https://doi.org/10.52973/rcfcv-e34444
Received: 28/04/2024 Accepted: 25/06/2024 Published: 19/09/2024
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Revista Científica, FCV-LUZ / Vol. XXXIV, rcfcv-e34444
ABSTRACT
Ovarian cancer is a widespread type of cancer among gynecologic
cancers and has a very high mortality rate. For this reason, the search
for new treatments continues. Tyrosol is a phenolic compound
with antioxidant and anti–inammatory activity. The study, it was
investigated the effect of Tyrosol on oxidative stress and inammatory
parameters in cisplatin–induced ovarian inammation and oxidative
stress in rats. For this purpose, twenty–four female Wistar albino
rats were divided into four groups: control, Cisplatin, Tyrosol, and
Cisplatin+Tyrosol. Cisplatin was administered intraperitoneally at
6 mg·kg
-1
twice, once a week. Tyrosol (20 mg·kg
-1
) was administered
daily by oral gavage for fourteen d. Oxidative stress and inammatory
biomarkers were measured in ovarian tissue. Cisplatin administration
increased Malondialdehyde (MDA), tumor necrosis factor alpha
(TNF–α), interleukin 6 (IL–6), and interleukin 1 beta (IL–1β) levels in the
ovaries, while Glutathione (GSH), Glutathione Peroxidase (GSH–Px), and
Catalase levels were decreased. Tyrosol administration was shown to
decrease oxidative stress parameters and inammatory cytokines.
In conclusion, it can be say that the protective activity of Tyrosol
against Cisplatin–Induced ovarian inammation and oxidative stress
is realised through antioxidant and anti–inammatory mechanisms.
Key words: Ovarian; cisplatin; tyrosol; protective effect; rat
RESUMEN
El cáncer de ovario es un tipo de cáncer muy extendido entre los
cánceres ginecológicos y tiene una tasa de mortalidad muy alta.
Por este motivo, continúa la búsqueda de nuevos tratamientos.
El Tirosol es un compuesto fenólico con actividad antioxidante y
antiinamatoria. En el estudio, investigamos el efecto del tirosol sobre
el estrés oxidativo y los parámetros inamatorios en la inamación
ovárica y el estrés oxidativo inducidos por cisplatino en ratas. Para
ello, veinticuatro ratas albinas Wistar se dividieron en cuatro grupos:
control, Cisplatino, Tirosol y Cisplatino+Ttirosol. El Cisplatino se
administró por vía intraperitoneal a 6 mg·kg
-1
dos veces, una vez por
semana. Se administró Tirosol (20 mg·kg
-1
) diariamente mediante
sonda oral durante catorce d. Se midieron el estrés oxidativo y los
biomarcadores inamatorios en el tejido ovárico. La administración
de Cisplatino aumentó los niveles de Malondialdehído (MDA), factor
de necrosis tumoral alfa (TNF–α), interleucina 6 (IL–6) e interleucina 1
beta (IL–1β) en los ovarios, mientras que, el glutatión (GSH), la glutatión
peroxidasa (GSH–Px), y los niveles de catalasa disminuyeron. Se
demostró que la administración de tirosol disminuye los parámetros
de estrés oxidativo y las citocinas inamatorias. En conclusión,
podemos decir que la actividad protectora del tirosol contra la
inamación ovárica y el estrés oxidativo inducidos por cisplatino se
realiza a través de mecanismos antioxidantes y antiinamatorios.
Palabras clave: Ovario; cisplatino; tirosol; efecto protector; rata
Protective Effect of Tyrosol on Cisplatin–Induced Ovarian Inammation and
Oxidative Stress in Rats
Efecto protector del tirosol sobre la inamación ovárica y el
estrés oxidativo inducidos por cisplatino en ratas
İshak Gökçek
1
* , Ahmet Gözer
2
, Tuncer Kutlu
3
,
Mehmet Güvenç
1
,
Leyla Aydın
4
, Gökhan Uyanık
5
1
Hatay Mustafa Kemal University, Faculty of Veterinary Medicine, Department of Veterinary Physiology. Hatay, Türkiye.
2
Hatay Mustafa Kemal University, Faculty of Veterinary Medicine, Department of Veterinary Obstetrics and Gynaecology. Hatay, Türkiye.
3
Hatay Mustafa Kemal University, Faculty of Veterinary Medicine, Department of Veterinary Pathology. Hatay, Türkiye.
4
Ankara Yıldırım Beyazıt University, Faculty of Medicine, Department of Physiology. Ankara, Türkiye.
5
Erciyes University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynaecology. Kayseri, Türkiye.
*Corresponding author: ishakgokcek@hotmail.com; igokcek@mku.edu.tr
Tyrosol effects on ovarian damage in rats / Gökçek et al. ___________________________________________________________________________
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INTRODUCTION
Cancer is the second leading cause of death globally and a common
cause of death in both developed and developing countries [1]. Ovarian
cancer is the second most common gynecological tumor in women
in the United States and the fth most common cause of cancer–
related death in women [2]. Therefore, research aimed at increasing
the effectiveness of ovarian cancer treatment and reducing the side
effects of chemotherapeutic drugs remains critical [1, 2].
The treatment of ovarian cancer primarily favors Cisplatin, one
of the most widely used anticancer drugs worldwide [3]. While the
multifaceted mechanism of Cisplatin’s anticancer effect and its ability
to damage the DNA of cancer cells are signicant advantages, its
toxicity to organs such as the kidneys, heart, and liver is a severe
disadvantage [4]. In addition, ovarian cancer patients treated with
Cisplatin often develop resistance to the drug, experience changes
in the cellular import and export processes of the drug, and suffer
severe toxic effects, ranging from alterations in DNA damage repair
mechanisms in healthy cells to disruptions in apoptosis and autophagy
[4, 5]. Cisplatin binds to DNA rings and blocks them, causing DNA
damage [5]. It also causes reproductive abnormalities such as early
ovarian failure, primordial follicle toxicity, oocyte death, a decrease
in hormones such as anti–Müllerian hormone (AMH) and inhibin,
and endocrine malfunction [6]. Considering that Cisplatin is a very
effective chemotherapeutic drug despite all these disadvantages,
the search for combined therapies to reduce the toxic effects of
Cisplatin has come to the forefront [7, 8].
Cancer patients employ a number of complementary and alternative
medicine methods to deal with the problems and diculties of cancer,
which can have an impact on their quality of life [1] For instance,
Ayazoglu et al. [9] reported that Gallic acid, a phenolic compound,
demonstrated an antioxidant protective effect in ovaries against
Cisplatin–induced ovarian damage. Many studies have emphasised
the antioxidant and anticancer properties of Tyrosol, one of the
natural phenolic compounds found in extra virgin Olive oil [10, 11, 12].
In a study of 2,411 healthy Italian women over 45 years of age and 1,031
Italian women with ovarian cancer, it was found that ovarian cancer
rates were lower in Italy compared to other European countries and
that this was associated with Olive oil consumption in the diet [13].
This study aimed to reveal the possible protective effects of Tyrosol on
ovarian inammatory status and the oxidative stress caused by Cisplatin.
MATERIAL AND METHODS
Ethics
The study received ethical approval from the Local Ethics Committee
for Experimental Animals at Hatay Mustafa Kemal University (Decision
No. 2023/01–08, Hatay, Turkey). The animals and the experimental
studies were provided and conducted by the Hatay Mustafa Kemal
University Experimental Research Centre
Study design
Wistar albino female rats (Rattus norvegicus) (6–8 weeks and
250–300 g) were used in the study. Animals were housed in standard
plastic cages with a 12–hour light/dark cycle, in an environment
controlled at 20–22°C and regulated humidity. Unrestricted access
to food and water was provided throughout the study. Rats were
randomly and equally divided into groups using a random number
generator to ensure unbiased allocation. Animal care and experimental
protocols adhered strictly to the National Institutes of Health (NIH)
Guide for the Care and Use of Laboratory Animals. The rats were
divided into four groups equally: control (C), Cisplatin (CP), Tyrosol
(Tyr), and Cisplatin+Tyrosol (CP+Tyr) groups (n= 24, per 6). Cisplatin (6
mg·kg
-1
) (Cisplatin Kocak 25 mg·50 ml
-1
) once a week, for a total of two
administrations [14]. Tyrosol (Sigma Aldrich, %98) was administered
in saline and administered by oral gavage at a dose of 20 mg·kg
-1
daily
for 14 days –d– [14]. The control group was administered 1 ml of solvent
orally, the same gavage volume as that given to the other groups.
At the end of the study, animals were sacriced under anesthesia
with xylazine (10 mg·kg
-1
) (Rompun, 20 mg·ml
-1
) and ketamine (100mg·kg
-1
)
(Ketalar, 100 mg·ml
-1
). Euthanasia was confirmed by monitoring
respiration and heart rate. Ovarian tissues were collected and stored
at -20°C until analysis. All analyses were performed on the obtained
ovarian tissue. To evaluate the effects of Tyrosol, ovarian weight was
measured, along with oxidative stress parameters (malondialdehyde
(MDA), glutathione (GSH), glutathione peroxidase (GSH–Px), and
catalase) and inammatory cytokines (TNF–α, IL–6, and IL–1β).
Ovarian weight
The right and left ovary samples were thoroughly cleaned, weighed
on a precision balance (Daihan, SC210, Turkey), and the averages were
used to express the ovarian weight in milligrammes.
Ovarian oxidative stress (MDA, GSH, GSH–Px, and Catalase) analysis
The two ovaries (left and right) were collected and thoroughly
homogenized using Tris–buffered saline (pH 7.4). The homogenate
was then centrifuged (Nuve, Nf 800R, Turkey) 3220 G for 60 min and
supernatant was seperated and the levels of malondialdehyde (MDA),
glutathione (GSH), glutathione peroxidase (GSH–Px), and catalase
(CAT) were measured using a spectrometer (Shimadzu, UV–1700,
Japan), as described in the studies by Arkali et al. [16]. The levels of
MDA and GSH were measured in nmol per gram of tissue, whereas
the amounts of GSH–Px and catalase were measured in IU per gram
of protein and ku per gram of protein, respectively.
Ovarian inammatory cytokine (TNF–α, IL–6, and IL–1β) analysis
The right and left ovarian tissues from each sample were mixed
and homogenized using phosphate–buffered saline (PBS) (pH 7.4) at
a concentration of 1/10 (w/v), following the guidelines provided by the
test kits. The resulting homogenate was subjected to centrifugation
(Nüve, Nf 800R, Turkey) with a force of 10000 G for a duration of 5 min
at a temperature of +4°C. The supernatant, was gathered and utilized
for analysis. The amounts of tumor necrosis factor alpha (TNF–α),
interleukin 6 (IL–6), and interleukin 1 beta (IL–1β) were were measured
on tissue serum samples with commercial ELISA kits (Bostonchem),
and microplate reader (Erba Manheim, Lisascan EM, Czech Republic)
and expressed in picograms per milliliter (pg·mL
-1
).
Statistical analysis
The study evaluated the data statistically. For all variables obtained,
parametric test assumptions were applied before proceeding to
signicance tests. The variables were analyzed by the Shapiro–Wilk
test for normality and Levene’s test for homogeneity. Then, one–way
analysis of variance (ANOVA) was used to control the difference between
variables statistically. For the variables in which the difference between
the groups was signicant, the Tukey test was used as a post–hoc test.
FIGURE 1. Ovarian weights (mg). Values are mean ± SEM, and letters (a, b, and
ab) on the columns indicate statistical dierences between groups
FIGURE 2. MDA, GSH, GSH–Px and Catalase levels in ovarian tissue. MDA,
*P=0.002. GSH, P=0.003. GSH–Px, P=0.010. Catalase, *P=0.001. Letters on columns
(a, b and ab) indicate statistical dierence
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All statistical analyses were analyzed with a minimum 5% margin of
error. The IBM SPSS software was used for all statistical analyses, and
all results were expressed as mean ± standard error of the mean (SEM)
RESULT AND DISCUSSION
Ovary weights
The mean ovarian weights of the C, CP, Tyr, and CP+Tyr groups were
34.17 ± 1.11, 28 ± 1.39, 30.67 ± 1.87, and 35 ± 1.84 mg, respectively (FIG. 1).
Statistically analyzed, it was observed that there was no difference
between the control group and the other groups. However, the CP
and CP+Tyr groups were different (P=0.019).
There are numerous studies investigating the effects of cisplatin
treatment on ovarian weights [17, 18, 19]. A study conducted on rats
demonstrated that various doses and durations of cisplatin administration
signicantly reduced both body weight and ovarian weights [17]. Similarly,
another study observed that administering cisplatin at a dose of 6 mg·kg
-1
once a week resulted in reduced ovarian weights [18]. Additionally, a
study proved that the weights of ovaries exposed to 2 mg·kg
-1
cisplatin
for ten days signicantly declined in C57 albino mice [19]. A further study
reported that cisplatin reduces ovarian weights, increases oxidative
stress, and signicantly decreases ovarian reserves [20]. In this study,
consistent with previous studies, cisplatin administration caused a
reduction in ovarian weights in rats; however, tyrosol treatment did not
result in a statistically signicant increase in ovarian weights.
Ovarian MDA, GSH, GSH–Px, and Catalase Levels
The CP group had the highest MDA levels, with a mean of 19.13 ± 1.41.
In comparison, the C, Tyr, and CP+Tyr groups had mean MDA levels
of 11.96 ± 1.36, 12.46 ± 0.69, and 13.48 ± 1.33, respectively (FIG. 2).
The difference between the CP group and the other groups was
statistically signicant (P=0.002).
The GSH levels of the groups were measured as 6.04 ± 0.11 in the
C group, 5.71 ± 0.19 in the CP group, 6.70 ± 0.20 in the Tyr group, and
6.24 ± 0.12 in the CP+Tyr group. While the difference between the
CP group and the C and Tyr groups was signicant, no signicant
difference was found between the CP and CP+Tyr groups (P=0.003).
FIGURE 3. TNF–α, IL–6 and IL–1β levels in ovarian tissue. TNF–α, *P=0.002. IL–6,
*P=0.001. IL–1β, *P=0.001
Tyrosol effects on ovarian damage in rats / Gökçek et al. ___________________________________________________________________________
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GSH–Px levels of the study groups (C, CP+Tyr, CP+Tyr) were
measured as 13.48 ± 1.03, 10.88 ± 0.51, 14.30 ±0.50, and 13.06 ± 0.38,
respectively (P=0.010). The CP group had the lowest GSH–Px levels,
which signicantly differed from the C and Tyr groups, in line with
the GSH ndings. The Tyr and CP+Tyr groups were similar to the
control group (P=0.010).
Catalase levels of the C, CP, Tyr, and CP+Tyr groups were 44.68 ± 2.53,
32.31 ± 1.79, 45.23 ± 2.92, and 44.16 ± 1.08, respectively. The catalase level
was the lowest in the CP group, and the difference between the other
groups was statistically signicant. The C, Tyr, and CP+Tyr groups were
similar to each other in terms of catalase levels (P=0.001).
Studies have reported that cisplatin administration induces
oxidative stress by causing lipid peroxidation and an imbalance
in antioxidant defense systems [9, 14, 21]. In rats, a single dose of
cisplatin has been observed to increase MDA levels and decrease
antioxidants such as GSH, GSH–Px, and catalase, leading to damage in
the ovary and uterus. Similarly, in this study, cisplatin administration
resulted in increased MDA levels and decreased GSH levels, as well as
reduced activities of GSH–Px and catalase in ovarian tissue. Numerous
phytochemical compounds have been reported to exert benecial
effects on the side effects induced by cisplatin treatment [22].
Polyphenolic compounds are known to mitigate the side effects of
chemotherapy drugs [23]. Natural antioxidants have been reported
to have signicant effects against oxidative stress–mediated ovarian
damage [24, 25]. Tyrosol, a prominent natural antioxidant found
in olive oil and wine, is highly stable, less prone to autooxidation,
and maintains its antioxidant activity under critical conditions [12].
Furthermore, Tyrosol is a compound capable of exerting antioxidant
effects by accumulating intracellularly [26]. Several studies have
demonstrated that Tyrosol exerts signicant antioxidant effects in
various tissues, thereby reducing oxidative stress [12, 15, 27]. In this
study, Tyrosol attenuated cisplatin–induced ovarian oxidative stress,
particularly by decreasing MDA levels and enhancing catalase activity.
Ovarian TNF–α, IL–6, and IL–1β levels
In the CP group, TNF–α, IL–6, and IL–1β levels were measured at the
highest values and were statistically different compared to the other
groups. Also, the C, Tyr, and CP+Tyr groups were statistically similar.
In all groups, respectively (C, CP, Tyr, CP+Tyr), TNF–α levels were
48.16 ± 4.77; 86.23 ± 10.13; 47.28 ± 4.98; 51.67 ± 6.36 pg·mL
-1
(P=0.002),
IL–6 levels were 67.51 ± 5.15; 97.73 ± 4.09; 68.28 ± 4.57; 71.67 ± 5.84
pg·mL
-1
(P=0.001), and IL–1β levels were 127.78 ± 9.16; 192.09 ± 11.57;
132.09 ± 9.15; 145.17 ± 11.65 pg·mL
-1
(P=0.001), are shown in FIG. 3.
Inammatory processes are reported to impair oocyte quality and
cause fertility problems such as early menopause [28]. Cisplatin induces
a strong inammatory response in ovarian tissue by upregulating the
expression of pro–inammatory enzymes such as tumor necrosis
factor and nuclear factor kappa–B [28]. Cisplatin stimulates various
intracellular molecular pathways, leading to an increase in pro–
inammatory cytokine levels, such as TNF–α, IL–1β, and IL–6, and
inducing inammation through additional molecular mechanisms [29,
30]. According to a study, administering cisplatin (6 mg·kg
-1
) twice, once
a week, adversely affects ovarian function by inuencing inammatory
processes [18]. In a study, it was observed that cisplatin increased the
levels of inammatory cytokines NFKB, TNF–α, IL–1β, IL–6, COX–2,
and iNOS in the ovary [21]. In line with earlier research, this study
observed an increase in ovarian TNF–α, IL–6, and IL–1β levels in rats
administered cisplatin. Cisplatin, one of the three chemotherapeutic
agents frequently used in chemotherapy, signicantly depletes ovarian
follicular reserves by affecting various cellular components of the
ovary, increasing the atresia of growing follicles, inducing damage in
the stromal compartment, and causing inammation.
To counteract these harmful effects, various compounds have
been investigated as potential protective agents over the past
20 years [3]. Tyrosol is known to have anti–inammatory effects
[31, 32]. Furthermore, Tyrosol derivatives also exhibit strong anti–
inammatory properties [33]. In this study, Tyrosol was observed
to mitigate cisplatin–induced ovarian damage by reducing elevated
pro–inammatory cytokine levels and restoring them to normal levels.
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CONCLUSION
As a result, it can be concluded that Tyrosol has anti–inammatory
and antioxidant effects on the ovarian inammatory and oxidative
stress situation caused by cisplatin and has positive effects on ovarian
activities. Future research on the effects of Tyrosol on other ovarian
activities is thought to be benecial.
Conict of Interests
The authors declare no conict of interest regarding the publication
of this manuscript.
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