Investigation of the Bioactivity of Hesperidin in an In Vivo Model of Staphylococcus Aureus -Induced Osteomyelitis
Abstract views: 165 / PDF downloads: 128Keywords:
Hesperidin, Nrf-2, NF-κB, osteomyelitis, ratAbstract
Osteomyelitis is a severe bone disease that is difficult to treat and causes serious socioeconomic problems. This study aimed to examine the bioactivity of hesperidin in an in vivo Staphylococcus aureus-induced osteomyelitis model. Total of 28 male Wistar Albino rats were randomly divided into 4 equal groups (n=7). Groups were designated as Group 1: Control group, Group 2: Sham group, Group 3: Osteomyelitis group, and Group 4: Treatment group (Hesperidin+Osteomyelitis). Unilateral tibial osteomyelitis was induced by administering arachidonic acid and 1×106 CFU-1 bacterial suspension through a hole drilled from the tibial crest. The rats in the treatment group were given hesperidin once a day by oral gavage for 28 days. At the end of the treatment, the effectiveness of the treatment was evaluated radiographically, biochemically, and histopathologically. The mean scores of intraosseous acute inflammation, intraosseous chronic inflammation, periosteal inflammation, and bone necrosis were evaluated histopathologically. The score was 0 in the control group, 0-2 in the sham group, 9-14 in the osteomyelitis group, and 2-6 in the treatment group. The median values of IAI, ICI, PI, BN, and total histopathological scores of the treatment group were significantly lower than the osteomyelitis group. Biochemically, oxidative stress increased significantly in the osteomyelitis model, however, it significantly decreased in the group treated with hesperidin. Nrf-2 translation levels increased by 0.2% in the sham group compared to the control group and decreased by 26% in the osteomyelitis group but increased by 42% in the treatment group compared to the osteomyelitis group. Compared to the control group, NF-kB translation levels increased by 6% and 21% in the sham and osteomyelitis groups, respectively. However, this value decreased by 9% in the treatment group compared to the osteomyelitis group. Radiographically, the combined score reduced by 65% in the treatment group in comparison to the osteomyelitis group. In conclusion, hesperidin showed anti-inflammatory activity by suppressing NF-kB and antioxidant activity by increasing Nrf-2, both of which play a role in inflammatory pathways. In light of all these findings, it can be said that hesperidin can be used as a potential therapeutic or an agent that can contribute to the treatment of osteomyelitis.
References
Alt V, Giannoudis PV. 2019. Musculoskeletal infections–A global burden and a new subsection in injury. Injury. 50 (12): 2152-2153.
Aly MS, Galaly SR, Moustafa N, Mohammed HM, Khadrawy SM, Mahmoud AM. 2017. Hesperidin protects against diethylnitrosamine/carbon tetrachloride-induced renal repercussions via up-regulation of Nrf2/HO-1 signaling and attenuation of oxidative stress. Journal of Applied Pharmaceutical Science, 7(11), 007-014.
An YH, Kang QK, Arciola CR. 2006. Animal models of osteomyelitis. The International journal of artificial organs, 29(4), 407-420.
Banji OJ, Banji D, Ch K. 2014. Curcumin and hesperidin improve cognition by suppressing mitochondrial dysfunction and apoptosis induced by D-galactose in rat brain. Food and chemical toxicology, 74, 51-59.
Birt MC, Anderson DW, Toby EB, Wang J. 2017. Osteomiyelit: recent advances in pathophysiology and therapeutic strategies. Journal of orthopaedics, 14(1):45-52.
Bondeson J, Foxwell B, Brennan F, Feldmann M. 1999. Defining therapeutic targets by using adenovirus: blocking NF-κB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. Proceedings of the National Academy of Sciences, 96(10), 5668-5673.
Burak M, Çimen Y. 1999. Flavonoidler ve antioksidan özellikleri. T Klin Tıp Bilimleri, 19, 296-304.
Calhoun JH, Manring MM, Shirtliff M. 2009. Osteomyelitis of the long bones. In Seminars in plastic surgery (Vol. 23, No. 02, pp. 059-072). © Thieme Medical Publishers.
Carballo-Villalobos AI, González-Trujano ME, Pellicer F, López-Muñoz FJ. 2016. Antihyperalgesic effect of hesperidin improves with diosmin in experimental neuropathic pain. BioMed research international, 1-12.
Carek PJ, Dickerson LM, Sackier JM. 2001. Diagnosis and management of osteomyelitis. American family physician, 63(12), 2413-2421.
Chadha HS, Fitzgerald Jr RH, Wiater P, Sud S, Nasser S, Wooley PH. 1999. Experimental acute hematogenous osteomyelitis in mice. I. Histopathological and immunological findings. Journal of orthopaedic research, 17(3), 376-381.
Elavarasan J, Velusamy P, Ganesan T, Ramakrishnan SK, Rajasekaran D, Periandavan K. 2012. Hesperidin-mediated expression of Nrf2 and upregulation of antioxidant status in senescent rat heart. Journal of Pharmacy and Pharmacology, 64(10), 1472-1482.
Fritz JM, McDonald JR. 2008. Osteomyelitis: approach to diagnosis and treatment. The Physician and sportsmedicine, 36(1), 50-54.
Garg A, Garg S, Zaneveld LJD, Singla AK. 2001. Chemistry and pharmacology of the citrus bioflavonoid hesperidin. Phytotherapy research, 15(8), 655-669.
Gillaspy AF, Hickmon SG, Skinner RA, Thomas JR, Nelson CL, Smeltzer MS. 1995. Role of the accessory gene regulator (agr) in pathogenesis of staphylococcal osteomyelitis. Infection and immunity, 63(9), 3373-3380.
Gratz S, Béhé M, Boerman OC, Kunze E, Schulz H, Eiffert, H, O'reilly T, Behr TM, Angerstein C, Nebendahl K, Kauer F, Becker W. 2001. 99mTc-E-selectin binding peptide for imaging acute osteomyelitis in a novel rat model. Nuclear medicine communications, 22(9), 1003-1013.
Guazelli CF, Fattori V, Ferraz CR, Borghi SM, Casagrande R, Baracat MM, Verri Jr WA. 2021. Antioxidant and anti-inflammatory effects of hesperidin methyl chalcone in experimental ulcerative colitis. Chemico-Biological Interactions, 333, 109315.
Güzel Y, Golge UH, Goksel F, Vural A, Akcay M, Elmas S, Turkon H, Unver, A. 2016. The efficacy of boric acid used to treat experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus: an in vivo study. Biological trace element research, 173(2), 384-389.
Iskender H, Dokumacioglu E, Sen TM, Ince I, Kanbay Y, Saral S. 2017. The effect of hesperidin and quercetin on oxidative stress, NF-κB and SIRT1 levels in a STZ-induced experimental diabetes model. Biomedicine & Pharmacotherapy, 90, 500-508.
Jain M, Parmar HS. 2011. Evaluation of antioxidative and anti-inflammatory potential of hesperidin and naringin on the rat air pouch model of inflammation. Inflammation research, 60(5), 483-491.
Kadry AA, Al-Suwayeh SA, Abd-Allah AR, Bayomi MA. 2004. Treatment of experimental osteomyelitis by liposomal antibiotics. Journal of Antimicrobial Chemotherapy, 54(6), 1103-1108.
Kalpana KB, Srinivasan M, Menon VP. 2009. Evaluation of antioxidant activity of hesperidin and its protective effect on H2O2 induced oxidative damage on pBR322 DNA and RBC cellular membrane. Molecular and cellular biochemistry, 323(1), 21-29.
Kamaraj S, Anandakumar P, Jagan S, Ramakrishnan G, Devaki T. 2010. Modulatory effect of hesperidin on benzo (a) pyrene induced experimental lung carcinogenesis with reference to COX-2, MMP-2 and MMP-9. European journal of pharmacology, 649(1-3), 320-327.
Kang SR, Park KI, Park HS, Lee DH, Kim JA, Nagappan A, Kim EH, Lee WS, Shin SC, Park MK, Han DY, Kim GS. 2011. Anti-inflammatory effect of flavonoids isolated from Korea Citrus aurantium L. on lipopolysaccharide-induced mouse macrophage RAW 264.7 cells by blocking of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathways. Food Chemistry, 129(4), 1721-1728.
Kawaguchi K, Kikuchi SI, Hasunuma R, Maruyama H, Yoshikawa T, Kumazawa Y. 2004. A citrus flavonoid hesperidin suppresses infection-induced endotoxin shock in mice. Biological and Pharmaceutical Bulletin, 27(5), 679-683.
Kim JY, Jung KJ, Choi JS, Chung HY. 2004. Hesperetin: a potent antioxidant against peroxynitrite. Free radical research, 38(7), 761-769.
Kostić M, Ivanov M, Stojković D, Ćirić A, Soković M. 2020. Antibacterial and antibiofilm activity of selected polyphenolic compounds: An in vitro study on Staphylococcus aureus. Lekovite sirovine, 40, 57-61.
Lebreton M. 1828. Sur la matiere cristalline des orangettes, et analyse de ces fruits non encore developpes, famille des. Hesperidees journal de Pharmacie et de sciences accessories, 14:377.
Lew DP, Waldvogel FA. 2004. Osteomyelitis. The Lancet, 364(9431):369-379.
Li C, Schluesener H. 2017. Health-promoting effects of the citrus flavanone hesperidin. Critical reviews in food science and nutrition, 57(3), 613-631.
Li QI, Verma M. 2002. NF-kappaB regulation in the immune system. Nature Reviews Immunology, 2(10), 725-734.
Massaccesi L, Galliera E, Pellegrini A, Banfi G, Corsi Romanelli MM. 2022. Osteomyelitis, Oxidative Stress and Related Biomarkers. Antioxidants, 11(6), 1061.
May C. 2002. Management of bacterial osteomyelitis in dogs and cats. In Practice, 24(6), 330-337.
Mendel V, Simanowski HJ, Scholz HC, Heymann H. 2005. Therapy with gentamicin-PMMA beads, gentamicin-collagen sponge, and cefazolin for experimental osteomyelitis due to Staphylococcus aureus in rats. Archives of orthopaedic and trauma surgery, 125(6), 363-368.
Mendel V, Simanowski HJ, Scholz HC. 2004. Synergy of HBO^ sub 2^ and a local antibiotic carrier for experimental osteomyelitis due to staphylococcus aureus in rats. Undersea & Hyperbaric Medicine, 31(4), 407.
Mustafa M, Yusof S, Iftikhar M. 2014. Osteomiyelit: pathogenesis, clinical and therapeutic challenge. International Journal of Medicine and Pharmaceutical Sciences, 4(1), 9-18.
Nguyen T, Nioi P, Pickett CB. 2009. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. Journal of biological chemistry, 284(20), 13291-13295.
Norden C, Gillespie WJ, Nade S. 1994. Clinical syndromes. In: Infections in bone and joints, Blackwell, USA, 137–387.
Norden CW, Kennedy E. 1970. Experimental osteomyelitis. I. A description of the model. The Journal of infectious diseases, 122(5), 410-418.
Pinho-Ribeiro FA, Hohmann MS, Borghi SM, Zarpelon AC, Guazelli CF, Manchope MF, Casagrande R, Verri Jr WA. 2015. Protective effects of the flavonoid hesperidin methyl chalcone in inflammation and pain in mice: role of TRPV1, oxidative stress, cytokines and NF-κB. Chemico-biological interactions, 228, 88-99.
Polat N, Ciftci O, Cetin A, Yılmaz T. 2016. Toxic effects of systemic cisplatin on rat eyes and the protective effect of hesperidin against this toxicity. Cutaneous and ocular toxicology, 35(1), 1-7.
Rezaeyan A, Haddadi GH, Hosseinzadeh M, Moradi M, Najafi M. 2016. Radioprotective effects of hesperidin on oxidative damages and histopathological changes induced by X-irradiation in rats heart tissue. Journal of Medical Physics/Association of Medical Physicists of India, 41(3), 182.
Rissing JP, Buxton TB, Fisher J, Harris R, Shockley RK. 1985. Arachidonic acid facilitates experimental chronic osteomyelitis in rats. Infection and immunity, 49(1), 141-144.
Roesgen M, Hierholzer G, Hax PM. 1989. Post-traumatic osteomyelitis. Archives of orthopaedic and trauma surgery, 108(1), 1-9.
Shrivastava M, Kar V, Shrivastava S. 2013. Cyclophosphamide altered the myocardial marker enzymes: Protection provoked by Hesperidin in Rats. International Journal of Phytomedicine, 5(2), 141.
Smeltzer MS, Thomas JR, Hickraon SG, Skinner RA, Nelson CL, Griffith D, Parr Jr TR, Evans RP. 1997. Characterization of a rabbit model of staphylococcal osteomyelitis. Journal of Orthopaedic Research, 15(3), 414-421.
Sybenga AB, Jupiter DC, Speights VO, Rao A. 2020. Diagnosing osteomyelitis: a histology guide for pathologists. The Journal of Foot and Ankle Surgery, 59(1), 75-85.
Wilmsen PK, Spada DS, Salvador M. 2005. Antioxidant activity of the flavonoid hesperidin in chemical and biological systems. Journal of agricultural and food chemistry, 53(12), 4757-4761.
Xiao S, Liu W, Bi J, Liu S, Zhao H, Gong N, Xing D, Gao H, Gong M. 2018. Anti-inflammatory effect of hesperidin enhances chondrogenesis of human mesenchymal stem cells for cartilage tissue repair. Journal of inflammation, 15(1), 1-8.
Xin X, Li Y, Liu H. 2020. Hesperidin ameliorates hypobaric hypoxia-induced retinal impairment through activation of Nrf2/HO-1 pathway and inhibition of apoptosis. Scientific reports, 10(1), 1-10.
Yurtal Z, Altug ME, Unsaldi E, Secinti IE, Kucukgul A. 2020. Investigation of Neuroprotective and Therapeutic Effects of Hesperidin in Experimental Spinal Cord Injury. Turkish Neurosurgery, 30(6), 899-906.
Zhang F, Wang B, Liu S, Chen Y, Lin Y, Liu Z, Zhang X, Yu B. 2021. Bacillus subtilis revives conventional antibiotics against Staphylococcus aureus osteomyelitis. Microbial Cell Factories, 20(1), 1-15.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2022 International Journal of Veterinary and Animal Research (IJVAR)
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
