Syaban MFR, Anoraga SG, Sabila FL (2022) Molecular docking approach of bryophyllum pinnatum compounds as atherosclerosis therapy by targeting adenosine monophosphate-activated protein kinase and inducible nitric oxide synthase. Acta Informatica Medica 30:91

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang Q, Liu J, Zhang M, Wei S, Li R, Gao Y, Peng W, Wu C (2019) Apoptosis induction of fibroblast-like synoviocytes is an important molecular-mechanism for herbal medicine along with its active components in treating rheumatoid arthritis. Biomolecules 9:795

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Funding

The study was performed using self-funding support.

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Authors and Affiliations

  1. College of Pharmacy, University of Sargodha, Sargodha, 40100, Pakistan

    Shoaib Nawaz & Hafiz Muhammad Irfan

  2. Doctor Institute of Health Sciences, Sargodha, Punjab, Pakistan

    Shoaib Nawaz

  3. Department of Pharmacology, Punjab University College of Pharmacy, University of the Punjab, Lahore, 54000, Pakistan

    Alamgeer

  4. Department of Pharmacy, Forman Christian College (A Chartered University), Ferozpur Road, Lahore, Pakistan

    Laiba Arshad

  5. Department of Immunology, University of Health Sciences, Lahore, 54600, Pakistan

    Shah Jahan

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  1. Shoaib Nawaz
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  2. Hafiz Muhammad Irfan
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  4. Laiba Arshad
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  5. Shah Jahan
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Contributions

The study conceptualization was designed by HMI and Alamgeer; methodology and research work were developed by SN, the manuscript draft was prepared by LA, PCR analysis was performed under the supervision of SJ.

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Correspondence to Hafiz Muhammad Irfan.

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All the experimentation conducted on animals was performed according to animal ethics guidelines with Approval No. SU/ORIC/2859-21.

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Nawaz, S., Irfan, H.M., Alamgeer et al. Attenuation of CFA-induced chronic inflammation by a bicyclic monoterpene fenchone targeting inducible nitric oxide, prostaglandins, C-reactive protein and urea. Inflammopharmacol 31, 2479–2491 (2023). https://doi.org/10.1007/s10787-023-01333-7

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