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      Protective Effect of Methylxanthine Fractions Isolated from Bancha Tea Leaves against Doxorubicin-Induced Cardio- and Nephrotoxicities in Rats

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          Abstract

          Doxorubicin is an anthracycline antibiotic that is used for the treatment of various types of cancer. However, its clinical usage is limited due to its potential life-threatening adverse effects, such as cardio- and nephrotoxicities. Nonetheless, simultaneous administration of doxorubicin and antioxidants, such as those found in green tea leaves, could reduce cardiac and renal tissue damage caused by oxidative stress. The methylxanthine fraction isolated from Bancha tea leaves were tested in vitro for its antioxidant activity and in vivo for its organoprotective properties against doxorubicin-induced cardio- and nephrotoxicities in a rat model. The in vivo study was conducted on male Wistar rats divided into 6 groups. Methylxanthines were administered at high (5 mg/kg body weight) and low (1 mg/kg body weight) doses, while doxorubicin was administered at a cumulative dose of 20 mg/kg body weight. Serum creatinine, uric acid, and urea concentrations, as well as serum enzyme levels (creatinine kinase (CK), creatinine kinase MB fraction (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH)) and electrolytes (Na +, K +, and Cl ), were analysed. In addition, histological analysis was performed to assess cardiac and renal tissue damage. The concomitant administration of Bancha methylxanthines and doxorubicin showed a dose-dependent reduction in the serum biochemical parameters, indicating a decrease in the cardiac and renal tissue damage caused by the antibiotic. Histological analysis showed that pretreatment with methylxanthines at the dose of 5 mg/kg resulted in an almost normal myocardial structure and a significant decrease in the morphological kidney changes caused by doxorubicin exposure compared with the group that received doxorubicin alone. The putative mechanism is most likely related to a reduction in the oxidative stress caused by doxorubicin.

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          Antioxidants from black and green tea: from dietary modulation of oxidative stress to pharmacological mechanisms.

          The consumption of tea (Camellia sinensis) has been correlated with a low incidence of chronic pathologies, such as cardiovascular disease and cancer, in which oxidative stress plays a critical role. Tea catechins and theaflavins are, respectively, the bioactive phytochemicals responsible for the antioxidant activity of green tea (GT) and black tea (BT). In addition to their redox properties, tea catechins and theaflavins could have also pharmacological activities, such as the ability to lower glucose, lipid and uric acid (UA) levels. These activities are mediated by pharmacological mechanisms such as enzymatic inhibition and interaction with transporters. Epigallocatechin gallate is the most active compound at inhibiting the enzymes involved in cholesterol and UA metabolism (hydroxy-3-methyl-glutaryl-CoA reductase and xanthine oxidase respectively) and affecting glucose transporters. The structural features of catechins that significantly contribute to their pharmacological effect are the presence/absence of the galloyl moiety and the number and positions of the hydroxyl groups on the rings. Although the inhibitory effects on α-glucosidase, maltase, amylase and lipase, multidrug resistance 1, organic anion transporters and proton-coupled folate transport occur at higher concentrations than those apparent in the circulation, these effects could be relevant in the gut. In conclusion, despite the urgent need for further research in humans, the regular consumption of moderate quantities of GT and BT can effectively modulate their antioxidant capacity, mainly in people subjected to oxidative stress, and could improve the metabolism of glucose, lipid and UA.
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            In vitro antioxidant activity of coffee compounds and their metabolites.

            In this paper we report the antioxidant activity of different compounds which are present in coffee or are produced as a result of the metabolism of this beverage. In vitro methods such as the ABTS*+ [ABTS = 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)] decolorization assay and the oxygen radical absorbance capacity assay (ORAC) were used to assess the capacity of coffee compounds to scavenge free radicals. The importance of caffeine metabolites and colonic metabolites in the overall antioxidant activity associated with coffee consumption is shown. Colonic metabolites such as m-coumaric acid and dihydroferulic acid showed high antioxidant activity. The ability of these compounds to protect human low-density lipoprotein (LDL) oxidation by copper and 2,2'-azobis(2-amidinopropane) dihydrochloride was also explored. 1-Methyluric acid was particularly effective at inhibiting LDL oxidative modification. Different experiments showed that this caffeine metabolite is not incorporated into LDL particles. However, at physiologically relevant concentrations, it was able to delay for more than 13 h LDL oxidation by copper.
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              Cardioprotective mechanisms of phytochemicals against doxorubicin-induced cardiotoxicity.

              Doxorubicin (DOX) is an anthracycline antibiotic, which is effectively used in the treatment of different malignancies, such as leukemias and lymphomas. Its most serious side effect is dose-dependent cardiotoxicity, which occurs through inducing oxidative stress apoptosis. Due to the myelosuppressive effect of dexrazoxane, a commonly-used drug to alleviate DOX-induced cardiotoxicity, researchers investigated the potential of phytochemicals for prophylaxis and treatment of this condition. Phytochemicals are plant chemicals that have protective or disease preventive properties. Preclinical trials have shown antioxidant properties for several plant extracts, such as those of Aerva lanata, Aronia melanocarpa, Astragalus polysaccharide, and Bombyx mori plants. Other plant extracts showed an ability to inhibit apoptosis, such as those of Astragalus polysaccharide, Azadirachta indica, Bombyx mori, and Allium stavium plants. Unlike synthetic agents, phytochemicals do not impair the clinical activity of DOX and they are particularly safe for long-term use. In this review, we summarized the results of preclinical trials that investigated the cardioprotective effects of phytochemicals against DOX-induced cardiotoxicity. Future human trials are required to translate these cardioprotective mechanisms into practical clinical implications.
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                Author and article information

                Contributors
                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi
                2314-6133
                2314-6141
                2020
                11 August 2020
                : 2020
                : 4018412
                Affiliations
                1Department of Pharmacology, Toxicology and Pharmacotherapy, Faculty of Pharmacy, Medical University “Prof. Dr. Paraskev Stoyanov”, Varna 9000, Bulgaria
                2Department of Biology, Faculty of Pharmacy, Medical University “Prof. Dr. Paraskev Stoyanov”, Varna 9000, Bulgaria
                3Department of General and Clinical Pathology, Forensic Medicine and Deontology, Division of General and Clinical Pathology, Faculty of Medicine, Medical University “Prof. Dr. Paraskev Stoyanov”, Varna 9000, Bulgaria
                Author notes

                Academic Editor: Mauro S. Oliveira

                Author information
                https://orcid.org/0000-0001-5778-4043
                https://orcid.org/0000-0003-1839-1452
                https://orcid.org/0000-0002-8760-8654
                https://orcid.org/0000-0002-0528-0289
                https://orcid.org/0000-0001-6678-2461
                https://orcid.org/0000-0002-0731-3937
                https://orcid.org/0000-0001-7893-8822
                Article
                10.1155/2020/4018412
                7439203
                6ae77b4e-b084-4149-99b7-c2c4633d27e0
                Copyright © 2020 Maya P. Radeva-Ilieva et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 February 2020
                : 18 June 2020
                : 21 July 2020
                Funding
                Funded by: Science Fund of Medical University “Prof. Dr. Paraskev Stoyanov,”
                Categories
                Research Article

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