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      Assessment of the effects of levosimendan and thymoquinone on lung injury after myocardial ischemia reperfusion in rats

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          Abstract

          Aim

          The aim of this study was to investigate the effects of levosimendan and thymoquinone (TQ) on lung injury after myocardial ischemia/reperfusion (I/R).

          Materials and methods

          Twenty-four Wistar albino rats were included in the study. The animals were randomly assigned to 1 of 4 experimental groups. In Group C (control group), left anterior descending artery was not occluded or reperfused. Myocardial I/R was induced by ligation of the left anterior descending artery for 30 min, followed by 2 h of reperfusion in the I/R, I/R-levosimendan (24 µg/kg) (IRL) group, and I/R-thymoquinone (0.2 mL/kg) (IRTQ) group. Tissue samples taken from the lungs of rats were histochemically stained with H&E and immunohistochemically stained with p53, Bcl 2, Bax, and caspase 3 primer antibodies.

          Results

          Increased expression of p53 and Bax was observed (4+), especially in the I/R group. In IRTQ and IRL groups, expression was also observed at various locations (2+, 3+). H&E staining revealed that that the lungs were severely damaged and the walls of the alveoli were too thick, the number of areas examined was increased during the evaluation. Caspase 3 expression was observed to be at an (1+, 2+) intensity that was usually weak and diffuse in multiple areas. Bcl 2 was not found to be expressed in any of the tissues. H&E staining revealed that that the lungs were severely damaged in the I/R group, with the walls of the channels and alveoli thickened and edematous, and also an intense inflammatory cell migration was observed. Immunohistochemical staining was more prominent in inflammatory areas and structures around the terminal bronchioles.

          Conclusion

          The findings in our study have shown that administration of levosimendan and TQ during I/R increases expression of caspase 3, p53, and Bax in lung tissue and has a protective effect on lung as distant organ. We suggest that findings of this study be elucidated with further large-scale clinical studies.

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          Most cited references 37

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          Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan.

          The molecular background of the Ca(2+)-sensitizing effect of levosimendan relates to its specific interaction with the Ca(2+)-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K(+) channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP-sensitive K(+) channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug-receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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            Inhibition of GSK3beta by postconditioning is required to prevent opening of the mitochondrial permeability transition pore during reperfusion.

            Opening of the mitochondrial permeability transition pore (mPTP) is a crucial event in lethal reperfusion injury. Phosphorylation (inhibition) of glycogen synthase kinase-3beta (GSK3beta) has been involved in cardioprotection. We investigated whether phosphorylated GSK3beta may protect the heart via the inhibition of mPTP opening during postconditioning. Wild-type and transgenic GSK3beta-S9A mice (the cardiac GSK3beta activity of which cannot be inactivated) underwent 60 minutes of ischemia and 24 hours of reperfusion. At reperfusion, wild-type and GSK3beta-S9A mice received no intervention (control), postconditioning (3 cycles of 1 minute ischemia and 1 minute of reperfusion), the mPTP inhibitor cyclosporine A (CsA; 10 mg/kg IV), or the GSK3beta inhibitor SB216763 (SB21; 70 microg/kg IV). Infarct size was assessed by triphenyltetrazolium chloride staining. The resistance of the mPTP to opening after Ca(2+) loading was assessed by spectrofluorometry on mitochondria isolated from the area at risk. In wild-type mice, infarct size was significantly reduced by postconditioning, CsA, and SB21, averaging 39+/-2%, 35+/-5%, and 37+/-4%, respectively, versus 58+/-5% of the area at risk in control mice (P<0.05). In GSK3beta-S9A mice, only CsA, but not postconditioning or SB21, reduced infarct size. Postconditioning, CsA, and SB21 all improved the resistance of the mPTP in wild-type mice, but only CsA did so in GSK3beta-S9A mice. These results suggest that S9-phosphorylation of GSK3beta is required for postconditioning and likely acts by inhibiting the opening of the mitochondrial permeability transition pore.
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              Thymoquinone: a promising anti-cancer drug from natural sources.

              There has been growing interest in naturally occurring compounds with anti-cancer potential. Black seed is one of the most extensively studied plants. This annual herb grows in countries bordering the Mediterranean Sea and India. Thymoquinone (TQ) is the bioactive constituent of the volatile oil of black seed. It has been shown to exert anti-neoplastic and anti-inflammatory effects. The molecular pathways of TQ action are not clear. Nevertheless, TQ is known to induce apoptosis by p53-dependent and p53-independent pathways in cancer cell lines. Growth inhibition is associated with induction of cell cycle arrest. TQ also acts on the immune system by modulating the levels of inflammatory mediators. To date, the chemotherapeutic potential of TQ in the clinic has not been tested, but numerous studies have shown its promising anti-cancer effects in animal models. The combination of TQ with clinically used anti-cancer drugs has led to improvements in their therapeutic index and prevents non-tumor tissues from sustaining chemotherapy-induced damage.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                22 May 2018
                : 12
                : 1347-1352
                Affiliations
                [1 ]Department of Histology and Embryology, Kirikkale University Medical Faculty, Kirikkale, Turkey
                [2 ]Department of Physiology, Dumlupinar University Medical Faculty, Kutahya, Turkey
                [3 ]Department of Cardiovascular Surgery, Gazi University Medical Faculty, Ankara, Turkey
                [4 ]Pediatric Cardiovascular Surgery Clinic, Dr Siyami Ersek Cardiovascular and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey
                [5 ]Department of Anaesthesiology and Reanimation, Gazi University Medical Faculty, Ankara, Turkey
                [6 ]Department of Histology and Embryology, Afyon Kocatepe University Medical Faculty, Afyonkarahisar, Turkey
                Author notes
                Correspondence: Mustafa Arslan, Department of Anesthesiology and Reanimation, Gazi University Medical Faculty, 06510 Ankara, Türkiye, Tel +90 312 202 6739; +90 533 422 8577, Fax +90 312 202 4166, Email marslan36@ 123456yahoo.com ; mustarslan@ 123456gmail.com
                Article
                dddt-12-1347
                10.2147/DDDT.S160092
                5968782
                © 2018 Sezen et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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