Doxorubicin-induced Cardiomyopathy In Rats Research Articles

Infliximab substantially re-silenced Wnt/β-catenin signaling and ameliorated doxorubicin-induced cardiomyopathy in rats.

The release of inflammatory cytokines, namely tumor necrosis factor-α (TNF-α), plays an important role in the pathogenesis of cardiomyopathy. TNF-α increases in plasma and in myocardium of heart failure patients. We aimed to investigate the role of TNF-α inhibitor (infliximab; IFX) in regulating dilated cardiomyopathy (DCM) induced in rats. DCM was induced in rats by doxorubicin (DOX; 3.5 mg. kg-1 , i.p) twice weekly for 3 weeks (21 mg. kg-1 cumulative dose). DCM rats were treated with RPL (1 mg. kg-1 orally, daily), IFX (5 mg. kg-1 ; i.p. once) or their combination for 4 weeks starting next day of last DOX dose. Echocardiography was conducted followed by a collection of blood and left ventricle (LV) for biochemical and histological investigations. DCM rats revealed deteriorated cardiac function (increased CK-MB activity, LVIDs, LVIDd, ESV, and EDV, while decreased EF% and FS%), hypertrophy (increased HW/TL, β-MHC, and α-actin), inflammation (increased IL-1β, IL-6, and TNF-α). The activation of Wnt/β-catenin along with increased gene expression of RAS components (RENIN, ACE, and AT1) were evident. LV architecture also revealed abnormalities and some degree of fibrosis. Treatment with RPL and/or IFX suppressed TNF-α and consequently improved most of these parameters suppressing Wnt/β-catenin/RAS axis. Combined RPL and IFX treatment was the best among all treatments. In conclusion, Wnt/β-catenin/RAS axis is implicated in DOX-induced cardiomyopathy. The upstream TNF-α was proved for the first time in-vivo to stimulate this axis where its inhibition by RPL or IFX prevented DCM. Targeting this axis at two points using RPL and IFX showed better therapeutic efficacy.

Potential roles of 4HNE-adducted protein in serum extracellular vesicles as an early indicator of oxidative response against doxorubicin-induced cardiomyopathy in rats

Late-onset cardiomyopathy is becoming more common among cancer survivors, particularly those who received doxorubicin (DOXO) treatment. However, few clinically available cardiac biomarkers can predict an unfavorable cardiac outcome before cell death. Extracellular vesicles (EVs) are emerging as biomarkers for cardiovascular diseases and others. This study aimed to measure dynamic 4-hydroxynonenal (4HNE)-adducted protein levels in rats treated chronically with DOXO and examine their link with oxidative stress, antioxidant gene expression in cardiac tissues, and cardiac function. Twenty-two male Wistar rats were randomly assigned to receive intraperitoneal injection of normal saline (n = 8) or DOXO (3 mg/kg, 6 doses, n = 14). Before and after therapy, serum EVs and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were determined. Tunable resistive pulse sensing was used to measure EV size and concentration. ELISA was used to assess 4HNE-adducted protein in EVs and cardiac tissues. Differential-display reverse transcription-PCR was used to quantitate cardiac Cat and Gpx1 gene expression. Potential correlations between 4HNE-adducted protein levels in EVs, cardiac oxidative stress, antioxidant gene expression, and cardiac function were determined. DOXO-treated rats showed more serum EV 4HNE-adducted protein than NSS-treated rats at day 9 and later endpoints, whereas NT-proBNP levels were not different between groups. Moreover, on day 9, surviving rats' EVs had higher levels of 4HNE-adducted protein, and these correlated positively with concentrations of heart tissue 4HNE adduction and copy numbers of Cat and Gpx1, while at endpoint correlated negatively with cardiac functions. Therefore, 4HNE-adducted protein in serum EVs could be an early, minimally invasive biomarker of the oxidative response and cardiac function in DOXO-induced cardiomyopathy.

Cardio-protective effects of terminalia catappa leaves and terminalia chebula fruit extract in doxorubicin-induced cardiomyopathy in rats

Background The cardio-protective effects of Terminalia catappa and Terminalia chebula are well-recognized in Ayurveda for its antimicrobial, antidiabetic and antioxidant potentials. The present study evaluates the effects of T. catappa leaves (Tct.LE) and T. chebula fruits (Tce.FE) against doxorubicin (DOX)-induced rats through analysis of the cardiac biomarkers, tricarboxylic acid (TCA) cycle enzymes and respiratory chain enzymes for their cardio-protective properties. Materials and methods This study includes 42 adult male Albino Wistar rats randomized into seven groups for 21-days. Groups were categorized as control; DOX (1.5 mg/kg) induced negative control; basal diet with 300 mg/kg of Tct.LE, with 300 mg/kg Tce.FE; DOX with 300 mg/kg of Tct.LE, Tce.FE, and propranolol (25 mg/kg). Results and discussion The doses of 300 mg/kg of both plants have a significant effect on the TCA cycle, respiratory and lysosomal enzymes activity. The troponin levels are significantly reduced in plant treated group than the DOX-treated rats when compared with the control and propranolol treated group. Likewise, the increased level of creatine kinase-muscle/MB, creatine kinase and lipid profile in the DOX-treated animals were significantly reduced upon being treated with extracts. Conclusion The cardio-protective activity of Tct.LE leaves and Tce.FE indicate its potential use in the management of cardiovascular diseases.

УЛЬТРАСТРУКТУРНАЯ ПЕРЕСТРОЙКА МИОКАРДА НА 60-e СУТКИ ПОСЛЕ ДОКСОРУБИЦИН-ИНДУЦИРОВАННОЙ КАРДИОМИОПАТИИ У КРЫС

Background. To assess the cardiotoxic effects of doxorubicin, it is of great importance to elucidate the nature and severity of tissue and cell damage, their ultrastructural changes, as well as to elucidate the features of myocardial remodeling in such conditions. Objective. The aim of the study was a qualitative and quantitative analysis of ultrastructural changes in the myocardium on the 60th day after doxorubicin-induced cardiomyopathy in rats. Material and methods. Cardiomyopathy in rats was induced by doxorubicin given at a cumulative dose of 15 mg/kg for 14 days. The animals were removed from the experiment on the 60th day after last administered dose of the medicine. An electron microscopic research method was used. Ultrastructural analysis was performed using a JEM-100 CX microscope, and morphometric evaluation was done using the ImageJ data processing software. Results. Ultrastructural disorders of the myocardium of rats on the 60th day after doxorubicin-induced cardiomyopathy were characterized by: alterative changes of contractile apparatus and nuclear compartment of cardiomyocytes, activation of autophagic and necrotic cell death and compensatory mitochondria hyperplasia with T-system channels dilation; a variety of reactive changes of capillary endothelium in the form of nuclear hypertrophy and organelle hyperplasia in some endothelial cells along with intracellular edema and destruction of organelles in others, which was accompanied by a significant decrease in cross-sectional area of capillaries; activation of fibroblasts with a formation of interstitial and perivascular fibrosis; activation of autophagy processes in cardiomyocytes, fibroblastic cells and capillary endothelium. Conclusions. The established ultrastructural changes in the rat’s myocardium on the 60th day after the doxorubicin- induced cardiomyopathy indicate the complex effect of metabolic and angiogenic mechanisms of pathology development. Activation of autophagy processes plays an important role in myocardial reorganization in the late stages of doxorubicin myocardial damage.

Analysis of Models of Doxorubicin-Induced Cardiomyopathy in Rats and Mice. A Modern View From the Perspective of the Pathophysiologist and the Clinician.

Today the pharmacological possibilities of treating cancer are expanding and as a result, life expectancy is increasing against the background of chemotherapy and supportive treatment. In the conditions of successful antitumor treatment, complications associated with its toxic effect on healthy tissues and organs began to come to the fore. Anthracycline cardiomyopathy was the first serious cardiovascular complication to draw the attention of oncologists and cardiologists around the world. Anthracycline drugs such as doxorubicin, epirubicin, idarubicin are still widely used in oncological practice to treat a wide range of solid and hematological malignancies. Doxorubicin-induced cardiomyopathy is closely associated with an increase in oxidative stress, as evidenced by reactive oxygen species (ROS) nduced damage such as lipid peroxidation, and decreased levels of antioxidants. Myofibrillar destruction and dysregulation of intracellular calcium are also important mechanisms, usually associated with doxorubicin-induced cardiotoxicity. Despite the abundance of data on various mechanisms involved in the implementation of doxorubicin-induced cardiotoxicity, a final understanding of the mechanism of the development of doxorubicin cardiomyopathy has not yet been formed. It poses the most significant challenges to the development of new methods of prevention and treatment, as well as to the unambiguous choice of a specific treatment regimen using the existing pharmacological tools. In order to resolve these issues new models that could reflect the development of the chemotherapy drugs effects are needed. In this review we have summarized and analyzed information on the main existing models of doxorubicin cardiomyopathy using small laboratory animals. In addition, this paper discusses further areas of research devoted to the development and validation of new improved models of doxorubicin cardiomyopathy suitable both for studying the mechanisms of its implementation and for the preclinical drugs effectiveness assessment.

Phenomapping for classification of doxorubicin-induced cardiomyopathy in rats

Cardiomyopathy resistant to treatment is the most serious adverse effect of doxorubicin (dox). The mechanisms of dox-induced cardiomyopathy (DCM) have been extensively studied in dilated forms of DCM. However, efficient treatment did not emerge. The aim of the present work was to revisit the experimental model of DCM in rats, to define phenotype/s and associate them to the changes in cardiac transcriptome. Male Wistar rats equipped with radiotelemetry device, were randomized in DOX group (5 mg/0,5 mL/kg, IV dox; n = 18) and CONT group (0,5 mL/kg IV saline; n = 6). Echocardiography, autonomic spectral markers and baroreceptor reflex evaluation was performed prior to, and after treatment. Blood samples were collected at the end of experimentation. Cardiac, renal and hepatic tissues were analysed post-mortem by histology. Changes in expression of key cardiac genes affected by dox were assessed by RT-qPCR. Phenotypes were identified by clustering non-redundant features using four different algorithms averaged by evidence accumulation cluster technique. The results emphasize the existence of two major phenotypes of DCM with comparably high mortality rates: phenotype 1 characterized by, left ventricular (LV) dilatation, thinning of LV posterior wall, reduced LV ejection fraction (LVEF) and fractional shortening (LVFS), decreased HR variability (HRV), decreased baroreceptor effectiveness index (BEI) and increased NT-proBNP; and phenotype 2 with LV hypertrophy - increased LV mass, preserved LVEF, LVFS, no changes in HRV and BEI and moderate NT-proBNP increase. Both phenotypes exhibited a genetic shift to a new-born program.

The influence of the preparation “Bendamin” on the morphological and biochemical indices of blood of rats in experimental modeling of heart failure

The purpose of this work was to study the influence of “Bendamin” on the morphological and biochemical indices of rat blood in experimental modeling of heart failure. The investigation were performed on white sexually mature young male-rats of Wistar line weighing 180–200 g, kept at the standard ration of the institute vivarium of the State Research Institute of Veterinary Preparations and Fodder Additives. To create a model of doxorubicin-induced cardiomyopathy, 24 male rats were selected. Animals were divided into 3 groups of 6 animals in each: control group – intact animals; experimental group E1, in which animals were modeled doxorubicin-induced cardiomyopathy by intraperitoneal injected of doxorubicin at a dose of 2.5 mg/kg 3 times a week for two weeks; experimental group E2, in which animals, after injection of doxorubicin, the preparation “Bendamin” was injected in the dose 20 mg/kg intragastrically. For experimental modeling of heart a decrease in the number of red blood cells was found in the blood of rats of the first experimental group by 34.7 % and hemoglobin level – by 24.2 %, with a simultaneous increase in the average hemoglobin content in one erythrocyte by 16.2 %. Doxorubicin-induced cardiomyopathy in rats of the first experimental group was accompanied by a decrease in leukocyte count by 22.2 %, an increase in uric acid level by almost in 2 times, creatinine by 11.4 %, cholesterol by 61.1 %. In the research of the protein synthesizing function of the liver of rats in experimental modeling of heart failure, a decrease in total protein by 9.6 % was found. These changes were accompanied by a slight decrease in albumin levels and a slight increase in globulin levels. By intoxication with doxorubicin, rats of the first experimental group showed a violation of the functional state of the liver, indicating an increase in the activity of aminotransferases in their blood, namely: AlAT by 34.2 %, AsAT – by 21.7 %, accordingly. Positive action of cardio preparation “Bendamin” on rats organism under conditions of creation of a model of doxorubicin-induced cardiomyopathy was installed, manifested by the normalization of hematological and biochemical parameters, functional status and protein synthesis of the liver.

Bisoprolol and linagliptin ameliorated electrical and mechanical isometric myocardial contractions in doxorubicin-induced cardiomyopathy in rats.

Doxorubicin is an anthracycline chemotherapeutic agent that causes cardiomyopathy as a side effect. Here, we aimed to investigate the effects of linagliptin and bisoprolol on the management of doxorubicin-induced cardiomyopathy in rats. Wistar rats were divided into six groups (n = 8). Group I received saline for 4weeks; group II received 1mg/kg bisoprolol for 8weeks; group III received 3mg/kg linagliptin for 8weeks; group IV received 1.25mg/kg doxorubicin for 4weeks for the induction of cardiomyopathy; group V received 1.25mg/kg doxorubicin for 4weeks plus 1mg/kg bisoprolol for 8weeks; and group VI received 1.25mg/kg doxorubicin for 4weeks plus 3mg/kg linagliptin for 8weeks. Electrocardiography and isometric mechanography were conducted to measure ventricular contractile responses. Myocardial tissue and serum samples were analyzed for oxidative and cardiotoxic markers by ELISA. Electrocardiography revealed that QRS, QT and Tp intervals were longer in group IV than group I. Doxorubicin caused a significant decrease in ventricular contraction, which was significantly prevented by bisoprolol. Doxorubicin resulted in myocardial fiber disorganization and disruption, but bisoprolol or linagliptin improved this myocardial damage. Glutathione peroxidase was significantly decreased in groups IV and V. Bisoprolol or linagliptin treatment attenuated the significant doxorubicin-mediated increase in malondialdehyde. Doxorubicin and linagliptin provided significant elevations in CK-MB activity and troponin-I levels. Doxorubicin resulted in pronounced oxidative stress. The beneficial effects of bisoprolol and linagliptin on myocardial functional, histopathological and biochemical changes could be related to the attenuation of oxidative load.

Doxorubicin-Induced Cardiomyopathy in Rats: Behavior of the Animals in the Open Field

Under conditions of the open field test, 30 control Wistar rats and 30 rats with experimental cardiomyopathy (CMP) were examined with recording of four behavioral indices, (i) number of crossed squares (intensity of locomotion), (ii) number of rearings (vertical stands), (iii) number of examined holes in the arena, and (iv) number of grooming episodes, within a 28-day-long observation period. The CMP state was induced by five i.p. injections of 5.0 mg/kg of doxorubicin with one-week-long intervals. As was found, all behavioral indices of control rats demonstrated considerable (sometime statistically significant) variations within the observation period (this fact has probably attracted insufficient attention in analogous experiments with long-lasting observation periods). The development of doxorubicininduced CMP resulted in considerable suppression of all types of behavioral activity, relatively moderate within the first week of observation and dramatic within late phases of the observation period. The dynamics of the numbers of rearings and grooming phenomena were complex, with noticeable increases on days 3 and 14. The dynamics of the numbers of rearings and inspection of the holes in both experimental groups were significantly dissimilar, which indicates that these behavioral phenomena are related to different aspects of the research/orientatinal activity. In general, a state of increased anxiety followed by the development of a depression-like state was observed in CMP rats. These negative shifts in behavioral activity are believed to result from general CMP-induced insufficiency of blood supply of the brain and development of hypoxia in the latter; specific direct effects of doxorubicin on some cerebral structures seem to be unlikely.

Antiapototic Effect of Tauroursodeoxycholic Acid Protects against Acute Doxorubicin Induced Cardiomyopathy in Rats

Background and purpose: Cardiotoxic carrdiomyopathy mediated by inflammation, oxidative stress lead to apoptosis with subsequently cell damage and heart failure. Tauroursodeoxycholic acid (TUDCA) is a bile acid that have anti-inflammatory and anti-oxidant effect, the current study aimed to examine the effect of administration of TUDCA on doxorubicin induced acute cardiomyopathy and explore the possible mechanism/s. Methods: Cardiomyopathy was induced in rats by single intraperitoneal (ip) injection of doxorubicin (DOX) (15 mg/kg). Results: doxorubicin administration exerted elevated levels of cereatine kinase-MB (CK-MB) and Lactate Dehydrogenase (LDH) in serum, in addition to myocardial TNF-α content, MDA levels, caspase-3, caspase-9 and caspase-12. However decrease in cardiac SOD and catalase content. Histopathological examination of myoendocardial section showed marked degeneration of cardiac muscle, distention of sarcoplasmic reticulum with marked accumulation of collagen fibers. Decrease immunoreactivity to antitroponin antibody. Echocardiography showed reduced LV fractional shortening, ejection fraction, and cardiac output. Treatment with TUDCA (250 mg/kg, ip) for 10 days significantly ameliorated histological changes and decreased the myocardium peroxidative damage in addition to decrease the cardiac markers for apoptosis. Conclusion: TUDCA can protect the heart from cardiotoxic effect of doxurubicin, The protective effects obtained by TUDCA is due to its inhibition of both endoplasmic stress and mitochondrial damage associated with chemotherapy treatment, with antioxidant and antiinflamatory properties. These results confirm the possible use of TUDCA to protect the heart during chemotherapy regimen.

Angiotensin-converting enzyme 2 overexpression protects against doxorubicin-induced cardiomyopathy by multiple mechanisms in rats

Angiotensin-converting enzyme 2 (ACE2) is considered a potential therapeutic target of the renin-angiotensin system (RAS) for the treatment of cardiovascular diseases. We aimed to explore the effects of ACE2 overexpression on doxorubicin-induced cardiomyopathy in rats. Rats were randomly divided into treatment and control groups. The rats of treatment group were injected intraperitoneally with 6 doses of doxorubicin (2.5 mg/kg) within a period of two weeks. Two weeks after the initial injection of doxorubicin, these rats were randomly divided into Mock, Ad-EGFP, Ad-ACE2, and Cilazapril groups. The rats of Ad-EGFP and Ad-ACE2 groups received intramyocardial injection of Ad-EGFP and Ad-ACE2, respectively. The rats of Cilazapril group received cilazapril (10 mg/kg/day) via intragastric intubation. Apoptosis, inflammation, oxidative stress, cardiac function, the extent of myocardial fibrosis, and levels of ACE2, ACE, angiotensin II (AngII), and angiotensin (1–7) were evaluated. Four weeks after ACE2 gene transfer, the Ad-ACE2 group showed not only reduced apoptosis, inflammatory response, oxidative stress, left ventricular (LV) volume, extent of myocardial fibrosis and mortality of rats, but also increased LV ejection fraction and ACE2 expression level compared with the Mock and Ad-EGFP groups. ACE2 overexpression was superior to cilazapril in improving doxorubicin-induced cardiomyopathy. The putative mechanisms may involve activation of the AMPK and PI3K-AKT pathways, inhibition of the ERK pathway, decrease of TGF-β1 expression, and interactions of shifting RAS components, such as decreased myocardium AngII levels, increased myocardium Ang (1–7) levels, and reduced ACE expression. Thus, ACE2 may be a novel therapeutic approach to prevent and treat doxorubicin-induced cardiomyopathy.

Short-term and long-term models of doxorubicin-induced cardiomyopathy in rats: A comparison of functional and histopathological changes

ObjectivesDoxorubicin (DXR), an anthracyclic antineoplastic agent, is one of the most commonly drug utilized to induce dilated cardiomyopathy (DCM) and heart failure (HF), but the well optimized protocol for cardiomyopathy induction leading to development of cardiac systolic dysfunction is unclear. This study aims to critically compare short-term and long-term DXR injection protocols for the induction of DCM in rats. MethodsAnimals were allocated into 3 experimental groups: a ST (short-term DXR injection) group, in which animals received 6 intraperitoneal (i.p.) injections of DXR (2.5mg/kg per dose) over a period of 2 weeks (cumulative dose of 15mg/kg); a LT (long-term DXR injection) group in which animals received weekly i.p. injections of DXR (2mg/kg per dose) over a period of 9 weeks (cumulative dose of 18mg/kg); and a control group in which animals received an appropriate volume of 0.9% saline i.p. All animals were submitted to echocardiography analysis at baseline and after completion treatment. Afterwards, the hearts were collected for conventional light microscopy and collagen quantification. ResultsMorphological myocardial analysis of both DXR-treated groups showed an identical pattern of swollen and vacuolated cardiomyocytes and disorganization of myofibrils. There was pronounced interstitial fibrosis in both groups of DXR-treated hearts as compared to controls, as assessed by the interstitial collagen volume fraction. There was no difference in interstitial fibrosis between the ST and LT groups. The echocardiography analysis of the LT group showed structural and functional findings compatible with DCM, including increased left ventricular systolic (5.02±0.96mm) and diastolic (7.68±0.96mm) dimensions and reduction of ejection fraction (69.40±8.51%) as compared to the ST group (4.10±0.89mm, 7.32±0.84, and 79.68±7.23%, respectively) and control group (4.07±0.72mm, 7.17±0.68mm and 80.08±4.71%, respectively), ANOVA p<0.01. ConclusionsThese results indicate that LT injection of DXR is more effective than ST injection in inducing left ventricular dysfunction and structural cardiac changes resembling those found in dilated cardiomyopathy.

Correction to: J Med Food 2015;18(9):950-959.

Journal of Medicinal FoodVol. 19, No. 9 CorrectionFree AccessCorrection to: J Med Food 2015;18(9):950–959Published Online:1 Sep 2016https://doi.org/10.1089/jmf.2014.0104.correxAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail In the September 2015 issue of Journal of Medicinal Food (vol. 18, no. 9; 950–959), the article “Yogurt Containing the Probacteria Lactobacillus acidophilus Combined with Natural Antioxidants Mitigates Doxorubicin-Induced Cardiomyopathy in Rats” by Abu-Elsaad et al. requires correction. An error was made in the measuring unit of heart/body weight ratio that appears in two places, on pages 952 and 954. The sentence “The heart weight to body weight (HW/BW) ratio was calculated in (mg/kg)” should be corrected to read: “The heart weight to body weight (HW/BW) ratio was calculated in g/kg.” Further, in Table 3 on page 954, listed under the heading Parameter, HW/BW should include (g/kg).The online version of the article has been corrected to reflect these changes.The authors apologize for the error in measurement unit.FiguresReferencesRelatedDetails Volume 19Issue 9Sep 2016 InformationCopyright 2016, Mary Ann Liebert, Inc. and Korean Society of Food Science and NutritionTo cite this article:Correction to: J Med Food 2015;18(9):950–959.Journal of Medicinal Food.Sep 2016.899-899.http://doi.org/10.1089/jmf.2014.0104.correxPublished in Volume: 19 Issue 9: September 1, 2016Online Ahead of Print:August 23, 2016PDF download

Lycopene Potentiates the Protective Effect of Aliskiren on Doxorubicin-Induced Cardiomyopathy in Rats

Objective: The present study was designed to explore the combination therapy of lycopene with aliskiren in doxorubicin induced cardiomyopathy.Methods: Cardiomyopathy was induced in Wistar rats by i.p. administration of Doxorubicin (DOX) (15 mg/kg, single dose). Haemodynamic parameters (Systolic, diastolic blood pressure, Heart rate), heart weight, heart weight/body weight ratio, serum lactate dehydrogenase (LDH), oxidative stress (TBARS) and antioxidant enzymes (Glutathione, SOD and catalase) as well as transmission electron microscopein heart tissue were carried out.Results: There was significant increase in blood pressure, serum, lactate dehydrogenase (LDH), oxidative stress (TBARS) and significant decrease in heart weight, heart weight/body weight ratio and antioxidant enzymes in cardiomyopathic rats. Combined therapy of lycopene (2 and 4mg/kg) with aliskiren (100 mg/kg) treatment showed pronounced beneficial effecton above parameters.Furthermore lycopene with aliskiren significantly improves the antioxidant defense by increasing reduced glutathione, SOD, catalase, heart size and heart weight/body weight ratio. It is clearly observed from Transmission electron microscopic slides of DOX treated rats, there was swelling of mitochondria with disruption of cristae, rupture of nuclear membrane, condensation and margination of nuclear chromatins which were well protected by lycopene along with aliskiren treatment.Conclusion: Therefore, combination therapy of lycopene with aliskiren offers better treatment for DOX-induced cardiomyopathy than ALK alone.

Yogurt Containing the Probacteria Lactobacillus acidophilus Combined with Natural Antioxidants Mitigates Doxorubicin-Induced Cardiomyopathy in Rats.

Probiotics and antioxidants have a definite improving effect in cardiovascular diseases. This study aims at mitigating doxorubicin toxicity on cardiac function through consuming a functional food. Five groups of adult male Sprague-Dawley rats were used along 22 weeks. Group I received 30 g/kg/day food enriched with yogurt, green tea extract, and carrots (80, 0.84, and 100 g/kg diet, respectively) from the first week, group II received carvedilol 30 mg/kg/day orally from week 17, group III received both carvedilol and tested food, and groups IV and V were +ve and -ve control groups, respectively. In week 17, cardiomyopathy was induced by i.p. injection of 2.5 mg/kg doxorubicin every 48 h for 2 weeks. Histopathological and electrophysiological examinations and biochemical analysis were done. Lipid peroxidation, antioxidant effect, heart failure compensatory mediators, and proinflammatory cytokines were assessed. Tested food normalized time between the start of Q wave and the end of T wave on electrocardiogram (QT interval) and heart rate compared to the doxorubicin group (P<.05). It also improved hypertrophy indicated by a significant (P<.05) decrease in heart/body weight ratio, angiotensin-II (Ang-II), and atrial natriuretic peptide (ANP) serum levels. Histopathological examination of cardiac sections from the tested food group revealed less marked vacuolization and low perivascular fibrosis percentage (0.7803 ± 0.04). A significant (P<.001) decrease in serum creatine kinase-membrane bound, lactate dehydrogenase, triglycerides, cholesterol, low-density lipoprotein cholesterol, and tissue malondialdehyde (MDA) levels was observed in addition to an increase in serum Na(+)/K(+) ATP1A1 and cardiac reduced glutathione (GSH) levels. Tested food also lowered the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) serum levels significantly (P<.01). Probiotic food containing Lactobacillus acidophilus, green tea, and carrots can improve membrane integrity and cardiac contractility in doxorubicin-induced cardiomyopathy by decreasing TNF-α, IL-6, MDA, increasing GSH, and modulating compensatory mediators such as Ang-II and ANP.

Bioactive Natural Matrices and Compounds

The demand for healthy ingredients and a natural way of preventing diseases is contributing to the increased use of natural matrices. There has been a lot of research indicating that general antioxidant properties are not the contributing factors to improving human health but rather the antioxidant properties of specific compounds involved in specific cell signaling mechanisms that need to be elucidated. In this way, beyond the composition of the usual macronutrients and micronutrients, it seems important to also provide information on the composition of natural bioactive compounds. Phytochemicals such as phenolic compounds, essential oils, steroids, vitamins, or pigments should assume high importance due to their documented antioxidant, antimicrobial, antitumour, and anti-inflammatory properties, among others, but the knowledge of the mechanisms of action involved is mandatory. The contributions for this special issue consist of five papers covering several aspects of nutraceuticals and phytochemicals in natural matrices with proven activities in various in vitro or in vivo models. The paper by R. P. Constantin et al. evaluated the effects of three citrus flavanones (hesperidin, hesperetin, and naringenin) on several parameters linked to fatty acid oxidation in mitochondria, peroxisomes, and perfused livers of rats. These results confirm the hypothesis that citrus flavanones are able to induce a more oxidised state in liver cells, altering parameters related to hepatic fatty acid oxidation. The prooxidant effect is most likely a consequence of the ability of these substances to oxidise NADH upon production of phenoxyl radicals in the presence of peroxidases and hydrogen peroxide. A. Chennuru and M. T. S. Saleem described the cardioprotective effects of sesamol against doxorubicin-induced cardiomyopathy in rats. The authors concluded that, sesamol has significant cardioprotection against doxorubicin that induced cardiomyopathy via amelioration of oxidative stress, lipid lowering, and membrane stabilization effect. C. Chaotham et al. evaluated the oral toxicity of a partially purified plaunotol extract (PPE), which is traditionally consumed for its antigastric ulcer properties, using in vivo assays. The acute toxicity study demonstrated that PPE was practically nontoxic based on its high median lethal dose value. The chronic toxicity studies also showed the absence of mortality and clinical symptoms in all treated rats. Therefore, the authors concluded that these results suggest that PPE is potentially safe for further development as a therapeutic agent in humans. In the research study presented by H. A. E. Rabey et al., the protective effect of natural bees' honey on the liver of male albino rats against melamine toxicity was reported. Treating the male albino rats (that were presupplemented regularly with 20000 ppm melamine) with natural bees' honey at a dose of 2.5 g/kg body weight for 28 days improved both liver functions and increased serum protein. In addition, a positive impact on the shape of the cells after treatment with honey, compared to the positive melamine supplemented group, was observed. The authors concluded that the use of natural bees' honey has the ability to protect the livers of rats against the toxic effects of melamine. A. Rasul et al. reviewed recent data on primary flavonoids isolated from plants. Pinocembrin exhibits pharmacological effects on almost all systems, and the authors reviewed its pharmacological and therapeutic applications with specific emphasis on mechanisms of actions. The review suggested that pinocembrin is a potentially promising pharmacological candidate, but additional studies and clinical trials are required to determine the specific intracellular sites of action and derivative targets in order to fully understand the mechanism of its anti-inflammatory, anticancer, and apoptotic effects to further validate pinocembrin medical applications.

Effects of Histidine and N-Acetylcysteine on Doxorubicin-Induced Cardiomyopathy in Rats

The amino acids histidine and n-acetylcysteine have many biological activities such as antioxidant effect. The present study investigated the effects of histidine and n-acetylcysteine on the heart lesions induced by doxorubicin (DOX) in rats. Forty-eight male Wistar rats were divided into two major groups treated intraperitoneally (i.p.) with normal saline and 4 mg/kg of DOX, respectively. Each group was further divided into four subgroups that were treated with separate and combined i.p. injections of histidine and n-acetylcysteine (NAC) at a same dose of 40 mg/kg. Electrocardiography (ECG) was recorded using lead II. The heart lesions were evaluated by light microscopy. Serum levels of creatine phosphokinase and lactate dehydrogenase and heart tissue malondialdehyde levels were measured. Histidine and especially NAC at a same dose of 40 mg/kg recovered ECG changes, improved heart lesions and prevented biochemical changes induced by DOX. Co-administration of histidine and NAC showed better responses when compared with them used alone. The results of the present study showed protective effects for histidine and NAC on the heart. Reduction in free radical-induced toxic effects may be involved in cardioprotective properties of histidine and NAC.

Antioxidant, Lipid Lowering, and Membrane Stabilization Effect of Sesamol against Doxorubicin-Induced Cardiomyopathy in Experimental Rats

The present study was designed to evaluate the cardioprotective effect of sesamol against doxorubicin-induced cardiomyopathy in rats. In this study, the cardioprotective effect of sesamol against doxorubicin induced cardiomyopathy in experimental rats was evaluated at the dosage of 50 mg/kg bw. Doxorubicin was administered to rats at a total cumulative dose of 15 mg/kg through intraperitoneal route for 2 weeks in six-divided dose on 8th, 10th, 14th, 16th, 18th, and 21st day. After the last dose administration, the endogenous antioxidants and lipid peroxidation were estimated in heart tissue homogenate. Cardiac biomarkers such as troponin T, LDH, CK, and AST and lipid profiles such as cholesterol, triglycerides, HDL, LDL, and VLDL were estimated in serum. Sesamol has cardioprotective activity through normalization of doxorubicin-induced-altered biochemical parameters. Biochemical study was further supported by histopathological study, which shows that sesamol offered myocardial protection from necrotic damage. From these findings, it has been concluded that the sesamol has significant cardioprotection against doxorubicin induced cardiomyopathy via amelioration of oxidative stress, lipid lowering, and membrane stabilization effect.

Cardioprotective activity of ethanolic extract of Callistemon lanceolatus leaves on doxorubicin-induced cardiomyopathy in rats

The cardioprotective effect of ethanol extract of Callistemon lanceolatus leaves (100 and 200 mg/kg) against doxorubicin-induced cardiomyopathy was studied. Rats were pretreated with the extract for 7 days and simultaneous treatment with doxorubicin along with the extracts for the next 14 days. After 24 hours of last dose of doxorubicin, ECG, invasive blood pressure, serum markers (creatine kinase-MB, lactate dehydrogenase, serum transaminases), tissue antioxidant markers (catalase, superoxide dismutase) and extent of lipid peroxidation (malondialdehyde) were studied. The elevated ST segment, decreased blood pressure, increased level of serum enzymes and decreased level of tissue antioxidant markers were observed in doxorubicin treatment (p<0.01). While 200 mg/kg extract significantly reduced the elevated levels of the serum enzymes and restores the ECG and blood pressure to normal, also significantly increased the tissue antioxidant levels, while decreased the malondialdehyde level (p<0.01) when compared with the control. The histopathological study confirmed the cardioprotection.

Diclofenac Sodium, a Nonselective Nonsteroidal Anti-Inflammatory Drug Aggravates Doxorubicin-Induced Cardiomyopathy in Rats

The cardiotoxic effects of selective cyclo-oxygenase-2 inhibitors are well documented. Recently, concerns have been raised over the cardiovascular safety of nonselective nonsteroidal antiinflammatory drugs. The aim of this study was to assess the cardiac effects of diclofenac sodium on doxorubicin-induced cardiomyopathy in rats. Male Wistar rats were treated with doxorubicin (15 mg/kg intraperitoneally, single dose), diclofenac sodium (2.5 and 10 mg/kg/day, respectively, by gavage for 5 days) alone and doxorubicin + diclofenac sodium treatment, 24 hours after doxorubicin administration. Doxorubicin-induced a significant (P < 0.001) increase in the serum lactate dehydrogenase, cardiac thiobarbituric acid-reactive substance and catalase levels and a significant (P < 0.001) decrease in the cardiac glutathione and superoxide dismutase levels, which were significantly (P < 0.001) aggravated by diclofenac sodium treatment. Diclofenac sodium alone also showed a significant change in these parameters compared with the control. Ultrastructural studies showed that doxorubicin causes apoptosis in myocardium, which was characterized by condensation of chromatin network at the margins of nuclear membrane. Apoptosis induced by doxorubicin was exacerbated by diclofenac sodium treatment. Thus, our study indicates that diclofenac sodium, a nonaspirin nonsteroidal anti-inflammatory drug, is not free from cardiotoxicity and aggravates doxorubicin-induced cardiomyopathy in rats.