Mechanisms of phytochemicals from murraya koenigii and stevia rebuadiana in cell model of diabetes, hepatocellular carcinoma and cholangiocarcinoma under hyperglycemic conditions

Abstract

Diabetes mellitus (DM) is a group of metabolic disorders in which high blood glucose levels over a prolonged period, caused by deficiency of insulin production from the pancreas, or by the insulin resistance. Several epidemiological studies suggest that diabetic population is not only at increased risk of cardiovascular complications, but also at substantially higher risk of many types of malignancies. Hyperglycemia induced free radical reactive oxygen species (ROS) production, which is a major cause of cell injury and organ damage, especially affects pancreatic beta cells. Whereas insulin resistance in skeletal muscle tissue and adipocyte are the major sites of postprandial glucose disposal, and enhancing glucose uptake into this tissue may decrease insulin resistance in type 2 diabetes patients. Moreover, Hyperglycemia and hyperinsulinemia in DM also showed the strong relation with cholangiocarcinoma proliferation and migration, the high prevalence cancer in the Northeast of Thailand. The study of phytochemical chemistry form Murraya koenigii and Stevia rebuadiana were conducted to investigate their pharmacological properties in various model that related to DM such as hyperglycemia, insulin resistance as well as in cancer cell line. Mahanine, a carbazole alkaloid from Murraya koenigii showed the outstanding protective effects in high glucose induced oxidative stress in RIN-m5F pancreatic beta cells via suppression of NADPH oxidase gene expression. Moreover, mahanine increased the insulin secretion by stimulating the pancreatic duodenum homeobox-1(PDX-1) expression and translocation, proinsulin (PRE-INS), and glucose transporter 2 (GLUT2) and glucokinase (GCK) gene expression. In addition mahanine enhanced the insulin sensitizing effects in skeletal muscle and adipocyte cells by increased glucose uptake and promoted glucose transporter 4 (GLUT4) translocation via activation of the Akt signaling pathway. Furthermore, mahanine showed the potent cytotoxicity in HepG2 human hepatocellular carcinoma and HuCCT1 and KKU-100 human cholangiocarcinoma cells, which was associated with increased the expression levels of MITF. Whereas the phytochemical chemistry from S. rebuadian; steviol, isosteviol and 7 β-OHisosteviol, also presented the anti-diabetes effects by increased the glucose uptake and GLUT 4 translocation but least potent than mahanine. These study suggested that mahanine have anti-diabetic potential for treating diabetes and anti-cancer, which potentially to use as concomitant herbal medicine in cancer and/or diabetes patient without concerning of cancer treatment-induced DM and DM treatment-induced cancer.