|Year : 2021 | Volume
| Issue : 4 | Page : 168-175
Taxifolin attenuates ischemia-reperfusion induced oxidative ovarian damage in rats
Sevil Kiremitli1, Tunay Kiremitli1, Umit Nayki1, Nesrin Yilmaz1, Can Turkler1, Kemal Dinc1, Renad Mammadov2, Gulce Naz Yazici3, Mine Gulaboglu4, Nihal Cetin5
1 Erzincan Binali Yildirim University Faculty of Medicine, Department of Obstetrics and Gynaecology, Erzincan, Turkey
2 Erzincan Binali Yildirim University Faculty of Medicine, Department of Pharmacology, Erzincan, Turkey
3 Erzincan Binali Yildirim University Faculty of Medicine, Department of Histology and Embryology, Erzincan, Turkey
4 Ataturk University Faculty of Pharmacy, Department of Biochemistry, Erzurum, Turkey
5 Selcuk University Faculty of Medicine, Department of Pharmacology, Konya, Turkey
|Date of Submission||13-May-2021|
|Date of Decision||25-Jun-2021|
|Date of Acceptance||30-Jun-2021|
|Date of Web Publication||20-Jul-2021|
Erzincan Binali Yildirim University Faculty of Medicine, Department of Obstetrics and Gynaecology, Erzincan
Source of Support: None, Conflict of Interest: None
Objective: To investigate preventive effects of taxifolin on ischemia-reperfusion induced oxidative ovarian damage in rats.
Methods: A total of 18 female Wistar albino rats were randomly and equally divided into three groups: the sham group, the ovarian ischemia reperfusion group, and the 50 mg/kg taxifolin+ovarian ischemia reperfusion group. The ovarian ischemia reperfusion and taxifolin+ovarian ischemia reperfusion groups were exposed to ischemia for 2 h and then followed by two-hour reperfusion protocol. Biochemical and histopathologic examinations were performed on the extracted ovaries.
Results: Levels of malondialdehyde and cyclooxygenase-2 were increased, while reduced-glutathione and cyclooxygenase-1 were decreased in the ovarian ischemia reperfusion group. However, these values were reversed in the taxifolin+ovarian ischemia reperfusion group. Similarly, the number of primordial and developing follicules decreased in the ovarian ischemia reperfusion group, while they were within normal range in the taxifolin+ovarian ischemia reperfusion group.
Conclusions: Ischemia followed by reperfusion leads to oxidative stress-related ovarian injury, and taxifolin may be useful for protecting ovarian tissue from such injury.
Keywords: Antioxidants; Ischemia-reperfusion; Ovarian damage; Rat; Taxifolin; Oxidative stress; Ovarian torsion
|How to cite this article:|
Kiremitli S, Kiremitli T, Nayki U, Yilmaz N, Turkler C, Dinc K, Mammadov R, Yazici GN, Gulaboglu M, Cetin N. Taxifolin attenuates ischemia-reperfusion induced oxidative ovarian damage in rats. Asian Pac J Reprod 2021;10:168-75
|How to cite this URL:|
Kiremitli S, Kiremitli T, Nayki U, Yilmaz N, Turkler C, Dinc K, Mammadov R, Yazici GN, Gulaboglu M, Cetin N. Taxifolin attenuates ischemia-reperfusion induced oxidative ovarian damage in rats. Asian Pac J Reprod [serial online] 2021 [cited 2021 Jul 27];10:168-75. Available from: http://www.apjr.net/text.asp?2021/10/4/168/321124
| 1. Introduction|| |
Ovarian torsion, which accounts for 3% of gynecologic emergencies, is one of the common causes of gynecologic acute pelvic pain,. Reperfusion, increased blood flow to the ovary with reversal of the torsion, causes ovarian ischemia-reperfusion (I/R) injury.
Ischemia-reperfusion-induced inflammatory response can lead to vascular endothelial cell damage and microcirculation disorders. The production of excessive reactive oxygen species (ROS) depends on the exposure of elevated levels molecular oxygen in the reperfusion process. We know that ROS are the mediators of reperfusion injury. These ROS cause cellular damage through peroxidation of polyunsaturated fattyacids in cell membranes. The exacerbation of cell damage is mediated by malondialdehyde (MDA), which is the toxic endproduct of lipid-peroxidation and antioxidative activity can be assessed by MDA levels. It has been determined that ischemia-reperfusion cause an increase in the amount of MDA and a reduction in the amount of reduced-glutathione (tGSH), which is known as an endogenous antioxidant. Ischemia-reperfusion induced oxidative stress causes damage in cellular DNA, protein, and lipids in ovarian cells. Base change in nucleic acid and chain breaks in DNA are caused by free radical reactions. If this change cannot be repaired, mutagenic DNA is formed.
Another mechanism of ischemia-reperfusion injury is expressed as activation of phospholipase-A2 due to intracellular calcium increase during ischemia, increased production of arachidonic acid from membrane phospholipids, the release of pro-inflammatory activity of prostaglandins and free oxygen radicals from the arachidonic acid via the cyclooxygenase-2 (COX-2) enzyme.
A recent study has shown a direct link between oxidant/antioxidant balance and COX-1/COX-2 activity in I/R-injury. The I/R-injury is a complex histopathological process. After insufficient oxygenation of the tissue and production of free oxygen radicals, the inflammatory response occurs and expands.
Taxifolin (3,3’,4’, 5, 7-pentahydroxiflavanone) is naturally present in onion, milk thistle, French maritime and Douglas fir bark. Taxifolin has antioxidant and anti-inflammatory effects as well as removing free radicals from the environment. Taxifolin has been reported to suppress oxidative-stress mediators and COX-2 production in ovaries, which are responsible for inflammation. Based on the data, taxifolin may be useful in ameliorating ischemia-reperfusion injury in tissues. Although there are many experimental studies investigating the anti-oxidative and anti-inflammatory effects of taxifolin in many organs such as brain, liver, skin, heart, kidney and thyroid,,,,,, we could not find any study examining the effects of taxifolin on I/R-induced ovarian damage. Therefore in this study we aimed to investigate the preventive effects of taxifolin on ischemia-reperfusion-induced ovarian damage.
| 2. Materials and methods|| |
In this study, 18 female Wistar albino rats (about 6-7 months old) weighing 260-273 g were obtained from Atatürk University Laboratory Animals Breeding and Experimental Research Center and the study was conducted in the same center. Rats were housed in groups in cages at (21-22) °C, 55%-60% humidity and a 12 h light: 12 h dark cycle (lights on at 07:00 a.m.). Rats were allowed free access to food and water.
2.2. Experiment procedure
Balanced completely randomized block design was used. Rats were divided randomly into three groups including six rats each as follows: the ovarian-ischemia-reperfusion group, the 50 mg/kg taxifolin+ovarian-ischemia-reperfusion group, the healthy control group scheduled for a sham operation group.
During the experiment, every morning between 8:00-9:00 a.m. each animal cage was carried to the experimental room. Vaginal smear was collected with a plastic pipette filled with 10 μL of normal saline (NaCl 0.9%) by inserting the tip superficially into the rat vagina. Vaginal smear samples taken from each rat were put on different slides and examined under a light microscope at 400× magnification. Three types of cells could be recognized: round and nucleated ones are epithelial cells; irregular ones without nucleus are the cornified cells; and the little round ones are the leukocytes. The proportion among them was used for the determination of the estrous-cycle phases,.
2.3. Surgical and pharmacological procedures
The surgical procedures were carried out under sterile conditions in an appropriate laboratory environment. All rats were administered 25 mg/kg intraperitoneal thiopental sodium (I.E. Ulagay Chemical Company, Turkey) anesthesia. One hour before administration of anesthesia, the taxifolin+ovarian ischemia reperfusion group was given 50 mg/kg body weight taxifolin (Evalar Company; Russia) orally since previous studies have found this dose of taxifolin to be effective,. At the same time, saline (0.9% NaCl) was administered as solvent orally to the ovarian ischemia reperfusion and sham groups in the same route. Following the administration of anesthesia, a 2.0-2.5 cm long vertical incision was made in the lower abdomen and ovaries were visualized. Then two-hour ischemia and following two-hour reperfusion was performed in the right ovaries of the rats in the ovarian ischemia reperfusion and taxifolin+ovarian ischemia reperfusion groups by applying a vascular clip to vascular pedicle. At the end of these processes, all rats were sacrificed and the right ovaries were removed for the biochemical and histopathological examinations.
2.4. Biochemical analysis of MDA and tGSH
The samples of ovarian tissue were dissected out from each rat. The tissues were rinsed immediately with physiological saline, blotted, and placed on petri dishes. Ovarian tissues were stored at -80 °C until use. The frozen tissues were grinded to a fine powder in liquid nitrogen with a mortar and pestle. For determination of tGSH, MDA and protein concentration, the tissue samples were homogenized. For the tGSH and protein assay, tissue samples were homogenized with 50 mM cold phosphate buffer, pH 6-7, containing 1 mM ethylenediaminetetraacetic acid, and centrifuged at 10 000×g for 15 min at 4 °C. Then the supernatant was stored on ice. For the MDA assay, 250 μL RIPA buffer was used to sonicate tissue samples. After sonication, the homogenate was centrifuged at 1 600×g for 10 min at 4 °C. The supernatant was stored on ice. The supernatants were used to determine tGSH, MDA, and protein levels. The protein concentration of the supernatant was measured by using the method described by Bradford. MDA and tGSH concentrations were measured by commercial kits (Glutathion Assay Kit Item No: 703002 and TBARS Assay Kit Item No:10009055, Cayman Chemical Company, USA).
2.5. Analysis of COX activity
We used a COX activity assay kit (Cayman, Ann Arbor, MI, USA; Item No.760151) for measuring the activity of COX in rat’s ovaries. Removed ovarian tissues were washed thoroughly with ice-cold Tris buffer, pH 7.4, containing 0.16 mg/mL of heparin, to remove any red blood cells and clots, and then stored at -80 °C. For each rat, a sample of ovarian tissue was homogenized in 5 mL of cold buffer (0.1 M Tris-HCl, pH 7.8, containing 1 mM EDTA) per gram of tissue and centrifuged at 10 000 ×g for 15 min at 4 °C. Removed supernatant was kept on ice. The peroxidase activity of COX was measured by the COX activity assay kit. This was assayed colorimetrically by monitoring the appearance of oxidized N,N,N,N’-tetramethyl-p-phenylenediamine at 590 nm. COX-2 activity was measured by using the COX-1-specific inhibitor. Results for COX activities were given as units per milligram of protein. The activity of COX was expressed as nmol/min/mg protein (U/ mg protein).
2.6. Histopathological examination
Ovarian tissue samples were first embedded into 10% formaldehyde solution for fixation. After the fixation process, tissue samples were washed under tap water in cassettes for 24 h. Then samples were treated with conventional grade of alcohol (70%, 80%, 90%, 100%) to remove the water within tissues. Tissues were then passed through xylol and embedded in paraffin. Four-to-five micron sections were cut from the paraffin blocks and hematoxylin–eosin staining was performed. Images were acquired by using an Olympus DP2-SAL software program (Olympus® Inc.Tokyo, Japan). Histopathological assessment was carried out by a pathologist, who was blinded to the all experimental data. Ovarian degeneration criteria were graded between 0-3. While the normal histological structure appearance was scored as grade 0, the degenerative changes were scored as mild (grade 1), moderate (grade 2) and severe (grade 3). While histochemical scoring was performed, scoring was done by evaluating one central and five peripheral areas.
2.7. Statistical analysis
The statistical analyses were performed by using IBM SPSS Statistics version 21(IBM Co.Armonk, NY, USA). A statistical evaluation of the results was carried out by using one-way ANOVA. The Tukey multiple comparison test was used to determine the differences between groups. Data were expressed as mean±standard deviation (mean±SD). P<0.05 was considered as statistically significant.
2.8. Ethics statement
The experimental procedure was approved by the Committee for Animal Research of Atatürk University (Ethics Committee Number: 30.03.2018/81). This study was carried out in accordance with international guidelines on ethical use of animals.
| 3. Results|| |
3.1. MDA analysis results
MDA levels of the ovarian tissues in the sham, ovarian ischemia reperfusion and taxifolin+ovarian ischemia reperfusion groups were (4.70±0.40), (14.30±2.50), (5.50±0.49) μmol/g protein, respectively. MDA production in the ovarian tissue of rats in the ovarian ischemia reperfusion group significantly increased compared to those in the sham and taxifolin+ovarian ischemia reperfusion groups. The difference in MDA levels between the sham and ovarian ischemia reperfusion groups was statistically significant (P<0.01). The difference in MDA levels between the ovarian ischemia reperfusion and taxifolin+ovarian ischemia reperfusion groups was statistically significant (P<0.01), while MDA production in the sham and taxifolin+ovarian ischemia reperfusion groups was not statistically significant (P>0.05) [Figure 1]A.
|Figure 1: The effect of taxifolin on malondialdehyde (MDA) level (A) and reduced-glutathione (tGSH) level (B). Values are expressed as mean±SD. ##: Compared with the sham group, P<0.01; **: Compared with the ovarian ischemia reperfusion (OIR) group, P<0.01. TOIR: the taxifolin+ovarian ischemia reperfusion group.|
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3.2. tGSH analysis results
tGSH levels of the ovarian tissues in the sham, ovarian ischemia reperfusion and taxifolin+ovarian ischemia reperfusion groups were (8.2±0.6), (1.4±0.4) and (7.5±0.4) nmol/g protein, respectively. The difference between the tGSH levels in the sham and ovarian ischemia reperfusion groups was statistically significant (P<0.01). The difference between the tGSH levels in the ovarian ischemia reperfusion and taxifolin+ovarian ischemia reperfusion groups (P<0.01) was statistically significant, administration of taxifolin led to an increased tGSH level in the ovarian tissue of rats. The amount of tGSH between the sham and taxifolin+ovarian ischemia reperfusion groups was not found to be significantly different (P>0.05) [Figure 1]B.
3.3. COX-1 and COX-2 activity analysis results
The COX-1 activity was suppressed in the ovarian ischemia reperfusion group [(2.1±0.4) U/mg protein)] compared to the sham group [(9.0±0.5) U/mg protein] and the difference was statistically significant (P<0.01). A statistically significant increase in the taxifolin+ovarian ischemia reperfusion group [(8.2±0.3) U/mg protein)] was observed when compared with the ovarian ischemia reperfusion group (P<0.01) but the difference between thesham and taxifolin+ovarian ischemia reperfusion groups was significant (P<0.05) for COX-1 activity [Figure 2].
|Figure 2: The effect of taxifolin on the levels of cyclooxygenase (COX)-1 and COX-2. Values are expressed as mean±SD. ##: Compared with the sham group, P<0.01; **: Compared with the ovarian ischemia reperfusion (OIR) group, P<0.01. TOIR: the taxifolin+ovarian ischemia reperfusion group.|
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However, COX-2 activity was significantly increased in the ovarian ischemia reperfusion group when compared to the sham group [(9.8±0.6) U/mg protein vs. (0.19±0.05) U/mg protein)] (P<0.01). Also, a significant decrease was found in the taxifolin+ovarian ischemia reperfusion group compared to the ovarian ischemia reperfusion group [(2.1±0.4) U/mg protein and (9.8±0.6) U/mg protein)] (P<0.01). The difference between the sham and taxifolin+ovarian ischemia reperfusion groups was significant (P<0.01) for COX-2 activity [Figure 2].
3.4. Histopathological assessment results
Histological examination of ovaries in the sham group revealed that the ovaries had normal appareance in cortex and medulla [Figure 3]A. In the ovarian ischemia reperfusion group, microscopic examinations showed distinct ovarian damage. There were intersititial edema, diffuse amount of vascular congestion, hemorrhage in ovarian cortex and medulla. Developing follicules had appearent regression with fluid filled cavities and follicular oocytes showed clear degeneration [Figure 3]B,[Figure 3]C. In the taxifolin+ovarian ischemia reperfusion group, there was a marked amelioration in the general cortex and medulla. Mild vascular congestion, mild to moderate interstitial edema, normal follicular structure and increased number of developing follicules were showed as compared to the ovarian ischemia reperfusion group [Figure 3]D,[Figure 3]E.
|Figure 3: Histological appearance of the ovary in the experimental groups (hematoxylin–eosin sections in rat ovaries). A: Sections from ovarian tissue show normal histological structure of developing follicules (DF), interstitium (Int), corpus luteum (CL), and blood vessel (asterisk) in the sham group (100×). B-C: Degenerated developing follicules with fluid filled cavity (DF), severe edema in intersititial area (Int), corpus luteum (CL), congested blood vessel (asterisk) and hemorrhage (arrow) in the ovarian ischemia reperfusion group (200×) are observed. D-E: Mostly normal developing follicules (DF), mild to moderate edema in the interstitium (Int), corpus luteum (CL), and mild congestion in blood vessel (asterisk) in the taxifolin+ovarian ischemia reperfusion group (200×) are seen.|
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Histopathological evaluation was performed in six rats for each group. One central and five peripheral areas of each sample were histopathologically examined. The degeneration intensity was graded semiquantitatively as 1, 2, or 3 (mild, moderate or severe), as seen in [Table 1].
Mean number of ovarian primordial follicules was (13.3±1.2) in the sham group, (11.1±0.7) in the ovarian ischemia reperfusion group, and (13.3±0.8) in the taxifolin+ovarian ischemia reperfusion group, respectively, and this difference was statistically significant (the ovarian ischemia reperfusion group < the sham group; the ovarian ischemia reperfusion group < the taxifolin+ovarian ischemia reperfusion group) (P<0.05). Additionally, mean number of ovarian developing follicules was (23.0±1.0) in the sham group, (20.0±1.4) in the ovarian ischemia reperfusion group and (23.0±1.2) in the taxifolin+ovarian ischemia reperfusion group, respectively. There was statistically significant in mean number of ovarian developing follicules between the groups (the ovarian ischemia reperfusion group < the sham group, the ovarian ischemia reperfusion group< the taxifolin+ovarian ischemia reperfusion group) (P<0.05). For atretic follicles and corpus luteum, there were no statistically significant difference between the ovarian ischemia reperfusion group and the taxifolin+ovarian ischemia reperfusion group (P>0.05) [Figure 4].
|Figure 4: The effect of taxifolin on the mean number of primoidal follicules, developing follicules, atretic follicules, and corpus luteum. Values are expressed as mean±SD. #: Compared with the sham group, P<0.05; *: Campared with the ovarian ischemia reperfusion (OIR) group, P<0.05. TOIR: the taxifolin+ovarian ischemia reperfusion group.|
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| 4. Discussion|| |
Previous studies have reported that multiple mechanisms participate ischemia reperfusion-induced tissue damage such as increased production of ROS, elevation of inflammatory mediators, and the initiation of apoptotic factors in different tissues. Normally in the human body, the formation and elimination of ROS are in balance. Oxidative stress occurs when some pathological status produce excessive amount of ROS and human body would not be capable of eliminating this excessive amount of ROS. The elevated levels of ROS could cause damage to significant macromolecules including DNA, protein, lipids and they play a major role in the development of some pathologies such as I/R-induced ovarian damage.
Antioxidants hinder radical formation before injury, repair oxidative damage, remove damaged molecules and prevent mutations. Different antioxidants have been examined for the prevention of ROS overproduction and oxidative stress-induced damage of many tissues. Anti-inflammatory and anti-oxidative effects of taxifolin were demonstrated in many organs,,,,. Herein we investigated the preventive effects of taxifolin on I/R-induced ovarian injury in rats biochemically and histopathologically.
In this study, the effects of taxifolin in rat ovarian tissues following two hour ischemia and two hour reperfusion have been investigated. In this study, we showed that taxifolin can prevent oxidative stress in rat ovaries exposed to ischemia reperfusion. Taxifolin at 50 mg/kg protected ovaries from an oxidant parameter, MDA and prevented a decrease in antioxidant tGSH. MDA is the main product of lipid-peroxidation and is also a good marker to evaluate oxidative damage in tissue,. MDA is formed as a result of the significant increase in lipid peroxidation after overproduction of ROS.
As is known, MDA aggravates tissue injury by causing polymerization and production of cross links between membrane compounds. tGSH is one of the most important antioxidant capacity indicator, also tGSH can protect body from damage of oxidative-stress. Literature has shown that ischemia reperfusion-induced oxidative stress may lead to the deleterious effects in ovarian tissues such as an increase in the levels of MDA and a decrease in the levels of tGSH.
As can be understood from the literature, tGSH plays an important role in preventing damage to cellular components caused by ROS such as free radicals, peroxides, lipid peroxides and heavy metals. In the taxifolin+ovarian ischemia reperfusion group, taxifolin increased the concentration of tGSH while the level of MDA was significantly reduced compared to ovarian ischemia reperfusion group. In concordance with our results, Eken et al showed ameliorative effects of taxifolin in gastric tissue similarly. An important approach that can be used to reduce the side effects of current treatments is to use strong antioxidant agents along with these treatments. Both the biochemical and histopathological results obtained from our study and the existing literature show that taxifolin has strong antioxidant effects.
As is known, COX-1 enzyme is responsible for the synthesis of cyto-protective prostaglandins whereas COX-2 is responsible for the synthesis of pro-inflammatory prostaglandins. Consequently, while COX-1 enzyme inhibition leads to tissue injury, COX-2 inhibition protects the tissue from inflammatory injury. Under normal physiological conditions, the level of COX-1 produced by the cells is measured at a higher level than COX-2. However, if the cells are under the control of pathological conditions, it is known that the level of COX-2 increases significantly. When the experimental studies of ischemia reperfusion-induced ovarian damage on animals are examined, there is a decrease in COX-1 activity and an increase in COX-2 activity. In this study, we found that taxifolin increased the COX-1 levels and also decreased the COX-2 levels in the taxifolin+ovarian ischemia reperfusion group. However, COX-1 level was low and COX-2 level was high in the ovarian ischemia reperfusion group. This is the anti-inflamatory effect of taxifolin as demonstrated by Pan et al. The results obtained from this study coincide with the present literature. When we compare the experimental results of the taxifolin+ovarian ischemia reperfusion group with the ovarian ischemia reperfusion group, the COX-1 and COX-2 levels observed suggest that taxifolin, which has anti-inflammatory effects, may be protective in the ischemia reperfusion damage that occurs in the ovarian tissue. In our study, there is a statistically significant difference between the sham and taxifolin+ovarian ischemia reperfusion groups in the COX-1 and COX-2 results. This statistic shows that there is an anti-inflammatory effect of taxifolin on ischemia reperfusion, but it cannot provide a full recovery. This also suggests that further studies should focus more on the effects of taxifolin on the COX-1 and COX-2 mechanism.
In this study, we observed that the biochemical and histopathological findings of this experiment support each other. Hemorrhage, edema, cell degeneration and vascular congestion in the ovarian ischemia reperfusion group indicate prooxidant and proinflammatory lesions of ovarian tissue. Nayki et al demonstrated that ischemia reperfusion-induced ovarian injury causes dilated and congested vessels, hemorrhage, PMNL infiltration and edema. We found similar histopathological findings and all histopathological examinations were consistent with biochemical results. In this sense, there is a statistically significant injury in the ovarian ischemia reperfusion group compared to the sham and taxifolin+ovarian ischemia reperfusion groups in cell degeneration, vascular congestion, interstitial edema and hemorrhage results obtained in these histopathological examinations. Also 50 mg/kg taxifolin administered in this study significantly improved the histopathological effects of ischemia reperfusion-induced ovarian damages. These results are in agreement with the findings from the literature.
In addition, ischemia reperfusion-induced ovarian injury caused a decrease in the number of follicles. The difference between the sham and ovarian ischemia reperfusion groups for primordial folicules and developing folicules were statistically significant. Therefore, we hypothesize that ischemia reperfusion-damage may affect fertility and may cause infertility. Also, there was statistically significant difference in this regard between the taxifolin+ovarian ischemia reperfusion and ovarian ischemia reperfusion groups, indicating that taxifolin may prevent the ovarian follicules from negative effects of ischemia reperfusion damage.
However, there are some limitations of this study. In this study, we examined only a single dose of taxifolin. Besides, we decided the dose based on the previous studies. Therefore, we need more studies for different comparative doses to find the exact dose. Additionally, total oxidant antioxidant, proinflammatory cytokine measurements and cell apoptosis should be investigated to clarify the mechanism of action of taxifolin.
In conclusion, we show that ischemia reperfusion-procedure leads to ovarian injury related to oxidative stress. Suppression of ROS will provide a treatment for the ischemia reperfusion injury. As shown in this study, taxifolin significantly improves the biochemical and histopathological findings and it may prevent the ovarian follicules from negative effects of ischemia reperfusion damage. As a result, taxifolin may be useful in prevention of ovarian injury related to ischemia reperfusion caused by torsion–detorsion. There is also a need for other studies in the future that can reveal taxifolin and its protective properties and elucidate their mechanism of action on this subject.
Conflict of interest statement
There is no conflict of interest associated with this work.
We thank Professor Halis Suleyman, Erzincan Binali Yildirim University Faculty of Medicine, Department of Pharmacology, for his technical support and suggestions.
This work was carried out in collaboration between all authors. Author Sevil Kiremitli designed the study and contributed the statistical analysis. She also contributed literature search. She equally definated of intellectual content and wrote the first draft of the manuscript. Author Tunay Kiremitli wrote the first draft of the manuscript. He reviewed the paper and created the paper final state. Author Renad Mammadov contributed conception and design. And he performed paper’s initial editing with author Can Turkler. Author Nihal Çetin carried out most of the literature searches. Authors Umit Arslan Nayki, Nesrin Yilmaz performed the experiment, handling the tissue processing for histology and biochemistry. Sevil Kiremitli, Tunay Kiremitli, Renad Mamadov and Nihal Cetin also assisted Umit Nayki and Nesrin Yilmaz in conducting the experiment. Authors Mine Gulaboglu and Gülce Naz Yazici performed the histological and biochemical analysis. Author Kemal Dinc performed the statistical analysis. Before the article was submitted, the article was read and approved by all authors. All responsibilities that may arise regarding the content are accepted by the authors.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]