Hesperetin: A Potent Phytochemical Constituent for the Treatment of Rheumatoid Arthritis: Hesperetin for the Treatment of Rheumatoid Arthritis

Tasawar Iqbal; Sidra Altaf; Iman Basit; Muhammad Ahsan Naeem; Qaiser Akram; Muhammad Rizwan Saeed; . Asmara; Shahbaz Hyder; Ume Salma

doi:10.54393/pbmj.v7i08.1099

Authors

Tasawar Iqbal Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan
Sidra Altaf Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
Iman Basit Department of Chemistry, Superior University, Lahore, Pakistan
Muhammad Ahsan Naeem Department of Basic Sciences (Pharmacology), University of Veterinary and Animal Sciences, Narowal, Pakistan
Qaiser Akram Department of Pathobiology (Microbiology), University of Veterinary and Animal Sciences, Lahore, Pakistan
Muhammad Rizwan Saeed Department of Pathobiology (Microbiology), University of Veterinary and Animal Sciences, Narowal, Pakistan
. Asmara Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan
Shahbaz Hyder Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan
Ume Salma Department of Zoology, University of Agriculture, Faisalabad, Pakistan

DOI:

https://doi.org/10.54393/pbmj.v7i08.1099

Keywords:

Hesperetin, Phytochemical, Rheumatoid Arthritis, Autoimmune Disorder, Tumor Necrosis Factor-Alpha

Abstract

Hesperetin, a flavonoid abundant in citrus fruits and various vegetables, has emerged as a promising phytochemical for the treatment of rheumatoid arthritis (RA). With its strong anti-inflammatory and antioxidant properties, hesperidin offers a multifaceted approach to reducing the symptoms and progression of rheumatoid arthritis. The pathogenesis of RA involves a complex interplay between inflammatory cytokines, immune dysregulation, and oxidative stress. Hesperidin exerts its therapeutic effects by modulating these pathways. This drug prevents the production of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β, thus reducing inflammation and joint damage. Hesperidin shows immunomodulatory effects by modulating the function of immune cells. It inhibits the activity of inflammatory cells such as macrophages and neutrophils, which play an important role in the development of rheumatoid arthritis. In addition, hesperetin inhibits the activation of nuclear factor κB, an important transcription factor involved in the expression of inflammatory genes, and exhibits broad anti-inflammatory effects. Hesperetin supplementation improves clinical symptoms and inflammatory markers in patients with rheumatoid arthritis. Hesperetin is a natural compound obtained from food sources and has fewer side effects than traditional rheumatoid arthritis drugs, making it an attractive alternative or complementary treatment. Hespertin is a promising approach for the treatment of rheumatoid arthritis. Its pleiotropic mechanisms of action, including anti-inflammatory, antioxidant and immunomodulatory effects, have great therapeutic potential to reduce the symptoms of rheumatoid arthritis, stop the progression of the disease and improve the quality of life of patients. This review article highlights the clinical trials needed to fully elucidate the therapeutic benefits of hesperetin and determine its role in the conventional treatment of rheumatoid arthritis.

References

Altaf S and Iqbal T. Bee Venom Used for the Treatment of Rheumatoid Arthritis. Biomedical Journal of Scientific & Technical Research. 2023; 53(2): 44503-7. doi: 10.26717/BJSTR.2023.53.008370. DOI: https://doi.org/10.26717/BJSTR.2023.53.008370

Akram M, Daniyal M, Sultana S, Owais A, Akhtar N, Zahid R et al. Traditional and modern management strategies for rheumatoid arthritis. International Journal of Clinical Chemistry. 2021 Jan; 512: 142-55. doi: 10.1016/j.cca.2020.11.003. DOI: https://doi.org/10.1016/j.cca.2020.11.003

Smolen JS. Insights into the treatment of rheumatoid arthritis: a paradigm in medicine. Journal of Autoimmunity. 2020 Jun; 110: 102425. doi: 10.1016/j.jaut.2020.102425. DOI: https://doi.org/10.1016/j.jaut.2020.102425

Hua C, Buttgereit F, Combe B. Glucocorticoids in rheumatoid arthritis: current status and future studies. Rheumatic and Musculoskeletal Diseases Open. 2020 Jan; 6(1): e000536. doi: 10.1136/rmdopen-2017-000536. DOI: https://doi.org/10.1136/rmdopen-2017-000536

Ghabri S, Lam L, Bocquet F, Spath HM. Systematic literature review of economic evaluations of biological treatment sequences for patients with moderate to severe rheumatoid arthritis previously treated with disease-modifying anti-rheumatic drugs. Pharmacoeconomics. 2020 May; 38(5): 459-71. doi: 10.1007/s40273-020-00887-6. DOI: https://doi.org/10.1007/s40273-020-00887-6

Landgren E, Bremander A, Lindqvist E, Nylander M, Van der Elst K, Larsson I. “Mastering a New Life Situation”–Patients’ Preferences of Treatment Outcomes in Early Rheumatoid Arthritis–A Longitudinal Qualitative Study. Patient Preference and Adherence. 2020 Aug; 1421-33. doi: 10.2147/PPA.S253507. DOI: https://doi.org/10.2147/PPA.S253507

Wdowiak K, Walkowiak J, Pietrzak R, Bazan-Woźniak A, Cielecka-Piontek J. Bioavailability of hesperidin and its aglycone hesperetin—compounds found in citrus fruits as a parameter conditioning the pro-health potential (neuroprotective and antidiabetic activity)—mini-review. Nutrients. 2022 Jun; 14(13): 2647. doi: 10.3390/nu14132647. DOI: https://doi.org/10.3390/nu14132647

Wdowiak K, Rosiak N, Tykarska E, Żarowski M, Płazińska A, Płaziński W et al. Amorphous inclusion complexes: molecular interactions of hesperidin and hesperetin with HP-Β-CD and their biological effects. International Journal of Molecular Sciences. 2022 Apr; 23(7): 4000. doi: 10.3390/ijms23074000. DOI: https://doi.org/10.3390/ijms23074000

Khan A, Ikram M, Hahm JR, Kim MO. Antioxidant and anti-inflammatory effects of citrus flavonoid hesperetin: Special focus on neurological disorders. Antioxidants. 2020 Jul; 9(7): 609. doi: 10.3390/antiox9070609. DOI: https://doi.org/10.3390/antiox9070609

Berköz M, Yalın S, Özkan-Yılmaz F, Özlüer-Hunt A, Krośniak M, Francik R et al. Protective effect of myricetin, apigenin, and hesperidin pretreatments on cyclophosphamide-induced immunosuppression. Immunopharmacology and Immunotoxicology. 2021 May; 43(3): 353-69. doi: 10.1080/08923973.2021.1916525. DOI: https://doi.org/10.1080/08923973.2021.1916525

Hosawi S. Current update on role of hesperidin in inflammatory lung diseases: chemistry, pharmacology, and drug delivery approaches. Life. 2023 Apr; 13(4): 937. doi: 10.3390/life13040937. DOI: https://doi.org/10.3390/life13040937

Gujar K and Wairkar S. Nanocrystal technology for improving therapeutic efficacy of flavonoids. Phytomedicine. 2020 Jun; 71: 153240. doi: 10.1016/j.phymed.2020.153240. DOI: https://doi.org/10.1016/j.phymed.2020.153240

Salehi B, Cruz-Martins N, Butnariu M, Sarac I, Bagiu IC, Ezzat SM et al. Hesperetin’s health potential: Moving from preclinical to clinical evidence and bioavailability issues, to upcoming strategies to overcome current limitations. Critical Reviews in Food Science and Nutrition. 2022 Jun; 62(16): 4449-64. doi: 10.1080/10408398.2021.1875979. DOI: https://doi.org/10.1080/10408398.2021.1875979

Guo X, Cao X, Fang X, Guo A, Li E. Involvement of phase II enzymes and efflux transporters in the metabolism and absorption of naring in, hesperidin and their aglycones in rats. International Journal of Food Sciences and Nutrition. 2022 May; 73(4): 480-90. doi: 10.1080/09637486.2021.2012562. DOI: https://doi.org/10.1080/09637486.2021.2012562

Das SK, Sen K, Sanyal T, Saha A, Madhu NR. Flavonoids: A Promising Neuro protectant and Its Salutary Effects on Age-Related Neurodegenerative Disorders. In Neuroprotective Effects of Phytochemicals in Brain Ageing. Singapore: Springer Nature Singapore; 2024 Jun; 221-255. doi: 10.1007/978-981-99-7269-2_11. DOI: https://doi.org/10.1007/978-981-99-7269-2_11

Sohel M, Sultana H, Sultana T, Al Amin M, Aktar S, Ali MC et al. Chemotherapeutic potential of hesperetin for cancer treatment, with mechanistic insights: A comprehensive review. Heliyon. 2022 Jan; 8(1): e08815. doi: 10.1016/j.heliyon.2022.e08815. DOI: https://doi.org/10.1016/j.heliyon.2022.e08815

Yap KM, Sekar M, Wu YS, Gan SH, Rani NN, Seow LJ et al. Hesperidin and its aglycone hesperetin in breast cancer therapy: A review of recent developments and future prospects. Saudi Journal of Biological Sciences. 2021 Dec; 28(12): 6730-47. doi: 10.1016/j.sjbs.2021.07.046. DOI: https://doi.org/10.1016/j.sjbs.2021.07.046

Gandhi GR, Hillary VE, Athesh K, da Cruz Ramos ML, de Oliveira Krauss GP, Jothi G et al. The Use of Nanocarriers to Enhance the Anti-neuroinflammatory Potential of Dietary Flavonoids in Animal Models of Neurodegenerative Diseases: A Systematic Review. Mini Reviews in Medicinal Chemistry. 2024 Jul; 24(13): 1293-305. doi: 10.2174/1389557523666230907093441. DOI: https://doi.org/10.2174/1389557523666230907093441

Aggarwal V, Tuli HS, Thakral F, Singhal P, Aggarwal D, Srivastava S et al. Molecular mechanisms of action of hesperidin in cancer: Recent trends and advancements. Experimental Biology and Medicine. 2020 Mar; 245(5): 486-97. doi: 10.1177/1535370220903671. DOI: https://doi.org/10.1177/1535370220903671

H. Ribeiro M and Severo AC. Advances on Resources: Biosynthesis Pathway, Bioavailability, Bioactivity, and Pharmacology of Hesperetin. InHandbook of Dietary Flavonoids. Cham: Springer International Publishing. 2023 Sep. p. 1-26. doi: 10.1007/978-3-030-94753-8_30-1. DOI: https://doi.org/10.1007/978-3-030-94753-8_30-1

Zuccari G and Alfei S. Development of Orally Administrable Phytochemicals by Nano-Suspension and Nano-Emulsion Techniques. 2023. doi: 10.20944/preprints202305.0658.v1. DOI: https://doi.org/10.20944/preprints202305.0658.v1

Rocha S, Lucas M, Ribeiro D, Corvo ML, Fernandes E, Freitas M. Nano-based drug delivery systems used as vehicles to enhance polyphenols therapeutic effect for diabetes mellitus treatment. Pharmacological Research. 2021 Jul; 169: 105604. doi: 10.1016/j.phrs.2021.105604. DOI: https://doi.org/10.1016/j.phrs.2021.105604

Barry Z, Park B, Corson TW. Pharmacological potential of small molecules for treating corneal neovascularization. Molecules. 2020 Jul; 25(15): 3468. doi: 10.3390/molecules25153468. DOI: https://doi.org/10.3390/molecules25153468

Lazer LM, Kesavan Y, Gor R, Ramachandran I, Pathak S, Narayan S, et al. Targeting colon cancer stem cells using novel doublecortin like kinase 1 antibody functionalized folic acid conjugated hesperetin encapsulated chitosan nanoparticles. Colloids and Surfaces B: Biointerfaces. 2022 Sep; 217: 112612. doi: 10.1016/j.colsurfb.2022.112612. DOI: https://doi.org/10.1016/j.colsurfb.2022.112612

Butnariu M. Plant genome engineering for improved flavonoids production. Plants as Bioreactors for Industrial Molecules. 2023 Feb; 215-40. doi: 10.1002/9781119875116.ch8. DOI: https://doi.org/10.1002/9781119875116.ch8

Morresi C. Role of Paraoxonase2 in intestinal cells and its modulation by dietary factors. 2020.

Almurjan AK. Optimising therapeutic outcomes in CNS disorders: pharmaceutical and pharmacokinetic approaches [Dissertation]. Aston University; 2021

Agrawal PK, Agrawal C, Blunden G. Pharmacological significance of hesperidin and hesperetin, two citrus flavonoids, as promising antiviral compounds for prophylaxis against and combating COVID-19. Natural Product Communications. 2021 Oct; 16(10). doi: 10.1177/1934578X211042540. DOI: https://doi.org/10.1177/1934578X211042540

Pradhan N and Jana NR. Nanomodulators That Target Alzheimer’s Disease: A Review. ACS Applied Nano Materials. Feb; 7(4): 3515-45. doi: 10.1021/acsanm.3c04846. DOI: https://doi.org/10.1021/acsanm.3c04846

Fan YN, Zhao G, Zhang Y, Ye QN, Sun YQ, Shen S et al. Progress in nanoparticle-based regulation of immune cells. Medical Review. 2023 Apr; 3(2): 152-79. doi: 10.1515/mr-2022-0047. DOI: https://doi.org/10.1515/mr-2022-0047

Zhou H, Zhang Z, Mu Y, Yao H, Zhang Y, Wang DA. Harnessing Nanomedicine for Cartilage Repair: Design Considerations and Recent Advances in Biomaterials. ACS Nano. 2024 Apr; 18(16): 10667-87. doi: 10.1021/acsnano.4c00780. DOI: https://doi.org/10.1021/acsnano.4c00780

Altaf S, Iqbal T, Majeed W, Farooq MA, Naseer D, Saleem M et al. Plasma membrane camouflaged nanoparticles: an emerging antibacterial approach. One Health Triad, Unique Scientific Publishers, Faisalabad, Pakistan. 2023; 2: 193-200. doi: 10.47278/book.oht/2023.60. DOI: https://doi.org/10.47278/book.oht/2023.60

Choi SS, Lee SH, Lee KA. A comparative study of hesperetin, hesperidin and hesperidin glucoside: Antioxidant, anti-inflammatory, and antibacterial activities in vitro. Antioxidants. 2022 Aug; 11(8): 1618. doi: 10.3390/antiox11081618. DOI: https://doi.org/10.3390/antiox11081618

Nishino S, Fujiki Y, Sato T, Kato Y, Shirai R, Oizumi H et al. Hesperetin, a citrus flavonoid, ameliorates inflammatory cytokine-mediated inhibition of oligodendroglial cell morphological differentiation. Neurology International. 2022 May; 14(2): 471-87. doi: 10.3390/neurolint14020039. DOI: https://doi.org/10.3390/neurolint14020039

Iqbal T and Altaf S. Nigella Sativa use for the Treatment of Cancer. Biomedical Journal of Scientific & Technical Research. 2024; 55(1): 46693-7. doi: 10.26717/BJSTR.2024.55.008660. DOI: https://doi.org/10.26717/BJSTR.2024.55.008660

Lee A, Gu H, Gwon MH, Yun JM. Hesperetin suppresses LPS/high glucose-induced inflammatory responses via TLR/MyD88/NF-κB signaling pathways in THP-1 cells. Nutrition Research and Practice. 2021 Oct; 15(5): 591. doi: 10.4162/nrp.2021.15.5.591. DOI: https://doi.org/10.4162/nrp.2021.15.5.591

Li Q, Miao Z, Wang R, Yang J, Zhang D. Hesperetin induces apoptosis in human glioblastoma cells via p38 MAPK activation. Nutrition and Cancer. 2020 Apr; 72(3): 538-45. doi: 10.1080/01635581.2019.1638424. DOI: https://doi.org/10.1080/01635581.2019.1638424

Jiang S, Wang S, Zhang L, Tian L, Li L, Liu Z et al. Hesperetin as an adjuvant augments protective anti‐tumour immunity responses in B16F10 melanoma by stimulating cytotoxic CD8+ T cells. Scandinavian Journal of Immunology. 2020 Apr; 91(4): e12867. doi: 10.1111/sji.12867. DOI: https://doi.org/10.1111/sji.12867

Iqbal T, Ahmad A, Naveed MT, Ali A, Ahmad M. Potential Role of Zoonoses in Bioterrorism. Zoonosis, Unique Scientific Publishers, Faisalabad, Pakistan. 2023; 1: 499-512. doi: 10.47278/book.zoon/2023.038. DOI: https://doi.org/10.47278/book.zoon/2023.038

Yosif HM, Hasoon BA, Jabir MS, Yaqoob SH, Samir H, Swelum AA. Antibacterial Activity of Laser Ablated Gold and Hydroxyapatite Nanoparticles Conjugated Cefuroxime against Staphylococcus saprophyticus. Pakistan Veterinary Journal. 2024 Jan; 44(1).

Lin Z, Fu C, Yan Z, Wu Y, Zhan J, Lou Z et al. The protective effect of hesperetin in osteoarthritis: an in vitro and in vivo study. Food and Function. 2020; 11(3): 2654-66. doi: 10.1039/C9FO02552A. DOI: https://doi.org/10.1039/C9FO02552A

Iqbal T, Altaf S, Fatima M, Rasheed R, Laraib K, Azam M et al. A narrative review on effective use of medicinal plants for the treatment of parasitic foodborne diseases. Agrobiological Records. 2024; 16: 79-92.

Altaf S, Khan S, Iqbal T, Farooq MA, Muzaffar H. Potential treatment of anthrax infection. Zoonosis, Unique Scientific Publishers, Faisalabad, Pakistan. 2023; 3: 576-88. doi: 10.47278/book.zoon/2023.125. DOI: https://doi.org/10.47278/book.zoon/2023.125

Christman LM, Gu L. Efficacy and mechanisms of dietary polyphenols in mitigating rheumatoid arthritis. Journal of Functional Foods. 2020 Aug; 71: 104003. doi: 10.1016/j.jff.2020.104003. DOI: https://doi.org/10.1016/j.jff.2020.104003

Hussain Y, Khan H, Efferth T, Alam W. Regulation of endoplasmic reticulum stress by hesperetin: Focus on antitumor and cytoprotective effects. Phytomedicine. 2022 Jun; 100: 153985. doi: 10.1016/j.phymed.2022.153985. DOI: https://doi.org/10.1016/j.phymed.2022.153985

Mohanty S, Pal A, Si SC. Flavonoid as nutraceuticals: A therapeutic approach to rheumatoid arthritis. Research Journal of Pharmacy and Technology. 2020; 13(2): 991-8. doi: 10.5958/0974-360X.2020.00184.5. DOI: https://doi.org/10.5958/0974-360X.2020.00184.5

Ali H, Tohamy HG, Al-Hattali R, Al-Habsi H, Al-Habsi K, Elshafie EI et al. Encephalitic Listeriosis in Small Ruminants in Oman: Pathophysiology, Antimicrobial Sensitivity and Molecular Characterization. Pakistan Veterinary Journal. 2024 Jan; 44(1). doi: 10.2139/ssrn.4479407. DOI: https://doi.org/10.2139/ssrn.4479407

Ortiz AD, Fideles SO, Reis CH, Bellini MZ, Pereira ED, Pilon JP et al. Therapeutic effects of citrus flavonoids neohesperidin, hesperidin and its aglycone, hesperetin on bone health. Biomolecules. 2022 Apr; 12(5): 626. doi: 10.3390/biom12050626. DOI: https://doi.org/10.3390/biom12050626

Adefegha SA, Bottari NB, Leal DB, de Andrade CM, Schetinger MR. Interferon gamma/interleukin-4 modulation, anti-inflammatory and antioxidant effects of hesperidin in complete Freund’s adjuvant (CFA)-induced arthritis model of rats. Immunopharmacology and Immunotoxicology. 2020 Sep; 42(5): 509-20. doi: 10.1080/08923973.2020.1814806. DOI: https://doi.org/10.1080/08923973.2020.1814806

Gambari L, Cellamare A, Grassi F, Grigolo B, Panciera A, Ruffilli A et al. Overview of anti-inflammatory and anti-nociceptive effects of polyphenols to halt osteoarthritis: from preclinical studies to new clinical insights. International Journal of Molecular Sciences. 2022 Dec; 23(24): 15861. doi: 10.3390/ijms232415861. DOI: https://doi.org/10.3390/ijms232415861

Gonçalves AC, Rodrigues S, Rodrigues R, Silva LR. The Role of Dietary Phenolic Compounds in the Prevention and Treatment of Rheumatoid Arthritis: Current Reports. 2024. doi: 10.20944/preprints202404.0585.v1. DOI: https://doi.org/10.20944/preprints202404.0585.v1

Altaf S, Iqbal T, Salma U, Sajid M, Basit I, Sabir MZ et al. Gold nanoparticles for the detection of organophosphate. Agrobiological Records. 2024; 16: 11-18. doi: 10.47278/journal.abr/2024.007. DOI: https://doi.org/10.47278/journal.abr/2024.007

Shin JY, Kwon YS, Lee SK, Lee KJ, Park JK, Bae SG. Undifferentiated Hepatic Pleomorphic Sarcoma (Malignant Fibrous Histiocytoma) in a Dog: A Case Report. Pakistan Veterinary Journal. 2024 Jan; 44(1).

Ferraz CR, Carvalho TT, Manchope MF, Artero NA, Rasquel-Oliveira FS, Fattori V et al. Therapeutic potential of flavonoids in pain and inflammation: mechanisms of action, pre-clinical and clinical data, and pharmaceutical development. Molecules. 2020 Feb; 25(3): 762. doi: 10.3390/molecules25030762. DOI: https://doi.org/10.3390/molecules25030762

Shin SA, Joo BJ, Lee JS, Ryu G, Han M, Kim WY et al. Phytochemicals as anti-inflammatory agents in animal models of prevalent inflammatory diseases. Molecules. 2020 Dec; 25(24): 5932. doi: 10.3390/molecules25245932. DOI: https://doi.org/10.3390/molecules25245932

Rufino AT, Freitas M, Proença C, Ferreira de Oliveira JM, Fernandes E, Ribeiro D. Rheumatoid arthritis molecular targets and their importance to flavonoid‐based therapy. Medicinal Research Reviews. 2024 Mar; 44(2): 497-538. doi: 10.1002/med.21990. DOI: https://doi.org/10.1002/med.21990

Almuzaini AM. Flow of Zoonotic Toxoplasmosis in Food Chain. Pakistan Veterinary Journal. 2023 Jan; 43(1).

Al-Sefri HA. Therapeutic Effect of Naringin and Hesperidin on Cardiac Dysfunction Induced by Adriamycin in Experimental Animals [Dissertation]. King Abdulaziz University Jeddah; 2020.

Bansal K, Bhati H, Bajpai M. New insights into therapeutic applications and nanoformulation approaches of Hesperidin: An updated review. Pharmacological Research-Modern Chinese Medicine. 2024 Jan; 100363. doi: 10.1016/j.prmcm.2024.100363. DOI: https://doi.org/10.1016/j.prmcm.2024.100363

Ahmed OM, AbouZid SF, Ahmed NA, Zaky MY, Liu H. An up-to-date review on citrus flavonoids: chemistry and benefits in health and diseases. Current Pharmaceutical Design. 2021 Mar; 27(4): 513-30. doi: 10.2174/1381612826666201127122313. DOI: https://doi.org/10.2174/1381612826666201127122313

Meneguzzo F, Ciriminna R, Zabini F, Pagliaro M. Review of evidence available on hesperidin-rich products as potential tools against COVID-19 and hydrodynamic cavitation-based extraction as a method of increasing their production. Processes. 2020 May; 8(5): 549. doi: 10.3390/pr8050549. DOI: https://doi.org/10.3390/pr8050549

Long Z, Xiang W, He Q, Xiao W, Wei H, Li H et al. Efficacy and safety of dietary polyphenols in rheumatoid arthritis: A systematic review and meta-analysis of 47 randomized controlled trials. Frontiers in Immunology. 2023 Mar; 14: 1024120. doi: 10.3389/fimmu.2023.1024120. DOI: https://doi.org/10.3389/fimmu.2023.1024120

Patidar V, Shah S, Kumar R, Singh PK, Singh SB, Khatri DK. A molecular insight of inflammatory cascades in rheumatoid arthritis and anti-arthritic potential of phytoconstituents. Molecular Biology Reports. 2022 Mar; 1-7.

Ji M, Ryu HJ, Hong JH. Signalling and putative therapeutic molecules on the regulation of synoviocyte signalling in rheumatoid arthritis. Bone & joint research. 2021 Apr; 10(4): 285-97. doi: 10.1302/2046-3758.104.BJR-2020-0331.R1. DOI: https://doi.org/10.1302/2046-3758.104.BJR-2020-0331.R1

Kour G, Haq SA, Bajaj BK, Gupta PN, Ahmed Z. Phytochemical add-on therapy to DMARDs therapy in rheumatoid arthritis: In vitro and in vivo bases, clinical evidence and future trends. Pharmacological Research. 2021 Jul; 169: 105618. doi: 10.1016/j.phrs.2021.105618. DOI: https://doi.org/10.1016/j.phrs.2021.105618

Singh S, Singh TG, Mahajan K, Dhiman S. Medicinal plants used against various inflammatory biomarkers for the management of rheumatoid arthritis. Journal of Pharmacy and Pharmacology. 2020 Oct; 72(10): 1306-27. doi: 10.1111/jphp.13326. DOI: https://doi.org/10.1111/jphp.13326

Chatterjee A, Jayaprakasan M, Chakrabarty AK, Lakkaniga NR, Bhatt BN, Banerjee D. Comprehensive insights into rheumatoid arthritis: Pathophysiology, current therapies and herbal alternatives for effective disease management. Phytotherapy Research. 2024 Mar; 38(6); 2764-2799. doi: 10.1002/ptr.8187. DOI: https://doi.org/10.1002/ptr.8187

Ali M, Benfante V, Stefano A, Yezzi A, Di Raimondo D, Tuttolomondo A et al. Anti-arthritic and anti-cancer activities of polyphenols: A review of the most recent in vitro assays. Life. 2023 Jan; 13(2): 361. doi: 10.3390/life13020361. DOI: https://doi.org/10.3390/life13020361

Liu X, Wang Z, Qian H, Tao W, Zhang Y, Hu C et al. Natural medicines of targeted rheumatoid arthritis and its action mechanism. Frontiers in Immunology. 2022 Aug; 13: 945129. doi: 10.3389/fimmu.2022.945129. DOI: https://doi.org/10.3389/fimmu.2022.945129