| Title | Inhibitory effect of novel diallyldisulfide analogs on HMG-CoA reductase expression in hypercholesterolemic rats: CREB as a potential upstream target. | | Author(s) | Rai SK, Sharma M, Tiwari M | | Institution | Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi-110007, India. | | Source | Life Sci 2009 Jul 31; 85(5-6):211-9. | | MeSH | Allyl Compounds
Animals
Antilipemic Agents
Blotting, Western
CREB-Binding Protein
Cholesterol
Disease Models, Animal
Disulfides
Electrophoretic Mobility Shift Assay
Garlic
Gene Expression Regulation, Enzymologic
Hydroxymethylglutaryl CoA Reductases
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hypercholesterolemia
Lipid Peroxidation
Lipoproteins, LDL
Liver
Male
NF-kappa B
RNA, Messenger
Rats
Rats, Wistar
Reverse Transcriptase Polymerase Chain Reaction
Sterol Regulatory Element Binding Proteins
Triglycerides
| | Abstract | AIMS: Diallyldisulfide (DADS), an active principle of garlic (Allium sativum) is known for its antihyperlipidemic properties. The present study was designed to evaluate the effect of novel synthesized DADS analogs, on the lipid profile of hypercholesterolemic rats and to investigate the molecular correlates of their activity at the cellular level. MAIN
METHODS: Wistar rats, weighing 100-120 g each, were administered with 5% cholesterol for one week, and subsequently administered with lovastatin, allicin and DADS (20 mg/kg wt) analogs in the second week along with 5% cholesterol. All animals were sacrificed after overnight starvation. KEY
FINDINGS: Our results show that DADS analogs are effective in reducing the total lipid levels which could be correlated with a significant decrease in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) activity. DADS analogs strongly inhibit HMGR activity in vivo but not in vitro. These results can be attributed to the significant decrease in the mRNA levels and protein expression of HMGR. Further, we show that DADS analogs significantly inhibited the activation of sterol regulatory element-binding protein-2 (SREBP-2) and interfered with DNA binding activity of cAMP response element-binding protein (CREB) but not nuclear factor-Y (NF-Y), with upstream regulatory sequences of HMGR. Moreover, DADS analogs are also effective in reducing the levels of oxidized low-density lipoprotein (ox-LDL), lipid peroxidation as well as NF-kappaB activity, showing good anti-inflammatory and antioxidant properties.
SIGNIFICANCE: The unique anti-inflammatory effect and hypolipidemic action of DADS analogs may be beneficial in preventing the vascular complications that are induced by hyperlipidemia and provide a new therapeutic approach for the treatment of cardiovascular and related diseases. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, Non-U.S. Gov't
| | PubMed ID | 19523964 |
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