Elsevier

Phytomedicine

Volume 21, Issue 11, 25 September 2014, Pages 1237-1248
Phytomedicine

In vivo anti-diabetic, antioxidant and molecular docking studies of 1, 2, 8-trihydroxy-6-methoxy xanthone and 1, 2-dihydroxy-6-methoxyxanthone-8-O-β-d-xylopyranosyl isolated from Swertia corymbosa

https://doi.org/10.1016/j.phymed.2014.06.011Get rights and content

Abstract

1, 2, 8-trihydroxy-6-methoxy xanthone (1) and 1, 2- dihydroxy-6-methoxyxanthone-8-O-β-d-xylopyranosyl (2) are the main constituents of petroleum ether and ethyl acetate extracts from Swertia corymbosa (Gentinaceae), a medicinal plant used in Indian traditional system for the treatment of diabetes. The present study was designed to examine the antihypoglycemic, antihyperlipidemic and antioxidant effect of compounds 1 and 2 in streptozotocin (STZ) induced diabetic rats. Diabetes was induced in male Wistar rats by a single intraperitoneal injection of STZ (60 mg/kg b.w.). The isolated compounds 1 and 2 at a dose of 50 mg/kg b.w., produced the maximum fall of 83% in the blood glucose level in the diabetic rats after 3 h of the treatment. The administration of 1 and 2 (50 mg/kg b.w.) daily for 28 days in STZ induced diabetic rats, resulted in a significant decrease in blood glucose, glycosylated hemoglobin, SGOT, SGPT, ALP serum urea and creatinine with significant rise in plasma insulin level. Test compounds 1 and 2 showed antihyperlipidemic activities as evidenced by significant decrease in serum TC, TG, LDL-C, VLDL-C levels coupled together with elevation of HDL-C level in diabetic treated rats when compared to diabetic untreated rats, indicate the protective role against liver and kidney damage. The results of histopathology also showed 1 and 2 protected tissues (pancreas, liver and kidney) against peroxidation damage and maintained tissue integrity. Further, the molecular interaction study of the ligands 1, 2 and glibenclamide with various diabetes mellitus related protein targets like glucokinase (PDB ID: 1V4S), fructose-1, 6-bisphosphatase 1 (PDB ID: 2JJK) 11-β-hydroxysteroid dehydrogenase (PDB ID: 2BEL) and modeled protein sulfonylurea receptor 1 (SUR1) showed that ligand 1 and 2 possess binding affinity with all protein targets except for 2BEL target protein for which ligand 1 has no interaction. The ligand pose with 2BEL and SUR1 protein target of ligand 2 gave the best binding conformation. Hence 1 and 2 can be considered for developing into a potent antidiabetic drug.

Introduction

Diabetes mellitus is caused by an abnormal carbohydrate metabolism and mainly linked to abnormal blood insulin levels or insensitivity of target organs to insulin (Hahm et al. 2011). According to the International Diabetes Federation (IDF), the global prevalence of diabetes is predicted to grow from 366 million in 2011 to 552 million by 2030 (IDF 2011). The major part of this numerical increase will occur in Asia, mainly China and India (57 million in India) (Liu et al., 2013, Mahendran et al., 2014a). Diabetes mellitus is a group of diseases characterized by chronic hyperglycemia due to deficiency of insulin action. The deficiency of insulin action, a common basis of diabetes, leads to characteristic abnormalities in the metabolism of carbohydrate, lipid, protein and so on (Kuzuya et al. 2002). Although different hypoglycemic drugs have been synthesized for the treatment of diabetes mellitus, many synthetic drugs have a number of serious side effects (May et al. 2002). Management of hyperglycemia with minimal side effects in clinical experience and relatively low costs is still a challenge to the medical system (Sun et al. 2008). Comparatively low side-effects and low cost, phytochemicals from natural resources open new avenues for the treatment of various diseases including diabetes (Li et al. 2011).

The genus Swertia (Gentinaceae) comprises a group of more than 170 different species, are mainly distributed in Asia, Africa and North America. Swertia corymbosa Wight ex C.B. Clarke is a well known medicinal plant and all parts of this plant have been employed for the treatment of diarrhea, fever, jaundice, diabetic, inflammation and nervous disorders in Indian traditional systems of medicine. Medicinal value especially anti-diabetic property of S. corymbosa is well recorded in traditional literature (Abraham, 1981, Oudhia, 2012). Recently pharmacological studies showed that its extensive biological activities such as antioxidant, anti-proliferative, anti-inflammatory, anti-diabetic, anticonvulsant, sedative and anxiolytic (Mahendran and NarmathaBai, 2013a, Mahendran and NarmathaBai, 2013b, Mahendran et al., 2014a, Mahendran et al., 2014b). And our recently published study showed that the xanthones in Swertia corymbosa display anti-inflammatory and anti-nociceptive activities (Mahendran et al. 2013). Some plants in the Swertia genus, like Swertia japonica (Basnet et al. 1994) Swertia chirayita (Chandrasekar et al., 1990, Kar et al., 2003, Saxena et al., 2007, Renu et al., 2011) Swertia punicea (Pen and Fang, 2003, Tian et al., 2010) Swertia minor (Selvameena et al. 2011), Swertia kouitchensis (Wan et al. 2013) Swertia macrosperma (Wang et al. 2013) and Swertia corymbosa (Mahendran et al. 2014a) have been reported for their anti-diabetic activity. In recent years, a certain number xanthones have been proved effective with diabetes, such as mangiferin, bellidifolin and methylswertianin (Muruganandan et al., 2005, Tian et al., 2010). However, there is still no direct scientific report of Swertia corymbosa for its anti-diabetic active constitutions. We traced the active constituents of the petroleum ether and ethyl acetate fraction using bioassay-guided fractionation and isolation procedures and found the two xanthones, 1, 2, 8-trihydroxy-6-methoxy xanthone (1) and 1, 2-dihydroxy-6-methoxyxanthone-8-O-β-d-xylopyranosyl (2). So the present investigation was designed to evaluate the anti-hyperglycemic, antihyperlipidemic and antioxidant effect of the 1, 2, 8-trihydroxy-6-methoxy xanthone (1) and 1, 2, dihydroxy-6-methoxyxanthone-8-O-β-d-xylopyranosyl (2) on STZ induced diabetic rats. The diabetes mellitus protein targets such as 1V4S, 2JJK, 2BEL and modeled protein of sulfonylurea receptor 1 (SUR1) were subjected to in silico molecular docking with a view to investigate whether compounds 1 and 2 could be a better candidate to treat diabetes and to confirm the pharmacological basis for its anti-diabetic use in Indian traditional medicine.

Section snippets

Plant material and isolation

The aerial parts of S. corymbosa were collected from Vellingiri hills. The plant material was authenticated by Dr. R. Ramachandran, Professor, Department of Botany, Bharathiar University, Coimbatore. Vouchers Specimen (No: 006144) of the plant material is deposited at the Department herbarium center, Department of Botany, Bharathiar University. The extraction and isolation of 1, 2, 8-trihydroxy-6-methoxy xanthone (1) and 1, 2, dihydroxy-6-methoxyxanthone-8-O-β-d-xylopyranosyl (2) from S.

Acute toxicity study

In acute toxicity study, oral administration of compounds 1 and 2 at a dose of 2000 mg/kg did not produce any signs of toxicity and no animals were died up to 3 days. It showed that compounds 1 and 2 was non-toxic in mice up to an oral dose of 2000 mg/kg b.w. Therefore, further investigation of hypoglycemic activity was carried out using 25 and 50 mg/kg dose levels.

Effects of compounds 1 and 2 on oral glucose tolerance test (OGTT) in STZ-diabetic rats

Results of OGTT conducted on control and different experimental groups are shown in Fig. 2. After the oral dose of glucose in normal

Discussion

Streptozotocin (STZ) is commonly used for experimental induction of type-I diabetes mellitus, which causes selective pancreatic islet β-cell cytotoxicity mediated through the release of nitric oxide (NO). This results in rapid reduction in pancreatic islet pyridine nucleotide concentration and subsequent β-cell necrosis. The action of STZ on mitochondria generates SOD anions, which leads to diabetic complications (Papaccio et al., 2000, Szkudelski, 2001). Based on the above perspectives, in the

Conclusion

In conclusion, from the present findings, it is well documented that the compounds 1 and 2 plays a part in the management of diabetes and the prevention of its vascular complications in STZ-induced diabetic rats and it may be useful in the treatment of antihyperglycemic and antihyperlipidemic in diabetic patients. Finally, we propose these compounds as antidiabetic agents as hit structures for design more potent and specific drugs.

References (78)

  • Y. Liu et al.

    Antihyperglycemic, antihyperlipidemic and antioxidant activities of polysaccharides from Catathelasma ventricosum in streptozotocin-induced diabetic mice

    Food Chem. Toxicol.

    (2013)
  • M. Maghrani et al.

    Effects of an aqueous extract of Triticum repens on lipid metabolism in normal and recent-onset diabetic rats

    J. Ethnopharmacol.

    (2004)
  • G. Mahendran et al.

    Anti-diabetic activity of Swertia corymbosa (Griseb.) Wight ex C.B. Clarke aerial parts extract in streptozotocin induced diabetic rats

    J. Ethnopharmacol.

    (2014)
  • M.S. Moron et al.

    Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver

    Biochim. Biophys. Acta

    (1979)
  • S. Muruganandan et al.

    Effect of mangiferin on hyperglycemia and atherogenicity in streptozotocin diabetic rats

    J. Ethnopharmacol.

    (2005)
  • S.R. Naik et al.

    Anti-diabetic activity of embelin: involvement of cellular inflammatory mediators, oxidative stress and other biomarkers

    Phytomedicine

    (2013)
  • P.K. Prabhakar et al.

    Synergistic interaction of ferulic acid with commercial hypoglycemic drugs in streptozotocin induced diabetic rats

    Phytomedicine

    (2013)
  • K. Ravi et al.

    Effect of Eugenia jambolana seed kernel on antioxidant defense system in streptozotocin-induced diabetes in rats

    Life Sci.

    (2004)
  • J.E. Sun et al.

    Antihyperglycemic and antilipid peroxidative effects of dry matter of culture broth of Inonotus obliquus in submerged culture on normal and alloxan-diabetes mice

    J. Ethnopharmacol.

    (2008)
  • R. Sundaram et al.

    Modulatory effect of green tea extract on hepatic key enzymes of glucose metabolism in streptozotocin and high fat diet induced diabetic rats

    Phytomedicine

    (2013)
  • L.Y. Tian et al.

    Anti-diabetic effect of methylswertianin and bellidifolin from Swertia punicea Hemsl. and its potential mechanism

    Phytomedicine

    (2010)
  • L. Wan et al.

    In vitro and in vivo anti-diabetic activity of Swertia kouitchensis extract

    J. Ethnopharmacol.

    (2013)
  • Y.L. Wang et al.

    Antidiabetic effects of Swertia macrosperma extracts in diabetic rats

    J. Ethnopharmacol.

    (2013)
  • L. Zhang et al.

    Discovery of novel dual-action antidiabetic agents that inhibit glycogen phosphorylase and activate glucokinase

    Eur. J. Med. Chem.

    (2012)
  • Z. Abraham

    Ethnobotany of the Todas, the Kotas, the Irulas of the Nilgiris

  • A. Alfy et al.

    Protective effect of red grape seed sproanthocyanidins against induction of diabetes by alloxan in rats

    Pharmacol. Res.

    (2005)
  • P. Anagnostis et al.

    Clinical review: the pathogenetic role of cortisol in the metabolic syndrome: a hypothesis

    J. Clin. Endocrinol. Metab.

    (2009)
  • P. Basnet et al.

    Bellidifolin: a potent hypoglycemic agent in streptozotocin (STZ)-induced diabetic rats from Swertia japonica

    Planta Med.

    (1994)
  • A. Bessadok et al.

    Recognition of sulfonylurea receptor (ABCC8/9) ligands by the multidrug resistance transporter P glycoprotein (ABCB1): functional similarities based on common structural features between two multi specific ABC proteins

    J Biol Chem

    (2010)
  • Bethesda

    US Renal Data System. Annual Data Report: Atlas of End Stage Renal Disease in the United States

    (2001)
  • B. Chandrasekar et al.

    Hypoglycemic activity of Swertia chirayita (Roxb ex Flem) Karst

    Indian J. Exp. Biol.

    (1990)
  • R. Chen et al.

    7 Glucose-stimulated and self-limiting insulin production by glucose 6-phosphatase promoter driven insulin expression in hepatoma cells

    Gene Ther.

    (2000)
  • M.D. Eldridge et al.

    Empirical scoring functions: the development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes

    J. Comput. Aided Mol. Des.

    (1997)
  • T. Ferre et al.

    Evidence from transgenic mice that glucokinase is rate limiting for glucose utilization in the liver

    FASEB J.

    (1996)
  • J. Grimsby et al.

    Allosteric activators of glucokinase: potential role in diabetes therapy

    Science

    (2003)
  • H. Hikino et al.

    Mechanisms of hypoglycemic activity of aconitan A, a glycan from Aconitum carmichaeli roots

    J. Ethnopharmacol.

    (1989)
  • IDF

    Diabetes Atlas News, 5th Edition of the Diabetes Atlas Released on World Diabetes Day

    (2011)
  • S.S. Irudayaraj et al.

    Antidiabetic and antioxidant activities of Toddalia asiatica (L.) Lam. leaves in streptozotocin induced diabetic rats

    J. Ethnopharmacol.

    (2012)
  • N. Kamalakkannan et al.

    Antihyperglycaemic and antioxidant effect of rutin, a polyphenolic flavonoid, in streptozotocin-induced diabetic Wistar rats

    Basic Clin. Pharmacol. Toxicol.

    (2006)
  • Cited by (50)

    • Effects of Centella asiatica on skeletal muscle structure and key enzymes of glucose and glycogen metabolism in type 2 diabetic rats

      2019, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      The observed excess thirst and frequent urination in diabetes have been attributed to the presence of a high level of glucose in the blood which is excreted in the urine. The excretion of glucose in urine requires more water to be removed so that the intracellular osmotic balance is maintained leading to a state of dehydration that is recognized by the brain osmoreceptors and interpreted as excessive thirst [33]. Hence, the glucose-lowering effect and amelioration of polydipsia and polyphagia as seen in rats treated with CA and metformin suggest an improvement of glucose metabolism by the treatments.

    View all citing articles on Scopus
    View full text