|Year : 2022 | Volume
| Issue : 78 | Page : 267-272
Goniothalamin-mediated amelioration of doxorubicin-induced myocardial damage and regulation of nuclear factor-κB/HO-1/NQO-1 signaling biomarkers in cardiotoxic rats
Chong Liu1, Qiuju Wang2
1 Department of Cardiology, Chengwu People's Hospital, Heze 274200, China
2 Foreign Joint Office, Chengwu People's Hospital, Heze, China
|Date of Submission||22-Apr-2021|
|Date of Decision||16-Jul-2021|
|Date of Acceptance||14-Dec-2021|
|Date of Web Publication||07-Jul-2022|
Chengwu People's Hospital, Heze 637000
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Chronic use of doxorubicin (DOX) as an anticancer and antineoplastic agent has a chief jeopardy of cardiotoxicity. About 10% of the treated population has logged to cause cardiac damage. Objectives: This study principally engrossed on inspecting the effective cardioprotective activity of goniothalamin (GTN) against DOX-induced cardiotoxic rats. Materials and Methods: Group I – control, Group II – inducer (DOX) alone (2.5 mg/kg body weight [BW]) given on alternate days, Group III – DOX + GTN (2.5 mg/kg BW + 200 mg/kg BW), and Group IV – GTN alone (200 mg/kg BW). First, it employed its protective effects over the isolated cardiac tissues in which the status of HO-1 and NQO-1 were upregulated. Results: GTN administered with DOX induced rats were showed the increased the status of antioxidant levels, elevation of reactive oxygen species, which is also reduced the inflammatory and stress markers contributing to its cardio protective activity. Furthermore, GTN also downregulated the mRNA expression status of inflammatory markers and HO-1, NAD (P) H, and NQO-1 in DOX-induced rats, thereby weakening the cardiac damage. Conclusion: GTN is an effective protective agent against DOX-induced cardiotoxicity in rats.
Keywords: Antioxidant, cardiotoxicity, doxorubicin, goniothalamin, nuclear factor-κB pathway
|How to cite this article:|
Liu C, Wang Q. Goniothalamin-mediated amelioration of doxorubicin-induced myocardial damage and regulation of nuclear factor-κB/HO-1/NQO-1 signaling biomarkers in cardiotoxic rats. Phcog Mag 2022;18:267-72
|How to cite this URL:|
Liu C, Wang Q. Goniothalamin-mediated amelioration of doxorubicin-induced myocardial damage and regulation of nuclear factor-κB/HO-1/NQO-1 signaling biomarkers in cardiotoxic rats. Phcog Mag [serial online] 2022 [cited 2022 Aug 10];18:267-72. Available from: http://www.phcog.com/text.asp?2022/18/78/267/350106
- Goniothalamin (GTN) enlarged the antioxidant activity of doxorubicin (DOX)-induced cardiac rats.
- GTN also repressed the mRNA expression levels of inflammatory markers and HO-1, NAD (P) H, and NQO-1 in DOX-induced rats.
Abbreviations used: W: Body weight; DOX: Doxorubicin; TOP II: Topoisomerase II; NF-κB: Nuclear factor-κB; BP: Blood pressure; CAT: Catalase; DAP: Diastolic arterial pressure; GPx: Glutathione peroxidase; SOD: Superoxide dismutase; GSH: Glutathione; GTN: Goniothalamin; GR: Glutathione reductase; GST: Glutathione-S-transferase; CK: Creatine kinase; BNP: B-type natriuretic peptide; HR: Heart rate; LDH: Lactate dehydrogenase; SAP: Systolic arterial pressure; AST: Aspartate transferase; CK-MB: Creatine kinase-muscle/brain; MYO: Myoglobin; PETIA: Particle-enhanced turbidimetric immunoassay; MCP-1: Monocyte chemotactic protein-1; MAP: Mean arterial pressure; INF-γ: Interferon-gamma; cTnI: Cardiac troponin I; HW: Heart weight; LPO: Lipid peroxidase.
| Introduction|| |
Anthracycline antibiotic group of doxorubicin (DOX) fits to the secondary metabolite produced by Streptomyces peucetius var. caesius. It is extensively used for treating multiple assortments of tumors and hematological malignancies affected in both adults and infants. DOX is an effective chemotherapeutic agent that induces severe cardiotoxicity myocardial dysfunction even from heart failure to death, which relics a challenge., It exerts its anticancer effects by blocking topoisomerase II (TOP II) in cancer cells and causing irreversible heart injury with functional cardiac cells by apoptosis. However, it has a dissimilar mechanism of action that is not comparative to cardiac dysfunction as it causes cardiac toxicity though TOP II is not articulated in cardiac cells., However, further reports advise that elevated free radicals and cell death in cardiomyocytes contribute to DOX-induced cardiotoxicity. As the underlying pathological mechanism remains unknown, it is more tough to measure or envisage its adverse effects in patients.,
DOX treated rats were showed the chronic oxidative stress and elevated the nuclear factor-kB (NF-kB), and tumour necrosis TNF-alpha to the cardiac cells inducing its damage. Cardiac damage due to the DOX treatment persuades apoptosis through mitochondria, increasing cyt-c release and prompting caspase-3-induced cell death.,,, HO-1, NQO1, and superoxide dismutase (SOD) are the downstream effectors of Nrf2 due to chronic oxidative stress. Even though there are many effective antioxidant agents, they have side effects of cardiac toxicity; there is a necessity for therapeutic agents to treat DOX-induced toxicity.
Goniothalamin (GTN) is a styryl lactone, isolated from the Goniothalamus species of the Annonaceae family. They possess valuable properties according to clinical aspects, such as anticancer, anti-inflammatory, and antineoplastic properties.,, Compared with DOX, GTN displayed no toxicity against liver cells with specific cytotoxicity against cancer cells. Although numerous natural phytochemicals isolated from plants have a critical role in cancer treatment, many of the molecular mechanisms governing the anticancer effects remain uncharted. Different results also portray maybe their anticancer effects were attributed to the apoptosis-induced cell death. Owing to its outstanding pharmacological properties, we highlight that it could be an effective cardioprotective agent.
This study were investigated that the cardiopreotective effect of GTN against DOX-induced heart damage by reduced the cardiac stress by induced anti-oxidative enzymes, thereby reguting NFkB/HO-1/NQO-1 signalling pathways. We accentuate that GTN may be a protective agent bypassing and suppressing the cardiac toxicity induced by DOX-treated rats.
| Materials and Methods|| |
DOX, GTN, and other chemicals for the study were also gained from Sigma-Aldrich Chemicals, St. Louis, MO, USA.
Male Wistar rats (6–7 weeks old) weighing about 190–220 g, were selected and the animals were maintained with controlled humidity (65% ± 5%) and temperature (25°C ± 2°C) in a sterile room. The rats were sustained under 12-h light and dark cycles and kept on standard pellet diet and fresh water ad libitum. As per the Institutional Animal Ethics Committee's norms, the study was permitted by the Chengwu People's Hospital Animal Ethical Committee (Approved No: HZCW-827).
Animal experimental design
All experimental rats were considered into four groups covering 6 rats each, i.e., Group I – control, Group II – inducer (DOX) alone (2.5 mg/kg body weight [BW]) given on alternate days, Group III – DOX + GTN (2.5 mg/kg BW + 200 mg/kg BW), and Group IV – GTN alone (200 mg/kg BW). All animals were forfeited by cardiac puncture at the termination of the experiment. The blood was extracted via cardiac puncture, centrifuged to extract the serum for 20 min, and processed for further biochemical analysis at −20°C. The BW and heart weight (HW) of the animals were chronicled. In addition, blood pressure (BP) determinants were analyzed using the non-invasive electronic tail-cuff technique.
Before exposing to the histopathologic analysis, the heart was isolated from the induced and treated animals. Then, the heart detached was fixed with neutral formalin buffer (10%) and embedded with paraffin wax. After fixation, the tissues were sliced around 4–6 mm in size and stained with hematoxylin-eosin (H and E) and analyzed under a microscope.
A cardiac puncture sacrificed animals after the experiment; the heart tissues were exposed to molecular and biochemical examination. Heart tissues were homogenized by a 10% tissue homogenization lysis buffer of pH 7.6, and the lysates were conserved at − 20°C for future use. Heart tissues were homogenized by a 10% tissue homogenization lysis buffer of pH 7.6, and the lysates were preserved at − 20°C for future use.
The cell lysates were exposed to biochemical analysis after homogenization. The TBARS production was established per Ohkawa et al. 1979. The levels catalase (CAT), GPx, SOD, glutathione (GSH), glutathione reductase (GR), and glutathione-S-transferase (GST) were examined as per the method Sinha, Rotruck et al., Kakkar et al. (1984) technique, Omura and Sato (1964) technique, Carlberg and Mannervik (1985), and Habig et al. (1974), respectively.
Enzyme levels such as creatine kinase (CK), lactate dehydrogenase (LDH), and aspartate transferase (AST) were measured in the serum by a Hitachi automated analyzer. The CK-muscle/brain (CK-MB) levels were restrained by using a colorimetric test kit (Cat. No. KT-12247) procured from Spinreact, Girona, Spain. The serum levels of MYO were measured using a particle-enhanced turbidimetric immunoassay (PETIA) kit (Cat. No. KT-60345) from Kamiya Biomedical Company, Washington, USA.
Determination of cardiac, cytokines and inflammatory mediators by ELISA method
The cytometric bead array kits were bought from Thermo Fisher
Scientific, Waltham, MA, USA, and assessed the serum cytokine levels, including MCP-1 (Cat. No. BD-558342) and interferon-gamma (INF-γ) (Cat. No. BDB-558305) as per manufacturer protocol. In addition, the cytokines HFABP (Cat. No. ab-242240), GP-BB (Cat. No. ab-267585), Cardiac troponin I (cTnI) (Cat. No. ab-246529), BNP (Cat. No. ab-108816), and transforming growth factor-β (TGF-β) (Cat. No. ab-119558) levels were measured by using the enzyme-linked immunosorbent assay (ELISA) kits procured from Abcam, Cambridge, MA, USA, as per manufacturer protocol.
mRNA expression levels of cardiac and stress markers
Inflammatory and cardiac stress markers of the mRNA expression levels of such as NF-κB, IL-1β, TNF-α, HO-1, NAD (P) H, and NQO-1 were surveyed reverse transcription-polymerase chain reaction. The quantitative RT-PCR (Applied Biosystems) mixture system was set subsequent to the manufacturer protocol. The primers were acquired from Integrated DNA Technologies, US, as shown in [Table 1]. Each reaction was completed in triplicates, and the Δct method was employed to recognize the fold changes.
Data were examined by analysis of variance and post hoc test Least Significant Difference (LSD) regarding the ethylene glycol group using GraphPad software and articulated in mean ± standard deviation. The data from us were measured significantly if P < 0.05.
| Results|| |
Effect of goniothalamin on body weight and heart weight
In DOX-induced rats presented significantly (P < 0.05) condensed BW and HW compared to the control. The effect of GTN on the experimental animals has recuperated the BW and HW to the average levels. There was no momentous difference distinguished in the BCP- alone treated group versus the control [Figure 1].
|Figure 1: Effect of goniothalamin on changes of HW to BW. Bars are expressed as mean ± standard deviation for six rats in each group. Values did not share a familiar superscript note (#, *) between the groups at P < 0.05 (DMRT)|
Click here to view
Effect of goniothalamin on cardiac rate and blood pressure
Compared to control rats, DOX-induced animals had signs of bradycardia. As confirmed in Group III animals, the HR variations were improved by GTN administration. Compared to control rats, significant reductions in all BP indices, namely systolic arterial pressure (SAP), mean arterial pressure (MAP), and diastolic arterial pressure (DAP), were detected in DOX-treated animals. As shown in [Figure 2], treatment with GTN improved MAP, SAP, and DAP levels relative to DOX-induced rats.
|Figure 2: Effect of goniothalamin on hemodynamic parameters. Bars are expressed as mean ± standard deviation for six rats in each group. Values did not share a familiar superscript note (*, **) between the groups at P < 0.05 (DMRT)|
Click here to view
Effect of goniothalamin on antioxidant enzymes
DOX-induced rats show strangely augmented TBARS and depletion in the function of antioxidant enzymes levels such as SOD, CAT, GSH, GST, GR, and GPx in Group II rats. Conversely, oral treatment of GTN (Group III) efficiently improves antioxidants, thereby plummeting LPO levels in DOX-induced cardiomyopathy rats. However, GTN-alone treatment has no noteworthy fluctuations in antioxidant levels compared to control [Figure 3].
|Figure 3: Effect of goniothalamin on levels of and LPO and antioxidant enzymes in cardiac markers in cardiac tissues. Bars are expressed as mean ± standard deviation for six animals in each group. Values do not share a familiar superscript note (#, *) between the groups at P < 0.05 (DMRT)|
Click here to view
Effect of goniothalamin on levels of cardiac marker enzymes
The levels of antioxidant and cardiac markers, were analyzed such as AST, GP-BB, CK-MB, Myo, H-FABP, CK, and LDH, in experimental animals [Figure 4]. Group II animals stated substantial deviations in GP-B, H-FABP, CK-MB, CK, LDH, Myo, and AST markers compared with control rats. Compared with test animals, treatment with GTN (200 mg/kg BW) pointedly declined all these marker enzyme levels. There are no important differences in cardiac markers found between the control and rats treated with GTN.
|Figure 4: Effect of goniothalamin on status of the cardiac marker. Bars are expressed as mean ± standard deviation for six rats in each group. Values do not share a familiar superscript note (#, *) between the groups at P < 0.05 (DMRT)|
Click here to view
Effect of goniothalamin on inflammatory markers
The results of cytokine production are shown in [Figure 5]. The results exposed that DOX-induced animals displayed a considerable surge in MCP-1, INF-γ, TGF-β, BNP, and cTnI. On the contrary, inflammatory markers in GTN-treated animals had a noteworthy downregulation effect. In addition, non-significant upsurges in inflammatory markers have been recognized in GTN-treated rats compared to the controls.
|Figure 5: Effect of goniothalamin on inflammatory markers in control and experimental rats. Values do not share a familiar superscript note (#, *) between the groups at P < 0.05 (DMRT)|
Click here to view
Histopathological changes in cardiac tissue
As evidenced by pathological variations in the heart anatomy with extreme leukocyte infiltration and necrosis, the rats administered with DOX (Group II) advanced a severe heart dysfunction [Figure 6]. Group III rats display enhanced cardioprotection as inspected in the hearts of DOX-induced rats due to the absenteeism of complicated pathological adjustments. The standard tissue architecture of control was seen in animals treated with GTN alone (Group IV).
|Figure 6: Histological sections of the cardiac tissues. Control (Group I), doxorubicin-induced (Group II), doxorubicin + goniothalamin (Group III), and goniothalamin alone (Group IV)|
Click here to view
Reverse transcription-polymerase chain reaction expression of inflammatory stress markers
The production of inflammatory stress markers such as NF-κB, IL-1β, and TNF-α has been augmented in rats induced with DOX compared to control rats [Figure 7]. Condensed inflammatory marker expression was meaningfully contemporary when treated with GTN. A reduction in HO-1 and NQO-1 levels has also been detected, as per the control-assessed DOX-induced rats' results. There was an enlarged status of HO-1 and NQO-1 expression in GTN-treated rats.
|Figure 7: mRNA expression levels of cytokines, gene transcription, and antioxidant pathway regulators. Values do not share a familiar superscript note (#, *) between the groups at P < 0.05 (DMRT)|
Click here to view
| Discussion|| |
By redox cycling, DOX can produce reactive oxygen species (ROS) causing an imbalance in the endogenous enzymes accountable for antioxidant activity., However, heart failure is due to the apoptosis of cardiomyocytes unswervingly or indirectly related to oxidative stress. Thus, the two chief means of DOX-mediated cardiotoxicity are anti-oxidative and anti-apoptotic therapeutic agents. Lower expression in the BP related to the untreated control group in the DOX-induced animals decides with the earlier reports due to cardiac development. CK-MB and troponins I have been concerned in myocardial damage, which is released to the blood circulation and serves as an indicator for myocardial damage identification. The levels of MCP-1, INF-γ, AST, CK-MB, LDH, CK, and cTnI were augmented in DOX-induced animals, which have been later assuaged due to the action of GTN. Alterations in LDH and CK-MB levels may be due to the necrotic lesions with disruption in the membrane's integrity developed in the DOX-induced rats, released to the blood circulation on the onset of myocardial damage., In the present study, GTN-treated animals have conserved the myocardial membrane's integrity, thereby keeping their level substantially equal to the controls. They have augmented ROS generation, which has been broadly occupied in the myocardial damage-inducing formation of myocardium malondialdehyde (MDA) formation, signifying the amplified accumulation of lipid peroxidase (LPO). Besides, the GTN reduced LPO and TBARS levels, tumbling ROS generation levels, which has useful effects over reducing oxidative stress.,
In line with prior results, preeminent levels of GP-BB, myoglobin, and H-FABP reminiscent of cardiac damage as a biomarker were pragmatic in DOX-treated cardiotoxic rats serum in this research., GTN therapy has also significantly diminished the serum levels in DOX-induced rats. By converting superoxide radicals to H2O2, CAT can eventually convert to oxygen and water; the functions of SOD are a pivotal role in protecting against oxidative damage. Augmented development of superoxide radicals condensed antioxidant activity and myocardium damage.
A condensed substrate concentration, such as GSH, may be ascribed to lessened GST and GPx activities. The key cause for mitochondrial mechanism inequality is a diminution in the level of GSH. GR is an energetic enzyme for the conservation of GSH levels, so it makes an essential role as a substrate for GST and GPx. In our study, in line with preceding results, DOX-treated rats have been revealed to have declined SOD, GSH, GST, GPx, CAT, and GR activities in the heart. GTN has meaningfully amplified the mitochondrial levels of antioxidants mentioned above and the reduced LPO levels, highlighting its antioxidant activity, thereby having cardioprotective properties during ischemia. Similar to the GTN, catechin has also applied its cardioprotective effects over adriamycin-treated cardiotoxicity.
In cultured cardiomyoblasts, DOX is a potent inducer of NF-κB, while the foremost pro-inflammatory mediator interferon-γ leads to DOX activity in the metabolic pathways., The cut in GSH detected through ISO therapy could rise TNF-alpha production. Cell breakdown were increased by BNP production and TGF-β level in DOX-induced cardiotoxicity, measured the primary cardiomyopathy marker. Increased production of ROS due to DOX triggering could have subsidized to overexpression of TNF-α, TGF-β, IL-1β, BNP, and NF-κB in our present data. The earlier research also shows the DOX-induced increased expression of these inflammatory mediators in line with the contemporary work. Nrf2 functions as a vital downregulation of DOX-induced cardiomyopathy signifying the possibility that the Nrf2 target might be an effective drug strategy to lessen DOX-induced cardiotoxicity., The levels of the mRNA expressions of TNF-α, TGF-β, IL-1β, BNP, HO-1, NQO-1, and NF-κB were also radically condensed in comparison to the control, which designates the cardioprotective nature of GTN.
| Conclusion|| |
In summary, it is apparent from the verdicts that GTN has strong cardioprotective activity in rats against DOX-induced cardiotoxicity by the lower appearance of the status of TNF-α, TGF-β, IL-1β, BNP, HO-1, NQO-1, and NF-κB. In addition, it also regulated the levels of cardiac, inflammatory stress and oxidative stress markers such as AST, GP-BB, CK-MB, Myo, H-FABP, CK, LDH and CP-1, INF-γ, TGF-β, BNP, and cTnI, respectively, in par with the levels of the animal control demonstrating the cardioprotective effects of GTN. Thus, GTN is an important protective agent against cardiotoxicity caused by DOX.
The authors would like to thank the Chengwu People's Hospital for instrumentation and facility support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Lomovskaya N, Otten SL, Doi-Katayama Y, Fonstein L, Liu XC, Takatsu T, et al.
Doxorubicin overproduction in Streptomyces peucetius: Cloning and characterization of the dnrU ketoreductase and dnrV genes and the doxA cytochrome P-450 hydroxylase gene. J Bacteriol 1999;181:305-18.
Hassan MQ, Akhtar MS, Afzal O, Hussain I, Akhtar M, Haque SE, et al.
Edaravone and benidipine protect myocardial damage by regulating mitochondrial stress, apoptosis signalling and cardiac biomarkers against doxorubicin-induced cardiotoxicity. Clin Exp Hypertens 2020;42:381-92.
Yeh ET, Tong AT, Lenihan DJ, Yusuf SW, Swafford J, Champion C, et al.
Cardiovascular complications of cancer therapy: Diagnosis, pathogenesis, and management. Circulation 2004;109:3122-31.
Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 2004;56:185-229.
Capranico G, Tinelli S, Austin CA, Fisher ML, Zunino F. Different patterns of gene expression of topoisomerase II isoforms in differentiated tissues during murine development. Biochim Biophys Acta 1992;1132:43-8.
Khiati S, Dalla Rosa I, Sourbier C, Ma X, Rao VA, Neckers LM, et al.
Mitochondrial topoisomerase I (top1mt) is a novel limiting factor of doxorubicin cardiotoxicity. Clin Cancer Res 2014;20:4873-81.
Chen B, Peng X, Pentassuglia L, Lim CC, Sawyer DB. Molecular and cellular mechanisms of anthracycline cardiotoxicity. Cardiovasc Toxicol 2007;7:114-21.
Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: Pathological mechanisms and modern pharmacologic therapies. Bone Res 2018;6:15.
Ghigo A, Li M, Hirsch E. New signal transduction paradigms in anthracycline-induced cardiotoxicity. Biochim Biophys Acta 2016;1863:1916-25.
Whelan RS, Kaplinskiy V, Kitsis RN. Cell death in the pathogenesis of heart disease: Mechanisms and significance. Annu Rev Physiol 2010;72:19-44.
Zhao L, Zhang B. Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes. Sci Rep 2017;7:44735.
Auter KA, Wood LJ, Wong J, Iordanov M, Magun BE. Doxorubicin and daunorubicin induce processing and release of interleukin-1β through activation of the NLRP3 inflammasome. Cancer Biol Ther 2011;11:1008-16.
Qi W, Boliang W, Xiaoxi T, Guoqiang F, Jianbo X, Gang W. Cardamonin protects against doxorubicin-induced cardiotoxicity in mice by restraining oxidative stress and inflammation associated with Nrf2 signaling. Biomed Pharmacother 2020;122:109547.Mitry MA, Edwards JG. Doxorubicin induced heart failure: Phenotype and molecular mechanisms. Int J Cardiol Heart Vasc 2016;10:17-24.
Mitry MA, Edwards JG. 14.Doxorubicin induced heart failure: Phenotype and molecular mechanisms. Int J Cardiol Heart Vasc 2016;10:17-24.
Shi J, Abdelwahid E, Wei L. Apoptosis in anthracycline cardiomyopathy. Curr Pediatr Rev 2011;7:329-36.
Keum YS, Choi BY. Molecular and chemical regulation of the Keap1-Nrf2 signaling pathway. Molecules 2014;19:10074-89.
Wu Z, Zai W, Chen W, Han Y, Jin X, Liu H. Curdione ameliorated doxorubicin-induced cardiotoxicity through suppressing oxidative stress and activating Nrf2/HO-1 pathway. J Cardiovasc Pharmacol 2019;74:118-27.
Vendramini-Costa DB, Spindola HM, de Mello GC, Antunes E, Pilli RA, de Carvalho JE. Anti-inflammatory and antinociceptive effects of racemic goniothalamin, a styryl lactone. Life Sci 2015;139:83-90.
Pilli RA, de Toledo I, Meirelles MA, Grigolo TA. Goniothalamin-related styryl lactones: Isolation, synthesis, biological activity and mode of action. Curr Med Chem 2019;26:7372-451.
Meirelles MA, Braga CB, Ornelas C, Pilli RA. Synthesis of nitrogen-containing goniothalamin analogues with higher cytotoxic activity and selectivity against cancer cells. ChemMedChem 2019;14:1403-17.
Seyed MA, Jantan I, Bukhari SN. Emerging anticancer potentials of goniothalamin and its molecular mechanisms. Biomed Res Int 2014;2014:536508.
Sinha AK. Colorimetric assay of catalase. Anal Biochem 1972;47:389-94.
Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: Biochemical role as a component of glutathione peroxidase. Science 1973;179:588-90.
Kakkar P, Das B, Viswanathan PN. A modified spectrophotometric assay of superoxide dismutase. Indian J Biochem Biophys 1984;21:130-2.
Habig WH, Pabst MJ, Jakoby WB. Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem 1974;249:7130-9.
Ludke AR, Al-Shudiefat AA, Dhingra S, Jassal DS, Singal PK. A concise description of cardioprotective strategies in doxorubicin-induced cardiotoxicity. Can J Physiol Pharmacol 2009;87:756-63.
Doroshow JH, Locker GY, Myers CE. Enzymatic defenses of the mouse heart against reactive oxygen metabolites: Alterations produced by doxorubicin. J Clin Invest 1980;65:128-35.
Sun J, Sun G, Cui X, Meng X, Qin M, Sun X. Myricitrin protects against doxorubicin-induced cardiotoxicity by counteracting oxidative stress and inhibiting mitochondrial apoptosis via ERK/P53 pathway. Evid Based Complement Alternat Med 2016;2016:6093783.
Li H, Xia B, Chen W, Zhang Y, Gao X, Chinnathambi A, et al.
Nimbolide prevents myocardial damage by regulating cardiac biomarkers, antioxidant level, and apoptosis signaling against doxorubicin-induced cardiotoxicity in rats. J Biochem Mol Toxicol 2020;34:e22543.
Zare MF, Rakhshan K, Aboutaleb N, Nikbakht F, Naderi N, Bakhshesh M, et al.
Apigenin attenuates doxorubicin induced cardiotoxicity via reducing oxidative stress and apoptosis in male rats. Life Sci 2019;232:116623.
Deepa PR, Varalakshmi P. Protective effect of low molecular weight heparin on oxidative injury and cellular abnormalities in adriamycin-induced cardiac and hepatic toxicity. Chem Biol Interact 2003;146:201-10.
Gnanapragasam A, Ebenezar KK, Sathish V, Govindaraju P, Devaki T. Protective effect of Centellaasiatica on antioxidant tissue defense system against adriamycin induced cardiomyopathy in rats. Life Sci 2004;76:585-97.
Yoshizawa T, Takizawa S, Shimada S, Tokudome T, Shindo T, Matsumoto K. Effects of adrenomedullin on doxorubicin-induced cardiac damage in mice. Biol Pharm Bull 2016;39:737-46.
Vupputuri A, Sekhar S, Krishnan S, Venugopal K, Natarajan KU. Heart-Type Fatty Acid-Binding Protein (H-FABP) as an early diagnostic biomarker in patients with acute chest pain. Indian Heart J 2015;67:538-42.
Nazari Soltan Ahmad S, Sanajou D, Kalantary-Charvadeh A, Hosseini V, Roshangar L, Khojastehfard M, et al.
β-LAPachone ameliorates doxorubicin-induced cardiotoxicity via regulating autophagy and Nrf2 signalling pathways in mice. Basic Clin Pharmacol Toxicol 2020;126:364-73.
Ratliff BB, Abdulmahdi W, Pawar R, Wolin MS. Oxidant mechanisms in renal injury and disease. Antioxid Redox Signal 2016;25:119-46.
Abd El-Aziz TA, Mohamed RH, Pasha HF, Abdel-Aziz HR. Catechin protects against oxidative stress and inflammatory-mediated cardiotoxicity in adriamycin-treated rats. Clin Exp Med 2012;12:233-40.
Guo RM, Xu WM, Lin JC, Mo LQ, Hua XX, Chen PX, et al.
Activation of the p38 MAPK/NF-κB pathway contributes to doxorubicin-induced inflammation and cytotoxicity in H9c2 cardiac cells. Mol Med Rep 2013;8:603-8.
Ni C, Ma P, Wang R, Lou X, Liu X, Qin Y, et al.
Doxorubicin-induced cardiotoxicity involves IFNγ-mediated metabolic reprogramming in cardiomyocytes. J Pathol 2019;247:320-32.
Kalantary-Charvadeh A, Sanajou D, Hemmati-Dinarvand M, Marandi Y, Khojastehfard M, Hajipour H, et al.
Micheliolide protects against doxorubicin-induced cardiotoxicity in mice by regulating PI3K/Akt/NF-kB signaling pathway. Cardiovasc Toxicol 2019;19:297-305.
Li S, Wang W, Niu T, Wang H, Li B, Shao L, et al.
Nrf2 deficiency exaggerates doxorubicin-induced cardiotoxicity and cardiac dysfunction. Oxid Med Cell Longev 2014;2014:748524.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]