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Anti-hyperlipidaemic effects of synthetic analogues of nordihydroguaiaretic acid in dyslipidaemic rats.

ABSTRACT: BACKGROUND AND PURPOSE:Previous studies have shown that Creosote bush-derived nordihydroguaiaretic acid (NDGA) exerts beneficial actions on the key components of metabolic syndrome including dyslipidaemia, insulin resistance and hypertension in several relevant rodent models. Here, we synthesized and screened a total of 6 anti-hyperlipidaemic analogues of NDGA and tested their efficacy against hepatic lipid metabolism in a high-fructose diet (HFrD) fed dyslipidaemic rat model. EXPERIMENTAL APPROACH:HFrD fed Sprague-Dawley rats treated with NDGA or one of the six analogues were used. Serum samples were analysed for blood metabolites, whereas liver samples were quantified for changes in various mRNA levels by real-time RT-PCR. KEY RESULTS:Oral gavage of HFrD-fed rats for 4 days with NDGA analogues 1 and 2 (100 mg·kg-1 ·day-1 ) suppressed the hepatic triglyceride content, whereas the NDGA analogues 2, 3 and 4, like NDGA, decreased the plasma triglyceride levels by 70-75%. qRT-PCR measurements demonstrated that among NDGA analogues 1, 2, 4 and 5, analogue 4 was the most effective at inhibiting the mRNA levels of some key enzymes and transcription factors involved in lipogenesis. All four analogues almost equally inhibited the key genes involved in triglyceride synthesis and fatty acid elongation. Unlike NDGA, none of the analogues affected the genes of hepatic fatty acid oxidation or transport. CONCLUSIONS AND IMPLICATIONS:Our data suggest that NDGA analogues 1, 2, 4 and 5, particularly analogue 4, exert their anti-hyperlipidaemic actions by negatively targeting genes of key enzymes and transcription factors involved in lipogenesis, triglyceride synthesis and fatty acid elongation. These analogues have therapeutic potential.

SUBMITTER: Singh M

PROVIDER: S-EPMC6329620 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Anti-hyperlipidaemic effects of synthetic analogues of nordihydroguaiaretic acid in dyslipidaemic rats.

Singh Madhurima M Bittner Stefanie S Li Yihang Y Bittner Alex A Han Lu L Cortez Yuan Y Inayathullah Mohammed M Arif Zeeshan Z Parthasarathi Ramakrishnan R Rajadas Jayakumar J Shen Wen-Jun WJ Nicolls Mark R MR Kraemer Fredric B FB Azhar Salman S

British journal of pharmacology 20181210 3

<h4>Background and purpose</h4>Previous studies have shown that Creosote bush-derived nordihydroguaiaretic acid (NDGA) exerts beneficial actions on the key components of metabolic syndrome including dyslipidaemia, insulin resistance and hypertension in several relevant rodent models. Here, we synthesized and screened a total of 6 anti-hyperlipidaemic analogues of NDGA and tested their efficacy against hepatic lipid metabolism in a high-fructose diet (HFrD) fed dyslipidaemic rat model.<h4>Experim ...[more]

PMID: 30374952

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Project description:INTRODUCTION:Essential amino acid ?-keto acid analogs are used in the treatment of chronic kidney disease to delay the symptoms of uremia. However, it is unknown whether essential amino acid ?-keto acid analogs affect the oxidative stress and the inflammation in acute renal injury such as those produced by ischemia-reperfusion. OBJECTIVE:To evaluate the effect of essential amino acid ?-keto acid analogs on renal ischemia-reperfusion injury in Wistar rats. MATERIALS AND METHODS:Rats were divided into 11 groups (n=6/group): Two groups received physiological saline with or without ischemia-reperfusion injury (45 min/24 h), six groups received essential amino acid ?-keto acid analogs (400, 800, or 1,200 mg/kg/24 h/7d) with or without ischemia-reperfusion injury (essential amino acid ?-keto acid analogs + ischemia-reperfusion), and two groups received allopurinol (50 mg/kg/24 h/7d) with or without ischemia-reperfusion injury. Biochemical markers included creatinine and blood urea nitrogen (BUN), proinflammatory cytokines (IL-1?, IL-6, and TNF-?), renal damage markers (cystatin C, KIM-1, and NGAL), and markers of oxidative stress such as malondialdehyde (MDA) and total antioxidant activity. RESULTS:The essential amino acid ?-keto acid analog- and allopurinol-treated groups had lower levels of creatinine, BUN, renal damage markers, proinflammatory cytokines, and MDA than their corresponding ischemia-reperfusion groups. These changes were related to the essential amino acid ?-keto acid analogs dosage. Total antioxidant activity was lower in essential amino acid ?-keto acid analog- and allopurinol-treated groups than in the corresponding ischemia-reperfusion groups. CONCLUSIONS:This is a new report on the nephroprotective effects of essential amino acid ?-keto acid analogs against ischemia-reperfusion injury. Essential amino acid ?-keto acid analogs decreased the levels of biochemical markers, kidney injury markers, proinflammatory cytokines, and MDA while minimizing total antioxidant consumption.

Project description:All-trans-retinoic acid (ATRA) and its synthetic analogues EC23 and EC19 direct cellular differentiation by interacting as ligands for the retinoic acid receptor (RARα, β and γ) family of nuclear receptor proteins. To date, a number of crystal structures of natural and synthetic ligands complexed to their target proteins have been solved, providing molecular level snap-shots of ligand binding. However, a deeper understanding of receptor and ligand flexibility and conformational freedom is required to develop stable and effective ATRA analogues for clinical use. Therefore, we have used molecular modelling techniques to define RAR interactions with ATRA and two synthetic analogues, EC19 and EC23, and compared their predicted biochemical activities to experimental measurements of relative ligand affinity and recruitment of coactivator proteins. A comprehensive molecular docking approach that explored the conformational space of the ligands indicated that ATRA is able to bind the three RAR proteins in a number of conformations with one extended structure being favoured. In contrast the biologically-distinct isomer, 9-cis-retinoic acid (; 9CRA), showed significantly less conformational flexibility in the RAR binding pockets. These findings were used to inform docking studies of the synthetic retinoids EC23 and EC19, and their respective methyl esters. EC23 was found to be an excellent mimic for ATRA, and occupied similar binding modes to ATRA in all three target RAR proteins. In comparison, EC19 exhibited an alternative binding mode which reduces the strength of key polar interactions in RARα/γ but is well-suited to the larger RARβ binding pocket. In contrast, docking of the corresponding esters revealed the loss of key polar interactions which may explain the much reduced biological activity. Our computational results were complemented using an in vitro binding assay based on FRET measurements, which showed that EC23 was a strongly binding, pan-agonist of the RARs, while EC19 exhibited specificity for RARβ, as predicted by the docking studies. These findings can account for the distinct behaviour of EC23 and EC19 in cellular differentiation assays, and additionally, the methods described herein can be further applied to the understanding of the molecular basis for the selectivity of different retinoids to RARα, β and γ.

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Anti-hyperlipidaemic effects of synthetic analogues of nordihydroguaiaretic acid in dyslipidaemic rats.

Publications

Anti-hyperlipidaemic effects of synthetic analogues of nordihydroguaiaretic acid in dyslipidaemic rats.

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