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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In recent years&#44; cancer has become more prevalent&#44; and it is estimated that 13&#46;1 million people will die of cancer by 2030&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">1&#44;2</span></a> Treating cancer has become a highly complex process&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">3</span></a> Anthracyclines are a class of chemotherapeutic drugs used to treat various malignancies in both adult and pediatric patients&#46; The most popular anthracycline&#44; doxorubicin &#40;also called adriamycin&#41; &#40;DOX&#41;&#44; is used to treat a variety of malignant tumors&#44; such as acute leukemia&#44; lymphomas&#44; ovarian&#44; testicular&#44; lung&#44; thyroid&#44; breast&#44; among others&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">4&#44;5</span></a> It is one of the most efficient anthracycline antibiotics and a frontline chemotherapeutic agent for the treatment of cancer&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">6&#44;7</span></a> While doxorubicin has broad anticancer efficacy&#44; due to its negative consequences&#44; its therapeutic application is restricted&#44; particularly in life-threatening cardiac toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">8</span></a> Clinically&#44; DOX-induced cardiotoxicity is defined by an increase in ventricular wall thickening that can result in mortality&#44; aberrant arrhythmias&#44; congestive heart failure &#40;HF&#41;&#44; and a reduction in left ventricular ejection fraction&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">9</span></a> It shows dose-dependent cardiotoxicity&#44; which is linked to a decrease in left ventricular function or HF in 7&#8211;26&#37; of patients treated with doxorubicin &#40;550 mg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">10&#44;11</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Arrhythmias&#44; ischemia&#44; systolic dysfunction&#44; and HF are all manifestations of doxorubicin-induced cardiotoxicity&#44; and the major causes are cardiac cell death and necrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">12</span></a> Cardiomyocytes are more prone to doxorubicin toxicity than other tissues because they have lower antioxidant levels&#44; a higher reliance on oxidative substrate metabolism&#44; and a higher mitochondria volume than tumor cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">13&#44;14</span></a> Chelidonic acid &#40;CA&#41; is a secondary metabolite found in several plants&#44; such as <span class="elsevierStyleItalic">Chelidonium majus</span> L&#46; It possesses anti-inflammatory&#44; anti-allergic&#44; anti-ulcerative colitis&#44; and neurological sedative properties&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">15&#8211;18</span></a> CA also has many known therapeutic effects&#44; such as being a mild analgesic&#44; antimicrobial&#44; and oncostatic&#59; in the central nervous system&#44; it acts as a sedative&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">19</span></a> It also inhibits TNF-&#945; production in ulcerative colitis in rats&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">15</span></a> CA inhibits nuclear factor kappa B &#40;Nf-kB&#41; and activates mast cell caspase-1&#44; a component of the AMP-activated protein kinase signaling pathway&#44; to decrease the generation of IL-6&#46; Our previous study reported the beneficial effects of CA in cisplatin-induced nephrotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">20</span></a> CA can be useful to relieve the toxic effects of doxorubicin in myocardial tissue without interfering with its anticancer activity&#46; This study&#44; therefore&#44; aimed to investigate any possible defense that CA might have against the cardiotoxicity that DOX causes in rats&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Objective</span><p id="par0015" class="elsevierStylePara elsevierViewall">This study was designed to investigate the possible cardioprotective effect of CA in DOX-induced cardiac toxicity in rats&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methods</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Chemicals</span><p id="par0020" class="elsevierStylePara elsevierViewall">Chelidonic acid&#44; 5-5-dithio bis-&#40;2-nitrobenzoic acid&#41;&#44; and thiobarbituric acid were procured from Sigma Aldrich &#40;St&#46; Louis&#44; MO&#44; USA&#41;&#46; Doxorubicin hydrochloride USP &#40;Batch&#35; 062103092&#41; was received as a gift sample from Khandelwal Laboratories&#44; India&#46; Kits of creatine kinase-MB and lactate dehydrogenase were purchased from Transasia Biomedicals Ltd&#46;&#44; India&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Experimental animals</span><p id="par0025" class="elsevierStylePara elsevierViewall">Male Wistar rats &#40;170&#8211;200 g&#41; were purchased from the National Institute of Biosciences in Pune&#44; Maharashtra&#44; India&#44; and kept in an environment with a 12-hour light&#47;dark cycle&#46; Purified water and multi-nutritional pellet food &#40;Nutrimix Laboratory Animal Feed&#44; India&#41; were available at all times&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Doxorubicin-induced cardiac toxicity in rats</span><p id="par0030" class="elsevierStylePara elsevierViewall">Doxorubicin was solubilized in the normal saline solution and injected intraperitoneally at 1&#46;25 mg&#47;kg&#44; four times per week for four weeks&#44; the total cumulative dose was 20 mg&#47;kg&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">21&#8211;23</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Experimental design</span><p id="par0035" class="elsevierStylePara elsevierViewall">A total of 42 male Wistar rats were used in this study&#46; They were split up into six groups at random&#44; each containing seven rats&#46; The details of each group are as follows&#58;</p><p id="par0040" class="elsevierStylePara elsevierViewall">0&#46;5&#37; carboxymethyl cellulose and saline solution were used as vehicles for CA and doxorubicin&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">24&#44;25</span></a><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><p id="par0045" class="elsevierStylePara elsevierViewall">Group 1&#46; <span class="elsevierStyleItalic">Normal</span>&#58; Rats were administered 0&#46;5&#37; carboxymethyl cellulose &#40;1 ml&#47;kg&#47;day&#44; <span class="elsevierStyleItalic">p&#46;o&#46;</span>&#41; using oral gavage for a period of four weeks and saline solution &#40;vehicle of DOX&#41; &#40;1 ml&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41; four times per week for four weeks&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Group 2&#46; <span class="elsevierStyleItalic">DOX</span>&#58; Rats were administered 0&#46;5&#37; carboxymethyl cellulose &#40;1 ml&#47;kg&#47;day&#44; <span class="elsevierStyleItalic">p&#46;o&#46;</span>&#41; using oral gavage for four weeks and DOX &#40;1&#46;25 mg&#47;kg&#44; cumulative dose 20 mg&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41; four times per week for four weeks&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><p id="par0055" class="elsevierStylePara elsevierViewall">Group 3&#46; <span class="elsevierStyleItalic">DOX&#43;DEX</span>&#58; Rats were administered DOX &#40;1&#46;25 mg&#47;kg&#44; cumulative dose 20 mg&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41; and DEX &#40;50 mg&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41; 30 minutes before DOX administration&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><p id="par0060" class="elsevierStylePara elsevierViewall">Group 4&#46; <span class="elsevierStyleItalic">DOX&#43;CA &#40;10 mg&#47;kg</span>&#41;&#58; Rats were administered DOX &#40;1&#46;25 mg&#47;kg&#44; cumulative dose 20 mg&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41; and CA 10 mg&#47;kg&#47;day <span class="elsevierStyleItalic">p&#46;o&#46;</span> for four weeks&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><p id="par0065" class="elsevierStylePara elsevierViewall">Group 5&#46; <span class="elsevierStyleItalic">DOX&#43;CA &#40;20 mg&#47;kg</span>&#41;&#58; Rats were administered DOX &#40;1&#46;25 mg&#47;kg&#44; cumulative dose 20 mg&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41; and CA 20 mg&#47;kg&#47;day <span class="elsevierStyleItalic">p&#46;o&#46;</span> for four weeks&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><p id="par0070" class="elsevierStylePara elsevierViewall">Group 6&#46; <span class="elsevierStyleItalic">DOX&#43;CA &#40;40 mg&#47;kg</span>&#41;&#58; Rats were administered DOX &#40;1&#46;25 mg&#47;kg&#44; cumulative dose 20 mg&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41; and CA 40 mg&#47;kg&#47;day <span class="elsevierStyleItalic">p&#46;o&#46;</span> for four weeks&#46;</p></li></ul></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Electrocardiogram and hemodynamic parameters</span><p id="par0075" class="elsevierStylePara elsevierViewall">At the end of the study&#44; rats were anesthetized with urethane &#40;1&#46;25 gm&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41;&#46; Each animal was positioned supine on an ECG board&#44; and ECG was continuously recorded using normal three-lead skin electrodes&#44; &#43;ve&#44; &#8722;ve&#44; and neutral &#40;the needle electrodes 29-gauge&#44; 12 mm&#41; in lead II position using a data acquisition system &#40;AD Instruments&#44; Australia&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Blood pressure</span><p id="par0080" class="elsevierStylePara elsevierViewall">To perform a tracheotomy&#44; the neck region of the rat was opened with a ventral midline incision&#44; and then the right carotid artery was cannulated with a polyethylene tube attached to a three-way cannula and the mean arterial pressure&#44; systolic pressure&#44; and diastolic pressure were measured&#46; Left ventricular end-diastolic pressure &#40;LVEDP&#41;&#44; and maximum and minimum rate of ventricular contraction &#40;&#43;dp&#47;dt&#44; 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Total protein in heart tissue homogenate was measured using the Bradford Protein Assay as per Bradford<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">26</span></a> method&#46;</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Estimation of oxidative stress</span><p id="par0100" class="elsevierStylePara elsevierViewall">Lipid peroxidation &#40;LPO&#41; was measured as a malondialdehyde &#40;MDA&#41; concentration&#44; and MDA level in heart tissue was measured by thiobarbituric acid reactive substances &#40;TBARS&#41; assay described by Ohkawa &#40;1979&#41;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">27</span></a>&#46; In the TBARS assay&#44; total homogenate was used to determine thiobarbituric acid reactive substances&#46; Reduced glutathione levels in heart tissue were estimated using the method given by Ellman&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">28</span></a> Post-nuclear fraction of homogenate which was prepared by centrifugation at 2500 <span class="elsevierStyleItalic">g</span> for 10 min was used to estimate catalase activity in heart tissue as per the method described by Luck&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">29</span></a> Superoxide dismutase activity was measured in post-mitochondrial fraction of homogenate&#44; which was prepared by centrifugation at 10<span class="elsevierStyleHsp" style=""></span>000 <span class="elsevierStyleItalic">g</span> for 20 minutes as per the method described by Paoletti and Mocali&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">30</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Estimation of nitric oxide</span><p id="par0105" class="elsevierStylePara elsevierViewall">The tissue homogenate was mixed with an equal quantity of Griess reagent&#44; and absorbance was determined at 540 nm using a microplate spectrophotometer &#40;BioTek-Epoch 2&#41;&#46; NO concentration was expressed as &#956;M&#47;L of NO&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Estimation of Nrf2 and release of pro-inflammatory cytokines</span><p id="par0110" class="elsevierStylePara elsevierViewall">Nrf2 and the release of TNF-&#945; and IL-6 were measured by using sandwich ELISA methods according to the manufacturer&#39;s protocol &#40;Abbkine&#44; USA&#41;&#46; Levels of C-reactive protein &#40;CRP&#41; were determined using diagnostic kits &#40;Transasia Bio-Medicals Ltd&#46;&#44; India&#41;&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Histopathological examination</span><p id="par0115" class="elsevierStylePara elsevierViewall">Heart tissue was stored in a 10&#37; neutral buffer formalin solution&#46; The organ specimens were treated with xylene for dehydration and alcohol for 2 h&#46; The infiltration and impregnation were carried out by treatment with paraffin wax twice&#46; Specimens were cut into sections of 3&#8211;5 &#956;m thickness and embedded in paraffin&#46; Serial sections &#40;3 &#956;m&#41; were cut using a microtome&#46; The sections were stained with hematoxylin and eosin and Masson&#39;s trichrome&#46; Sections were examined under the light microscope for myocardial injury and progression of fibrosis &#40;Motic&#44; Canada&#41;&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Statistical analysis</span><p id="par0120" class="elsevierStylePara elsevierViewall">The data were expressed as mean&#177;SEM for each group&#46; Statistical analysis was performed using the one-way analysis of variance followed by Dunnett&#39;s post-hoc test&#46; The data was analyzed using Graph Pad Prism 8 software &#40;California&#44; USA&#41;&#46;</p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Results</span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Effect of chelidonic acid on body weight and heart weight&#47;body weight ratio &#40;HW&#47;BW ratio&#41;</span><p id="par0125" class="elsevierStylePara elsevierViewall">DOX &#8211; treated group showed a significant decrease in body weight when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at a dose of 10&#44; 20&#44; and 40 mg&#47;kg significantly elevated the body weight of animals as compared to the DOX-treated group &#40;p&#60;0&#46;001&#41;&#46; Standard dexrazoxane-treated rats showed a significant increase in body weight when compared with DOX-treated rats &#40;p&#60;0&#46;01&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>A&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">DOX-treated rats showed significant elevation in HW&#47;BW ratio when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly reduced the HW&#47;BW ratio as compared with the DOX &#8211; treated rats&#46; Dexrazoxane treated animals showed a significant decrease in HW&#47;BW ratio as compared with only DOX-treated animals &#40;p&#60;0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>B and C&#41;&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Effect of chelidonic acid on electrocardiogram</span><p id="par0135" class="elsevierStylePara elsevierViewall">Chelidonic acid treatment normalized the electrocardiogram pattern in rats&#46; The DOX - treated group showed significant elevation in ST height when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly reduced the ST height when compared with DOX &#8211; treated rats &#40;p&#60;0&#46;001 and p&#60;0&#46;01&#41;&#46; Dexrazoxane-treated animals showed a significant decline in the ST height when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;01&#41; &#40;<a class="elsevierStyleCrossRefs" href="#fig0010">Figures 2 and 3A</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">DOX - treated rats showed had increased QT interval when compared with the normal animals &#40;p&#60;0&#46;01&#41;&#46; CA at dose range significantly decreased the QT interval when compared with DOX &#8211; treated rats &#40;p&#60;0&#46;01 and p&#60;0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>B&#41;&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">QRS interval and QTc were significantly increased in DOX &#8211; treated animals when compared with the normal group &#40;p&#60;0&#46;01 and p&#60;0&#46;001&#41;&#46; CA treatment at doses of 10 and 20 mg&#47;kg significantly reduced the QRS interval when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;01 and p&#60;0&#46;05&#41;&#46; Dexrazoxane treated animals showed a significant decrease in the QRS interval&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly decreased the QTc&#46; Standard dexrazoxane-treated animals showed a significant decrease in the QTc &#40;p&#60;0&#46;01&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>C and D&#41;&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Effect of chelidonic acid on hemodynamic parameters</span><p id="par0150" class="elsevierStylePara elsevierViewall">DOX &#8211; treated group of animals exhibited an increase in heart rate when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly declined the heart rate when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;001 and p&#60;0&#46;05&#41;&#46; Dexrazoxane treated rats showed a significant decrease in heart rate when compared with the DOX - treated animals &#40;p&#60;0&#46;01&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>A&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">Hemodynamic parameters in DOX-treated animals were significantly altered&#46; DOX &#8211; treated animals showed a decrease in systolic blood pressure when compared with the normal group &#40;p&#60;0&#46;01&#41;&#46; CA at a dose of 40 mg&#47;kg significantly increased the systolic blood pressure when compared with only DOX-treated group &#40;p&#60;0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>B&#41;&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">The DOX-treated animals showed a significant reduction in diastolic blood pressure when compared with the normal group &#40;p&#60;0&#46;01&#41;&#46; CA treatment at the entire dose range significantly increased the diastolic blood pressure when compared with the DOX - treated group &#40;p&#60;0&#46;05 and p&#60;0&#46;01&#41;&#46; Mean blood pressure was significantly reduced in DOX &#8211; treated animals when compared with the normal group &#40;p&#60;0&#46;01&#41;&#46; CA treatment at doses of 20 and 40 mg&#47;kg significantly increased the mean arterial blood pressure when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;05&#41;&#46; These changes in hemodynamic parameters were prevented by the CA treatments &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>C and D&#41;&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Effect of chelidonic acid on ventricular activity</span><p id="par0165" class="elsevierStylePara elsevierViewall">The DOX-treated group showed significant elevation in LVEDP when compared to the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly decreased it when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;05&#44; p&#60;0&#46;001&#44; and p&#60;0&#46;05&#41;&#46; Dexrazoxane treated rats showed a significant reduction in LVEDP when compared with the DOX - treated group &#40;p&#60;0&#46;05&#41;&#46; DOX &#8211; treated group showed a significant decrease in LVSP when compared to the normal group &#40;p&#60;0&#46;05&#41; and isovolumic relaxation constant &#40;tau&#41; was significantly decreased in the DOX &#8211; treated group when compared with the normal group &#40;p&#60;0&#46;05&#41;&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">There was a significant decrease in &#43;dp&#47;dt and &#8722;dp&#47;dt in the DOX &#8211; treated rats compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at doses of 20 and 40 mg&#47;kg led to a significant elevation in &#43;dp&#47;dt when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;01 and p&#60;0&#46;001&#41;&#46; Also&#44; CA treatment &#40;40 mg&#47;kg&#41; significantly increased &#8722;dp&#47;dt when compared with the DOX - treated group &#40;p&#60;0&#46;01&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Effect of chelidonic acid on cardiac markers</span><p id="par0175" class="elsevierStylePara elsevierViewall">The DOX &#8211; treated rats exhibited significant elevation in cardiac markers such as LDH and AST&#46; CA at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly reduced LDH and AST levels when compared with the DOX &#8211; treated group&#46; Dexrazoxane treated animals showed a significant decrease in the LDH when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;001&#41;&#46; CK-MB concentration was significantly increased in the DOX - treated group and treatment with CA &#40;10&#44; 20&#44; and 40 mg&#47;kg&#41; revealed a significant decrease in CK-MB when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;01&#44; p&#60;0&#46;05&#44; and p&#60;0&#46;001&#41;&#46; The dexrazoxane-treated group showed a significant reduction in the CK-MB&#46; In the DOX &#8211; treated group&#44; there was a significant increase in cTn-T level when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly decreased cTn-T level when compared with the DOX - treated group &#40;p&#60;0&#46;01&#44; p&#60;0&#46;001&#44; and p&#60;0&#46;001&#41;&#46; Dexrazoxane treated animals showed a significant decrease in the cTn-T when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;01&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Effect of chelidonic acid on inflammatory cytokines</span><p id="par0180" class="elsevierStylePara elsevierViewall">In the DOX &#8211; treated group&#44; there was an increase in CRP&#44; TNF-&#945; and IL-6 concentration when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment &#40;10&#44; 20&#44; and 40 mg&#47;kg&#41; significantly decreased the CRP&#44; TNF-&#945; and IL-6 concentration when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;001 and p&#60;0&#46;01&#41;&#46; In dexrazoxane-treated animals&#44; a significant decrease in TNF-&#945; and IL-6 concentrations was observed &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Figure 5</a>A&#8211;C&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Effect of chelidonic acid on oxidative stress&#44; NO and Nrf2 concentration</span><p id="par0185" class="elsevierStylePara elsevierViewall">In the DOX &#8211; treated animals&#44; there was a significant decrease in GSH and SOD levels and treatment with chelidonic acid &#40;10&#44; 20&#44; and 40 mg&#47;kg&#41; significantly increased GSH and SOD levels when compared with the DOX &#8211; treated group &#40;GSH&#58; p&#60;0&#46;01&#44; p&#60;0&#46;001&#44; p&#60;0&#46;001 and SOD&#58; p&#60;0&#46;01&#44; p&#60;0&#46;001&#44; p&#60;0&#46;01&#41;&#46; Among dexrazoxane-treated rats&#44; there was a significant increase in GSH and SOD levels&#46; In the DOX &#8211; treated group&#44; there was a noteworthy increase in the MDA level when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment &#40;10&#44; 20&#44; and 40 mg&#47;kg&#41; reduced the MDA level substantially&#46; Among standard dexrazoxane-treated rats&#44; there was a significant decrease in the MDA level when compared with DOX &#8211; treated group &#40;p&#60;0&#46;01&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Figure 6</a>A&#8211;C&#41;&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0190" class="elsevierStylePara elsevierViewall">Catalase concentration was significantly decreased in DOX &#8211; treated animals when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment &#40;10&#44; 20&#44; and 40 mg&#47;kg&#41; significantly increased the catalase concentration&#46; In the dexrazoxane-treated animals&#44; there was a notable increase in catalase concentration when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;01&#41;&#46; There was a noteworthy rise in NO concentration in the DOX &#8211; treated animals when compared with the normal group &#40;p&#60;0&#46;01&#41;&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg reduced the NO concentration substantially &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Figure 6</a>D and E&#41;&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">The Nrf2 concentration was significantly reduced in DOX &#8211; treated animals as compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly increased the Nrf2 concentration when compared with the DOX - treated animals &#40;p&#60;0&#46;01&#44; p&#60;0&#46;001&#44; and p&#60;0&#46;001&#41;&#46; There was a noteworthy rise in Nrf2 concentration in the standard dexrazoxane-treated group when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Figure 6</a>F&#41;&#46;</p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0190">Effect of chelidonic acid on myocardial histology</span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0195">H&#38;E staining</span><p id="par0200" class="elsevierStylePara elsevierViewall">H&#38;E stain was used to investigate DOX-induced cardiomyopathy&#46; The normal group displayed normal architecture in the cardiomyocytes&#46; Cardiomyocytes in the DOX-treated group displayed intermuscular edema&#44; myofibrillar loss&#44; inflammatory cell infiltration&#44; vacuolization&#44; and cardiomyocyte degradation&#46; CA treatment significantly reduced all these pathological alterations&#44; and the cardiomyocyte architecture was essentially identical to that of the normal group &#40;<a class="elsevierStyleCrossRef" href="#fig0035">Figure 7</a>A&#8211;F&#41;&#46;</p><elsevierMultimedia ident="fig0035"></elsevierMultimedia></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0200">Masson&#39;s trichome staining</span><p id="par0205" class="elsevierStylePara elsevierViewall">The cardiomyocytes of normal rats did not reveal any collagen deposition and fibrosis&#46; In the DOX &#8211; treated animals&#44; there was fibrosis and collagen deposition in the myocardium&#46; Treatment with CA at a dose of 10&#44; 20&#44; and 40 mg&#47;kg led to a reduction in collagen deposition and fibrosis&#46; In the cardiac tissue of the dexrazoxane group&#44; there was reduced collagen deposition &#40;<a class="elsevierStyleCrossRef" href="#fig0040">Figure 8</a>A&#8211;F&#41;&#46;</p><elsevierMultimedia ident="fig0040"></elsevierMultimedia></span></span></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0205">Discussion</span><p id="par0210" class="elsevierStylePara elsevierViewall">The most severe and detrimental side effect of doxorubicin is cardiotoxicity&#46; Doxorubicin-induced cardiotoxicity is caused by a number of processes&#44; including oxidative stress&#44; autophagy&#44; calcium dysregulation&#44; mitochondrial dysfunction&#44; apoptosis&#44; necroptosis&#44; and ferroptosis pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">32</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">The widespread therapeutic use of doxorubicin in oncology still faces significant clinical challenges due to its associated cardiotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">33</span></a> Therefore&#44; it is necessary to ascertain new&#44; reliable chemoprotective agents that could minimize or prevent the negative effects of doxorubicin&#46; In the present study&#44; probable benefits of CA were studied against DOX-induced cardiotoxicity&#46; Study findings demonstrated that CA treatment reduced oxidative stress&#44; inflammation&#44; cardiac fibrosis&#44; and necrosis caused by DOX in rats&#46; Interestingly&#44; CA also prevents DOX-induced cardiac dysfunction in rats&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Biologically active phytochemicals with health advantages are known as nutraceuticals&#46; The use of nutraceuticals in treating a wide range of illnesses is currently gaining attention on a global scale&#46; The field of nutraceuticals can be thought of as one of the pieces lacking an individual&#39;s overall health benefit&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">34</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">Rats given DOX displayed higher heart weight to body weight ratios and lower body weights&#46; The enlarged&#44; dilated&#44; and hypertrophic atrium and ventricles may be responsible for a rise in heart weight&#46; However&#44; in the rats given CA treatment&#44; all the aforementioned alterations were observed to be blocked&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Study findings on the heart&#39;s electrical potential investigations revealed that DOX challenge in rats caused cardiotoxicity&#44; as seen by the changes in ECG indices&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">35</span></a> The effects of DOX on the ECG include an inverted p-wave&#44; a longer PR interval&#44; a prolonged QT&#44; QRS&#44; and QTc interval&#44; as well as an elevation of the ST height&#46; Many studies have reported that p-wave prolongation or increased PR interval in Wistar rats might be associated with high susceptibility to supraventricular arrhythmias following myocardial infarction&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">36</span></a> Supraventricular arrhythmias are associated with QRS complex narrowing&#46; Large QRS complexes signify ventricular arrhythmias&#44; and right and left bundle branch blockages&#44; myocardial ischemia&#44; and cardiac insufficiency all cause disturbances in intraventricular conduction&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">37</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">Chelidonic acid at a dose of 20 and 40 mg&#47;kg considerably reduced the alterations in the p-wave&#44; QRS complex&#44; QT intervals&#44; and ST segments&#46; Heart rate was increased after prolonged doxorubicin treatment&#44; which was in line with earlier studies that supported the theory that disturbances in calcium homeostasis may result from reactive oxygen species formation&#46; The pacemaker cells in the SA node and other cells in the cardiac conducting system might increase or decrease excitability caused by the increase in intracellular calcium&#46; Cardiovascular function&#44; both systolic and diastolic&#44; is compromised by doxorubicin&#46; Additionally&#44; doxorubicin eliminates the cardiac sarcoplasmic reticulum vesicle&#39;s ability to load calcium&#46; Overall&#44; doxorubicin alters calcium homeostasis and affects hemodynamic physiology&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">38</span></a> Hence&#44; LVEDP&#44; dp&#47;dt max&#44; and dp&#47;dt min are the direct indicators of cardiac function&#46; In the present study&#44; treatment with CA significantly reversed the LVEDP&#44; systolic&#44; and diastolic blood pressure&#44; which indicates that cardiac function increased significantly&#46; Also&#44; the changes in dp&#47;dt max and dp&#47;dt min were significantly attenuated by CA at 20 and 40 mg&#47;kg&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Raised levels of AST&#44; LDH&#44; cTn-T&#44; and CK-MB in serum are considered indicators of myocardial injury&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">39</span></a> DOX has significantly elevated AST&#44; LDH&#44; cTn-T&#44; and CK-MB&#46; This demonstrates that DOX caused cardiotoxicity in rats&#46; These metabolic alterations caused by DOX were reversed by CA&#46; The considerable rise in blood levels of AST&#44; LDH&#44; cTn-T&#44; and CK-MB following DOX treatment is consistent with other studies that indicate DOX-induced oxidative stress can result in lipid peroxidation and the release of these enzymes into the serum&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">39&#44;40</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">Inflammation of the cardiac tissue is a serious adverse event that has repeatedly been observed in animals given DOX&#46; Additionally&#44; there is strong evidence that DOX triggers a cascade of inflammatory reactions inside the myocardium by activating NF-&#954;B and causing the release of several pro-inflammatory cytokines&#44; including TNF-&#945;&#44; IL-6&#44; and CRP levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">41&#44;42</span></a> Recent research reports have shown that pro-inflammatory cytokines are rising inside cardiac tissue&#44; which may be the pathophysiological cause of DOX-induced cardiomyopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">43</span></a> NF-&#954;B specifically regulates many chemokines&#44; including TNF-&#945;&#44; IL-6&#44; and many others&#44; which are elevated in patients with inflammatory diseases&#46; Consequently&#44; it has been established that TNF-&#945; and IL-6 are excellent targets for molecular treatments used to treat inflammatory illnesses&#46; Shin et al&#46;&#44; reported that&#44; CA suppresses NF-&#954;B translocation to the nucleus&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">16</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">According to the results of our research&#44; cardiac TNF-&#945;&#44; IL-6&#44; and CRP levels were significantly greater in the DOX group than in the normal group&#44; supporting earlier studies that inflammation plays a significant role in the pathophysiology of DOX-induced cardiotoxicity&#46; The results of the current study showed that CA therapy significantly decreased levels of TNF-&#945;&#44; IL-6&#44; and CRP&#44; indicating that CA has a reliable cytoprotective effect against the release of inflammatory mediators by DOX&#46; Also&#44; it was previously reported that CA reduces IL-6 production by blocking nuclear factor kappa B &#40;Nf-kB&#41; and activating caspase-1 in mast cells&#44; which is a part of the AMPK signaling pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">20</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">Doxorubicin administration resulted in a significant rise in lipid peroxidation in rats&#44; which was preceded by marked elevations in MDA&#44; a notable reduction in glutathione &#40;GSH&#41;&#44; and exhaustion of cardiac antioxidant enzymes such as catalase &#40;CAT&#41; and superoxide dismutase &#40;SOD&#41; due to excessive consumption by DOX-generated free radicals&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">44&#44;45</span></a> The elevated levels of GSH&#44; SOD&#44; and catalase and decreased levels of MDA in our study are due to CA&#39;s antioxidant properties&#44; which suppressed the oxidative process in the heart&#46; Nuclear factor erythroid 2-related factor &#40;Nrf2&#41; is expressed less when ROS levels are elevated&#44; which makes cells more susceptible to oxidative stress and death&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">46</span></a> DOX significantly raised the concentration of NO in the myocardium&#46; NOS is successfully converted by DOX from a source of nitric oxide &#40;NO&#41; to one that produces superoxide&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">47</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">According to the reported studies&#44; DOX reduces Nrf2 concentration which results in oxidative stress-related damage&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">48</span></a> Nrf2 activation can reduce the oxidative stress brought on by DOX and inhibit autophagy&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">49</span></a> These findings suggest that CA is involved in the regulation of Nrf2 concentration and that it has an inhibitory effect on oxidative stress&#44; as seen by a drop in MDA and a rise in GSH levels&#44; which points to its expected cardioprotective mechanism&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">DOX treatment led to significant myocardial edema&#44; cytoplasmic vacuolization&#44; perinuclear vacuolization&#44; disarray of myocardial fibers&#44; and myofibrillar loss&#44; which were all histological abnormalities&#46; These cellular and structural alterations are comparable with various earlier studies on rats in DOX-induced cardiotoxicity&#46;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">50&#44;51</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">The histopathological results of our study showed that CA can lessen cardiac tissue lesions caused by DOX&#44; as shown by the group receiving DOX experiencing a considerable improvement in severity&#46; Masson&#39;s trichrome stained histology of a left ventricular segment from the heart of a rat treated with CA revealed sparse collagen deposition and fibrosis&#46; These findings support earlier reports that CA has an anti-inflammatory response in addition to its direct impact on oxidative stress&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">14&#44;18</span></a></p></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0210">Conclusion</span><p id="par0275" class="elsevierStylePara elsevierViewall">The findings of this study demonstrated that CA restores blood pressure with ECG&#44; inhibits oxidative stress&#44; raises Nrf2 concentration&#44; and reduces fibrosis to protect the heart from DOX-induced cardiotoxicity&#46; Further studies are needed to prove the mechanism of CA in response to DOX-induced cardiotoxicity&#46;</p></span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0215">Ethical approval</span><p id="par0280" class="elsevierStylePara elsevierViewall">All animal experiments were approved by the Ethics Committee and followed the Guide for the Care and Use of Laboratory Animals&#46; The Institutional Animal Ethics Committee &#40;IAEC&#41; of Shri Vile Parle Kelavani Mandal accepted and approved the protocol &#40;protocol approval number &#8211; CPCSEA&#47;IAEC&#47;P-42&#47;2021&#41;&#46;</p></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0220">Funding</span><p id="par0285" class="elsevierStylePara elsevierViewall">This research did not receive any specific grant from any funding agency&#46;</p></span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0225">Authors&#8217; contributions</span><p id="par0290" class="elsevierStylePara elsevierViewall">Y&#46;K&#46;&#44; K&#46;S&#46; and S&#46;K&#46; designed the experiments&#46; S&#46;K&#46; performed the animal experiments&#46; S&#46;K&#46;&#44; Y&#46;K&#46; and K&#46;S&#46; interpreted the results and wrote the manuscript&#46;</p></span><span id="sec0175" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0230">Conflicts of interest</span><p id="par0295" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span><span id="sec0180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0235">Data availability</span><p id="par0300" class="elsevierStylePara elsevierViewall">The data underlying this article will be shared on reasonable request to the corresponding author&#46;</p></span></span>"
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              "titulo" => "Estimation of Nrf2 and release of pro-inflammatory cytokines"
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    "fechaRecibido" => "2023-06-24"
    "fechaAceptado" => "2024-06-12"
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            3 => "Cytokines"
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            0 => "Doxorrubicina"
            1 => "&#193;cido quelid&#243;nico"
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The current study evaluates the effect of chelidonic acid on doxorubicin-induced cardiac toxicity&#46; Chelidonic acid &#40;CA&#41; is a natural pyran-skeleton heterocyclic compound found in rhizomes of the perennial plant&#44; celandine &#40;<span class="elsevierStyleItalic">Chelidonium majus</span>&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Wistar rats were given an intraperitoneal injection of doxorubicin &#40;1&#46;25 mg&#47;kg&#44; cumulative dose of 20 mg&#47;kg&#41; four times per week for a duration of four weeks to induce cardiotoxicity&#46; CA treatment &#40;10&#44; 20&#44; and 40 mg&#47;kg orally for four weeks&#41; was started together with doxorubicin&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">CA treatment reduced myocardial damage and improved cardiac dysfunction in doxorubicin-treated rats&#46; It improved blood pressure&#44; restored ST wave height and normalized the QTc interval compared to the rats treated only with doxorubicin&#46; Administration of CA for four weeks reduced left ventricular end-diastolic pressure&#46; Moreover&#44; CA treatment decreased the level of cardiac markers such as creatine kinase-myocardial band &#40;CK-MB&#41;&#44; lactate dehydrogenase &#40;LDH&#41;&#44; aspartate aminotransferase &#40;AST&#41;&#44; and cardiac troponin-T&#46; Masson&#39;s trichrome&#44; hematoxylin&#44; and eosin staining of heart tissue revealed that CA attenuated the deleterious effects of doxorubicin and prevented further damage and fibrosis in rats&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The study findings confirm that CA treatment can protect the myocardium against doxorubicin-induced cardiotoxicity&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
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            "titulo" => "Introduction and objectives"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introdu&#231;&#227;o e objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">O presente estudo avalia o efeito do &#225;cido quelid&#243;nico na toxicidade card&#237;aca induzida pela doxorrubicina&#46; O &#225;cido quelid&#243;nico &#233; um composto heteroc&#237;clico natural do esqueleto pirano encontrado nos rizomas da planta perene&#44; celid&#243;nia &#40;<span class="elsevierStyleItalic">Chelidonium majus</span>&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Ratos Wistar receberam inje&#231;&#227;o intraperitoneal de doxorrubicina &#40;1&#44;25 mg&#47;kg&#44; dose cumulativa de 20 mg&#47;kg&#41; quatro vezes por semana durante quatro semanas para induzir cardiotoxicidade&#46; O tratamento com &#225;cido quelid&#243;nico &#40;10&#44; 20 e 40 mg&#47;kg por via oral durante quatro semanas&#41; foi iniciado juntamente com a doxorrubicina&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">O tratamento com &#225;cido quelid&#243;nico reduziu o dano mioc&#225;rdico e melhorou a disfun&#231;&#227;o card&#237;aca em ratos tratados com doxorrubicina&#46; O tratamento com &#225;cido quelid&#243;nico melhorou a press&#227;o arterial&#44; bem como restaurou a altura ST e normalizou o intervalo QTc em compara&#231;&#227;o com os &#250;nicos ratos tratados com doxorrubicina&#46; A administra&#231;&#227;o de &#225;cido quelid&#243;nico por quatro semanas reduziu a press&#227;o diast&#243;lica final do ventr&#237;culo esquerdo&#46; Al&#233;m disso&#44; o tratamento com &#225;cido quelid&#243;nico diminuiu o n&#237;vel de marcadores card&#237;acos como creatina quinase-banda mioc&#225;rdica &#40;CK-MB&#41;&#44; lactato desidrogenase &#40;LDH&#41;&#44; aspartato aminotransferase &#40;AST&#41; e troponina T card&#237;aca&#46; A colora&#231;&#227;o com tricr&#243;mico&#44; hematoxilina e eosina de Masson do tecido card&#237;aco revelou que o &#225;cido quelid&#243;nico atenuou os efeitos delet&#233;rios da doxorrubicina e preveniu maiores danos e fibrose em ratos&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclus&#227;o</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Os achados do presente estudo confirmam que o tratamento com &#225;cido quelid&#243;nico pode proteger o mioc&#225;rdio contra a cardiotoxicidade induzida pela doxorrubicina&#46;</p></span>"
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Effect of chelidonic acid on oxidative stress&#44; NO&#44; and Nrf2 concentration&#46; &#40;A&#41; Glutathione &#40;GSH&#41;&#44; &#40;B&#41; malondialdehyde &#40;MDA&#41;&#44; &#40;C&#41; superoxide dismutases &#40;SOD&#41;&#44; &#40;D&#41; catalase &#40;CAT&#41;&#44; &#40;E&#41; nitric oxide &#40;NO&#41; and &#40;F&#41; nuclear factor erythroid 2-related factor 2 &#40;Nrf2&#41;&#46; All values are expressed as mean&#177;SEM &#40;n&#61;7&#41;&#44; &#42;&#42;&#42;p&#60;0&#46;001&#44; &#42;&#42;p&#60;0&#46;01&#44; and &#42;p&#60;0&#46;05 when compared with the DOX &#8211; treated group&#46; <span class="elsevierStyleSup">&#35;&#35;&#35;</span>p&#60;0&#46;001 and <span class="elsevierStyleSup">&#35;&#35;</span>p&#60;0&#46;01 when compared with the normal group&#46;</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "fig0035"
        "etiqueta" => "Figure 7"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr7.jpeg"
            "Alto" => 1029
            "Ancho" => 2050
            "Tamanyo" => 417702
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Effect of chelidonic acid on hematoxylin and eosin staining&#46; &#40;A&#41; Normal&#44; &#40;B&#41; DOX&#44; &#40;C&#41; DOX&#43;DEX&#44; &#40;D&#41; DOX&#43;chelidonic acid &#40;10 mg&#47;kg&#41;&#44; &#40;E&#41; DOX&#43;chelidonic acid &#40;20 mg&#47;kg&#41;&#44; and &#40;F&#41; DOX&#43;chelidonic acid &#40;40 mg&#47;kg&#41; &#40;n&#61;7&#41;&#44; black arrows indicated the damage and cell infiltration&#44; while green arrows indicate the protection against myocardial damage&#46;</p>"
        ]
      ]
      7 => array:7 [
        "identificador" => "fig0040"
        "etiqueta" => "Figure 8"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr8.jpeg"
            "Alto" => 1075
            "Ancho" => 2050
            "Tamanyo" => 635867
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Effect of chelidonic acid on fibrosis &#40;Masson&#39;s trichome staining&#41;&#46; &#40;A&#41; Normal&#44; &#40;B&#41; DOX&#44; &#40;C&#41; DOX&#43;DEX&#44; &#40;D&#41; DOX&#43;chelidonic acid &#40;10 mg&#47;kg&#41;&#44; &#40;E&#41; DOX&#43;chelidonic acid &#40;20 mg&#47;kg&#41;&#44; and &#40;F&#41; DOX&#43;chelidonic acid &#40;40 mg&#47;kg&#41; &#40;n&#61;7&#41;&#46;</p>"
        ]
      ]
      8 => array:8 [
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        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
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            "identificador" => "at1"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">All values are expressed as mean&#177;SEM &#40;n&#61;7&#41;&#44; &#42;&#42;&#42;p&#60;0&#46;001&#44; &#42;&#42;p&#60;0&#46;01&#44; and &#42;p&#60;0&#46;05 when compared with the DOX &#8211; treated group&#46; <span class="elsevierStyleSup">&#35;&#35;&#35;</span>p&#60;0&#46;001 when compared with the normal group&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#43;dp&#47;dt &#40;mmHg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#8722;dp&#47;dt &#40;mmHg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">LVEDP &#40;mmHg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">LVSP &#40;mmHg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Tau &#40;s&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2397&#177;68&#46;74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1903&#177;76&#46;33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">2&#46;52&#177;0&#46;60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">137&#46;9&#177;8&#46;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;078&#177;0&#46;0068&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DOX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1290&#177;60&#46;15<span class="elsevierStyleSup">&#35;&#35;&#35;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#8722;970&#46;7&#177;63&#46;70<span class="elsevierStyleSup">&#35;&#35;&#35;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#46;71&#177;0&#46;69<span class="elsevierStyleSup">&#35;&#35;&#35;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">97&#46;9&#177;6&#46;67<span class="elsevierStyleSup">&#35;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;051&#177;0&#46;0073<span class="elsevierStyleSup">&#35;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DOX&#43;DEX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1408&#177;72&#46;45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1176&#177;43&#46;99&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;94&#177;0&#46;92&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">124&#46;1&#177;8&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;066&#177;0&#46;0057&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DOX&#43;CA &#40;10 mg&#47;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1433&#177;61&#46;19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1215&#177;70&#46;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;21&#177;1&#46;04&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">123&#46;8&#177;9&#46;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;069&#177;0&#46;0078&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DOX&#43;CA &#40;20 mg&#47;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1607&#177;52&#46;38&#42;&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1100&#177;85&#46;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;76&#177;0&#46;90&#42;&#42;&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">124&#46;9&#177;10&#46;92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;064&#177;0&#46;0092&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DOX&#43;CA &#40;40 mg&#47;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2032&#177;82&#46;73&#42;&#42;&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1318&#177;65&#46;18&#42;&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;96&#177;0&#46;75&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">130&#46;6&#177;8&#46;69&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;072&#177;0&#46;0045&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Effect of chelidonic acid on the ventricular activity&#46;</p>"
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      9 => array:8 [
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          "leyenda" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">All values are expressed as mean&#177;SEM &#40;n&#61;7&#41;&#44; &#42;&#42;&#42;p&#60;0&#46;001&#44; &#42;&#42;p&#60;0&#46;01&#44; and &#42;p&#60;0&#46;05 when compared with the DOX &#8211; treated group&#46; <span class="elsevierStyleSup">&#35;&#35;&#35;</span>p&#60;0&#46;001 when compared with the normal group&#46;</p>"
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                0 => """
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">AST &#40;IU&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">cTn-T &#40;ng&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Normal&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">26&#46;46&#177;2&#46;54&nbsp;\t\t\t\t\t\t\n
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Original Article
Cardioprotective effect of chelidonic acid against doxorubicin-induced cardiac toxicity in rats
Efeito cardioprotetor do ácido quelidónico contra a toxicidade cardíaca induzida pela doxorrubicina em ratos
Shraddha I. Khairnar, Yogesh A. Kulkarni, Kavita Singh
Autor para correspondência
kspharma05@gmail.com

Corresponding author.
Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, Mumbai, India
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In recent years&#44; cancer has become more prevalent&#44; and it is estimated that 13&#46;1 million people will die of cancer by 2030&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">1&#44;2</span></a> Treating cancer has become a highly complex process&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">3</span></a> Anthracyclines are a class of chemotherapeutic drugs used to treat various malignancies in both adult and pediatric patients&#46; The most popular anthracycline&#44; doxorubicin &#40;also called adriamycin&#41; &#40;DOX&#41;&#44; is used to treat a variety of malignant tumors&#44; such as acute leukemia&#44; lymphomas&#44; ovarian&#44; testicular&#44; lung&#44; thyroid&#44; breast&#44; among others&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">4&#44;5</span></a> It is one of the most efficient anthracycline antibiotics and a frontline chemotherapeutic agent for the treatment of cancer&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">6&#44;7</span></a> While doxorubicin has broad anticancer efficacy&#44; due to its negative consequences&#44; its therapeutic application is restricted&#44; particularly in life-threatening cardiac toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">8</span></a> Clinically&#44; DOX-induced cardiotoxicity is defined by an increase in ventricular wall thickening that can result in mortality&#44; aberrant arrhythmias&#44; congestive heart failure &#40;HF&#41;&#44; and a reduction in left ventricular ejection fraction&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">9</span></a> It shows dose-dependent cardiotoxicity&#44; which is linked to a decrease in left ventricular function or HF in 7&#8211;26&#37; of patients treated with doxorubicin &#40;550 mg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">10&#44;11</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Arrhythmias&#44; ischemia&#44; systolic dysfunction&#44; and HF are all manifestations of doxorubicin-induced cardiotoxicity&#44; and the major causes are cardiac cell death and necrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">12</span></a> Cardiomyocytes are more prone to doxorubicin toxicity than other tissues because they have lower antioxidant levels&#44; a higher reliance on oxidative substrate metabolism&#44; and a higher mitochondria volume than tumor cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">13&#44;14</span></a> Chelidonic acid &#40;CA&#41; is a secondary metabolite found in several plants&#44; such as <span class="elsevierStyleItalic">Chelidonium majus</span> L&#46; It possesses anti-inflammatory&#44; anti-allergic&#44; anti-ulcerative colitis&#44; and neurological sedative properties&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">15&#8211;18</span></a> CA also has many known therapeutic effects&#44; such as being a mild analgesic&#44; antimicrobial&#44; and oncostatic&#59; in the central nervous system&#44; it acts as a sedative&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">19</span></a> It also inhibits TNF-&#945; production in ulcerative colitis in rats&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">15</span></a> CA inhibits nuclear factor kappa B &#40;Nf-kB&#41; and activates mast cell caspase-1&#44; a component of the AMP-activated protein kinase signaling pathway&#44; to decrease the generation of IL-6&#46; Our previous study reported the beneficial effects of CA in cisplatin-induced nephrotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">20</span></a> CA can be useful to relieve the toxic effects of doxorubicin in myocardial tissue without interfering with its anticancer activity&#46; This study&#44; therefore&#44; aimed to investigate any possible defense that CA might have against the cardiotoxicity that DOX causes in rats&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Objective</span><p id="par0015" class="elsevierStylePara elsevierViewall">This study was designed to investigate the possible cardioprotective effect of CA in DOX-induced cardiac toxicity in rats&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methods</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Chemicals</span><p id="par0020" class="elsevierStylePara elsevierViewall">Chelidonic acid&#44; 5-5-dithio bis-&#40;2-nitrobenzoic acid&#41;&#44; and thiobarbituric acid were procured from Sigma Aldrich &#40;St&#46; Louis&#44; MO&#44; USA&#41;&#46; Doxorubicin hydrochloride USP &#40;Batch&#35; 062103092&#41; was received as a gift sample from Khandelwal Laboratories&#44; India&#46; Kits of creatine kinase-MB and lactate dehydrogenase were purchased from Transasia Biomedicals Ltd&#46;&#44; India&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Experimental animals</span><p id="par0025" class="elsevierStylePara elsevierViewall">Male Wistar rats &#40;170&#8211;200 g&#41; were purchased from the National Institute of Biosciences in Pune&#44; Maharashtra&#44; India&#44; and kept in an environment with a 12-hour light&#47;dark cycle&#46; Purified water and multi-nutritional pellet food &#40;Nutrimix Laboratory Animal Feed&#44; India&#41; were available at all times&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Doxorubicin-induced cardiac toxicity in rats</span><p id="par0030" class="elsevierStylePara elsevierViewall">Doxorubicin was solubilized in the normal saline solution and injected intraperitoneally at 1&#46;25 mg&#47;kg&#44; four times per week for four weeks&#44; the total cumulative dose was 20 mg&#47;kg&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">21&#8211;23</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Experimental design</span><p id="par0035" class="elsevierStylePara elsevierViewall">A total of 42 male Wistar rats were used in this study&#46; They were split up into six groups at random&#44; each containing seven rats&#46; The details of each group are as follows&#58;</p><p id="par0040" class="elsevierStylePara elsevierViewall">0&#46;5&#37; carboxymethyl cellulose and saline solution were used as vehicles for CA and doxorubicin&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">24&#44;25</span></a><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><p id="par0045" class="elsevierStylePara elsevierViewall">Group 1&#46; <span class="elsevierStyleItalic">Normal</span>&#58; Rats were administered 0&#46;5&#37; carboxymethyl cellulose &#40;1 ml&#47;kg&#47;day&#44; <span class="elsevierStyleItalic">p&#46;o&#46;</span>&#41; using oral gavage for a period of four weeks and saline solution &#40;vehicle of DOX&#41; &#40;1 ml&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41; four times per week for four weeks&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Group 2&#46; <span class="elsevierStyleItalic">DOX</span>&#58; Rats were administered 0&#46;5&#37; carboxymethyl cellulose &#40;1 ml&#47;kg&#47;day&#44; <span class="elsevierStyleItalic">p&#46;o&#46;</span>&#41; using oral gavage for four weeks and DOX &#40;1&#46;25 mg&#47;kg&#44; cumulative dose 20 mg&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41; four times per week for four weeks&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><p id="par0055" class="elsevierStylePara elsevierViewall">Group 3&#46; <span class="elsevierStyleItalic">DOX&#43;DEX</span>&#58; Rats were administered DOX &#40;1&#46;25 mg&#47;kg&#44; cumulative dose 20 mg&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41; and DEX &#40;50 mg&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41; 30 minutes before DOX administration&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><p id="par0060" class="elsevierStylePara elsevierViewall">Group 4&#46; <span class="elsevierStyleItalic">DOX&#43;CA &#40;10 mg&#47;kg</span>&#41;&#58; Rats were administered DOX &#40;1&#46;25 mg&#47;kg&#44; cumulative dose 20 mg&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41; and CA 10 mg&#47;kg&#47;day <span class="elsevierStyleItalic">p&#46;o&#46;</span> for four weeks&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><p id="par0065" class="elsevierStylePara elsevierViewall">Group 5&#46; <span class="elsevierStyleItalic">DOX&#43;CA &#40;20 mg&#47;kg</span>&#41;&#58; Rats were administered DOX &#40;1&#46;25 mg&#47;kg&#44; cumulative dose 20 mg&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41; and CA 20 mg&#47;kg&#47;day <span class="elsevierStyleItalic">p&#46;o&#46;</span> for four weeks&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><p id="par0070" class="elsevierStylePara elsevierViewall">Group 6&#46; <span class="elsevierStyleItalic">DOX&#43;CA &#40;40 mg&#47;kg</span>&#41;&#58; Rats were administered DOX &#40;1&#46;25 mg&#47;kg&#44; cumulative dose 20 mg&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41; and CA 40 mg&#47;kg&#47;day <span class="elsevierStyleItalic">p&#46;o&#46;</span> for four weeks&#46;</p></li></ul></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Electrocardiogram and hemodynamic parameters</span><p id="par0075" class="elsevierStylePara elsevierViewall">At the end of the study&#44; rats were anesthetized with urethane &#40;1&#46;25 gm&#47;kg&#44; <span class="elsevierStyleItalic">i&#46;p&#46;</span>&#41;&#46; Each animal was positioned supine on an ECG board&#44; and ECG was continuously recorded using normal three-lead skin electrodes&#44; &#43;ve&#44; &#8722;ve&#44; and neutral &#40;the needle electrodes 29-gauge&#44; 12 mm&#41; in lead II position using a data acquisition system &#40;AD Instruments&#44; Australia&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Blood pressure</span><p id="par0080" class="elsevierStylePara elsevierViewall">To perform a tracheotomy&#44; the neck region of the rat was opened with a ventral midline incision&#44; and then the right carotid artery was cannulated with a polyethylene tube attached to a three-way cannula and the mean arterial pressure&#44; systolic pressure&#44; and diastolic pressure were measured&#46; Left ventricular end-diastolic pressure &#40;LVEDP&#41;&#44; and maximum and minimum rate of ventricular contraction &#40;&#43;dp&#47;dt&#44; &#8722;dp&#47;dt&#41; were recorded using a data acquisition system&#44; Power Lab &#40;AD Instruments&#44; Australia&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Heart weight to body weight ratio &#40;HW&#47;BW ratio&#41;</span><p id="par0085" class="elsevierStylePara elsevierViewall">Heart weight and body weight ratio were calculated after the measurement of blood pressure&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Estimation of cardiac injury markers</span><p id="par0090" class="elsevierStylePara elsevierViewall">Blood was withdrawn from animals from the retro-orbital plexus&#46; A blood sample was collected from each animal in two separate Eppendorf tubes&#46; One Eppendorf contains an anticoagulant for obtaining plasma and another without an anticoagulant for serum separation&#46; Serum and plasma samples were separated and stored at &#8722;20<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; and the same were used for the determination of cardiac injury markers&#46; Levels of CK-MB&#44; LDH&#44; and AST in serum were determined using diagnostic kits &#40;Transasia Bio-Medicals Ltd&#46;&#44; India&#41;&#46; cTn-I level in plasma was determined using an ELISA kit provided by Abbkine&#44; USA&#46; All the parameters were estimated by using a biochemical analyzer &#40;Erba Chem 7&#44; Germany&#41;&#46;</p><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Preparation of tissue homogenate</span><p id="par0095" class="elsevierStylePara elsevierViewall">After the recording of hemodynamic parameters&#44; animals were sacrificed&#46; Heart tissue homogenate was prepared in ice-cold 50 mM phosphate buffer saline &#40;pH 7&#46;4&#41; using a homogenizer &#40;Polytron&#44; Kinematica&#44; Switzerland&#41;&#46; The homogenate was centrifuged at 2000 <span class="elsevierStyleItalic">g</span> for 20 min at 4<span class="elsevierStyleHsp" style=""></span>&#176;C and the aliquots of the supernatant were collected and stored at &#8722;20<span class="elsevierStyleHsp" style=""></span>&#176;C for further evaluation&#46; Total protein in heart tissue homogenate was measured using the Bradford Protein Assay as per Bradford<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">26</span></a> method&#46;</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Estimation of oxidative stress</span><p id="par0100" class="elsevierStylePara elsevierViewall">Lipid peroxidation &#40;LPO&#41; was measured as a malondialdehyde &#40;MDA&#41; concentration&#44; and MDA level in heart tissue was measured by thiobarbituric acid reactive substances &#40;TBARS&#41; assay described by Ohkawa &#40;1979&#41;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">27</span></a>&#46; In the TBARS assay&#44; total homogenate was used to determine thiobarbituric acid reactive substances&#46; Reduced glutathione levels in heart tissue were estimated using the method given by Ellman&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">28</span></a> Post-nuclear fraction of homogenate which was prepared by centrifugation at 2500 <span class="elsevierStyleItalic">g</span> for 10 min was used to estimate catalase activity in heart tissue as per the method described by Luck&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">29</span></a> Superoxide dismutase activity was measured in post-mitochondrial fraction of homogenate&#44; which was prepared by centrifugation at 10<span class="elsevierStyleHsp" style=""></span>000 <span class="elsevierStyleItalic">g</span> for 20 minutes as per the method described by Paoletti and Mocali&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">30</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Estimation of nitric oxide</span><p id="par0105" class="elsevierStylePara elsevierViewall">The tissue homogenate was mixed with an equal quantity of Griess reagent&#44; and absorbance was determined at 540 nm using a microplate spectrophotometer &#40;BioTek-Epoch 2&#41;&#46; NO concentration was expressed as &#956;M&#47;L of NO&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Estimation of Nrf2 and release of pro-inflammatory cytokines</span><p id="par0110" class="elsevierStylePara elsevierViewall">Nrf2 and the release of TNF-&#945; and IL-6 were measured by using sandwich ELISA methods according to the manufacturer&#39;s protocol &#40;Abbkine&#44; USA&#41;&#46; Levels of C-reactive protein &#40;CRP&#41; were determined using diagnostic kits &#40;Transasia Bio-Medicals Ltd&#46;&#44; India&#41;&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Histopathological examination</span><p id="par0115" class="elsevierStylePara elsevierViewall">Heart tissue was stored in a 10&#37; neutral buffer formalin solution&#46; The organ specimens were treated with xylene for dehydration and alcohol for 2 h&#46; The infiltration and impregnation were carried out by treatment with paraffin wax twice&#46; Specimens were cut into sections of 3&#8211;5 &#956;m thickness and embedded in paraffin&#46; Serial sections &#40;3 &#956;m&#41; were cut using a microtome&#46; The sections were stained with hematoxylin and eosin and Masson&#39;s trichrome&#46; Sections were examined under the light microscope for myocardial injury and progression of fibrosis &#40;Motic&#44; Canada&#41;&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Statistical analysis</span><p id="par0120" class="elsevierStylePara elsevierViewall">The data were expressed as mean&#177;SEM for each group&#46; Statistical analysis was performed using the one-way analysis of variance followed by Dunnett&#39;s post-hoc test&#46; The data was analyzed using Graph Pad Prism 8 software &#40;California&#44; USA&#41;&#46;</p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Results</span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Effect of chelidonic acid on body weight and heart weight&#47;body weight ratio &#40;HW&#47;BW ratio&#41;</span><p id="par0125" class="elsevierStylePara elsevierViewall">DOX &#8211; treated group showed a significant decrease in body weight when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at a dose of 10&#44; 20&#44; and 40 mg&#47;kg significantly elevated the body weight of animals as compared to the DOX-treated group &#40;p&#60;0&#46;001&#41;&#46; Standard dexrazoxane-treated rats showed a significant increase in body weight when compared with DOX-treated rats &#40;p&#60;0&#46;01&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>A&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">DOX-treated rats showed significant elevation in HW&#47;BW ratio when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly reduced the HW&#47;BW ratio as compared with the DOX &#8211; treated rats&#46; Dexrazoxane treated animals showed a significant decrease in HW&#47;BW ratio as compared with only DOX-treated animals &#40;p&#60;0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>B and C&#41;&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Effect of chelidonic acid on electrocardiogram</span><p id="par0135" class="elsevierStylePara elsevierViewall">Chelidonic acid treatment normalized the electrocardiogram pattern in rats&#46; The DOX - treated group showed significant elevation in ST height when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly reduced the ST height when compared with DOX &#8211; treated rats &#40;p&#60;0&#46;001 and p&#60;0&#46;01&#41;&#46; Dexrazoxane-treated animals showed a significant decline in the ST height when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;01&#41; &#40;<a class="elsevierStyleCrossRefs" href="#fig0010">Figures 2 and 3A</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">DOX - treated rats showed had increased QT interval when compared with the normal animals &#40;p&#60;0&#46;01&#41;&#46; CA at dose range significantly decreased the QT interval when compared with DOX &#8211; treated rats &#40;p&#60;0&#46;01 and p&#60;0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>B&#41;&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">QRS interval and QTc were significantly increased in DOX &#8211; treated animals when compared with the normal group &#40;p&#60;0&#46;01 and p&#60;0&#46;001&#41;&#46; CA treatment at doses of 10 and 20 mg&#47;kg significantly reduced the QRS interval when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;01 and p&#60;0&#46;05&#41;&#46; Dexrazoxane treated animals showed a significant decrease in the QRS interval&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly decreased the QTc&#46; Standard dexrazoxane-treated animals showed a significant decrease in the QTc &#40;p&#60;0&#46;01&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>C and D&#41;&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Effect of chelidonic acid on hemodynamic parameters</span><p id="par0150" class="elsevierStylePara elsevierViewall">DOX &#8211; treated group of animals exhibited an increase in heart rate when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly declined the heart rate when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;001 and p&#60;0&#46;05&#41;&#46; Dexrazoxane treated rats showed a significant decrease in heart rate when compared with the DOX - treated animals &#40;p&#60;0&#46;01&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>A&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">Hemodynamic parameters in DOX-treated animals were significantly altered&#46; DOX &#8211; treated animals showed a decrease in systolic blood pressure when compared with the normal group &#40;p&#60;0&#46;01&#41;&#46; CA at a dose of 40 mg&#47;kg significantly increased the systolic blood pressure when compared with only DOX-treated group &#40;p&#60;0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>B&#41;&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">The DOX-treated animals showed a significant reduction in diastolic blood pressure when compared with the normal group &#40;p&#60;0&#46;01&#41;&#46; CA treatment at the entire dose range significantly increased the diastolic blood pressure when compared with the DOX - treated group &#40;p&#60;0&#46;05 and p&#60;0&#46;01&#41;&#46; Mean blood pressure was significantly reduced in DOX &#8211; treated animals when compared with the normal group &#40;p&#60;0&#46;01&#41;&#46; CA treatment at doses of 20 and 40 mg&#47;kg significantly increased the mean arterial blood pressure when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;05&#41;&#46; These changes in hemodynamic parameters were prevented by the CA treatments &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>C and D&#41;&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Effect of chelidonic acid on ventricular activity</span><p id="par0165" class="elsevierStylePara elsevierViewall">The DOX-treated group showed significant elevation in LVEDP when compared to the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly decreased it when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;05&#44; p&#60;0&#46;001&#44; and p&#60;0&#46;05&#41;&#46; Dexrazoxane treated rats showed a significant reduction in LVEDP when compared with the DOX - treated group &#40;p&#60;0&#46;05&#41;&#46; DOX &#8211; treated group showed a significant decrease in LVSP when compared to the normal group &#40;p&#60;0&#46;05&#41; and isovolumic relaxation constant &#40;tau&#41; was significantly decreased in the DOX &#8211; treated group when compared with the normal group &#40;p&#60;0&#46;05&#41;&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">There was a significant decrease in &#43;dp&#47;dt and &#8722;dp&#47;dt in the DOX &#8211; treated rats compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at doses of 20 and 40 mg&#47;kg led to a significant elevation in &#43;dp&#47;dt when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;01 and p&#60;0&#46;001&#41;&#46; Also&#44; CA treatment &#40;40 mg&#47;kg&#41; significantly increased &#8722;dp&#47;dt when compared with the DOX - treated group &#40;p&#60;0&#46;01&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Effect of chelidonic acid on cardiac markers</span><p id="par0175" class="elsevierStylePara elsevierViewall">The DOX &#8211; treated rats exhibited significant elevation in cardiac markers such as LDH and AST&#46; CA at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly reduced LDH and AST levels when compared with the DOX &#8211; treated group&#46; Dexrazoxane treated animals showed a significant decrease in the LDH when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;001&#41;&#46; CK-MB concentration was significantly increased in the DOX - treated group and treatment with CA &#40;10&#44; 20&#44; and 40 mg&#47;kg&#41; revealed a significant decrease in CK-MB when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;01&#44; p&#60;0&#46;05&#44; and p&#60;0&#46;001&#41;&#46; The dexrazoxane-treated group showed a significant reduction in the CK-MB&#46; In the DOX &#8211; treated group&#44; there was a significant increase in cTn-T level when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly decreased cTn-T level when compared with the DOX - treated group &#40;p&#60;0&#46;01&#44; p&#60;0&#46;001&#44; and p&#60;0&#46;001&#41;&#46; Dexrazoxane treated animals showed a significant decrease in the cTn-T when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;01&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Effect of chelidonic acid on inflammatory cytokines</span><p id="par0180" class="elsevierStylePara elsevierViewall">In the DOX &#8211; treated group&#44; there was an increase in CRP&#44; TNF-&#945; and IL-6 concentration when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment &#40;10&#44; 20&#44; and 40 mg&#47;kg&#41; significantly decreased the CRP&#44; TNF-&#945; and IL-6 concentration when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;001 and p&#60;0&#46;01&#41;&#46; In dexrazoxane-treated animals&#44; a significant decrease in TNF-&#945; and IL-6 concentrations was observed &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Figure 5</a>A&#8211;C&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Effect of chelidonic acid on oxidative stress&#44; NO and Nrf2 concentration</span><p id="par0185" class="elsevierStylePara elsevierViewall">In the DOX &#8211; treated animals&#44; there was a significant decrease in GSH and SOD levels and treatment with chelidonic acid &#40;10&#44; 20&#44; and 40 mg&#47;kg&#41; significantly increased GSH and SOD levels when compared with the DOX &#8211; treated group &#40;GSH&#58; p&#60;0&#46;01&#44; p&#60;0&#46;001&#44; p&#60;0&#46;001 and SOD&#58; p&#60;0&#46;01&#44; p&#60;0&#46;001&#44; p&#60;0&#46;01&#41;&#46; Among dexrazoxane-treated rats&#44; there was a significant increase in GSH and SOD levels&#46; In the DOX &#8211; treated group&#44; there was a noteworthy increase in the MDA level when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment &#40;10&#44; 20&#44; and 40 mg&#47;kg&#41; reduced the MDA level substantially&#46; Among standard dexrazoxane-treated rats&#44; there was a significant decrease in the MDA level when compared with DOX &#8211; treated group &#40;p&#60;0&#46;01&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Figure 6</a>A&#8211;C&#41;&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0190" class="elsevierStylePara elsevierViewall">Catalase concentration was significantly decreased in DOX &#8211; treated animals when compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment &#40;10&#44; 20&#44; and 40 mg&#47;kg&#41; significantly increased the catalase concentration&#46; In the dexrazoxane-treated animals&#44; there was a notable increase in catalase concentration when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;01&#41;&#46; There was a noteworthy rise in NO concentration in the DOX &#8211; treated animals when compared with the normal group &#40;p&#60;0&#46;01&#41;&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg reduced the NO concentration substantially &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Figure 6</a>D and E&#41;&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">The Nrf2 concentration was significantly reduced in DOX &#8211; treated animals as compared with the normal group &#40;p&#60;0&#46;001&#41;&#46; CA treatment at doses of 10&#44; 20&#44; and 40 mg&#47;kg significantly increased the Nrf2 concentration when compared with the DOX - treated animals &#40;p&#60;0&#46;01&#44; p&#60;0&#46;001&#44; and p&#60;0&#46;001&#41;&#46; There was a noteworthy rise in Nrf2 concentration in the standard dexrazoxane-treated group when compared with the DOX &#8211; treated group &#40;p&#60;0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Figure 6</a>F&#41;&#46;</p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0190">Effect of chelidonic acid on myocardial histology</span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0195">H&#38;E staining</span><p id="par0200" class="elsevierStylePara elsevierViewall">H&#38;E stain was used to investigate DOX-induced cardiomyopathy&#46; The normal group displayed normal architecture in the cardiomyocytes&#46; Cardiomyocytes in the DOX-treated group displayed intermuscular edema&#44; myofibrillar loss&#44; inflammatory cell infiltration&#44; vacuolization&#44; and cardiomyocyte degradation&#46; CA treatment significantly reduced all these pathological alterations&#44; and the cardiomyocyte architecture was essentially identical to that of the normal group &#40;<a class="elsevierStyleCrossRef" href="#fig0035">Figure 7</a>A&#8211;F&#41;&#46;</p><elsevierMultimedia ident="fig0035"></elsevierMultimedia></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0200">Masson&#39;s trichome staining</span><p id="par0205" class="elsevierStylePara elsevierViewall">The cardiomyocytes of normal rats did not reveal any collagen deposition and fibrosis&#46; In the DOX &#8211; treated animals&#44; there was fibrosis and collagen deposition in the myocardium&#46; Treatment with CA at a dose of 10&#44; 20&#44; and 40 mg&#47;kg led to a reduction in collagen deposition and fibrosis&#46; In the cardiac tissue of the dexrazoxane group&#44; there was reduced collagen deposition &#40;<a class="elsevierStyleCrossRef" href="#fig0040">Figure 8</a>A&#8211;F&#41;&#46;</p><elsevierMultimedia ident="fig0040"></elsevierMultimedia></span></span></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0205">Discussion</span><p id="par0210" class="elsevierStylePara elsevierViewall">The most severe and detrimental side effect of doxorubicin is cardiotoxicity&#46; Doxorubicin-induced cardiotoxicity is caused by a number of processes&#44; including oxidative stress&#44; autophagy&#44; calcium dysregulation&#44; mitochondrial dysfunction&#44; apoptosis&#44; necroptosis&#44; and ferroptosis pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">32</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">The widespread therapeutic use of doxorubicin in oncology still faces significant clinical challenges due to its associated cardiotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">33</span></a> Therefore&#44; it is necessary to ascertain new&#44; reliable chemoprotective agents that could minimize or prevent the negative effects of doxorubicin&#46; In the present study&#44; probable benefits of CA were studied against DOX-induced cardiotoxicity&#46; Study findings demonstrated that CA treatment reduced oxidative stress&#44; inflammation&#44; cardiac fibrosis&#44; and necrosis caused by DOX in rats&#46; Interestingly&#44; CA also prevents DOX-induced cardiac dysfunction in rats&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Biologically active phytochemicals with health advantages are known as nutraceuticals&#46; The use of nutraceuticals in treating a wide range of illnesses is currently gaining attention on a global scale&#46; The field of nutraceuticals can be thought of as one of the pieces lacking an individual&#39;s overall health benefit&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">34</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">Rats given DOX displayed higher heart weight to body weight ratios and lower body weights&#46; The enlarged&#44; dilated&#44; and hypertrophic atrium and ventricles may be responsible for a rise in heart weight&#46; However&#44; in the rats given CA treatment&#44; all the aforementioned alterations were observed to be blocked&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Study findings on the heart&#39;s electrical potential investigations revealed that DOX challenge in rats caused cardiotoxicity&#44; as seen by the changes in ECG indices&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">35</span></a> The effects of DOX on the ECG include an inverted p-wave&#44; a longer PR interval&#44; a prolonged QT&#44; QRS&#44; and QTc interval&#44; as well as an elevation of the ST height&#46; Many studies have reported that p-wave prolongation or increased PR interval in Wistar rats might be associated with high susceptibility to supraventricular arrhythmias following myocardial infarction&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">36</span></a> Supraventricular arrhythmias are associated with QRS complex narrowing&#46; Large QRS complexes signify ventricular arrhythmias&#44; and right and left bundle branch blockages&#44; myocardial ischemia&#44; and cardiac insufficiency all cause disturbances in intraventricular conduction&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">37</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">Chelidonic acid at a dose of 20 and 40 mg&#47;kg considerably reduced the alterations in the p-wave&#44; QRS complex&#44; QT intervals&#44; and ST segments&#46; Heart rate was increased after prolonged doxorubicin treatment&#44; which was in line with earlier studies that supported the theory that disturbances in calcium homeostasis may result from reactive oxygen species formation&#46; The pacemaker cells in the SA node and other cells in the cardiac conducting system might increase or decrease excitability caused by the increase in intracellular calcium&#46; Cardiovascular function&#44; both systolic and diastolic&#44; is compromised by doxorubicin&#46; Additionally&#44; doxorubicin eliminates the cardiac sarcoplasmic reticulum vesicle&#39;s ability to load calcium&#46; Overall&#44; doxorubicin alters calcium homeostasis and affects hemodynamic physiology&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">38</span></a> Hence&#44; LVEDP&#44; dp&#47;dt max&#44; and dp&#47;dt min are the direct indicators of cardiac function&#46; In the present study&#44; treatment with CA significantly reversed the LVEDP&#44; systolic&#44; and diastolic blood pressure&#44; which indicates that cardiac function increased significantly&#46; Also&#44; the changes in dp&#47;dt max and dp&#47;dt min were significantly attenuated by CA at 20 and 40 mg&#47;kg&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Raised levels of AST&#44; LDH&#44; cTn-T&#44; and CK-MB in serum are considered indicators of myocardial injury&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">39</span></a> DOX has significantly elevated AST&#44; LDH&#44; cTn-T&#44; and CK-MB&#46; This demonstrates that DOX caused cardiotoxicity in rats&#46; These metabolic alterations caused by DOX were reversed by CA&#46; The considerable rise in blood levels of AST&#44; LDH&#44; cTn-T&#44; and CK-MB following DOX treatment is consistent with other studies that indicate DOX-induced oxidative stress can result in lipid peroxidation and the release of these enzymes into the serum&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">39&#44;40</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">Inflammation of the cardiac tissue is a serious adverse event that has repeatedly been observed in animals given DOX&#46; Additionally&#44; there is strong evidence that DOX triggers a cascade of inflammatory reactions inside the myocardium by activating NF-&#954;B and causing the release of several pro-inflammatory cytokines&#44; including TNF-&#945;&#44; IL-6&#44; and CRP levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">41&#44;42</span></a> Recent research reports have shown that pro-inflammatory cytokines are rising inside cardiac tissue&#44; which may be the pathophysiological cause of DOX-induced cardiomyopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">43</span></a> NF-&#954;B specifically regulates many chemokines&#44; including TNF-&#945;&#44; IL-6&#44; and many others&#44; which are elevated in patients with inflammatory diseases&#46; Consequently&#44; it has been established that TNF-&#945; and IL-6 are excellent targets for molecular treatments used to treat inflammatory illnesses&#46; Shin et al&#46;&#44; reported that&#44; CA suppresses NF-&#954;B translocation to the nucleus&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">16</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">According to the results of our research&#44; cardiac TNF-&#945;&#44; IL-6&#44; and CRP levels were significantly greater in the DOX group than in the normal group&#44; supporting earlier studies that inflammation plays a significant role in the pathophysiology of DOX-induced cardiotoxicity&#46; The results of the current study showed that CA therapy significantly decreased levels of TNF-&#945;&#44; IL-6&#44; and CRP&#44; indicating that CA has a reliable cytoprotective effect against the release of inflammatory mediators by DOX&#46; Also&#44; it was previously reported that CA reduces IL-6 production by blocking nuclear factor kappa B &#40;Nf-kB&#41; and activating caspase-1 in mast cells&#44; which is a part of the AMPK signaling pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">20</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">Doxorubicin administration resulted in a significant rise in lipid peroxidation in rats&#44; which was preceded by marked elevations in MDA&#44; a notable reduction in glutathione &#40;GSH&#41;&#44; and exhaustion of cardiac antioxidant enzymes such as catalase &#40;CAT&#41; and superoxide dismutase &#40;SOD&#41; due to excessive consumption by DOX-generated free radicals&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">44&#44;45</span></a> The elevated levels of GSH&#44; SOD&#44; and catalase and decreased levels of MDA in our study are due to CA&#39;s antioxidant properties&#44; which suppressed the oxidative process in the heart&#46; Nuclear factor erythroid 2-related factor &#40;Nrf2&#41; is expressed less when ROS levels are elevated&#44; which makes cells more susceptible to oxidative stress and death&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">46</span></a> DOX significantly raised the concentration of NO in the myocardium&#46; NOS is successfully converted by DOX from a source of nitric oxide &#40;NO&#41; to one that produces superoxide&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">47</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">According to the reported studies&#44; DOX reduces Nrf2 concentration which results in oxidative stress-related damage&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">48</span></a> Nrf2 activation can reduce the oxidative stress brought on by DOX and inhibit autophagy&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">49</span></a> These findings suggest that CA is involved in the regulation of Nrf2 concentration and that it has an inhibitory effect on oxidative stress&#44; as seen by a drop in MDA and a rise in GSH levels&#44; which points to its expected cardioprotective mechanism&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">DOX treatment led to significant myocardial edema&#44; cytoplasmic vacuolization&#44; perinuclear vacuolization&#44; disarray of myocardial fibers&#44; and myofibrillar loss&#44; which were all histological abnormalities&#46; These cellular and structural alterations are comparable with various earlier studies on rats in DOX-induced cardiotoxicity&#46;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">50&#44;51</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">The histopathological results of our study showed that CA can lessen cardiac tissue lesions caused by DOX&#44; as shown by the group receiving DOX experiencing a considerable improvement in severity&#46; Masson&#39;s trichrome stained histology of a left ventricular segment from the heart of a rat treated with CA revealed sparse collagen deposition and fibrosis&#46; These findings support earlier reports that CA has an anti-inflammatory response in addition to its direct impact on oxidative stress&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">14&#44;18</span></a></p></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0210">Conclusion</span><p id="par0275" class="elsevierStylePara elsevierViewall">The findings of this study demonstrated that CA restores blood pressure with ECG&#44; inhibits oxidative stress&#44; raises Nrf2 concentration&#44; and reduces fibrosis to protect the heart from DOX-induced cardiotoxicity&#46; Further studies are needed to prove the mechanism of CA in response to DOX-induced cardiotoxicity&#46;</p></span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0215">Ethical approval</span><p id="par0280" class="elsevierStylePara elsevierViewall">All animal experiments were approved by the Ethics Committee and followed the Guide for the Care and Use of Laboratory Animals&#46; The Institutional Animal Ethics Committee &#40;IAEC&#41; of Shri Vile Parle Kelavani Mandal accepted and approved the protocol &#40;protocol approval number &#8211; CPCSEA&#47;IAEC&#47;P-42&#47;2021&#41;&#46;</p></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0220">Funding</span><p id="par0285" class="elsevierStylePara elsevierViewall">This research did not receive any specific grant from any funding agency&#46;</p></span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0225">Authors&#8217; contributions</span><p id="par0290" class="elsevierStylePara elsevierViewall">Y&#46;K&#46;&#44; K&#46;S&#46; and S&#46;K&#46; designed the experiments&#46; S&#46;K&#46; performed the animal experiments&#46; S&#46;K&#46;&#44; Y&#46;K&#46; and K&#46;S&#46; interpreted the results and wrote the manuscript&#46;</p></span><span id="sec0175" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0230">Conflicts of interest</span><p id="par0295" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span><span id="sec0180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0235">Data availability</span><p id="par0300" class="elsevierStylePara elsevierViewall">The data underlying this article will be shared on reasonable request to the corresponding author&#46;</p></span></span>"
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              "titulo" => "Estimation of cardiac injury markers"
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              "titulo" => "Estimation of oxidative stress"
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              "titulo" => "Estimation of nitric oxide"
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              "titulo" => "Estimation of Nrf2 and release of pro-inflammatory cytokines"
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              "titulo" => "Effect of chelidonic acid on body weight and heart weight&#47;body weight ratio &#40;HW&#47;BW ratio&#41;"
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              "titulo" => "Effect of chelidonic acid on oxidative stress&#44; NO and Nrf2 concentration"
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    "fechaRecibido" => "2023-06-24"
    "fechaAceptado" => "2024-06-12"
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            0 => "Doxorubicin"
            1 => "Chelidonic acid"
            2 => "ROS"
            3 => "Cytokines"
            4 => "NO"
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            0 => "Doxorrubicina"
            1 => "&#193;cido quelid&#243;nico"
            2 => "ROS"
            3 => "Citocinas"
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    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The current study evaluates the effect of chelidonic acid on doxorubicin-induced cardiac toxicity&#46; Chelidonic acid &#40;CA&#41; is a natural pyran-skeleton heterocyclic compound found in rhizomes of the perennial plant&#44; celandine &#40;<span class="elsevierStyleItalic">Chelidonium majus</span>&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Wistar rats were given an intraperitoneal injection of doxorubicin &#40;1&#46;25 mg&#47;kg&#44; cumulative dose of 20 mg&#47;kg&#41; four times per week for a duration of four weeks to induce cardiotoxicity&#46; CA treatment &#40;10&#44; 20&#44; and 40 mg&#47;kg orally for four weeks&#41; was started together with doxorubicin&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">CA treatment reduced myocardial damage and improved cardiac dysfunction in doxorubicin-treated rats&#46; It improved blood pressure&#44; restored ST wave height and normalized the QTc interval compared to the rats treated only with doxorubicin&#46; Administration of CA for four weeks reduced left ventricular end-diastolic pressure&#46; Moreover&#44; CA treatment decreased the level of cardiac markers such as creatine kinase-myocardial band &#40;CK-MB&#41;&#44; lactate dehydrogenase &#40;LDH&#41;&#44; aspartate aminotransferase &#40;AST&#41;&#44; and cardiac troponin-T&#46; Masson&#39;s trichrome&#44; hematoxylin&#44; and eosin staining of heart tissue revealed that CA attenuated the deleterious effects of doxorubicin and prevented further damage and fibrosis in rats&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The study findings confirm that CA treatment can protect the myocardium against doxorubicin-induced cardiotoxicity&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction and objectives"
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          1 => array:2 [
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            "titulo" => "Methods"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introdu&#231;&#227;o e objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">O presente estudo avalia o efeito do &#225;cido quelid&#243;nico na toxicidade card&#237;aca induzida pela doxorrubicina&#46; O &#225;cido quelid&#243;nico &#233; um composto heteroc&#237;clico natural do esqueleto pirano encontrado nos rizomas da planta perene&#44; celid&#243;nia &#40;<span class="elsevierStyleItalic">Chelidonium majus</span>&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Ratos Wistar receberam inje&#231;&#227;o intraperitoneal de doxorrubicina &#40;1&#44;25 mg&#47;kg&#44; dose cumulativa de 20 mg&#47;kg&#41; quatro vezes por semana durante quatro semanas para induzir cardiotoxicidade&#46; O tratamento com &#225;cido quelid&#243;nico &#40;10&#44; 20 e 40 mg&#47;kg por via oral durante quatro semanas&#41; foi iniciado juntamente com a doxorrubicina&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">O tratamento com &#225;cido quelid&#243;nico reduziu o dano mioc&#225;rdico e melhorou a disfun&#231;&#227;o card&#237;aca em ratos tratados com doxorrubicina&#46; O tratamento com &#225;cido quelid&#243;nico melhorou a press&#227;o arterial&#44; bem como restaurou a altura ST e normalizou o intervalo QTc em compara&#231;&#227;o com os &#250;nicos ratos tratados com doxorrubicina&#46; A administra&#231;&#227;o de &#225;cido quelid&#243;nico por quatro semanas reduziu a press&#227;o diast&#243;lica final do ventr&#237;culo esquerdo&#46; Al&#233;m disso&#44; o tratamento com &#225;cido quelid&#243;nico diminuiu o n&#237;vel de marcadores card&#237;acos como creatina quinase-banda mioc&#225;rdica &#40;CK-MB&#41;&#44; lactato desidrogenase &#40;LDH&#41;&#44; aspartato aminotransferase &#40;AST&#41; e troponina T card&#237;aca&#46; A colora&#231;&#227;o com tricr&#243;mico&#44; hematoxilina e eosina de Masson do tecido card&#237;aco revelou que o &#225;cido quelid&#243;nico atenuou os efeitos delet&#233;rios da doxorrubicina e preveniu maiores danos e fibrose em ratos&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclus&#227;o</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Os achados do presente estudo confirmam que o tratamento com &#225;cido quelid&#243;nico pode proteger o mioc&#225;rdio contra a cardiotoxicidade induzida pela doxorrubicina&#46;</p></span>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Effect of chelidonic acid on body weight and heart to body weight ratio&#46; &#40;A&#41; Body weight&#44; &#40;B&#41; heart weight to body weight ratio&#44; and &#40;C&#41; heart weight&#46; All values are expressed as mean&#177;SEM &#40;n&#61;7&#41;&#44; &#42;&#42;&#42;p&#60;0&#46;001&#44; &#42;&#42;p&#60;0&#46;01&#44; and &#42;p&#60;0&#46;05 when compared with the DOX &#8211; treated group&#46; <span class="elsevierStyleSup">&#35;</span>p&#60;0&#46;05 and <span class="elsevierStyleSup">&#35;&#35;&#35;</span>p&#60;0&#46;001 when compared with the normal group&#46;</p>"
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            "imagen" => "gr4.jpeg"
            "Alto" => 2103
            "Ancho" => 2466
            "Tamanyo" => 251900
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        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Effect of chelidonic acid on hemodynamic parameters&#46; &#40;A&#41; Heart rate&#44; &#40;B&#41; systolic blood pressure&#44; &#40;C&#41; diastolic blood pressure&#44; and &#40;D&#41; mean blood pressure&#46; All values are expressed as mean&#177;SEM &#40;n&#61;7&#41;&#44; &#42;&#42;&#42;p&#60;0&#46;001&#44; &#42;&#42;p&#60;0&#46;01&#44; and &#42;p&#60;0&#46;05 when compared with the DOX &#8211; treated group&#46; <span class="elsevierStyleSup">&#35;&#35;&#35;</span>p&#60;0&#46;001 and <span class="elsevierStyleSup">&#35;&#35;</span>p&#60;0&#46;01 when compared with the normal group&#46;</p>"
        ]
      ]
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        "identificador" => "fig0025"
        "etiqueta" => "Figure 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 998
            "Ancho" => 3417
            "Tamanyo" => 176468
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        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Effect of chelidonic acid on inflammatory cytokines&#46; &#40;A&#41; C-reactive protein &#40;CRP&#41;&#44; &#40;B&#41; tumor necrosis factor-alpha &#40;TNF-&#945;&#41; and interleukin-6 &#40;IL-6&#41;&#46; All values are expressed as mean&#177;SEM &#40;n&#61;7&#41;&#44; &#42;&#42;&#42;p&#60;0&#46;001&#44; &#42;&#42;p&#60;0&#46;01&#44; and &#42;p&#60;0&#46;05 when compared with the DOX &#8211; treated group&#46; <span class="elsevierStyleSup">&#35;&#35;&#35;</span>p&#60;0&#46;001 when compared with the normal group&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "fig0030"
        "etiqueta" => "Figure 6"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr6.jpeg"
            "Alto" => 1920
            "Ancho" => 3417
            "Tamanyo" => 354330
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Effect of chelidonic acid on oxidative stress&#44; NO&#44; and Nrf2 concentration&#46; &#40;A&#41; Glutathione &#40;GSH&#41;&#44; &#40;B&#41; malondialdehyde &#40;MDA&#41;&#44; &#40;C&#41; superoxide dismutases &#40;SOD&#41;&#44; &#40;D&#41; catalase &#40;CAT&#41;&#44; &#40;E&#41; nitric oxide &#40;NO&#41; and &#40;F&#41; nuclear factor erythroid 2-related factor 2 &#40;Nrf2&#41;&#46; All values are expressed as mean&#177;SEM &#40;n&#61;7&#41;&#44; &#42;&#42;&#42;p&#60;0&#46;001&#44; &#42;&#42;p&#60;0&#46;01&#44; and &#42;p&#60;0&#46;05 when compared with the DOX &#8211; treated group&#46; <span class="elsevierStyleSup">&#35;&#35;&#35;</span>p&#60;0&#46;001 and <span class="elsevierStyleSup">&#35;&#35;</span>p&#60;0&#46;01 when compared with the normal group&#46;</p>"
        ]
      ]
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        "identificador" => "fig0035"
        "etiqueta" => "Figure 7"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr7.jpeg"
            "Alto" => 1029
            "Ancho" => 2050
            "Tamanyo" => 417702
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        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Effect of chelidonic acid on hematoxylin and eosin staining&#46; &#40;A&#41; Normal&#44; &#40;B&#41; DOX&#44; &#40;C&#41; DOX&#43;DEX&#44; &#40;D&#41; DOX&#43;chelidonic acid &#40;10 mg&#47;kg&#41;&#44; &#40;E&#41; DOX&#43;chelidonic acid &#40;20 mg&#47;kg&#41;&#44; and &#40;F&#41; DOX&#43;chelidonic acid &#40;40 mg&#47;kg&#41; &#40;n&#61;7&#41;&#44; black arrows indicated the damage and cell infiltration&#44; while green arrows indicate the protection against myocardial damage&#46;</p>"
        ]
      ]
      7 => array:7 [
        "identificador" => "fig0040"
        "etiqueta" => "Figure 8"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr8.jpeg"
            "Alto" => 1075
            "Ancho" => 2050
            "Tamanyo" => 635867
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Effect of chelidonic acid on fibrosis &#40;Masson&#39;s trichome staining&#41;&#46; &#40;A&#41; Normal&#44; &#40;B&#41; DOX&#44; &#40;C&#41; DOX&#43;DEX&#44; &#40;D&#41; DOX&#43;chelidonic acid &#40;10 mg&#47;kg&#41;&#44; &#40;E&#41; DOX&#43;chelidonic acid &#40;20 mg&#47;kg&#41;&#44; and &#40;F&#41; DOX&#43;chelidonic acid &#40;40 mg&#47;kg&#41; &#40;n&#61;7&#41;&#46;</p>"
        ]
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      8 => array:8 [
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">All values are expressed as mean&#177;SEM &#40;n&#61;7&#41;&#44; &#42;&#42;&#42;p&#60;0&#46;001&#44; &#42;&#42;p&#60;0&#46;01&#44; and &#42;p&#60;0&#46;05 when compared with the DOX &#8211; treated group&#46; <span class="elsevierStyleSup">&#35;&#35;&#35;</span>p&#60;0&#46;001 when compared with the normal group&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#43;dp&#47;dt &#40;mmHg&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#8722;dp&#47;dt &#40;mmHg&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">LVEDP &#40;mmHg&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">LVSP &#40;mmHg&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Tau &#40;s&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">2397&#177;68&#46;74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">137&#46;9&#177;8&#46;23&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">DOX&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1290&#177;60&#46;15<span class="elsevierStyleSup">&#35;&#35;&#35;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">11&#46;71&#177;0&#46;69<span class="elsevierStyleSup">&#35;&#35;&#35;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">97&#46;9&#177;6&#46;67<span class="elsevierStyleSup">&#35;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;051&#177;0&#46;0073<span class="elsevierStyleSup">&#35;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">DOX&#43;DEX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1408&#177;72&#46;45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1176&#177;43&#46;99&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;94&#177;0&#46;92&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">124&#46;1&#177;8&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;066&#177;0&#46;0057&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DOX&#43;CA &#40;10 mg&#47;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1433&#177;61&#46;19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#8722;1215&#177;70&#46;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">8&#46;21&#177;1&#46;04&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">123&#46;8&#177;9&#46;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;069&#177;0&#46;0078&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DOX&#43;CA &#40;20 mg&#47;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1607&#177;52&#46;38&#42;&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1100&#177;85&#46;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;76&#177;0&#46;90&#42;&#42;&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">124&#46;9&#177;10&#46;92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;064&#177;0&#46;0092&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DOX&#43;CA &#40;40 mg&#47;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">2032&#177;82&#46;73&#42;&#42;&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#8722;1318&#177;65&#46;18&#42;&#42;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">7&#46;96&#177;0&#46;75&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">130&#46;6&#177;8&#46;69&#42;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;072&#177;0&#46;0045&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Effect of chelidonic acid on the ventricular activity&#46;</p>"
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ISSN: 08702551
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