Phytochemical, Cytoprotective Profiling, and Anti-Inflammatory Potential of in Rheumatoid Arthritis: An Experimental and Simulation Study

Overview

Journal Nutrients

Date 2024 Dec 17

PMID 39683414

Authors

Huda Abbasi

Maria Sharif

Peter John

Attya Bhatti

Muhammad Qasim Hayat

Qaisar Mansoor

Affiliations

Soon will be listed here.

Abstract

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by severe pain, inflammation, and joint deformity. Currently, it affects 1% of the population, with a projection to exceed 23 million cases by 2030. Despite significant advancements, non-steroidal anti-inflammatory drugs (NSAIDs), the first line of treatment, are associated with a range of adverse effects. Consequently, plant-based derivatives are being utilized as an effective alternative. This study evaluates the anti-inflammatory and safety profile of hydroethanolic extract (CLHE) in comparison to NSAIDs, with a focus on COX-2 and TNFα inhibition.

Methods: CLHE potential was evaluated by phytochemical screening and in vitro bioactivity assays. Toxicity profile was conducted in Human Colon Epithelial Cells (HCEC) and Balb/c mice. Anti-inflammatory potential was explored in a collagen-induced arthritic (CIA) mice model. Bioactive compounds were identified computationally from GCMS data and subjected to docking and simulation studies against COX2 and TNFα.

Results: CLHE demonstrated significant antioxidant (IC-50 = 6.78 µg/mL) and anti-inflammatory (IC-50 = 97.39 µg/mL) activity. It maintained 50% cell viability at 78.5 μg/µL in HCEC cells and exhibited no toxicity at a dose of 5000 mg/kg in mice. In the CIA model, CLHE significantly reduced paw swelling, arthritic scoring, C-reactive protein levels, and spleen indices, outperforming ibuprofen. Expression analysis confirmed the downregulation of COX-2, TNFα, and MMP-9. Histopathological analysis indicated the superior efficacy of CLHE compared to ibuprofen in reducing inflammation, synovial hyperplasia, and bone erosion. Computational studies identified compound-15 (CL15), (4-(4,7-dimethoxy-1,3-benzodioxol-5-yl)-2-oxo pyrrolidine-3-carboxylic acid), a non-toxic compound with strong binding affinities to COX-2 (-12.9 KJ/mol), and TNF-α (-5.8 KJ/mol).

Conclusions: The findings suggest the potential of as a safer, anti-inflammatory, and multi-targeted alternative to NSAIDs for RA treatment.

References

Luan J, Hu Z, Cheng J, Zhang R, Yang P, Guo H . Applicability and implementation of the collagen-induced arthritis mouse model, including protocols (Review). Exp Ther Med. 2021; 22(3):939. PMC: 8290431. DOI: 10.3892/etm.2021.10371. View

Teixeira J, Silva A, Almeida M, Bessa-Goncalves M, Cunha C, Barbosa M . The Systemic Immune Response to Collagen-Induced Arthritis and the Impact of Bone Injury in Inflammatory Conditions. Int J Mol Sci. 2019; 20(21). PMC: 6862543. DOI: 10.3390/ijms20215436. View

Jimenez R, Szalai A . Therapeutic Lowering of C-Reactive Protein. Front Immunol. 2021; 11:619564. PMC: 7901964. DOI: 10.3389/fimmu.2020.619564. View

Oniga S, Pacureanu L, Stoica C, Palage M, Craciun A, Rusu L . COX Inhibition Profile and Molecular Docking Studies of Some 2-(Trimethoxyphenyl)-Thiazoles. Molecules. 2017; 22(9). PMC: 6151395. DOI: 10.3390/molecules22091507. View

Nair V, Kumar R, Singh S, Gupta Y . Investigation into the anti-inflammatory and antigranuloma activity of Colchicum luteum Baker in experimental models. Inflammation. 2011; 35(3):881-8. DOI: 10.1007/s10753-011-9389-2. View

Lewgowd W, Stanczak A . Cinnoline derivatives with biological activity. Arch Pharm (Weinheim). 2007; 340(2):65-80. DOI: 10.1002/ardp.200500194. View

Nair V, Singh S, Gupta Y . Evaluation of the disease modifying activity of Colchicum luteum Baker in experimental arthritis. J Ethnopharmacol. 2010; 133(2):303-7. DOI: 10.1016/j.jep.2010.09.027. View

Radu A, Bungau S . Management of Rheumatoid Arthritis: An Overview. Cells. 2021; 10(11). PMC: 8616326. DOI: 10.3390/cells10112857. View

Zhang L, Ravipati A, Koyyalamudi S, Jeong S, Reddy N, Smith P . Antioxidant and anti-inflammatory activities of selected medicinal plants containing phenolic and flavonoid compounds. J Agric Food Chem. 2011; 59(23):12361-7. DOI: 10.1021/jf203146e. View

10.

Hor S, Ahmad M, Farsi E, Yam M, Hashim M, Lim C . Safety assessment of methanol extract of red dragon fruit (Hylocereus polyrhizus): acute and subchronic toxicity studies. Regul Toxicol Pharmacol. 2012; 63(1):106-14. DOI: 10.1016/j.yrtph.2012.03.006. View

11.

Frolov N, Vereshchagin A . Piperidine Derivatives: Recent Advances in Synthesis and Pharmacological Applications. Int J Mol Sci. 2023; 24(3). PMC: 9917539. DOI: 10.3390/ijms24032937. View

12.

Volobueva A, Yarovaya O, Kireeva M, Borisevich S, Kovaleva K, Mainagashev I . Discovery of New Ginsenol-Like Compounds with High Antiviral Activity. Molecules. 2021; 26(22). PMC: 8619001. DOI: 10.3390/molecules26226794. View

13.

Nash P, Clegg D . Psoriatic arthritis therapy: NSAIDs and traditional DMARDs. Ann Rheum Dis. 2005; 64 Suppl 2:ii74-7. PMC: 1766880. DOI: 10.1136/ard.2004.030783. View

14.

Erhirhie E, Ihekwereme C, Ilodigwe E . Advances in acute toxicity testing: strengths, weaknesses and regulatory acceptance. Interdiscip Toxicol. 2018; 11(1):5-12. PMC: 6117820. DOI: 10.2478/intox-2018-0001. View

15.

Aryal S, Baniya M, Danekhu K, Kunwar P, Gurung R, Koirala N . Total Phenolic Content, Flavonoid Content and Antioxidant Potential of Wild Vegetables from Western Nepal. Plants (Basel). 2019; 8(4). PMC: 6524357. DOI: 10.3390/plants8040096. View

16.

Jannat A, John P, Bhatti A, Hayat M . Tomorou attenuates progression of rheumatoid arthritis through alteration in ULK-1 independent autophagy pathway in collagen induced arthritis mice model. Cell Death Discov. 2019; 5:142. PMC: 6838101. DOI: 10.1038/s41420-019-0222-2. View

17.

Ongtanasup T, Prommee N, Jampa O, Limcharoen T, Wanmasae S, Nissapatorn V . The Cholesterol-Modulating Effect of the New Herbal Medicinal Recipe from Yellow Vine ( (Goetgh.)), Ginger ( Roscoe.), and Safflower ( L.) on Suppressing PCSK9 Expression to Upregulate LDLR Expression in HepG2 Cells. Plants (Basel). 2022; 11(14). PMC: 9318486. DOI: 10.3390/plants11141835. View

18.

Lianxu C, Hongti J, Changlong Y . NF-kappaBp65-specific siRNA inhibits expression of genes of COX-2, NOS-2 and MMP-9 in rat IL-1beta-induced and TNF-alpha-induced chondrocytes. Osteoarthritis Cartilage. 2005; 14(4):367-76. DOI: 10.1016/j.joca.2005.10.009. View

19.

Sarkar S, Modak D, Roy S, Biswas A, Islam M, Baishya R . In silico, in vitro, and in vivo acute and sub-acute toxicity profiling of whole plant methanol extract of Equisetum diffusum D. Don from the sub-Himalayan West Bengal, India, having ethnobotanical uses. BMC Complement Med Ther. 2024; 24(1):324. PMC: 11365236. DOI: 10.1186/s12906-024-04606-y. View

20.

Hosseinzadeh L, Aliabadi A, Rahnama M, Mohammad Sadeghi H, Rahmani Khajouei M . Synthesis and cytotoxic evaluation of some new 3-(2-(2-phenylthiazol-4-yl) ethyl)-quinazolin-4(3H) one derivatives with potential anticancer effects. Res Pharm Sci. 2017; 12(4):290-298. PMC: 5566003. DOI: 10.4103/1735-5362.212046. View