Sains Malaysiana 52(2)(2023): 579-588

http://doi.org/10.17576/jsm-2023-5202-19

 

Hypoglycemic Effect of Flavonoid Glabridin Prevents Homeostatic Disruption of Native Achilles Tendon in Streptozotocin-Induced Type 1 Diabetic Rats

 (Kesan Hipoglisemik Flavonoid Glabridin Mencegah Gangguan Homeostatik Tendon Achilles Asal pada Tikus Diabetik Jenis 1 Aruhan Streptozotosin)

 

JONGDEE NOPPARAT^1,2, WIPAPAN KHIMMAKTONG ¹, CHUMPOL PHOLPRAMOOL ³ & CHITTIPONG TIPBUNJONG^1,*

 

¹Department of Anatomy, Division of Health and Applied Sciences, Faculty of Science, Prince of Songkhla University, Songkhla 90110, Thailand

²Trace Analysis and Biosensor Research Center, Prince of Songkhla University, Songkhla 90110, Thailand

³Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand

 

Received: 9 June 2022/Accepted: 16 November 2022

 

Abstract

Diabetic mellitus is a complex and serious disorder characterized by poor glycemic control leading to tendon architectural alterations and inflammation. This study aimed to investigate the protective effects of glabridin, a polyphenolic flavonoid, on architecture and inflammation of the Achilles tendon in streptozotocin-induced type 1 diabetic rats. Type 1 diabetes was induced by a single intraperitoneal injection of streptozotocin (60 mg/kg b.wt.). After confirmation of the diabetic state, the rats were divided into four groups; normal control, diabetic control, diabetic + glabridin (40 mg/kg b.wt.), and diabetic + glyburide (5 mg/kg b.wt.) as a positive control group. After 8 weeks of treatment, the Achilles tendons were collected and subjected to histopathological examinations with hematoxylin and eosin, Masson’s trichrome, periodic acid Schiff, and toluidine blue staining. Immunohistochemical staining (IHC) was also performed to study the inflammation of the tendon tissues. Histopathological examinations showed the protective effects of glabridin against hyperglycemia-induced collagen disorganization and deposition of glycoproteins in the extracellular matrix of the tendon. Treatment with glabridin significantly decreased the interfibrillar length, interfibrillar space, and number of infiltrated mast cells in the tendon tissue of diabetic rats. In addition, IHC staining showed that administration of glabridin drastically attenuated advance glycation end products (AGEs) formation and accumulation, and decreased the IL-1β and TNF-α positive stains compared to the non-treated diabetic control group. Taken together, this study showed glabridin prevents architectural alterations and suppresses inflammation in the Achilles tendon of diabetic rats.

 

Keywords: Achilles tendon; collagen fibre; hyperglycemia; inflammation; phytoestrogen

 

Abstrak

Diabetes mellitus merupakan gangguan yang kompleks dan serius dan dicirikan oleh kawalan glisemik yang lemah yang membawa kepada perubahan dan keradangan struktur tendon. Kajian ini bertujuan untuk mengkaji kesan perlindungan glabridin, flavonoid polifenol pada tendon Achilles pada tikus diabetes jenis 1 aruhan streptozotosin. Diabetes jenis 1 diaruh oleh satu suntikan intraperitoneum streptozotosin (60 mg/kg b.wt.). Selepas pengesahan keadaan diabetes, tikus dibahagikan kepada empat kumpulan; kawalan normal, kawalan diabetes, diabetes + glabridin (40 mg/kg b.wt.) dan diabetes + glyburide (5 mg/kg b.wt.) sebagai kumpulan kawalan positif. Selepas 8 minggu rawatan, tendon Achilles dikumpul dan tertakluk kepada pemeriksaan histopatologi dengan hematoksilin dan eosin, trichrome Masson, asid berkala Schiff dan pewarnaan toluidina biru. Pewarnaan imunohistokimia (IHC) juga dilakukan untuk mengkaji keradangan tisu tendon. Pemeriksaan histopatologi menunjukkan kesan perlindungan glabridin terhadap gangguan kolagen aruhan hiperglisemia dan pemendapan glikoprotein dalam matriks ekstrasel tendon. Rawatan dengan glabridin mengurangkan panjang antarafibril, ruang antarafibril dan bilangan sel mast yang menyusup ke dalam tisu tendon tikus diabetes. Di samping itu, pewarnaan IHC menunjukkan bahawa penyuntikan glabridin secara drastik melemahkan pembentukan dan pengumpulan produk akhir glikasi awal (AGEs) dan mengurangkan kesan positif IL-1β dan TNF-α berbanding kumpulan kawalan diabetes yang tidak dirawat. Secara keseluruhan, kajian ini menunjukkan glabridin menghalang perubahan struktur dan menyekat keradangan pada tendon Achilles tikus diabetes.

 

Kata kunci: Fitoestrogen; hiperglisemia; keradangan; serat kolagen; tendon Achilles

 

REFERENCES

Chin, Y.W., Jung, H.A., Liu, Y., Su, B.N., Castoro, J.A., Keller, W.J., Pereira, M.A. & Kinghorn, A.D. 2007. Anti-oxidant constituents of the roots and stolons of licorice (Glycyrrhiza glabra). Journal of Agricultural and Food Chemistry 55: 4691-4697.

El-Ghffar, E.A. Abd. 2016. Ameliorative effect of glabridin, a main component of Glycyrrhiza glabra L. roots in streptozotocin induced Type 1 diabetes in male albino rats. Indian Journal of Traditional Knowledge 15: 570-579.

Fong, D.S., Aiello, L., Gardner, T.W., King, G.L., Blankenship, G., Cavallerano, J.D., Ferris 3^rd, F.L., Klein, R. & American Diabetes Association. 2004. Retinopathy in diabetes. Diabetes Care 27: 84-87.

Gross, J.L., De Azevedo, M.J., Silveiro, S.P., Canani, L.H., Caramori, M.L. & Zelmanovitz, T. 2005. Diabetic nephropathy: Diagnosis, prevention, and treatment. Diabetes Care 28: 164-176.

Guerquin, M.J., Charvet, B., Nourissat, G., Havis, E., Ronsin, O., Bonnin, M.A., Ruggiu, M., Olivera-Martinez, I., Robert, N., Lu, Y., Kadler, K.E., Baumberger, T., Doursounian, L., Berenbaum, F. & Duprez, D. 2013. Transcription factor EGR1 directs tendon differentiation and promotes tendon repair. Journal of Clinical Investigation 123: 3564-3576.

Hunt, J.V., Dean, R.T. & Wolff, S.P. 1988. Hydroxyl radical production and autoxidative glycosylation. Glucose autoxidation as the cause of protein damage in the experimental glycation model of diabetes mellitus and ageing. Biochemical Journal 256: 205-212.

Kim, H.S., Suh, K.S., Ko, A., Sul, D., Choi, D., Lee, S.K. & Jung, W.W. 2013. The flavonoid glabridin attenuates 2-deoxy-D-ribose-induced oxidative damage and cellular dysfunction in MC3T3-E1 osteoblastic cells. International Journal of Molecular Medicine 31: 243-251.

Komolkriengkrai, M., Nopparat, J., Vongvatcharanon, U., Anupunpisit, V. & Khimmaktong, W. 2019. Effect of glabridin on collagen deposition in liver and amelioration of hepatocyte destruction in diabetes rats. Experimental and Therapeutic Medicine 18: 1164-1174.

Kruse, I. & Edelman, S. 2006. Evaluation and treatment of diabetic foot ulcers. Clinical Diabetes 24: 91-93.

Kwon, H.S., Oh, S.M. & Kim, J.K. 2008. Glabridin, a functional compound of liquorice, attenuates colonic inflammation in mice with dextran sulphate sodium-induced colitis. Clinical and Experimental Immunology 151: 165-173.

Lee, J.M. & Veres, S.P. 2019. Advanced glycation end-product cross-linking inhibits biomechanical plasticity and characteristic failure morphology of native tendon. Journal of Applied Physiology 126: 832-841.

Lee, J.W., Choe, S.S., Jang, H., Kim, J., Jeong, H.W., Jo, H., Jeong, K.H., Tadi, S., Park, M.G., Kwak, T.H., Kim, J.M., Hyun, D.H. & Kim, J.B. 2012. AMPK activation with glabridin ameliorates adiposity and lipid dysregulation in obesity. Journal of Lipid Research 53: 1277-1286.

Leung, M., Folkes, G., Ramamurthy, N. & Schneir, M. 1986. Diabetes stimulated procollagen degradation in rat tendon in vitro. Biochimica et Biophysica Acta 880: 147-152.

Liu, K., Pi, F., Zhang, H., Ji, J., Xia, S., Cui, F., Sun, J. & Sun, X. 2017. Metabolomics analysis to evaluate the anti-inflammatory effects of polyphenols: Glabridin reversed metabolism change caused by LPS in RAW 264.7 cells. Journal of Agricultural and Food Chemistry 65: 6070-6079.

Li, Y., Fessel, G., Georgiadis, M. & Snedeker, J.G. 2013. Advanced glycation end-products diminish tendon collagen fiber sliding. Matrix Biology 32: 169-177.

Madhusudhanan, J., Suresh, G. & Devanathan, V. 2020. Neurodegeneration in type 2 diabetes: Alzheimer's as a case study. Brain and Behavior 10: e01577.

Maher, P. & Hanneken, A. 2005. Flavonoids protect retinal ganglion cells from oxidative stress-induced death. Investigative Ophthalmology & Visual Science 46: 4796-4803.

Maksoud, H.A., Magid, A.D.A., Mostafa, Y., Elharrif, M.G., Sorour, R.I. & Sorour, M.I. 2019. Ameliorative effect of liquorice extract versus silymarin in experimentally induced chronic hepatitis: A biochemical and genetical study. Clinical Nutrition Experimental 23: 69-79.

Ma, H., Ren, H., Wang, J., Yuan, X., Wu, X. & Shi, X. 2021. Targeting PI3K/Akt/Nrf2 pathway by glabridin alleviates acetaminophen-induced hepatic injury in rats. Arabian Journal of Chemistry 14: 102968.

McCreesh, K. & Lewis, J. 2013. Continuum model of tendon pathology - where are we now?. International Journal of Experimental Pathology 94: 242-247.

Mohamed, J., Nafizah, A.N., Zariyantey, A. & Budin, S. 2016. Mechanisms of diabetes-induced liver damage: The role of oxidative stress and inflammation. Sultan Qaboos University Medical Journal 16: e132.

Nopparat, J., Nualla-ong, A. & Phongdara, A. 2019. Ethanolic extracts of Pluchea indica (L.) leaf pretreatment attenuates cytokine-induced β-cell apoptosis in multiple low-dose streptozotocin-induced diabetic mice. PLoS ONE 14: e0212133.

Obafemi, T., Akinmoladun, A., Olaleye, M., Agboade, S.O. & Onasanya, A.A. 2017.  Antidiabetic potential of methanolic and flavonoid-rich leaf extracts of Synsepalum dulcificum in type 2 diabetic rats. Journal of Ayurveda and Integrative Medicine 8: 238-246.

Peluso, I., Miglio, C., Morabito, G., Ioannone, F. & Serafini, M. 2015. Flavonoids and immune function in human: A systematic review. Critical Reviews in Food Science and Nutrition 55: 383-395.

Rao, S.R., Saltzman, C.L., Wilken, J. & Yak, H.J. 2006. Increased passive ankle stiffness and reduced dorsiflexion range of motion in individuals with diabetes mellitus. Foot and Ankle International 27: 617-622.

Rice-Evans, C.A., Miller, N.J. & Paganga, G. 1996. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radical Biology and Medicine 20: 933-956.

Sawada, K., Yamashita, Y., Zhang, T., Nakagawa, K. & Ashida, H. 2014. Glabridin induces glucose uptake via the AMP-activated protein kinase pathway in muscle cells. Molecular and Cellular Endocrinology 393: 99-108.

Shaik, Y., Caraffa, A., Ronconi, G., Lessiani, G. & Conti, P. 2018. Impact of polyphenols on mast cells with special emphasis on the effect of quercetin and luteolin. Central European Journal of Immunology 43: 476-481.

Simmler, C., Pauli, G.F. & Chen, S.N. 2013. Phytochemistry and biological properties of glabridin. Fitoterapia 90: 160-184.

Singh, V.P., Bali, A., Singh, N. & Jaggi, A.S. 2014. Advanced glycation end products and diabetic complications. Korean Journal of Physiology and Pharmacology 18: 1-14.

Somjen, D., Knoll, E., Vaya, J., Stern, N. & Tamir, S. 2004. Estrogen-like activity of licorice root constituents: Glabridin and glabrene, in vascular tissues in vitro and in vivo. Journal of Steroid Biochemistry and Molecular Biology 91: 147-155.

Song, C.H., Kim, N., Kim, D.H., Lee, H.N. & Surh, Y.J. 2019. 17-β estradiol exerts anti-inflammatory effects through activation of Nrf2 in mouse embryonic fibroblasts. PLoS ONE 14(8): e0221650.

Spanheimer, R.G. 1992. Correlation between decreased collagen production in diabetic animals and in cells exposed to diabetic serum: response to insulin. Matrix 12: 101-107.

Vaya, J., Belinky, P.A. & Aviram, M. 1997. Antioxidant constituents from licorice roots: Isolation, structure elucidation and antioxidative capacity toward LDL oxidation. Free Radical Biology and Medicine 23: 302-313.

Wongdee, K. & Charoenphandhu, N. 2011. Osteoporosis in diabetes mellitus: Possible cellular and molecular mechanisms. World Journal of Diabetes 2: 41-48

Wu, F., Jin, Z. & Jin, J. 2013. Hypoglycemic effects of glabridin, a polyphenolic flavonoid from licorice, in an animal model of diabetes mellitus. Molecular Medicine Reports 7: 1278-1282.

Wu, Y.F., Wang, H.K., Chang, H.W., Sun, J., Sun, J.S. & Chao, Y.H. 2017. High glucose alters tendon homeostasis through downregulation of the AMPK/Egr1 pathway. Scientific Reports 7: 1-12.

 

^*Corresponding author; email: chittipong.t@psu.ac.th