ABSTRACT
The present study was designed to systematically investigate the antidiabetic potential of Amaranthus spinosus leaves which are traditionally known to have various medicinal properties and used for the treatment of diabetes mellitus. The ethanolic extract of leaves of Amaranthus spinosus was administered (150, 300 and 450 mg/kg bw) to type-1 and type-2 diabetic rats. Standard drugs, glibenclamide and metformin were used as a positive control for comparison. Changes in carbohydrate and lipid metabolism and antioxidants were assessed and compared with control and standard drug treated animals. Among the standardized extract doses tested (150, 300 and 450 mg/kg bw), higher doses significantly decreased plasma glucose levels (p<0.01 and p<0.001), hepatic glucose-6-phophatase activity (p<0.01 and p<0.001) and increased the hepatic glycogen content (p<0.01) with a concurrent increase in hexokinase activity in both type 1 and 2 diabetic rats (p<0.01 and p<0.001). Besides, the higher doses also significantly lowered the plasma and hepatic lipids, urea, creatinine levels (p<0.001) and lipid peroxidation with an improvement in the antioxidant profiles (p<0.001) of both type-1 and type-2 diabetic rats. It is concluded that Amaranthus spinosus has potential antidiabetic activity and significantly improves disrupted metabolisms and antioxidant defense in type-1 and type-2 diabetic rats.
Subject(s)
Amaranthus/chemistry , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Plant Preparations/therapeutic use , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 2/metabolism , Glucose-6-Phosphatase/metabolism , Glycogen/metabolism , Hypoglycemic Agents/isolation & purification , Lipid Metabolism/drug effects , Liver/drug effects , Liver/metabolism , Male , Plant Leaves/chemistry , Plant Preparations/isolation & purification , RatsABSTRACT
Misregulation of the canonical Wnt/ß-catenin pathway and aberrant activation of Wnt signaling target genes are common in colorectal cancer (CRC) and contribute to cancer progression. Altered expression of human enhancer of filamentation 1 (HEF1; also known as NEDD9 or Cas-L) has been implicated in progression of melanoma, breast, and CRC. However, the regulation of HEF1 and the role of HEF1 in CRC tumorigenesis are not fully understood. We here identify HEF1 as a novel Wnt signaling target. The expression of HEF1 was upregulated by Wnt-3a, ß-catenin, and Dvl2 in a dose-dependent manner, and was suppressed following ß-catenin downregulation by shRNA. In addition, elevated HEF1 mRNA and protein levels were observed in CRC cell lines and primary tumor tissues, as well as in the colon and adenoma polyps of Apc(Min/+) mice. Moreover, HEF1 levels in human colorectal tumor tissues increased with the tumor grade. Chromatin immunoprecipitation (ChIP) assays and promoter analyses revealed three functional T-cell factor (TCF)-binding sites in the promoter of HEF1 responsible for HEF1 induction by Wnt signaling. Ectopic expression of HEF1 increased cell proliferation and colony formation, while downregulation of HEF1 in SW480 cells by shRNA had the opposite effects and inhibited the xenograft tumor growth. Furthermore, overexpression of HEF1 in SW480 cells promoted cell migration and invasion. Together, our results determined a novel role of HEF1 as a mediator of the canonical Wnt/ß-catenin signaling pathway for cell proliferation, migration, and tumorigenesis, as well as an important player in colorectal tumorigenesis and progression. HEF1 may represent an attractive candidate for drug targeting in CRC.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Cell Movement , Colon/metabolism , Colorectal Neoplasms/metabolism , Phosphoproteins/metabolism , Adaptor Proteins, Signal Transducing/genetics , Animals , Blotting, Western , Caco-2 Cells , Cell Line , Cell Line, Tumor , Colon/cytology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Disease Progression , Gene Expression Regulation, Neoplastic , HT29 Cells , Humans , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Mice, Nude , Neoplasms, Experimental/genetics , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Phosphoproteins/genetics , Promoter Regions, Genetic/genetics , Protein Binding , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , TCF Transcription Factors/metabolism , Transplantation, Heterologous , Wnt Proteins/metabolism , beta Catenin/genetics , beta Catenin/metabolismABSTRACT
Oral administration of the ethanolic extract of the Butea monosperma seeds (300 mg/kg b.w.) exhibited significant antidiabetic, hypolipaemic and antiperoxidative effects in non-insulin dependent diabetes mellitus rats.
