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
Graphical abstract
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.
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