We present the design, synthesis, computational analysis, and biological assessment of several acrylonitrile derived imidazo4,5-bpyridines, which were evaluated for their anticancer and antioxidant ...properties. Our aim was to explore how the number of hydroxy groups and the nature of nitrogen substituents influence their biological activity. The prepared derivatives exhibited robust and selective antiproliferative effects against several pancreatic adenocarcinoma cells, most markedly targeting Capan-1 cells (IC50 1.2–5.3 μM), while their selectivity was probed relative to normal PBMC cells. Notably, compound 55, featuring dihydroxy and bromo substituents, emerged as a promising lead molecule. It displayed the most prominent antiproliferative activity without any adverse impact on the viability of normal cells. Furthermore, the majority of studied derivatives also exhibited significant antioxidative activity within the FRAP assay, even surpassing the reference molecule BHT. Computational analysis rationalized the results by highlighting the dominance of the electron ionization for the antioxidant features with the trend in the computed ionization energies well matching the observed activities. Still, in trihydroxy derivatives, their ability to release hydrogen atoms and form a stable O–H⋯O•⋯H–O fragment upon the H• abstraction prevails, promoting them as excellent antioxidants in DPPH• assays as well.
Display omitted
•Novel unsubstituted and N-substituted imidazo4,5-bpyridine derived acrylonitriles were prepared.•Antioxidant potential evaluated by DPPH and ABST assays, FRAP method and electrochemical oxidation ...potential measurements.•The effect of substituents and solvent polarity on antioxidant features evaluated and interpreted.•Most derivatives display significantly improved antioxidant activity relative to the standard BHT system.•DFT calculations show that investigated antioxidant properties rely on the H-atom transfer.
We describe the synthesis of novel unsubstituted and N-substituted imidazo4,5-bpyridine derived acrylonitriles, which were prepared by classical and microwave assisted organic synthesis. Their antioxidative potential was studied using spectroscopic DPPH and ABTS assays, FRAP method and electrochemical oxidation potential measurements. Targeted acrylonitriles were designed in order to study the influence of the methoxy, N,N-dimethylamino and N,N-diethylamino substituents on the antioxidative activity as well as the type of the substituent placed on the N-atom of the imidazo4,5-bpyridine nuclei. The most active derivatives with significantly improved activity relative to the standard BHT, were systems substituted with the N,N-(CH3)2 group 29 and the N,N-(CH2CH3)2 group at the para position of the phenyl ring 24, 30, 32 and 34. Computational analysis revealed that investigated antioxidative features are predominantly relying on the hydrogen atom transfer properties and can be efficiently enhanced through either the N-alkylation of the imidazole nitrogen or by introducing electron-donating substituents on the distant phenyl unit, where N,N-dialkylamines prevail over methoxy groups. Absorption spectra of chosen compounds were recorded in several organic solvents to further reveal the impact of the substituent effects and solvent polarity on spectroscopic features.
•Brain total lipid and fatty acid content is increased in sucrose treated rats.•Sucrose treatment decreases the brain content of n6 fatty acids including arachidonic acid.•In the sucrose treated rats ...the content of docosahexaenoic acid remains unchanged.
We investigated the influence of high sucrose intake, administered in drinking water, on the lipid profile of the brain and on the expression of SREBP1c and Δ-desaturase genes. Adult male rats received 30% sucrose solution for 20 weeks (Sucrose group), or plain water (Control group). After the 20th week of sucrose treatment, the Sucrose group showed permanent hyperglycemia. Sucrose treatment also increased the amount of total lipids and fatty acids in the brain. The brain fatty acid profile of total lipids as well as phosphatidylethanolamine, phosphatidylcholine and cardiolipin of the Sucrose group was extensively changed. The most interesting change was a significant decrease in n6 fatty acids, including the important arachidonic acid, whereas the content of oleic and docosahexaenoic acid remained unchanged. RT-qPCR revealed an increase in Δ-5-desaturase and SREBP1c gene expression. In conclusion, high sucrose intake via drinking water extensively changes rat brain fatty acid profile by decreasing n6 fatty acids, including arachidonic acid. In contrast, the content of docosahexaenoic acid remains constant in the brain total lipids as well as in phospholipids. Changes in the brain fatty acid profile reflect changes in the lipid metabolism of the rat lipogenic tissues and concentrations in the circulation.
The objective of this study was to evaluate the influence of high-fat (HF) and cafeteria diet (CAF) diets and sex on the metabolism of important fatty acids in the liver and perirenal fat tissue. ...Dietary treatments induced changes in the fatty acid profile in comparison to the untreated group, but the characteristic differences between treated groups were also observable. The HF diet induced an increase in the content of C16:1
-7 and C18:1
-7 in the liver phospholipids (PL) and triglycerides (TG) and perirenal fat tissue compared to the control and CAF diet. The CAF diet induced a more drastic decrease in both
-3 and
-6 polyunsaturated fatty acids (PUFA), including depletion of eicosapentaenoic acid (EPA). The CAF diet also increased the content of
-6 docosapentaenoic acid (DPA
-6) in the liver and decreased it in the perirenal fat. Sex also had a significant influence on the fatty acid profile, but the variables with the highest differences between the CAF and HF treatments were identical in the male and female rats. In this study, we have established that two dietary models of non-alcoholic fatty liver disease (NAFLD) led to characteristic changes in the hepatic and perirenal fat fatty acid profile, in contrast to the control diet and in comparison with each other. These differences could play an important role in the interpretation of the experimental results of nutritional studies.
Abstract We studied the influence of sucrose in drinking water on liver histology, fatty acid profile and lipogenic genes expression in rats maintained on high-fiber. The experimental groups were: ...control group (water) and sucrose group (sucrose solution in drinking water, 30% w/v). Liver histology of sucrose treated rats revealed steatosis and increased number of αSMA immunoreactive cells without the signs of fibrosis. Sucrose treatment increased de novo lipogenesis, lipid peroxidation and MUFA content and decreased PUFA content, C18:2n6 and C20:4n6 content in total phospholipids and phosphatidylethanolamine and C18:2n6 content in cardiolipin. RT-qPCR revealed increase in Δ-9-desaturase and SREBP1c gene expression and decrease in the Δ-5-desaturase and elongase 5 expression. Treatment with sucrose extensively changes fatty acid composition of hepatic lipid and phospholipid classes including cardiolipin, increases oxidative stress and causes pathological changes in liver in rats maintained on high-fiber diet.
We studied the influence of long-term treatment with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the liver, and kidney lipogenesis, inflammation and antioxidative gene expression. ...Male Wistar rats were divided into three groups on the basis of the different n6/n3 fatty acid ratios achieved by using different dietary oil blends: the control (CON, n6/n3 ratio was ~7), the N6 group (n6/n3 ratio was ~50) and the DHA group (n6/n3 ~1). Treatment significantly influenced the fatty acid profile of the liver and kidney tissues. The most characteristic changes were an increased content of EPA and DHA in the DHA group in both tissues, of the kidney and liver. The expression of transforming growth factor beta (TGF-ß) was downregulated in the liver tissue by long-term EPA/DHA supplementation. This could be attributed to a decrease in the production of arachidonic acid-derived proinflammatory mediators, and an increase in EPA and DHA derived eicosanoids. DHA and EPA supplementation also significantly increased expression of the NRF 2 gene. This finding suggests that n3 PUFA could influence the activation of the NRF 2 pathway, which is important in cell antioxidative defense. In conclusion, we have shown that long-term dietary supplementation with DHA and EPA could influence lipid metabolism, inflammation and antioxidative defense. Therefore, the long-term addition of dietary DHA and EPA could potentially influence the most important pathological processes in aging.
The black soldier fly (Hermetia illucens) has emerged as an interesting alternative protein source in animal feed due to its ability to grow on various substrates. Although it has many rearing ...benefits and possible applications, it has an unfavourable fatty acid profile if used for human consumption due to its high content of lauric acid and low content of polyunsaturated fatty acids. In order to investigate whether the lipid composition of black soldier fly larvae can be altered, the feeding media were supplemented with varying concentrations of fish, linseed or coconut oil (1, 2.5 and 5%). Two-week-old larvae were collected, measured and their tissue fatty acid composition was determined. The fatty acid profile of the larvae showed significant plasticity, depending on the life stage and the fatty acid composition of the feeding media. The addition of 2.5 and 5% of different oils significantly changed the fatty acid composition of larvae, depending on the type and percentage of oil. The n6/n3 ratio was considerably improved by supplementing fish and linseed oil. The addition of linseed oil increased the content of linolenic acid, but bioconversion to eicosapentaenoic and docosahexaenoic acids was low. In contrast, the addition of fish oil significantly increased the content of eicosapentaenoic and docosahexaenoic acids in the larvae. The content of lauric acid significantly increased after coconut addition. The trial showed that by using different oils, the lipid composition of black soldier fly larvae could be specifically changed to increase the beneficial long chain n3 polyunsaturated fatty acids, and the amount of lauric or linolenic acid.
Scope
We investigated the interaction between streptozotocin (STZ)‐induced diabetes and dietary n6/n3 ratio, and its influence on lipogenesis.
Methods and results
The animals were treated with STZ ...and fed with different dietary n6/n3 ratios: 1, 7, and 60, or supplemented with DHA/EPA. Gene expression was assessed by RT‐PCR and protein expression by western blotting and immunohistochemistry. Fatty acid profile was determined by GC‐MS. Pancreas and liver histology were assessed by hematoxylin and eosin (H&E) staining. STZ‐induced characteristic changes in all STZ treated groups, including: increased blood glucose, decreased body mass, increased lipid peroxidation and CD36 expression, decreased 16:1n7 and 18:1n7, increases in 20:3n6, decreases in phospholipid (PL) content of 20:4n6, as well as decreases in the expression of SREBP1c, Δ‐9‐desaturase (Δ9D), and Δ‐5‐desaturase (Δ5D). Additionally, other changes occurred that were dependent on the n6/n3 ratio. Among the diabetic groups, the lower n6/n3 ratio caused higher lipid peroxidation and CD36 expression, a greater decrease in 20:4n6 and decreased Δ6‐desaturase (Δ6D) expression, while the higher n6/n3 ratio caused increased partitioning of 20:4n6 into hepatic neutral lipids (NL), a decrease in 20:5n3 content, and increased β‐oxidation.
Conclusion
Presented data suggest that the n6/n3 ratio could significantly influence lipogenesis, lipid peroxidation, and β‐oxidation in STZ‐induced diabetes, which could have clinical significance.
In streptozocin‐treated rats, the higher n6/n3 ratio causes increased partitioning of 20:4n6 into hepatic neutral lipids (NL), a decrease in 20:5n3 content, and increased β‐oxidation, while the lower n6/n3 ratio caused higher lipid peroxidation and CD36 expression, a greater decrease in 20:4n6, and decreased Δ6‐desaturase (Δ6D)expression.
Crossbreeding of Holstein cattle with bulls of other breeds has garnered increasing interest with respect to efforts to improve performance traits and to decrease problems with fertility and health. ...Therefore, the objective of this study was to compare the effects of the fatty acid synthase (FASN) gene on milk production traits and fatty acid composition of Simmental and first-generation Holstein × Simmental crossbred cows. A total of 105 cows (72 Simmental and 33 crossbred Holstein) were genotyped using the PCR-RFLP method and their fatty acid profiles were analysed. The crossbred Holstein cows with diplotype TW/AR had significantly higher fat content and yield compared to the purebred Simmental cows of the same diplotype. The Holstein × Simmental cows with the diplotype AR/AR were also characterised by significantly lower content of C16:0 and saturated fatty acids, but higher C18:1n9, monounsaturated fatty acid and monounsaturated fatty acid/saturated fatty acid content compared to the same diplotype of the Simmental cattle. These results indicate that with accurate breeding plans, crossbreeding Holstein cows with Simmental bulls could be directed towards a more desirable fatty acid composition of milk and dairy products.
Fatty acid composition of milk has become an important trait in dairy production, but there has not been a large amount of research on milk fat composition in beef cows. The aim of this study was to ...evaluate the effects of polymorphisms in the fatty acid synthase (FASN) and acyl-CoA diacylglycerol acyltransferase (DGAT1) gene on milk and colostrum fatty acid composition, and their direct (calf) and indirect (cow/mother) relationships with calf birth weight and weight gain over 14 days. Eight Charolais cows and eight calves were genotyped using the PCR-RFLP method. The cows’ milk and colostrum fatty acid profiles and their calves’ weight at birth and 14 day weight gain were analysed. In the colostrum, cows with DGAT1 genotype KA had a significantly higher content of C4:0 and lower C10:0, and with FASN diplotype TW/AR a tendency for higher C14:0 and C16:0 colostrum FA content. In the milk, Charolais cows with diplotype TW/AR tended to have higher C14:1, C16:0 and C16:1, but lower C18:0 content. At the same time, no associations were found between DGAT1 genotypes and the fatty acid composition of milk. There were also no significant associations found between the studied SNPs and the calf’s birth weight and weight gain over 14 days, although calves with DGAT1 KA genotype tended to have higher birth weight.
![Novel imidazo[4,5-b]pyridin...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0167-7322/small "Novel imidazo[4,5-b]pyridine derived acrylonitriles: A combined experimental and computational study of their antioxidative potential")
PDF
