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- Title
Antihyperlipidemic effect of selected pyrimidine derivatives mediated through multiple pathways.
- Authors
Irshad, Nadeem; Khan, Arif‐ullah; Shah, Fawad Ali; Nadeem, Humaira; Ashraf, Zaman; Tipu, Muhammad Khalid; Li, Shupeng
- Abstract
Hyperlipidemia is worth‐mentioning risk factor in quickly expanding atherosclerosis, myocardial infarction, and stroke. This study attempted to determine effectiveness of selected pyrimidine derivatives: 5‐(3‐Hydroxybenzylidene)‐2, 4, 6(1H, 3H, 5H)‐pyrimidinetrione (SR‐5), 5‐(4‐Hydroxybenzylidene)‐2, 4, 6(1H, 3H, 5H)‐pyrimidinetrione (SR‐8), 5‐(3‐Chlorobenzylidene)‐2, 4, 6(1H, 3H, 5H)‐pyrimidinetrione (SR‐9), and 5‐(4‐Chlorobenzylidene)‐2, 4, 6(1H, 3H, 5H)‐pyrimidinetrione (SR‐10) against hyperlipidemia. Insilico results revealed that SR‐5, SR‐8, SR‐9, and SR‐10 exhibited high affinity with 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMGCoA) possessing binding energy values of −8.2, −8.4, −8.6, and −9.5 Kcal/mol, respectively, and moderate (<−8 Kcal/mol) against other selected targets. Invivo findings showed that test drugs (25 and 50 mg/Kg) significantly decreased HFD rat total cholesterol, triglycerides, low‐density lipoprotein, very‐low‐density lipoprotein, atherogenic index, coronary risk index, alkaline phosphatase, aspartate transaminase, alanine transaminase, and bilirubin and increased high‐density lipoprotein (p < 0.05, p < 0.01, p < 0.001 vs HFD group). In animal liver tissues, SR‐5, SR‐8, SR‐9, and SR‐10 inhibited HMGCoA reductase enzyme, enhanced glutathione‐s‐transferase, reduced glutathione, catalase levels, improved cellular architecture in histopathological examination, and decreased expression of inflammatory markers: cyclo‐oxygenase 2, tumor necrosis factor alpha, phosphorylated c‐Jun N‐terminal kinase, and phosphorylated‐nuclear factor kappa B, evidenced in immunohistochemistry and enzyme‐linked immunosorbent assay molecular investigations. This study indicates that SR‐5, SR‐8, SR‐9, and SR‐10 exhibit antihyperlipidemic action, mediated possibly through HMGCoA inhibition, hepatoprotection, antioxidant, and anti‐inflammatory pathways.
- Subjects
PYRIMIDINE derivatives; CATALASE; TUMOR necrosis factors; ENZYME-linked immunosorbent assay; ALANINE aminotransferase; ASPARTATE aminotransferase; BLOOD cholesterol; TRIGLYCERIDES
- Publication
Fundamental & Clinical Pharmacology, 2021, Vol 35, Issue 6, p1119
- ISSN
0767-3981
- Publication type
Article
- DOI
10.1111/fcp.12682