Design, synthesis, and evaluation of benzofuran-based chromenochalcones for antihyperglycemic and antidyslipidemic activities.

A series of benzofuran-based chromenochalcones (16-35) were synthesized and evaluated for in vitro and in vivo antidiabetic activities in L-6 skeletal muscle cells and streptozotocin (STZ)-induced diabetic rat models, respectively, and further in vivo dyslipidemia activity of the compounds was evaluated in a Triton-induced hyperlipidemic hamster model. Among them, compounds 16, 18, 21, 22, 24, 31, and 35 showed significant glucose uptake stimulatory effects in skeletal muscle cells and were further evaluated for in vivo efficacy. Compounds 21, 22, and 24 showed a significant reduction in blood glucose levels in STZ-induced diabetic rats. Compounds 16, 20, 21, 24, 28, 29, 34, 35, and 36 were found active in antidyslipidemic studies. Furthermore, compound 24 effectively improved the postprandial and fasting blood glucose levels, oral glucose tolerance, serum lipid profile, serum insulin level, and the HOMA-index of db/db mice, following 15 days of successive treatment.

A mechanism-based pharmacological evaluation of efficacy of Flacourtia indica in management of dyslipidemia and oxidative stress in hyperlipidemic rats.

BACKGROUND: Flacourtia indica (Burm. f.) Merr. is a medicinal plant indigenous to India and is broadly used worldwide for the treatment of a variety of health ailments. The present study was experimented on hyperlipidemic Charles Foster rats with the aim to explore the possible mechanism responsible for the antidyslipidemic activity of the hydromethanolic extract from F. indica leaves (FIL). METHODS: Hyperlipidemia was induced by a single intraperitoneal dose of Triton WR-1339 in Charles Foster rats. The plasma lipid levels were estimated in control and treated groups. The antioxidant potential of F. indica was assessed in both enzymatic and non-enzymatic systems. An acute toxicity study of high-performance liquid chromatography (HPLC)-fingerprinted extract was carried out in Swiss albino mice. RESULTS: The F. indica extract at a dose of 150 mg/kg significantly lowers the plasma level of total cholesterol (17%), triglycerides (13%), and phospholipids (16%) by increasing post-heparin lipolytic activity (19%) and lecithin-cholesterol-acyltransferase activity (20%) in Triton-induced hyperlipidemic rats. In addition, the F. indica extract showed significant in vitro antioxidant and anti-adipogenic activity. HPLC analysis indicates the presence of flavanones and flavones in the extract, and the extract was found to be non-toxic up to a dose of 2000 mg/kg body weight in the acute oral toxicity study. CONCLUSIONS: These finding suggest that F. indica holds significant potential in preventing clinical deterioration induced by dyslipidemia along with oxidative stress.

Antidyslipidemic effect and antioxidant activity of anthraquinone derivatives from Rheum emodi rhizomes in dyslipidemic rats.

The aim of the present study was to evaluate the antidyslipidemic effect of ethanolic extract of Rheum emodi rhizomes and its constituents in Triton-WR-1339 and high-fat diet (HFD)-induced dyslipidemic rats. In preliminary screening, the ethanolic extract showed significant activity in Triton-treated rats. Bioassay-guided fractionation of the ethanolic extract resulted in the identification of four anthraquinone derivatives, viz. chrysophanol, emodin, chrysophanol 8-O-ß-D-glucopyranoside and emodin 8-O-ß-D-glucopyranoside as active constituents. All these compounds significantly reduced plasma lipid levels. The most active compound emodin showed significant lipid-lowering activity in the HFD-fed model. In addition, these compounds showed significant antioxidant activity. The effect of emodin on enzymes modulating lipid metabolism confirms and supports the efficiency of emodin as a potent antidyslipidemic agent.

Antidyslipidemic and antioxidant activity of an unusual amino acid (2-amino-5-hydroxyhexanoic acid) isolated from the seeds of Crotalaria juncea.

In continuation of our drug discovery programme on Indian medicinal plants, we isolated an unusual amino acid, i.e. 2-amino-5-hydroxyhexanoic acid (1) from the seeds of Crotalaria juncea. The 2-amino-5-hydroxyhexanoic acid (1) showed dose dependent lipid lowering activity in the in vivo experiments and also showed good in vitro antioxidant activity. The cyclized compound, 3-amino-6-methyltetrahydro-2H-pyran-2-one (2) showed better lipid lowering and antioxidant profile than the parent compound 1.

A mechanism-based pharmacological evaluation of efficacy of Trigonella foenum graecum (fenugreek) seeds in regulation of dyslipidemia and oxidative stress in hyperlipidemic rats.

: Alcoholic extract of Trigonella foenum graecum seeds [fenugreek seed extract (FSE)] was studied in triton-induced and high-fat diet-induced hyperlipidemia to evaluate antidyslipidemic effect. Plasma cholesterol (26.19%) and triglycerides (36.6%) were found to be lowered by FSE maximum at a dose of 200 mg/kg body weight in triton-treated hyperlipidemic rats. Chronic feeding of FSE (200 mg/kg body weight) caused lowering in plasma and hepatic lipid levels by activating lecithin-cholesterol acyltransferase (47%), postheparin lipolytic activity (35%), triglyceride lipase (34%), lipoprotein lipase (20.8%), and increased excretion of fecal bile acids (36%-45%). The FSE shows potent antioxidant activity in both in vitro and in vivo systems. It inhibited generation of superoxide anion and hydroxyl free radicals in both enzymatic and nonenzymatic systems significantly at 200 µM concentration. Furthermore, FSE normalizes the activities of antioxidant enzymes, that is, superoxide dismutase and catalase, and reduces plasma lipid peroxidation (33.9%), hepatic 4-hydroxynonenal (27%), and isoprostanes (28%). Data of the present study demonstrated that the T. foenum graecum seed extract has both antidyslipidemic and antioxidant properties.

Lipid lowering and antioxidant effect of miglitol in triton treated hyperlipidemic and high fat diet induced obese rats.

Miglitol, an anti-diabetic drug, has been shown to reduce plasma lipids and inhibit free radical generation. The anti-hyperlipidemic and antioxidant effects of miglitol were studied in triton-induced hyperlipidemic rats and high fat diet-fed obese rats. Plasma cholesterol and triglycerides levels were significantly lowered by miglitol at 100 mg/kg body weight doses. Miglitol inhibited generation of superoxide anion and hydroxyl free radicals by 14 and 31 % in enzymatic systems and 19 and 25 % in non-enzymatic systems, respectively. The in-vitro effect of the drug on adipogenesis using 3T3-L1 preadipocytes at 2-, 5- and 10-µM concentrations showed significant inhibition of adipogenesis (34.2 %) at 10-µM concentration. High fat diet-fed rat model was used to investigate anti-hyperlipidemic, anti-obesity and antioxidant effect of miglitol. Miglitol increased the activities of lecithin-cholesterol-acyltransferase (19 %), post heparin lipolytic activity (26 %), lipoprotein lipase (26 %) and triglyceride lipase (31 %) which result in a decrease in plasma lipid levels. The antioxidant enzymes viz., catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and thioredoxin reductase were increased by the drug in the treated animals. The antihyperlipidemic and antioxidant effect of miglitol can be correlated to its effect on different enzymes and it can be used for inhibiting the development of cardiovascular diseases.

Antioxidant effect of Azadirachta indica on high fat diet induced diabetic Charles Foster rats.

Oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus. Excessively high levels of free radicals cause damage to cellular proteins, membrane lipids and nucleic acids, and eventually cell death. The present study was designed to investigate the possible effect of Azadirachta indica leaf extract in high fat diet induced diabetic Charles Foster rats. The increased level of lipidperoxidation and altered levels of enzymatic (superoxide dismutase, glutathione peroxidase and catalase) and non-enzymatic (glutathione) antioxidants were seen in high fructose fed animals. The treatment with A. indica leaf extract significantly normalized the altered levels of lipid peroxidation and antioxidant status at 400 mg/kg b.w. dose. The A. indica leaf extract was also tested for in vitro inhibition of generation of superoxide anion and hydroxyl free radical in both enzymatic and non-enzymatic systems. The A. indica leaf extract was found to inhibit generation of superoxide anion and hydroxyl free radical significantly at 200 µg/ml concentration. Data of present study demonstrated that the A. indica leaf extract has both antidiabetic and antioxidant properties.

Synthesis of 5-aryl-6-cinnamoyl-7-methyl-flavanones as novel antioxidants and antihyperlipidemics.

An economical and efficient one-pot synthesis of a series of novel 5-aryl-6-cinnamoyl-7-methyl-flavanones has been developed by simple refluxing of cinnamoyl chalcones with NaOAc in aqueous ethanol in quantitative yields. These flavanones were screened for their in vitro antioxidant and in vivo antidyslipidemic activities. Among 24 compounds screened, four compounds 28, 29, 30, and 48 showed significant antidyslipidemic activities. However, out of all the compounds, only compound 28 exhibited significant antioxidant activity and other compounds showed moderate antioxidant activities.

Synthesis of novel N-(2-hydroxy-2-p-tolylethyl)-amide and N-(2-oxo-2-p-tolylethyl)-amide derivatives and their antidyslipidemic and antioxidant activity.

In continuation of our drug discovery program on metabolic diseases, we identified an alkaloidal amide, that is, Aegeline (V) from the plant Aegle marmelos leaves as a dual acting agent (antihyperlipidemic and antihyperglycemic). We therefore synthesized a series of alkaloidal amides [N-(2-hydroxy-2-p-tolylethyl)-amides and N-(2-oxo-2-p-tolylethyl)-amide derivatives] related to Aegeline and screened for their in vivo antihyperlipidemic activity in Triton induced hyperlipidemia model. The synthetic compounds 4, 17 and 20 showed equipotent activity to the natural product, that is, Aegeline (V). These compounds also showed strong antioxidant activity, which support their antihyperlipidemic activity. Compound 12 showed better antihyperlipidemic and antioxidant profile than the natural product V.