In our previous studies we showed antitumor and anti-inflammatory activities of protein kinases inhibitor pyrrol derivate 1-(4-Cl-benzyl)-3-Cl-4-(CF3-fenylamino)-1H-pyrrol-2,5-dione (MI-1) on rat colon cancer model. Therefore anti-inflammatory effect of MI-1 on rat acetic acid induced ulcerative colitis (UC) model was aimed to be discovered. The anti-inflammatory effects of MI-1 (2.7 mg/kg daily) compared to reference drug Prednisolone (0.7 mg/kg daily) after 14-day usage were evaluated on macro- and light microscopy levels and expressed in 21-grade scale. Redox status of bowel mucosa was also estimated. It was shown that in UC group the grade of total injury (GTI) was equal to 9.6 (GTIcontrol = 0). Increase of malonic dialdehyde (MDA) by 89% and protein carbonyl groups (PCG) by 60% and decrease of superoxide dismutase (SOD) by 40% were also observed. Prednisolone decreased GTI to 3 and leveled SOD activity, but MDA and PCG remained higher than control ones by 52% and 42%, respectively. MI-1 restored colon mucosa integrity and decreased mucosa inflammation down to GTI = 0.5 and leveled PCG and SOD. Thus, MI-1 possessed anti-inflammatory properties, which were more expressed that Prednisolone ones, as well as normalized mucosa redox balance, and so has a prospect for correction of inflammatory processes.
Introduction. Pyrrol derivate 5-amyno-4-(1,3-benzothyazol-2-yn)-1-(3-methoxyphenyl)-1,2-dihydro-3H-pyrrol-3-one (D1) has shown antiproliferative activities in vitro, so investigation of the impact of D1 intake on gut organs in rats that experienced colon cancer seems to be necessary. Materials and Methods. D1 at the dose of 2.3 mg/kg was administered per os daily for 27 (from the 1st day of experiment) or 7 (from the 21st week of experiment) weeks to rats that experienced 1,2-dimethylhydrazine (DMH)-induced colon cancer for 20 weeks. 5-Fluorouracil (5FU) was chosen as reference drug and was administered intraperitoneally weekly for 7 weeks (from the 21st week of experiment) at the dose of 45 mg/kg. Results. Antitumor activity of D1 comparable with the 5FU one against DMH-induced colon cancer in rats was observed (decrease of tumor number and tumor total area up to 46%). D1 attenuated the inflammation of colon, gastric and jejunal mucosa, and the liver, caused by DMH, unlike 5FU, aggravating the latter. In addition, D1 partially normalized mucosa morphometric parameters suggesting its functional restore. Conclusions. D1 possesses, comparable with 5-fluorouracil antitumor efficacy, less damaging effects on the tissues beyond cancerous areas and contributes to partial morphological and functional gut organs recovery.
Inflammatory bowel disease (IBD) which includes ulcerative colitis (UC), is one of the most serious and currently unsolved problems in modern gastroenterology. In terms of severity and frequency of complications, IBD occupies one of the leading places in the structure of gastrointestinal tract diseases. The etiology of IBD is still not fully understood. It is probably of an autoimmune nature, and the main causes are considered to be hereditary predisposition, allergic reactions, nutrition, etc. Dystrophic and atrophic changes of the colonic mucosa, accompanied by its secretory and motor function alterations, digestive disorders, as well as extraintestinal manifestations (general intoxication, liver and skin injuries, joints) are main IBD features. Because tumor growth is usually accompanied by inflammation of tumor nodules in adjacent apparently normal tissue, and prolonged pharnaceutical suppression of inflammation significantly reduces the risk of tumor development, chronic UC is considered as a precursor condition. Moreover, the number of colorectal cancer cases among people with UC history exceeding 10 years, increases eightfold compared to the average population. In this regard, it is important to prevent this pathology, in particular with the help of food supplements of natural origin, such as vegetable oils of flax and milk thistle, which are used in traditional medicine, including inflammatory diseases of the digestive system. Studies on their possible anti-inflammatory effects on the colonic mucosa and biochemical parameters of blood in ulcerative colitis have not been performed. Therefore, the aim is to evaluate the anti-inflammatory effectiveness of vegetable oils (flaxseed and milk thistle, obtained by different methods of pressing) in a model of acute colitis in rats. Object of research: biochemical mechanisms of realization of influence of thistle and flaxseed oils of different methods of extraction at ulcerative colitis. The effects of linseed and milk thistle oils obtained by cold pressing (to 45°C) and hot pressing (to 95°C) on the development of acute colitis in rats, when administered with food, have been investigated. It was shown that the use of linseed oil both cold and hot-pressed under conditions of adding it to the feed in an amount of 10% for 2 weeks prevents the development of inflammatory and destructive changes in the colon of rats with acute colitis and its negative consequences in the liver (for approaching to the normal values of serum markers of its functional activity). These oil properties could be realized partially by unsaturated fatty acids, in particular ω3, including minor ones. The data obtained may indicate that one of the mechanisms of implementation of the anti-inflammatory action of these substances is their ability to reduce oxidative stress - one of the main factors and promoters of inflammation.
Background. Previously, we have detected the antitumor and anti-inflammatory activities of pyrrole-derived protein kinase inhibitors - MI-1 (1-(4-Cl-benzyl)-3-Cl-4-(CF3-phenylamino) -1H-pyrrole-2,5-dione 1) and D1 (5-amino-4-(1,3-benzothiazole-2-yl)-1-(3-methoxyphenyl)-1,2-dihydro-3H-pyrrole-3-one) using rat colon cancer model. Therefore, pyrrole derivatives was aimed at detecting the anti-inflammatory effect on the model of ulcerative colitis caused by acetic acid in rats. Materials and Methods. Prednisolone was used as a reference anti-inflammatory drug of glucocorticoid nature. It was administered intraperitoneally at a dose of 0.7 mg/kg. The compounds were administered in 2 h after the first administration of acetic acid. Total protein was estimated quantitatively, as described by Lowry et al., 1951. Content of the malonic dialdehyde, protein carbonyl groups, and the activity of antioxidant enzymes as indicators of colon mucosa redox status were measured spectrophotometrically. Statistical analysis of the results was performed using MS Excel-2013. Results and Discussion. In case of chronic colitis, the number of carbonyl groups and lipid peroxidation products in the colonic mucosa are increased, indicating the development of oxidative stress. The injection of pyrrole derivatives separately contributes to the approaching these indicators to normal. Adding prednisolone does not have this effect. Colitis has been shown to have a decrease in superoxide dismutase activity, which is a typical phenomenon for chronic inflammation and may indicate depletion of the enzyme. In case of colitis, alanine aminotransferase activity and the content of direct bilirubin are increased, which indicates a liver injury and are systemic manifestations of inflammation of the colon. Pyrrole derivatives help to reduce the liver injury, which indicates the restoration of normal alanine aminotransferase activity and direct bilirubin content. Conclusion. It has been found that at chronic colitis pyrrole derivatives reduce the manifestations of inflammation, contribute to the normal structure of the mucous membrane (comparative to prednisolone as a standard anti-inflammatory drug). It suggests their anti-inflammatory effectiveness, while an increase in total bilirubin under exposition to pyrrole derivatives may be a sign of the adverse effects on the rat’s liver.
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