Scholars International Journal of Anatomy and Physiology

Abbreviated Key Title: Sch Int J Anat Physiol

ISSN 2616-8618 (Print) |ISSN 2617-345X (Online)
Scholars Middle East Publishers, Dubai, United Arab Emirates
Journal homepage: https://saudijournals.com

Original Research Article

Deciphering the Ameliorative Potential of 5, 7-dihydroxyflavone (Chrysin) on

Doxorubicin-Induced Cardiotoxicity by Modulating Oxidative Stress in Rats
Ifeanyi Anthony Egwuatu1, Chiadikobi Lawrence Ozoemena1*, Emeka Williams Ugwuishi2, Christian Chiemeka Ozor1,
Augustine Oviosun3, Favour Onwene1
1Department of Anatomy, Faculty of Basic Medical Sciences, College of Medicine, Enugu State University of Science and Technology,
Enugu, Nigeria
2Department of Physiology, Faculty of Basic Medical Sciences, Enugu State University College of Medicine, Enugu, Nigeria.
3
Department of Anatomy, Faculty of Basic Medical Sciences, College of Medicine, Edo State University, Uzairue, Edo, Nigeria

DOI: 10.36348/sijap.2023.v06i11.005 | Received: 07.10.2023 | Accepted: 16.11.2023 | Published: 23.11.2023

*Corresponding author: Chiadikobi Lawrence Ozoemena
Department of Anatomy, Faculty of Basic Medical Sciences, College of Medicine, Enugu State University of Science and Technology,
Enugu, Nigeria

Abstract
Doxorubicin-induced cardiotoxicity is the leading cause of morbidity and mortality among cancer survivors. The present
study aimed to investigate the ameliorative effect of 5, 7-dihydroxyflavone (chrysin) against doxorubicin-induced
cardiotoxicity in Wistar rats. Thirty-five adult male Wistar albino rats were randomly allocated into seven groups (n = 5
each) which consisted of normal control (group 1) receiving phosphate buffer saline (0.4 ml), positive control (Group 2)
received 2mg\kg of doxorubicin (DOX) through an intraperitoneal route once weekly for 21 days, chrysin low dose and
chrysin high dose (Group 3 and 4) received oral administration of chrysin 50&100mg/kg for 21 days, chrysin low dose and
DOX, chrysin medium dose and DOX and chrysin high dose and DOX(group 5, 6, and 7) received 2mg/kg of DOX once
weekly with 50, 100 and 150mg/kg of chrysin for 21 days. Significant elevations in cardiac troponin I (cTnI) and
histological lesions, which corresponded with oxidative stress, inflammation, apoptotic indicators, and cardiotoxicity when
compared to controls, were indicative of DOX-induced cardiotoxicity. Malondialdehyde (MDA), a sign of oxidative stress,
SOD, CPK (creatinine phosphokinase), TBARS (thiobarbituric acid reactive substance), and CAT (catalase) were also
elevated in the DOX group. The DOX group also had increased levels of cardiac inflammatory markers, including as
interleukin-1 (IL-1), interleukin-6 (IL-6), and the apoptotic marker caspase-3. 5, 7-dihydroxyflavone (chrysin) significantly
mitigated, but did not entirely reverse, the cardiotoxicity caused by DOX by reducing the histopathological scores of
cardiomyopathies and lowering cTnI in comparison to the DOX group. Additionally, chrysin reduced MDA to substantially
similar levels as the control. Following chrysin administration, significant decreases in IL-1, IL-6, and caspase-3 were also
seen in comparison to the DOX-only group. All things considered, these findings point to chrysin's protective action against
DOX-induced cardiotoxicity, which may have been rendered possible by oxidative stress, inflammatory, and apoptotic
suppression.
Keywords: Chrysin, Doxorubicin, Cardiotoxicity, Oxidative Stress.
Copyright © 2023 The Author(s): This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International
License (CC BY-NC 4.0) which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original
author and source are credited.

1. INTRODUCTION dependent cardio-toxicity; irreversible degenerative

Doxorubicin (DOX) was introduced in cancer cardiomyopathy, and congestive heart failure (Smith et
therapy in the late 1960s. It has come forth as one of the al., 2010). With the increasing use of this anthracycline
most potent broad-spectrum anti-tumor anthracycline antibiotic, acute cardio-toxicity has been recognized as a
antibiotics. DOX can be administered as a single agent severe complication of DOX chemotherapy (Hayek et
or in conjunction with other chemotherapeutic agents. It al., 2005). The pathogenesis of DOX-induced cardio-
is broadly used in the treatment of a variety of cancer toxicity is not entirely clear, but a solid piece of evidence
types, including leukemia, lymphoma, soft-tissue indicates that oxidative stress, inflammation, and
sarcoma, and solid tumors. However, its clinical utility is apoptosis are involved (Minotti et al., 2004).
markedly hampered by the high incidence of dose- Doxorubicin continues to be a potent and effective

Citation: Ifeanyi Anthony Egwuatu, Chiadikobi Lawrence Ozoemena, Emeka Williams Ugwuishi, Christian Chiemeka Ozor, 181
Augustine Oviosun, Favour Onwene (2023). Deciphering the Ameliorative Potential of 5, 7-dihydroxyflavone (Chrysin) on
Doxorubicin-Induced Cardiotoxicity by Modulating Oxidative Stress in Rats. Sch Int J Anat Physiol, 6(11): 181-190.
 Ifeanyi Anthony Egwuatu et al; Sch Int J Anat Physiol, Nov, 2023; 6(11): 181-190
intervention in various types of cancers. Therefore, it is et al., 2001). Numerous studies indicate that the primary
still desirable to search for a safe and effective remedy mechanism responsible for DOX-induced cardiotoxicity
that can reverse DOX-induced cardio-toxicity. is oxidative stress (Sangomla et al., 2018; Abdel-Daim
et al., 2017). According to studies by Kuznetsov et al.,
Today, much awareness has been given to the (2011) and Signal et al., (2000), DOX decreases
usage of phytochemicals as a protective plan of action endogenous antioxidants and increases lipid
against DOX-induced cardio-toxicity (Xiao et al., 2012). peroxidation, which changes the structure and functions
Natural polyphenolic phytochemicals called flavonoids of cardiac cell membranes. DOX also causes excessive
are helpful in the prevention and treatment of a wide formation of reactive oxygen species (ROS) in the
range of illnesses, including diabetes, cancer, mitochondria, causing oxidative damage to biological
cardiovascular disease, and neurological diseases (Khan macromolecules, including lipids, proteins, and DNA.
et al., 2012). Natural polyphenolic phytochemicals
called flavonoids are helpful in the prevention and 2. MATERIALS AND METHODS
treatment of a wide range of illnesses, including diabetes, 2.1 Experimental Animals
cancer, cardiovascular disease, and neurological diseases Thirty-five male rats weighing 100-200g were
(Khan et al., 2012). This class includes chrysin (5,7- procured from and housed in the Department of
dihydroxyflavone), which is present in honey, propolis Anatomy, University of Nigeria Enugu Campus. The rats
from bees, and a variety of plants (Barbarić et al., 2011). were acclimatized to the environment for 2 weeks before
One of the flavonoids present in fruits, vegetables, and experimental use. They were allowed free access to clean
plants is chrysin; research suggests that its anti- water and standard livestock pellets (Guinea Food
inflammatory and antioxidant properties contribute to its Nigeria Limited). The body weights of the animals were
protective properties against cardiovascular disease. By recorded before, during, and after administration, using
enhancing the antioxidant system, inhibiting pro-oxidant an electronic weighing scale. The procedures of this
enzymes, scavenging free radicals, and chelating redox- study were conducted according to Animal Care and Use
active transition metal ions, chrysin scavenges free Standard Operating Procedures and Guidelines
radicals and has an antioxidant impact. Chrysin improves (SOPGs), and ethical approval was obtained from the
the blood lipid profile by decreasing lipid production and Ethics and Research Committee of the Faculty of Basic
increasing its metabolism. By making endothelial nitric Medical Sciences, Enugu State University of Science and
oxide more bioavailable, chrysin controls vascular Technology.
function. By reducing vascular inflammation, chrysin
prevents the onset of atherosclerosis. Chrysin's anti- 2.2 Drugs
inflammatory properties could be attributed to its Chrysin (5, 7-dihydroxyflavone) was procured
inhibition of the. It has various biological qualities such from Sigma-Aldrich Company, 3050 Spruce Street, St.
as antioxidant, anti-inflammatory, anti-apoptotic, and Louis, USA. Doxorubicin was purchased from Open-
anti-cancer (Sultana et al., 2012). Heaven Pharmaceutical Store, opposite ESUTH
Despite significant advancements in study Parklane, Enugu, Nigeria.
methods and investigation over the years, the precise
mechanism responsible for DOX-induced cardiotoxicity 2.3 Experimental Design
is still unknown. Cardiolipin is a negatively charged Thirty-five (35) adult male Wistar rats
phospholipid that is prevalent in the inner mitochondrial (weighing 100-200g) were used for this study. They were
membrane and builds up inside the mitochondria of randomly divided into seven (7) different groups of five
cardiomyocytes. DOX has a strong affinity for it (Parker animals (n=5) each. The experimental animals were
grouped and treated as tabulated below;

Table 1: Experimental animals grouping and design

Groups Rats Treatment
1 Negative Control 5 Distilled water and oral phosphate-buffered saline (0.4ml) for 21 days.
2 Positive Control 5 Intra-peritoneal Doxorubicin at a weekly dose of 2mg/kg BW for 21 days.
3 Low dose Chrysin only 5 Oral Chrysin at a daily dose of 50mg/kg BW for 21 days.
4 High dose Chrysin only 5 Oral Chrysin at a daily dose of 150mg/kg BW for 21 days.
5 Low dose Chrysin + DOX 5 Oral Chrysin at a daily dose of 50mg/kg BW and intra-peritoneal Doxorubicin
at a weekly dose of 2mg/kg BW for 21 days.
6 Medium dose Chrysin + DOX 5 Oral Chrysin at a daily dose of 100mg/kg BW and intra-peritoneal doxorubicin
at a weekly dose of 2mg/kg BW for 21 days.
7 High dose Chrysin + DOX 5 Oral Chrysin at a daily dose of 150mg/kg BW and Intra-peritoneal doxorubicin
at a weekly dose of 2mg/kg BW for 21 days.

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2.4 Biochemical Assays suspected or have been induced to undergo apoptosis are
2.4.1 Malondialdehyde (MDA) and Glutathione first lysed to collect their intracellular contents. The cell
(GSH) assay lysate can then be tested for protease activity by the
According to the methodology provided by addition of a caspase-3- 3 specific peptide that is
Satyam et al., the estimation of malondialdehyde (MDA) conjugated to the color reporter molecule p-nitroaniline
and glutathione (GSH) serum was examined for both (pNA). When caspase cleaves a peptide, it releases the
MDA and GSH (2013; 2014). Using an iMark microplate chromophore pNA, which has a wavelength of 405 nm
absorbance reader, the optical density for MDA and GSH and may be measured spectrophotometrically. The color
was measured at 540 nm and 412 nm, respectively. reaction is closely correlated with the amount of caspase
Based on their absorbance, serum MDA and GSH levels enzymatic activity present in the cell lysate. IL-6
were computed and represented as milligrams per (interleukin-6) and IL-I (interleukin-1) platinum ELISA
milliliter (mM/ml). for rats using an Elisa Kit in accordance with the
manufacturer's instructions.
2.4.2 Superoxide Dismutase (SOD) And Catalase
(CAT) assay 2.4.5 TBARS Assay
Antioxidant enzymes SOD and CAT were The index of lipid peroxidation in the heart
determined in cardiac tissue as per standard protocol tissues was also estimated via measuring TBARS using
activities of SOD measured by the method of Marklund 1% TBA in 0.05M sodium hydroxide (NaOH) incubated
and CAT activity was measured according to the method with the sample at 100°C for 15min and then measured
of Claiborne (Marklund & Marklund, 1974). at 530nm.

2.4.3 Cardiac Troponin, Creatinine Phosphokinase 2.5 Statistical Analysis

(CPK) And Lactate Dehydrogenase (LDH) All quantitative data were analyzed using
estimation GraphPad version 8 and SPSS Version 23 (IBM Corp.,
Cardiac troponin and CPK were estimated using test Armonk, NY, USA) software, using one-way ANOVA
strips, while LDH was estimated in serum by enzymatic followed by Tukey’s comparison test. Significance was
kit using a biochemistry semi-auto analyzer, Nicholas set at P <0.05 (95% confidence interval). The results
Piramal 5010. were represented in tables and bar charts to show the
mean and standard deviation error of the mean.
2.4.4 Apoptosis Analysis and Inflammatory
Cytokines 3. RESULTS
The activity of the caspase enzyme in the brain 3.1 BIOCHEMICAL RESULT
tissue homogenate is measured. The cells that are

Table 2: Result of the Mean ± Standard Deviation of the Anti-Oxidative Biomarkers

GROUPS SOD MDA GSH TBARS LDH CPK CAT
1 12.07±0.36 7.07±0.66 26.66±0.65A 2.10±0.34A 144.54±5.56 122.62±3.85A 36.70±0.90A
2 8.92±0.96* 8.97±0.18* 22.66±0.15* 3.59±0.11* 165.66±6.18* 147.41±6.55* 30.17±1.91*
A
3 11.94±0.32 7.43±0.24A 25.43±0.50A 3.88±0.34 148.91±3.09 127.52±0.77A 34.42±1.10A
* *
4 10.67±0.21 8.44±0.13 24.83±0.75 4.05±0.43 156.55±2.16 136.51±2.70A 32.93±0.80
A A *
5 10.80±0.48 7.82±0.13 25.19±0.15 3.89±0.43 158.73±8.03 130.52±2.70A 34.64±0.60A
A *
6 11.46±0.46 7.99±0.29 24.70±0.94 3.10±0.13 160.70±8.02 132.42±5.40 33.10±0.30
7 11.56±0.91A 8.08±0.11 24.94±0.60 3.81±0.41* 155.24±5.87 139.51±3.08* 32.79±0.80
Values were expressed as Mean ± Standard deviation; *p<0.05 showed a significant difference compared with the
control group 1, while AP<0.05 showed a significant difference comparing group 2 to groups 3,4,5,6,7.

*SOD = SUPEROXIDE DISMUTASE

*MDA=MALONEDIALDEHYDE
*GSH= GLUTATHIONE
*CAT= CATALASE
*LDH=LACTATE DEHYDROGENASE
*CPK= CREATININE PHOSPHOKINASE
*TBARS=THIOBARBITURIC ACID REACTIVE SUBSTANCE

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Table 3: Result of the Mean ± Standard Deviation of the Anti-Inflammatory Markers

GROUPS IL-6 IL-1 CASPASE- 3 CARDIAC TROPONIN
1 204.35±5.36 131.09±9.27 4.98±0.30A 0.04±0.02A
* * *
2 238.48±5.96 182.58±9.27 6.90±0.19 0.12±0.03*
A A A
3 215.31±0.60 138.58±6.62 5.40±0.32 0.08±0.02
4 219.94±3.58 157.30±2.65 5.52±0.16A 0.10±0.02
5 222.89±4.17 150.28±8.61A 5.61±0.23A 0.11±0.02
6 222.47±9.53 148.88±5.30A 6.07±0.23* 0.09±0.01
7 213.30±3.58A, 150.28±3.31A 5.93±0.16*A 0.10±0.03
Values were expressed as Mean ± Standard deviation; *p<0.05 showed a significant difference compared with the
control group 1, while AP<0.05 showed a significant difference comparing group 2 to groups 3,4,5,6,7.

*IL-1= INTERLEUKIN 1
*IL-6= INTERLEUKIN 6

3.2 BODYWEIGHT RESULT

Fig 1: Chart showing the distribution of the animals' body weight before (initially) and after induction, and finally
after treatment
WT= WEIGHT. Chart showing initial and final weight before and after induction.

3.3 EFFECT OF DOXORUBICIN (DOX) ON HISTOMORPHOLOGY OF THE MYOCARDIUM OF WISTAR

RATS TREATED WITH CHRYSIN FOLLOWING DOX-INDUCED CARDIOTOXICITY

(A) (B)

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(C) (D)

(E) (F)

(G)
Fig 2: H&E; Magnification ×200 (A) shows a photomicrograph of the Negative Control group demonstrating
interspersed cardiomyocytes with connective tissue septa - the heart appears normal. (B) Positive Control group
demonstrating cardiomyocytes with focal areas [black arrows] of myocardial infarct. (C) and (D) demonstrated
interspersed cardiomyocytes with connective tissue septa - the heart appears normal. (E) demonstrated
cardiomyocytes with focal areas showing hemorrhage [black arrows] and mild obliterative cardiomyopathy. (F)
showed obliterative cardiomyopathy and mild interstitial tissue enlargement. (G) showed cardiomyocytes
interspersed with connective tissue septa - heart tissue appears normal

4. DISCUSSION Abdelbasset, 2018). Oxidative stress is another

The mechanism of doxorubicin-induced mechanism of Doxorubicin (DOX) toxicity; damage of
cardiotoxicity is still unclear and more likely to be the myocardium by free radicals increases membrane
multifactorial (Rochette et al., 2015). One of the permeability enhancing the release of enzymes (Swamy
suggested mechanisms is a dysfunction of cardiac et al., 2011), which are released from damaged myocytes
muscle that may end up with heart failure (Kelleni & and are sensitive indicators of cardiac injury (Herman et

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 Ifeanyi Anthony Egwuatu et al; Sch Int J Anat Physiol, Nov, 2023; 6(11): 181-190
al., 2000). Usually, during cardiac damage greater anti-inflammatory effects and protects cells from
amount of troponin is released into the blood. oxidative damage that can lead to disease (Janabi et al.,
2020), preventing the effects of DOX.
The heart's overall enlargement, ventricular
dilatation, and inflammatory cells were all part of the An ameliorative effect was observed in group
common chronic response seen in the heart's gross seven which received doxorubicin and a high dose of
morphological changes after receiving DOX. Reduced chrysin (150mg/kg) where the heart tissue appeared
body weight and increased heart weight are two further normal. Consequently, chrysin at 150mg\kg dose was
effects of DOX-induced cardiotoxicity (Ascensão et al., ameliorative against doxorubicin-induced changes in the
2005). Results of this study confirmed that a dose of heart, and this agrees with the earlier report of Mantawy
2mg/kg of doxorubicin produced significant et al., (2014). The mean level of troponin group 2
cardiotoxicity as was observed in the focal area of (positive control) was significantly higher than group 1
myocardial infarction in heart tissue this was supported (Table 3) and was the highest compared to all other
by work done by (Mantawy et al., 2017) with 15mg/kg groups. The value in group 1 was significantly lower in
body weight of DOX was ameliorated by chrysin. The comparison to other groups.
increase in these biomarkers was further validated by
histopathological examination. The elevated troponin activity may result from
the release of lysosomal enzymes that worsen the injury
In this work, we assessed whether 5,7- or from the toxic metabolites of doxorubicin binding to
dyhydroxyflavone could protect rats from acute cardiac cardiac macromolecules, causing damage and necrosis
damage caused by DOX. The assessment of certain that releases intracellular contents into the systemic
cardiac tissue biomarkers, such as glutathione (GSH), circulation as well as free radicals. This outcome is
lipid peroxidation products like malondialdehyde compared to a report from a previous investigation
(MDA) level and superoxide dismutase and catalase conducted by Senthilkumar et al., (2006).
(SOD and CAT), inflammatory biomarkers activities,
and histopathological examination of heart tissue, was When compared to the toxic group, the
used to investigate doxorubicin-induced cardiotoxicity. ameliorative groups (5, 6, 7) displayed a minute drop in
The histopathological examination carried out on the troponin activity; nevertheless, this decrease was still
heart shows tissue of various groups. Group one significantly higher than that of the control group. The
(negative control) which was given phosphate buffer ameliorative agents' mediation of enhanced heart
saline appears normal with no pathology seen, there was function may be the cause of the decline (Bhaskar & Rao,
no inflammation, apoptosis, or hemorrhage found. Group 2002). Groups 3 and 4 were somewhat higher but lower
two (positive control) given doxorubicin only showed a than the DOX group, and they did not exhibit any
focal area of myocardial infarcts, this indicates that discernible changes from the control group. This may be
2mg/kg body weight of doxorubicin, used in this study due to chrysin's ability to control cellular activity and
had a cardiotoxic effect on the heart in support with other fend against free radicals, which put the body under
works like (Kwatra et al., 2016). Groups three and four oxidative stress (Saad et al., 2001).
which received low (50mg/kg) and high (150mg) doses
of chrysin respectively appeared normal and no When compared to the control group (group 1),
pathology was seen. This could be because of the effect GSH (glutathione), SOD (superoxide dismutase), and
of chrysin, which helps to regulate cellular activity and CAT (catalase) all increased in the DOX group (group
fight off free radicals that cause oxidative stress on the 2), with groups 3, 4, 5, 6, and 7 showing a statistically
body (Jethwani et al., 2022). significant increase compared to the group 2 (Table 2).
Depletion of antioxidants and increased oxidative stress
Groups five and six given DOX with chrysin may be the cause of cardiac tissue damage. The mean
low(50mg/kg) and medium(100mg/kg) doses showed levels of GSH, CAT, and SOD were significantly higher
hemorrhage with mild obliterative cardiomyopathy and in group 5, which received a low dose of chrysin (50
mild interstitial tissue enlargement and obliterative mg/kg), than in the DOX group. This contrasts with
cardiomyopathy, this shows that at 50 mg/kg and findings from a related study that showed no discernible
100mg/kg 5,7-dihydroxyflavone(chrysin) did not affect rise at 50 mg/kg when DOX was administered at 15
the result of 2mg/kg DOX-induced cardiotoxicity, the mg/kg body weight (Mantawy et al., 2017). This might
present findings were supported by earlier reports of be the case as it.
(Saad et al., 2001; Swamy et al., 2011; Saleem et al.,
2014; Su et al., 2015). Meanwhile, Mantawy et al., When compared to the other groups, the DOX
(2014) reported that the cardiotoxic effect from 15mg of group's mean level of malondialdehyde (MDA) was
DOX was ameliorated by 25mg/kg and 50mg/kg of higher than that of the normal control group. According
chrysin. This could be because the rats were pretreated to data, DOX administration in rats resulted in a
with these doses, before induction of DOX for a considerable increase in lipid peroxidation, which was
cardioprotective effect and chrysin which has beneficial demonstrated by marked elevations in MDA. This is

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 Ifeanyi Anthony Egwuatu et al; Sch Int J Anat Physiol, Nov, 2023; 6(11): 181-190
consistent with earlier research (Sarkar et al., 2015). Rats al., 2015). Similar to the findings published by Chen et
treated with 5,7-dihydroxyflavone showed a partial al., (2015), the results of this investigation demonstrated
restoration of tissue antioxidant capacity; MDA levels a considerable increase in caspase-3 activity in cardiac
were sufficiently impacted to resemble those in the tissue after DOX treatment (Chen et al., 2007). All things
control group, but the therapy did not significantly considered, it is plausible that our findings that 5, 7-
change MDA levels when compared to the DOX group. dihydroxyflavone-mediated decreases the inflammatory
This outcome is consistent with earlier research (Sarkar mediators and that the partial improvement in cardiac
et al., 2015; Shaker et al., 2018; Zhang et al., 2005; tissue's antioxidant capacity highlighted decreases in
Ahmed et al., 2005; Yilmaz et al., 2006). DOX-mediated increases in cellular caspase-3 level,
which were observed in groups (5, 6 and 7) as well as in
The DOX group had the lowest mean values of the chrysin only groups (3 and 4).
all the groups, with creatinine phosphokinase, lactate
dehydrogenase, and thiobarbituric acid reactive The DOX group's mean level of IL1 and IL6
substance (CPK, LDH, and TBARS) being greater than was lower than that of groups 3, 5, 6, and 7 and higher
those of the control group. There was a discernible rise than that of the control group (Table 3). The
in myocardial TBARS in contrast to group 1. (control pathophysiological basis for DOX-induced
group). It is possible that free radicals formed from the cardiomyopathy may be the increasing rise of pro-
interaction of superoxide radicals with hydrogen inflammatory cytokines inside heart tissue, as evidenced
peroxide or from the reaction of drug toxic radicals with by current research (Pecoraro et al., 2016). In line with
oxygen are what cause the toxic group's (DOX group) those publications, the current study's findings, which
significantly higher TBARS values compared to group 1 showed appreciable increases in cardiac IL-1 and IL-6 in
(Table 2). This suggests that increased lipid peroxidation the DOX group compared to controls, suggested an
may be linked to cellular damage. While the ameliorative important role for inflammation in the pathophysiology
group's TBARS increased in this study when compared of DOX-induced cardiotoxicity. Uncertainty surrounds
to the DOX-treated group, other studies indicate that the the main underlying mechanism driving this rise in
mean TBARS value of the ameliorative groups was inflammatory indicators, while potential triggers include
much lower than the group treated with doxorubicin. The reduced tissue antioxidant capacity, elevated ROS levels,
outcomes matched previous reports (Sharma et al., 2007; and consequent lipid peroxidation. It has been revealed
Swamy et al., 2011; Siddique et al., 2009). recently that there is a correlation between elevated
levels of oxidative stress and inflammatory mediators.
The study found that the DOX group had higher Oxidative stress is believed to initiate inflammatory
mean activity levels in CPK and LDH than group 1 did reactions by activating the NF-κB pathway, which in turn
(Table 3). The elevated levels of CPK and LDH could triggers the transactivation of cytokines (Sun et al., 2016;
potentially be attributed to the harmful byproducts of Dash et al., 2015). The results of this investigation
doxorubicin, which attached themselves to cardiac showed that chrysin therapy significantly decreased
macromolecules, inflicting harm and necrosis that cardiac IL-1 and IL-6 levels, indicating that chrysin has
allowed intracellular contents to be released into the a consistent reversing effect on the DOX-mediated
bloodstream. Additionally, the generation of free radicals release of inflammatory mediators inside cardiac tissues.
or the release of lysosomal enzymes may exacerbate the The final weight was measured prior to sacrifice, and
injury. In comparison to the toxic group, the ameliorative measurements were made of the body both before and
groups (5, 6, and 7) and the chrysin-only group (3 and 4) after induction. There was a considerable rise in body
displayed a moderate drop in CPK and LDH activity; weight in the DOX, chrysin-only, and control groups.
nevertheless, this decrease was still much higher than While the body weight did not significantly increase in
that of the control group. The ameliorative agents' the control group, it did decrease in the ameliorative
mediation of enhanced heart function may be the cause groups 6 and 7 and the low dosage ameliorative group 5.
of the decline (Senthilkumar et al., 2006; Siddique et al., Their toxic effects, particularly on heart tissue, may have
2009; Swamy et al., 2011; Minotti et al., 2004). disrupted basal metabolism, which has a negative impact
on body weight. These results are consistent with the
When compared to group 1, the DOX group reports of Kalender et al., (2022) and Kozluca et al.,
(group 2) in caspase-3 exhibited a rise and was the (1995).
highest of the other groups. When compared to group 2,
the ameliorative groups (5, 6, and 7) of Caspase 3 5. CONCLUSION
demonstrated an increase that was dose-dependent and This study shows that 5,7-dydroxyflavone at a
increased with a greater dose. The pathophysiology of dose of 150mg/kg body weight has an ameliorative effect
DOX-induced cardiotoxicity involves apoptosis (Minotti in the treatment of doxorubicin-induced cardiotoxicity in
et al., 2004). Increased oxidative stress brought on by adult Wistar rats.
DOX sets off a number of signaling cascades, one of
which is the activation of caspase-3, which causes the
death of cardiomyocytes (Octavia et al., 2012; Dash et

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 Ifeanyi Anthony Egwuatu et al; Sch Int J Anat Physiol, Nov, 2023; 6(11): 181-190
ETHICAL APPROVAL Biophysica Acta (BBA)-Biomembranes, 1514(2),
Ethical approval was obtained from the Faculty 206-216.
of Basic Medical Science research ethics committee, • Sangomla, S., Saifi, M. A., Khurana, A., & Godugu,
Enugu State University of Science and Technology C. (2018). Nanoceria ameliorates doxorubicin
College of Medicine (ESUCOM), with the Ethical Right induced cardiotoxicity: Possible mitigation via
Permission Number: (ESUCOM/FBMS/ETR/2022/013) reduction of oxidative stress and
and the research was conducted according to the inflammation. Journal of Trace Elements in
guidelines for the care and use of laboratory animals of Medicine and Biology, 47, 53-62.
ESUCOM. • Abdel-Daim, M. M., Kilany, O. E., Khalifa, H. A.,
& Ahmed, A. A. (2017). Allicin ameliorates
Conflict of Interests: The authors declared no conflict doxorubicin-induced cardiotoxicity in rats via
of interest. suppression of oxidative stress, inflammation and
apoptosis. Cancer chemotherapy and
Funding Statement pharmacology, 80, 745-753.
This research received no specific grant from • Kuznetsov, A. V., Margreiter, R., Amberger, A.,
any funding agency in the public, commercial, or not-for- Saks, V., & Grimm, M. (2011). Changes in
profit sectors. mitochondrial redox state, membrane potential and
calcium precede mitochondrial dysfunction in
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