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PPAR-Gamma as putative gene target involved in Butein mediated anti-diabetic effect

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Abstract

Type 2 diabetes mellitus (T2DM) is a metabolic disorder caused due to varied genetic and lifestyle factors. The search for a potential natural compound to enhance the treatment of diabetes is the need of the hour. Butein, a flavonoid, found sufficiently in Faba bean, is said to possess an anti-diabetic property. In-silico analysis, Butein is predicted as a potential anti-diabetic compound, due to its regulatory action on PPAR-Gamma. Based on this evidence, the Butein’s anti-diabetic action is studied in diabetic induced rat models. The drug property of Butein is studied through in-silico analysis to determine the metabolic properties. In animal models, the biochemical analysis, histopathological and gene expression against PPAR-Gamma were studied comparatively. Butein being a hydrophobic compound, the bioavailability is said to be minimum. Hence, Butein formulation was made using biopolymer Chitosan for the synergistic anti-diabetic action. The Butein Chitosan formulation was optimized and characterized using analytical techniques. Further, the anti-diabetic activity of Butein and Butein Chitosan formulation was studied in diabetic induced rats. The obtained in-silico analysis results showed that Butein is the most favorable drug. Apparently, in the rat model, Butein and Butein Chitosan formulation effectively controlled the blood glucose levels without any side effects. The histopathological observations of the tissue samples showed nontoxic activity. Additionally, the gene expression analysis predicted the possible mechanism of anti-diabetic action exhibited through the down regulation of PPAR-Gamma. Whereas, the Butein Chitosan formulation failed, to show synergetic anti-diabetic activity as expected. This study is vital in introducing Butein as a safe anti-diabetic compound, which can be used in the treatment of T2DM.

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References

  1. Cho NH, Shaw JE, Karuranga S et al (2018) IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 138:271–281. https://doi.org/10.1016/j.diabres.2018.02.023

    Article  CAS  PubMed  Google Scholar 

  2. Calderón-Salinas JV, Muñoz-Reyes EG, Guerrero-Romero JF et al (2011) Eryptosis and oxidative damage in type 2 diabetic mellitus patients with chronic kidney disease. Mol Cell Biochem 357:171–179. https://doi.org/10.1007/s11010-011-0887-1

    Article  CAS  PubMed  Google Scholar 

  3. Ahlqvist E, Van Zuydam NR, Groop LC, McCarthy MI (2015) The genetics of diabetic complications. Nat Rev Nephrol 11:277–287

    Article  CAS  Google Scholar 

  4. Seko Y, Sumida Y, Tanaka S et al (2018) Insulin resistance increases the risk of incident type 2 diabetes mellitus in patients with non-alcoholic fatty liver disease. Hepatol Res 48:E42–E51. https://doi.org/10.1111/hepr.12925

    Article  CAS  PubMed  Google Scholar 

  5. Rani R, Dahiya S, Dhingra D et al (2017) European journal of pharmaceutical sciences evaluation of anti-diabetic activity of glycyrrhizin-loaded nanoparticles in nicotinamide-streptozotocin-induced diabetic rats. Eur J Pharm Sci 106:220–230. https://doi.org/10.1016/j.ejps.2017.05.068

    Article  CAS  PubMed  Google Scholar 

  6. Patel B, Oza B, Patel K et al (2013) Pattern of antidiabetic drugs use in type-2 diabetic patients in a medicine outpatient clinic of a tertiary care teaching hospital. Int J Basic Clin Pharmacol 2:485. https://doi.org/10.5455/2319-2003.ijbcp20130826

    Article  CAS  Google Scholar 

  7. Azoulay L, Filion KB, Platt RW et al (2016) Incretin based drugs and the risk of pancreatic cancer: International multicentre cohort study. BMJ. https://doi.org/10.1136/bmj.i581

    Article  PubMed  PubMed Central  Google Scholar 

  8. Häggström C, Van Hemelrijck M, Zethelius B et al (2017) Prospective study of Type 2 diabetes mellitus, anti-diabetic drugs and risk of prostate cancer. Int J Cancer 140:611–617. https://doi.org/10.1002/ijc.30480

    Article  CAS  PubMed  Google Scholar 

  9. Bahmani M, Zargaran A, Rafieian-Kopaei M, Saki K (2014) Ethnobotanical study of medicinal plants used in the management of diabetes mellitus in the Urmia, Northwest Iran. Asian Pac J Trop Med 7:S348–S354. https://doi.org/10.1016/S1995-7645(14)60257-1

    Article  Google Scholar 

  10. James P, Davis SP, Ravisankar V et al (2017) Novel antidiabetic molecules from the medicinal plants of Western Ghats of India, identified through wide-spectrum in silico analyses. J Herbs Spices Med Plants 23:249–262. https://doi.org/10.1080/10496475.2017.1315675

    Article  CAS  Google Scholar 

  11. Xie JH, Jin ML, Morris GA et al (2016) Advances on bioactive polysaccharides from medicinal plants. Crit Rev Food Sci Nutr 56:S60–S84. https://doi.org/10.1080/10408398.2015.1069255

    Article  CAS  PubMed  Google Scholar 

  12. Kooti W, Farokhipour M, Asadzadeh Z et al (2016) The role of medicinal plants in the treatment of diabetes: a systematic review. Electron Phys 8:1832–1842

    Article  Google Scholar 

  13. Madar Z, Stark AH (2002) New legume sources as therapeutic agents. Br J Nutr 88:287–292. https://doi.org/10.1079/bjn2002719

    Article  Google Scholar 

  14. Abd El-Maksoud H, Hussein MA, Kassem A (2013) Biochemical effect of vicine and divicine extracted from fava beans (vicia faba) in rats. Benha Vet Med J 24:98–110

    Google Scholar 

  15. Lin PY, Lai HM (2006) Bioactive compounds in legumes and their germinated products. J Agric Food Chem 54:3807–3814. https://doi.org/10.1021/jf060002o

    Article  CAS  PubMed  Google Scholar 

  16. Siddhuraju P, Manian S (2007) The antioxidant activity and free radical-scavenging capacity of dietary phenolic extracts from horse gram (Macrotyloma uniflorum (Lam.) Verdc.) seeds. Food Chem 105:950–958. https://doi.org/10.1016/j.foodchem.2007.04.040

    Article  CAS  Google Scholar 

  17. Muzquiz M, Varela A, Burbano C et al (2012) Bioactive compounds in legumes: Pronutritive and antinutritive actions. implications for nutrition and health. Phytochem Rev 11:227–244. https://doi.org/10.1007/s11101-012-9233-9

    Article  CAS  Google Scholar 

  18. Vessal M, Hemmati M, Vasei M (2003) Antidiabetic effects of quercetin in streptozocin-induced diabetic rats. Comp Biochem Physiol C 135C:357–364. https://doi.org/10.1016/s1532-0456(03)00140-6

    Article  CAS  Google Scholar 

  19. Baginsky C, Peña-Neiraálvaro CA et al (2013) Phenolic compound composition in immature seeds of fava bean (Vicia faba L.) varieties cultivated in Chile. J Food Compos Anal 31:1–6. https://doi.org/10.1016/j.jfca.2013.02.003

    Article  CAS  Google Scholar 

  20. El-Mergawi R, Taie HAA (2014) Phenolic composition and antioxidant activity of raw seeds, green seeds and sprouts of ten faba bean (Vicia faba) cultivars consumed in Egypt. Int J Pharm Biol Sci

  21. Kumar A, Nidhi PN, Sinha SK (2014) Nutritional and antinutritional attributes of faba bean (Vicia faba L.) germplasms growing in Bihar. India Physiol Mol Biol Plants 21:159–162. https://doi.org/10.1007/s12298-014-0270-2

    Article  CAS  PubMed  Google Scholar 

  22. Semwal RB, Semwal DK, Combrinck S, Viljoen A (2015) Butein: from ancient traditional remedy to modern nutraceutical. Phytochem Lett 11:188–201. https://doi.org/10.1016/j.phytol.2014.12.014

    Article  CAS  Google Scholar 

  23. Prabhu DS, Rajeswari VD (2018) In vitro and in silico analyses of Vicia faba L. on peroxisome proliferator–activated receptor gamma. J Cell Biochem 119:7729–7737. https://doi.org/10.1002/jcb.27123

    Article  CAS  PubMed  Google Scholar 

  24. Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. https://doi.org/10.1038/srep42717

    Article  PubMed  PubMed Central  Google Scholar 

  25. Maunz A, Gütlein M, Rautenberg M et al (2013) Lazar: a modular predictive toxicology framework. Front Pharmacol 4:38. https://doi.org/10.3389/fphar.2013.00038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Masalova O, Kulikouskaya V, Shutava T, Agabekov V (2013) Alginate and chitosan gel nanoparticles for efficient protein entrapment. In: Physics procedia, pp 69–75

  27. Chandy T, Mooradian DL, Rao GHR (1998) Chitosan/polyethylene glycol-alginate microcapsules for oral delivery of hirudin. J Appl Polym Sci 70:2143–2153

    Article  CAS  Google Scholar 

  28. Radhakrishnan A, Jose GM, Kurup M (2015) PEG-penetrated chitosan–alginate co-polysaccharide-based partially and fully cross-linked hydrogels as ECM mimic for tissue engineering applications. Prog Biomater 4:101–112. https://doi.org/10.1007/s40204-015-0041-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kamboj S, Saini V, Bala S (2014) Formulation and characterization of drug loaded nonionic surfactant vesicles (Niosomes) for oral bioavailability enhancement. Sci World J. https://doi.org/10.1155/2014/959741

    Article  Google Scholar 

  30. Masiello P, Broca C, Gross R et al (1998) Experimental NIDDM: development of a new model in adult rats administered streptozotocin and nicotinamide. Diabetes 47:224–229. https://doi.org/10.2337/diab.47.2.224

    Article  CAS  PubMed  Google Scholar 

  31. Szkudelski T (2012) Streptozotocin-nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Exp Biol Med 237:481–490

    Article  CAS  Google Scholar 

  32. Prabhu S, Vinodhini S, Elanchezhiyan C, Rajeswari D (2018) Evaluation of antidiabetic activity of biologically synthesized silver nanoparticles using Pouteria sapota in streptozotocin-induced diabetic rats. J Diabetes 10:28–42. https://doi.org/10.1111/1753-0407.12554

    Article  CAS  PubMed  Google Scholar 

  33. Prabhu DS, Rajeswari VD (2018) In vitro and in silico analyses of Vicia faba L. on Peroxisome proliferator-activated receptor gamma. J Cell Biochem 119:7729–7737. https://doi.org/10.1002/jcb.27123

    Article  CAS  PubMed  Google Scholar 

  34. International Diabetes Federation - Home. https://idf.org/. Accessed 20 Jan 2020

  35. Paul E, Cherniack EP (2010) The potential influence of plant polyphenols on the aging process. Forsch Komplementmed 17:181–187. https://doi.org/10.1159/000319143

    Article  Google Scholar 

  36. Sharma M, Sharma R, Jain DK (2016) Nanotechnology based approaches for enhancing oral bioavailability of poorly water soluble antihypertensive drugs. Scientifica (Cairo)

  37. Uppal S, Italiya KS, Chitkara D, Mittal A (2018) Nanoparticulate-based drug delivery systems for small molecule anti-diabetic drugs: an emerging paradigm for effective therapy. Acta Mater Inc

  38. Campos EJ, Campos A, Martins J, Ambrósio AF (2017) Opening eyes to nanomedicine: where we are, challenges and expectations on nanotherapy for diabetic retinopathy. Nanomed Nanotechnol Biol Med 13:2101–2113. https://doi.org/10.1016/j.nano.2017.04.008

    Article  CAS  Google Scholar 

  39. Biradar S, Ravichandran P, Gopikrishnan R, et al (2011) Calcium carbonate nanoparticles: synthesis, characterization and biocompatibility. J Nanosci Nanotechnol. pp 6868–6874

  40. Woitiski CB, Neufeld RJ, Veiga F et al (2010) Pharmacological effect of orally delivered insulin facilitated by multilayered stable nanoparticles. Eur J Pharm Sci 41:556–563. https://doi.org/10.1016/j.ejps.2010.08.009

    Article  CAS  PubMed  Google Scholar 

  41. Arunagiri A, Safdar R, Thanabalan M et al (2018) Potential of Chitosan and its derivatives for controlled drug release applications—a review. J Drug Deliv Sci Technol 49:642–659. https://doi.org/10.1016/j.jddst.2018.10.020

    Article  CAS  Google Scholar 

  42. Wong CY, Al-Salami H, Dass CR (2018) Microparticles, microcapsules and microspheres: a review of recent developments and prospects for oral delivery of insulin. Int J Pharm 537:223–244. https://doi.org/10.1016/j.ijpharm.2017.12.036

    Article  CAS  PubMed  Google Scholar 

  43. Patel DK, Kumar R, Laloo D, Hemalatha S (2012) Diabetes mellitus: an overview on its pharmacological aspects and reported medicinal plants having antidiabetic activity. Asian Pac J Trop Biomed 2:411–420

    Article  CAS  Google Scholar 

  44. Mahapatra DK, Asati V, Bharti SK (2015) Chalcones and their therapeutic targets for the management of diabetes: structural and pharmacological perspectives. Eur J Med Chem 92:839–865

    Article  CAS  Google Scholar 

  45. Hasani-Ranjbar S, Jouyandeh Z, Abdollahi M (2013) A systematic review of anti-obesity medicinal plants—an update. J Diabetes Metab Disord 12:1. https://doi.org/10.1186/2251-6581-12-28

    Article  Google Scholar 

  46. Song NJ, Yoon HJ, Kim KH et al (2013) Butein is a novel anti-adipogenic compound. J Lipid Res 54:1385–1396. https://doi.org/10.1194/jlr.M035576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Larsen TM, Toubro S, Astrup A (2003) PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy? Int J Obes 27:147–161

    Article  CAS  Google Scholar 

  48. Barroso I, Gurnell M, Crowley VEF et al (1999) Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402:880–883. https://doi.org/10.1038/47254

    Article  CAS  PubMed  Google Scholar 

  49. Padmavathi G, Roy NK, Bordoloi D et al (2017) Butein in health and disease: a comprehensive review. Phytomedicine 25:118–127

    Article  CAS  Google Scholar 

  50. Ahad A, Mujeeb M, Ahsan H, Siddiqui WA (2014) Prophylactic effect of baicalein against renal dysfunction in type 2 diabetic rats. Biochimie 106:101–110. https://doi.org/10.1016/j.biochi.2014.08.006

    Article  CAS  PubMed  Google Scholar 

  51. Gong Z, Huang C, Sheng X et al (2009) The role of tanshinone IIA in the treatment of obesity through peroxisome proliferator-activated receptor γ antagonism. Endocrinology 150:104–113. https://doi.org/10.1210/en.2008-0322

    Article  CAS  PubMed  Google Scholar 

  52. Frkic RL, Marshall AC, Blayo AL et al (2018) PPARγ in complex with an antagonist and inverse agonist: a tumble and trap mechanism of the activation helix. IScience 5:69–79. https://doi.org/10.1016/j.isci.2018.06.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The author thanks VIT for providing all the research facilities and support to carry out the research process.

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  1. Department of Biomedical Sciences, School of Biosciences and Technology, VIT, Vellore, Tamil Nadu, 632 014, India

    D. Sathya Prabhu & V. Devi Rajeswari

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  1. D. Sathya Prabhu
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Correspondence to V. Devi Rajeswari.

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The study is approved by the Institutional Animal Ethics Committee (IAEC) at VIT (VIT/IAEC/14th/Nov4/15). The study is carried out according to the guidelines advocated by the Committee for the Purpose of Supervision and Control of Experiments on Animals (CPSCEA), Government of India.

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Prabhu, D.S., Rajeswari, V.D. PPAR-Gamma as putative gene target involved in Butein mediated anti-diabetic effect. Mol Biol Rep 47, 5273–5283 (2020). https://doi.org/10.1007/s11033-020-05605-1

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