Network pharmacology-based assessment to elucidate the molecular mechanism of anti-diabetic action of Tinospora cordifolia

Springer Science and Business Media LLC - Tập 5 - Trang 1-9 - 2019
Pukar Khanal1, B. M. Patil1, Bijendra K. Mandar1, Yadu Nandan Dey2, Taaza Duyu1
1Department of Pharmacology and Toxicology, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research (KAHER), Belagavi, India
2ICMR-National Institute of Traditional Medicine, Belagavi, India

Tóm tắt

Tinospora cordifolia is used traditionally for the treatment of diabetes and is used in various formulations. Scientific evidence is also available for its anti-diabetic potency under various animal models. However, the probable molecular mechanism of Tinospora cordifolia in the treatment of diabetes has not been illuminated yet. Hence, the present study dealt to elucidate the probable molecular mechanism of anti-diabetic effect of Tinospora cordifolia using network pharmacology approach. The structural information of bioactive phytoconstituents was retrieved from different open source databases. Compounds were then predicted for their hits with the probable targets involved in the diabetes mellitus. Phytoconstituents were also predicted for their druglikeness score, probable side effects, and ADMET profile. The modulated protein pathways were identified by using the Kyoto Encyclopedia of Genes and Genomes pathway analysis. The interaction between the compounds, proteins, and pathways was interpreted based on the edge count. The docking study was performed using Autodock4.0. Nine phytoconstituents from Tinospora cordifolia were identified to modulate the pathogenic protein molecules involved in diabetes mellitus. Among them, tembetarine scored highest druglikeness hit and had the maximum interaction with proteins involved in diabetes. Further, neuroactive ligand-receptor interaction was predicted as majorly modulated pathway. The current study identified an important antidiabetic constituent, tembetarine which modulated the majority of diabetic proteins majorly modulating neuroactive ligand-receptor interaction.

Tài liệu tham khảo

Prabhakar PK, Doble M. Effect of natural products on commercial oral antidiabetic drugs in enhancing 2-deoxyglucose uptake by 3T3-L1 adipocytes. Ther Adv Endocrinol Metab. 2011;2:103–4. Chaudhury A, Duvoor C, Dendi R, Sena V, Kraleti S, Chada A, Ravilla R, Marco A, Shekhawat NS, Montales MT, Kuriakose K. Clinical review of antidiabetic drugs: implications for type 2 diabetes mellitus management. Front Endocrinol. 2017;8:6. Sacks DB, McDonald JM. The pathogenesis of type II diabetes mellitus: a polygenic disease. Am J Clin Pathol. 1996;105:149–56. Chandran U, Mehendale N, Tillu G, Patwardhan B. Network pharmacology of ayurveda formulation Triphala with special reference to anti-cancer property. Comb Chem High Throughput Screen. 2015;18:846–54. Choudhury H, Pandey M, Hua CK, Mun CS, Jing JK, Kong L, Ern LY, Ashraf NA, Kit SW, Yee TS, Pichika MR. An update on natural compounds in the remedy of diabetes mellitus: a systematic review. J Tradit Complement Med. 2018;8:361–76. Rao VP, Madhavi K, Naidu DM, Gan SH. Rhinacanthus nasutus improves the levels of liver carbohydrate, protein, glycogen, and liver markers in streptozotocin-induced diabetic rats. Evid Based Complement Alternat Med. 2013;2013:102901. Li WL, Zheng HC, Bukuru J, De Kimpe N. Natural medicines used in the traditional chinese medical system for therapy of diabetes mellitus. J Ethnopharmacol. 2004;92:1–21. Chen J, Mangelinckx S, Adams A, Wang ZT, Li WL, De Kimpe N. Natural flavonoids as potential herbal medication for the treatment of diabetes mellitus and its complications. Nat Prod Commun. 2015;10:187–200. The Ayurvedic Pharmacopoeia of India. Ministry of Health and Family Welfare, Department of AYUSH. Government of India. 2016;Part-1, Volume −1:53. Sharma R, Amin H, Prajapati PK. Antidiabetic claims of Tinospora cordifolia (wild.) Miers: critical appraisal and role in therapy. Asian Pac J Trop Biomed. 2015;5:68–78. Puranik N, Kammar KF, Devi S. Anti-diabetic activity of Tinospora cordifolia (Willd.) in streptozotocin diabetic rats; does it act like sulfonylureas? Turkish J Med Sci. 2010;40:265–70. Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han L, He J, He S, Shoemaker BA, Wang J. PubChem substance and compound databases. Nucleic Acids Res. 2015;44:D1202–13. Gilson MK, Liu T, Baitaluk M, Nicola G, Hwang L, Chong J. BindingDB in 2015: a public database for medicinal chemistry, computational chemistry and systems pharmacology. Nucleic Acids Res. 2016;44:D1045–53. Li YH, Yu CY, Li XX, Zhang P, Tang J, Yang Q, Fu T, Zhang X, Cui X, Tu G, Zhang Y. Therapeutic target database update 2018: enriched resource for facilitating bench-to-clinic research of targeted therapeutics. Nucleic Acids Res. 2017;46:D1121–7. Consortium U. The universal protein resource (UniProt). Nucleic Acids Res. 2007;36:D190–5. Yang H, Lou C, Sun L, Li J, Cai Y, Wang Z, Li W, Liu G, Tang Y. admetSAR 2.0: web-service for prediction and optimization of chemical ADMET properties. Bioinformatics. 2018;35:1067–9. Ivanov SM, Lagunin AA, Rudik AV, Filimonov DA, Poroikov VV. ADVERPred-web service for prediction of adverse effects of drugs. J Chem Inf Model. 2017;58:8–11. Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT, Roth A, Bork P, Jensen LJ. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2016;45:D362–8. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–504. Halgren TA. Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J Comput Chem. 1996;17:490–519. Systèmes D. BIOVIA discovery studio modeling environment. San Diego: Dassault Systèmes Biovia; 2016. Schwede T, Kopp J, Guex N, Peitsch MC. SWISS-MODEL: an automated protein homology-modeling server. Nucleic Acids Res. 2003;31:3381–5. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem. 1998;19:1639–62. Khanal P, Patil BM. Gene set enrichment analysis of alpha-glucosidase inhibitors from Ficus benghalensis. Asian Pac J Trop Biomed. 2019;9:263–70. Sidders B, Karlsson A, Kitching L, Torella R, Karila P, Phelan A. Network-based drug discovery: coupling network pharmacology with phenotypic screening for neuronal excitability. J Mol Biol. 2018;430:3005–15. Zhang GB, Li QY, Chen QL, Su SB. Network pharmacology: a new approach for chinese herbal medicine research. Evid Based Complement Alternat Med. 2013;2013:621423. Kumar V, Mahdi F, Singh R, Mahdi AA, Singh RK. A clinical trial to assess the antidiabetic, antidyslipidemic and antioxidant activities of Tinospora cordifolia in management of type-2 diabetes mellitus. Int J Pharm Sci Res. 2016;7:757–64. Grover JK, Yadav S, Vats V. Medicinal plants of India with anti-diabetic potential. J Ethnopharmacol. 2002;81:81–100. Vicchi FL, Luque GM, Brie B, Nogueira JP, Tornadu IG, Becu-Villalobos D. Dopaminergic drugs in type 2 diabetes and glucose homeostasis. Pharmacol Res. 2016;109:74–80. Oh CM, Park S, Kim H. Serotonin as a new therapeutic target for diabetes mellitus and obesity. Diabetes Metab J. 2016;40:89–98. Forouhi NG, Misra A, Mohan V, Taylor R, Yancy W. Dietary and nutritional approaches for prevention and management of type 2 diabetes. BMJ. 2018;361:k2234. Reddy SS, Ramatholisamma P, Karuna R, Saralakumari D. Preventive effect of Tinospora cordifolia against high-fructose diet-induced insulin resistance and oxidative stress in male Wistar rats. Food Chem Toxicol. 2009;47:2224–9. Nadig PD, Revankar RR, Dethe SM, Narayanswamy SB, Aliyar MA. Effect of Tinospora cordifolia on experimental diabetic neuropathy. Indian J Pharmacol. 2012;44:580–3. KEGG Pathway. Pathway Entry: hsa04080. [Internet]. (Accessed on 23 Feb 2019) https://www.genome.jp/dbget-bin/www_bget?hsa04080 German JP, Wisse BE, Thaler JP, Oh S, Sarruf DA, Ogimoto K, Kaiyala KJ, Fischer JD, Matsen ME, Taborsky GJ, Schwartz MW. Leptin deficiency causes insulin resistance induced by uncontrolled diabetes. Diabetes. 2010;59:1626–34. Denroche HC, Huynh FK, Kieffer TJ. The role of leptin in glucose homeostasis. J Diabetes Investig. 2012;3:115–29. KEGG Pathway. Pathway Entry: map 04960. [Internet]. (Accessed on 23 Feb 2019) https://www.genome.jp/dbget-bin/www_bget?pathway:map04960 Kennedy BP. Role of protein tyrosine phosphatase-1B in diabetes and obesity. Biomed Pharmacother. 1999;53:466–70. Colbert CL, Kim CW, Moon YA, Henry L, Palnitkar M, McKean WB, Fitzgerald K, Deisenhofer J, Horton JD, Kwon HJ. Crystal structure of spot 14, a modulator of fatty acid synthesis. Proc Natl Acad Sci U S A. 2010;107:18820–5. Patel MB, Mishra S. Hypoglycemic activity of alkaloidal fraction of Tinospora cordifolia. Phytomedicine. 2011;18:1045–52. Kalekar SA, Munshi RP, Bhalerao SS, Thatte UM. Insulin sensitizing effect of 3 Indian medicinal plants: an in vitro study. Indian J Pharmacol. 2013;45:30–3. Sangeetha MK, Raghavendran HR, Gayathri V, Vasanthi HR. Tinospora cordifolia attenuates oxidative stress and distorted carbohydrate metabolism in experimentally induced type 2 diabetes in rats. J Nat Med. 2011;65:544–50. Wang J, Song Y, Wang Q, Kralik PM, Epstein PN. Causes and characteristics of diabetic cardiomyopathy. Rev Diabet Stud. 2006;3:108–17. Myagmar BE, Flynn JM, Cowley PM, Swigart PM, Montgomery MD, Thai K, Nair D, Gupta R, Deng DX, Hosoda C, Melov S. Adrenergic receptors in individual ventricular myocytes: the beta-1 and alpha-1b are in all cells, the alpha-1a is in a subpopulation, and the beta-2 and beta-3 are mostly absent. Circ Res. 2017;120:1103–15. MacLennan DH, Kranias EG. Calcium: Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol. 2003;4:566–77. Sandoo A, van Zanten JJ, Metsios GS, Carroll D, Kitas GD. The endothelium and its role in regulating vascular tone. Open Cardiovasc Med J. 2010;4:302–12. Wang J, Cheng J, Zhang C, Li X. Cardioprotection effects of sevoflurane by regulating the pathway of neuroactive ligand-receptor interaction in patients undergoing coronary artery bypass graft surgery. Comput Math Methods Med. 2017;2017:3618213. Sharma AK, Kishore K, Sharma D, Srinivasan BP, Agarwal SS, Sharma A, Singh SK, Gaur S, Jatav VS. Cardioprotective activity of alcoholic extract of Tinospora cordifolia (Wild.) Miers in calcium chloride-induced cardiac arrhythmia in rats. J Biomed Res. 2011;25:280–6. Rao PR, Kumar VK, Viswanath RK, Subbaraju GV. Cardioprotective activity of alcoholic extract of Tinospora cordifolia in ischemia-reperfusion induced myocardial infarction in rats. Biol Pharm Bull. 2005;28:2319–22.