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The Date palm (Phoenix dactylifera L.) pollen extract activity against cimetidine -induced testicular damage in albino mice
* Corresponding author E-mail address: 441203697@student.ksu.edu.sa (N. Alaqeel)
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Received: ,
Accepted: ,
Abstract
The present work investigated the date palm (Phoenix dactylifera L.) pollen (DPP) extract’s activity to reduce testicular injury induced by cimetidine (CM) in male albino mice. Male Swiss albino mice were divided into four groups with 10 mice in each. The first group served as the untreated control. The second group was treated with 500 mg/kg of DPP extract, third group with 400 mg/kg of CM, and the fourth group with DPP extract before CM treatment. The experiment lasted for 6 weeks. A CBC demonstrated increased WBC and platelets counts in the group treated with CM, which decreased in the group treated with the DPP extract before CM. Additionally, CM administration resulted in reduction of the testes index and the total sperm count and their viability%, but increased mortality %, whereas, treatment with the DPP extract before CM showed reverse of previous parameters. Hormonal analysis revealed decreased testosterone and increased prolactin in the group treated with CM, but the group treated with the DPP extract before CM showed marked increase of testosterone and decrease of prolactin. Oxidative stress marker malondialdehyde (MDA) was increased after CM treatment but the anti-oxidant marker glutathione (GSH) was decreased that modified by DPP extract treatment. Sperm morphology exhibited abnormal heads and coiled tails after CM treatment. Administration of the DPP extraction treatment before CM showed marked improvement in sperm morphology. Teste histopathological examination after CM treatment revealed observed vacuolar degeneration, absence of most spermatogenic stages with a decrease in Johnson’s pathological score, decrease in area and volume of seminiferous tubules. Treatment with DPP extract before CM displayed reduction of the testicular histopathological damage, an increase in Johnson’s score, and the morphometrics of seminiferous tubules. Immunohistochemical analysis against cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (inos) revealed a marked increase in the seminiferous tubules in the group treated with CM, but a decrease in the last group that was treated with DPP extract before CM. It was concluded that DPP extract could reverse the testicular damage induced by CM administration.
Keywords
Cimetidine
Date palm pollen
Oxidative stress
Johnson’s score
Testosterone
1. Introduction
Phoenix dactylifera L. belonging to the family Arecaceae, is a widely growing plant in tropical Asia and Africa (Al-Alawi et al., 2017). Phoenix dactylifera L. pollen is an increasingly recognized and used dietary supplement because of its beneficial components like proteins, amino acids, vitamins, dietary fibers, fatty acids, enzymes, hormones, and minerals. It also contains carbohydrates, alkaloids, steroids, flavonoids, vitamins, and tannins. Unlike other plants, the date palm (Phoenix dactylifera L.) pollen (DPP) does not contain starch (Abd EL Azim et al., 2015; Al-Shwyeh, 2019).
DPP has been used in traditional and herbal medicine throughout history. It has been used for treating infertility by the Arabs. Research suggests its use in improving male and female fertility by regulating gonadotrophin activity (El-Neweshy et al., 2013; Hassan et al., 2012). DPP suspension increases sperm count and motility, levels of the luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, estradiol, and diameters of seminiferous tubules. It also improves spermatogenesis, leading to an enhancement of fertility in rats and guinea pigs (Alchalabi, 2014; Mehraban et al., 2014).
There are many studies suggesting that DPP can reduce the dysfunction of the male reproductive system caused by thyroid disorders (El-Kashlan et al., 2015), testicular damage induced by cadmium (El-Neweshy et al., 2013), and amelioration of testicular toxicity due to formaldehyde (Zare et al., 2020). Clinical studies have shown that DPP attenuates oral mucositis in patients and shows anti-inflammatory as well as antiproliferative activities in rats (Martín-Sánchez et al., 2014).
Cimetidine (CM) has been used worldwide for about 20 years (Pino and Azer, 2020). It is commonly used for the treatment of gastrointestinal disorders as a result of hypergastric acidity conditions, such as duodenal and gastric ulcers and dyspepsia (Beltrame et al., 2015; Hamid et al., 2009). Recently, CM has shown use for the treatment of cancer (Shah et al., 2020). CM can have hazardous impacts on the male reproductive system, especially on the testes, due to its antiandrogenic impact (Sasso-Cerri & Cerri, 2008). The toxic impacts on the reproductive system are characterized by testicular atrophy due to shrinkage of the seminiferous tubules, degeneration of interstitial tissue, and disturbance of male hormones (Beltrame et al., 2015). CM is considered an androgen and histamine H2 receptor antagonist. These are found in the mucosa and smooth muscular layers of the vas deferens. This causes alternation of the male hormones and decreases testosterone (Koshimizu et al., 2013). Additionally, CM markedly decreased libido in men (Chen et al., 2019). On the other hand, it induced impotence and hormonal imbalance by decreasing the luteinizing hormone (LH) and increasing prolactin (Yarube, 2016; Zalok et al., 2019).
Therefore, the present study was aimed to investigate the protective effect of DPP on the testicular damage CM-induced in the male albino mice.
2. Materials and methods
2.1 DPP extract
Date palm (Phoenix dactylifera L.) dust grains were obtained from a farm in Najan, Ad-Dilam, KSA. Following collection, the pollen grains were separated from the bark, cleaned with water, allowed to air dry, ground into a fine powder at room temperature, and stored at 4°C until required. Ethanol (80%), 1600 mL, was used twice to extract 200 g of DPP powder for 24 hrs at room temperature. After filtering the extract in a Buchner funnel, it was centrifuged for 30 mins at 5000 radius centrifugation force (RCF). In a rotary evaporator, the obtained supernatant was vacuum-evaporated at 40°C until it was completely dry. The final dry concentrate and stock arrangement was safeguarded in dim glass bottles in the fridge at 4°C for additional examination. The DPP was re-scattered in refined H2O and orally intubated to treated rodents, at the time of experiment, utilizing an intragastric tube.
2.2 Animals
Forty healthy male Swiss albino mice weighing 25±5 g, aged 14 weeks, were obtained from Animal house of Zoology department, King Saud University, Riyadh. Animals were kept inside plastic cages under controlled temperature (23± 5°C), humidity and maintained under a 12/12 hrs light-dark cycle. Animal were given free access to a commercial pellet diet and tap water. The mice were acclimated for one week before the initiation of the experiment. The designed experiment was performed under the ethical approval no. KSU-SE-21-72.
2.3 Experimental design
40 male albino mice weighing 25±5 g were divided randomly into 4 groups, 10 in each. The first group served as control, the second received oral administration of 500 mg/kg of Phoenix dactylifera pollen extract (DPP), the third one received oral administration of 400 mg/kg of CM, and the fourth group received DPP extract one hour before CM with previous doses, the duration of experiment was 6 weeks. All groups were sacrificed one day after the end of the experiment.
2.4 CBC
Blood samples were subjected to a hematology analyzer for RBC and WBC counts.
2.5 Testes index
Each animal was weighed (total body weight) and one of its testes. Testes index was calculated by dividing the testis weight over the total body weight multiplied by 100.
2.6 Sperm count
Cauda epididymis was extracted and cut, then immersed in 1 mL phosphate-buffered solution (PBS, pH 7.4) at 37˚C. The sperm suspension (1 mL) was diluted with 1:20 PBS (pH 7.2) and mixed thoroughly. Ten µL of the diluted sperm suspension was put into a counting chamber of hemocytometer. The total, viable, and motile sperm were counted in 5 squares and multiplied by 106.
2.7 Biochemical analysis
2.7.1 Hormonal analysis
Testes were homogenized in cold PBS 1:5 for 3 mins and then centrifuged at 3000 rpm twice for 15 mins. The supernatants were separated and stored at -20˚C, then estimated using ELISA for testosterone and prolactin hormones.
2.7.2 Oxidative and anti-oxidant stress analysis
Animal livers were collected and homogenized in cold PBS 1:5 for 3 mins, and then centrifuged at 3000 rpm twice for 15 mins. The supernatants were separated and stored at -20˚C. The homogenized supernatant samples were subjected to determinate the activity of malondialdehyde enzyme (MDA) and Glutathione enzyme (GSH) according to Noeman et al. (2011).
2.8 Sperm morphology
Sperm smear was extracted from the cauda epididymis on sterile slides, smears were dried at room temperature for 2 hrs, then stained with hematoxylin and eosin. Sections were imaged using (Nikon55os- Japan) using an oil lens at 1000X magnification to demonstrate the sperm morphology.
2.9 Histopathological analysis
Testis samples were collected and fixed in 10% neutral buffered formalin. Following fixation, specimens were dehydrated, embedded in wax, and then sectioned at 6 µm thickness. Sections were stained with hematoxylin and eosin, then imaged using (Nikon55os- Japan). Images were analyzed using the ImageJ software to measure the area and volumes of seminiferous tubules. Sections were subjected to the testicular Johnson’s scoring system (Table 1).
| Score | Johnson’s scoring system |
|---|---|
| Description | |
| 10 | Full complete spermatogenesis and ideal tubules |
| 9 | spermatozoa present but disordered spermatogenesis |
| 8 | A few spermatozoa were present |
| 7 | No spermatozoa |
| 6 | A few spermatids |
| 5 | Many spermatocytes but no spermatozoa or spermatids were present |
| 4 | A few spermatocytes only |
| 3 | Spermatogonia only |
| 2 | No germ cells were present |
| 1 | No germ cells or Sertoli cells were present |
2.10 Immunohistochemistry
Sections were deparaffinized in xylene, rehydrated in descending grades of alcohol and finally distilled water. Sections were then unmasked in a citrate buffer (pH 6) in a microwave for 5 mins. Sections were washed with PBS buffer for 5 mins thrice and incubated in peroxidase blocking solution for 10 mins. Sections were incubated overnight at 4˚C in diluted primary antibody [COX2/PTGS2 Rabbit pAb and nitric oxide synthase (iNOS) Rabbit pAb]. The ections were incubated in biotinylated goat anti-rabbit (ab128976) as secondary antibody for 30 mins, followed by incubation in avidin-biotin complex for 30 mins, and then incubated in 3,3’Diaminobenzidine (DAB) (ab64238) as chromogenic substrate for 10 mins. Sections were stained with Mayer’s hematoxylin, and dehydrated in ethanol (95%), two changes of 100 % and two changes of xylene, then mounted with Dibutylphthalate polystyrene xylene (DPX) (all reagents from Abcam company). Sections were imaged and analyzed using the ImageJ and Fiji software to demonstrate the percentage of reaction incidence and optical density.
2.11 Statistical analysis
The data were expressed as mean ± SEM (standard error of mean). Statistical significance of the control and experimental groups will be evaluated by SPSS 16.0. p ≤ 0.05 was considered significant.
3. Results
3.1 DPP extract
The obtained paste extract exhibits a brown color and a distinctive odor; the final extract weighed 12 g, representing a yield of 6%.
3.2 CBC
The WBC count was highly raised in the group treated with CM, which was decreased in the group pre-treated with DPP extract compared to the CM group. Moreover, RBC count and hemoglobin (HGB) showed insignificant changes among groups. Furthermore, PLT count was significantly raised in the group treated with CM, but in the group treated with DPP extract before CM, the platelet (PLT) count was significantly lowered (Table 2).
| CBC | C | DPP | CM | DPP+CM |
|---|---|---|---|---|
| WBCs | 4.1± 0.3 | 5.4 ± 0.3 | 19 ± 1.5a | 11.2 ± 1.7a,b |
| RBC | 7.6 ± 0.2 | 8 ± 0.3 | 6 ± 0.4 | 7.81 ± 0.1 |
| HGB | 11± 0.1 | 12.2 ± 0.7 | 10.3 ± 0.9 | 11.3 ± 0.4 |
| PLT | 440 ± 31 | 460 ± 22 | 930 ± 187a | 810 ± 21a,b |
Data= Mean ± SEM, p≤0.05, a- significant against the control group, b- significant against Cimetidine 400 group.
3.3 Testes index
The testes index showed a significant decrease in the group treated with CM compared to the control group, and an insignificant increase in the group treated with the DPP extract before CM compared to the CM group only (Fig. 1).
- Bar chart of testes index showing significant decrease in group treated with CM compared to control group and insignificant increase in group treated with DPP extract before CM compared to cimetidine group only. Data=Mean ± SEM, p≤0.05, *a significant against control group.
3.4 Sperm profile analysis
In the total sperm count, viability, and mortality% of the group treated with DPP extract showed insignificant difference compared to the control group. Whereas, the group treated with CM revealed a significant decrease in total sperm count and viability but a significant increase in mortality compared to the control group. Moreover, the pre-treatment of DPP extract to CM displayed a significant increase in total count, viability% and a significant decrease of mortality compared to the group treated with CM only (Fig. 2).
- Bar graph revealing sperm profile (a) total sperm count displaying significant decrease in group treated with CM but raised in group treated with DPP extract before CM treatment, (b) sperm viability % was significantly decreased and mortality % was increased in group treated with CM but treatment with DPP extract before CM caused significant increase of viability% and significant decreased of mortality % compared to cimetidine group. Data=Mean ± SEM, p≤0.05, *a significant against control group, *b significant against Cimetidine 200 group.
3.5 Hormonal analysis
Testosterone and prolactin levels showed no difference between group treated with DPP extract and control group. While, the group received CM revealed significant decrease of testosterone level but insignificant increase of prolactin level compared to control group. Additionally, the pre-treatment with DPP extract to CM posted significant increase of testosterone level and insignificant decrease of prolactin level compared to the group treated with CM only (Fig. 3).
- Bar graph of hormonal analysis showing significant decrease of testosterone and increase of prolactin in the group treated with cimetidine and reset of hormones levels in group treated with DPP extract before cimetidine treatment. Data=Mean ± SEM, p≤0.05, *a significant against control group, *b significant against Cimetidine 200 group.
3.6 Determination of oxidative and anti-oxidant stress
DPP group revealed no significant difference in MDA and GSH levels compared to the control group. Whereas, the group that received CM revealed a significant elevation of MDA and a significant lowering of GSH compared to the control group. Furthermore, the pre-treatment with DPP extract to CM resulted in significant lowering of MDA and a significant elevating of GSH compared to the group treated with CM only (Fig. 4).
- Bar graph of oxidative and anti-oxidant stress (a) oxidative stress indicator MDA showing significant increase in group treated with CM and insignificant decrease in group treated with DPP extract before CM, (b) anti-oxidant indicator GSH revealing significant decrease in group treated with CM but significant increase in group treated with DPP extract before CM.
3.7 Sperm morphology
Sperm of the control and mice group treated with DPP extract showed normal sperm structures of the head and straight tails (Fig. 5a,b). Meanwhile, sperm of the group treated with CM displayed abnormal heads and bent tails (Fig. 5c). Furthermore, pre-treatment with PDP to CM revealed healthy sperm (Fig. 5d).
- Photomicrographs of mice sperm, (a) normal sperm of control (b) normal sperm of PDP control, (c) CM group showing sperm with abnormal head and bent tail, (d) group treated with DPP extract before CM revealing healthy sperm. (Hematoxylin and Eosin-400X) head (black arrow), tail (blue arrow).
3.8 Histopathological analysis
Control and testes of the group treated with DPP showed normal view of seminiferous tubules with oval shape lined with spermatogonia, also it was filled with all spermatogenesis process of primary spermatocytes, secondary spermatocytes, and spermatozoa, besides normal interstitial tissue with clusters of Leydig cells (Figs. 6a,b). However, testes of group treated with CM displayed severe pathological changes manifested by absence of the most stages, vacuolar degeneration, presence of edema, and interstitial tissue degeneration (Fig. 6c), also it displayed lowering of seminiferous tubules cells count, areas and volumes besides to the Johnson’s pathological score (Table 3). Furthermore, animals group treated with DPP extract before CM revealed marked improvement represented by the presence of more stages with less degeneration and healthy interstitial tissue (Fig. 6d) and an increase in seminiferous tubule cell count, areas, and volumes, besides Johnson’s pathological score (Table 3).
- Photomicrograph of testes (a) normal control showing spermatogonia (green arrow), primary spermatocyte (blue arrow), secondary spermatocyte (yellow arrow), spermatids (red arrow), sertoli cell (orange arrow), (b) group treated with DPP extract showing no pathological signs, (c) group treated with CM (400 mg/kg) showing edema (d) group treated with DPP extract before CM revealing primary spermatocyte (blue arrow), healthy interstitial tissue, (e) vacuolar degeneration (brown arrow), degeneration of interstitial tissue (black arrow). (Hematoxylin and Eosin-400X).
| Groups | Count of cells | Total area of x 106 µm2 | Volume of x 106 µm3 | Johnson’s scoring |
|---|---|---|---|---|
| C | 121 ± 3 | 120 ± 2.6 | 74 ± 2 | 10 |
| DPP | 120 ± 8 | 121 ± 0.8 | 76 ± 0.8 | 10 |
| CM | 20 ± 0.8a | 71 ± 0.6a | 34 ± 0.5a | 5 |
| DPP + CM | 65± 1.5a,b | 92 ± 1a,b | 50 ±1a,b | 8 |
Data= Mean ± SEM, p≤0.05, a- significant against control group, b- significant against CM group.
3.9 Immunohistochemical analysis
Testes stained immunohistochemically against cyclooxygenase-2 (COX-2) showed a negative response in control and that treated with DPP extract (Fig. 7a&b). Whereas, the testes of animals treated with CM displayed a high response compared to the control group (Fig. 7c), with high percentage and optical density percentage (Table 4). Moreover, animal testes treated with DPP extract and CM revealed less response against COX-2 (Fig. 7d) with less percentage and optical density percentage of stain (Table 4). Additionally, testes of control and animal group treated with DPP extract showed weak immune response against iNOs (Figs. 8a&b), animals testes treated with CM displayed more immune response against iNOs compared to control group (Fig. 8c), animals testes treated with DPP extract and CM revealed less immune response (Fig. 8d) and (Table 5).
- Photomicrographs of animal testes stained immunohistochemically against COX-2 showing (a) control testes revealing negative response (b) group treated with DPP extract showing negative response (c) group treated with CM (400mg/kg) revealing intense response (d) group treated with DPP extract before CM revealing less response (ABC-400X).
| Groups | Percentage | Optical density% |
|---|---|---|
| C | 49 ± 0.1 | 11 ± 0.3 |
| DPP | 46 ± 0.1 | 12 ± 0.5 |
| CM | 66 ± 0.5a | 31 ± 0.6a |
| DPP + CM | 58± 0.8a,b | 18 ± 1a,b |
Data= Mean ± SEM, p≤0.05, a- significant against control group, b- significant against CM group.
- Photomicrographs of animal testes stained immunohistochemically against iNOs showing (a) control testes revealing weak response (b) group treated with DPP extract showing weak response (c) group treated with CM (400 mg/kg) revealing intense response (d) group treated with DPP extract before CM revealing less response (Avidin-biotin complex stain-400X).
| Groups | Percentage | Optical density% |
|---|---|---|
| C | 26 ± 0.3 | 11 ± 0.3 |
| DPP | 26 ± 0.3 | 11 ± 0.3 |
| CM | 29 ± 0.3 | 15 ± 0.3 |
| DPP + CM | 27± 0.8 | 12 ± 0.6 |
Data= Mean ± SEM, p≤0.05, a- significant against control group, b- significant against CM group.
4. Discussion
The present study aimed to investigate the effect of DPP extract on testicular damage induced by CM in Swiss albino mice. In the present study, our method of DPP preparation agrees with the previous study, and the obtained paste extract exhibits a brown color and a distinctive odor; the final extract weighed 12 g, representing a yield of 6% (Elblehi et al., 2021).
It was found in the present results that CM administration resulted in significant increase in the WBC count compared to the control group. On the contrary, previous studies showed that intragastric administration of CM caused decreased WBC counts compared to the control group but the present results agreed with previous findings that CM administration revealed insignificant changes in RBC count and hemoglobin value (Ahmed Ibrahim, 2020). The present study also displayed that CM treatment highly increased platelet count. As mentioned in previous findings, DPP extract administration showed insignificant differences in hematological parameters compared to a control group, which is consistent with the current results. On the other hand, the same study revealed that treatment with DPP extract after paracetamol modulated the changes in hematological analysis (EL-Syed et al., 2024). The present study proved that DPP extract treatment one hour before CM treatment results in marked modifications in hematological analysis.
The current study presented that CM treatment significantly decreased the testes index as a result of testicular atrophy, compatible with other studies (Liu et al., 2018; Zalok et al., 2019). Additionally, according to the present findings, treatment with DPP extract before CM displayed remodulation of the testes index that decreased with CM treatment. Another study revealed that DPP extract treatment increased the testis index, which decreased due to thyroid dysfunction (El-Kashlan et al., 2015).
It was found in the present results that CM administration caused a decrease in total sperm count, viability% and an increase in mortality%. These findings agreed with other research that CM induced androgenic failure, leading to damage to sperm quality (Adelakun et al., 2022; Beltrame et al., 2019; Liu et al., 2018). Moreover, in patients subjected to coronary artery surgery who suffered from sexual dysfunction, leading to a decrease in sperm count and quality but treatment with DPP extract increased the count and the sperm quality (Hooshang et al., 2022). Furthermore, the present study revealed that treatment with DPP extract enhanced the sperm profile affected by CM administration.
Hormones that affect the spermatogenesis process might be disturbed by CM administration, as testosterone and FSH decreased, but LH and prolactin increased (Al-janabi et al., 2023; Zalok et al., 2019). The current findings demonstrated that CM treatment lowered testosterone and increased prolactin hormones, and these disturbances may be attributed to competition between CM and testosterone in binding to the testosterone receptor. DPP extract could prevent the levels of hormones from disturbance that coincided with the present results (Mehraban et al., 2014). Additionally, the present study declared that DPP extract treatment remodulated the testosterone and prolactin levels.
The present study concluded that CM treatment resulted in increasing MDA as a biomarker of oxidative stress, which was a product for increasing of lipid peroxidation. It was observed that the antioxidant system was disturbed, leading to a decrease in GSH. Moreover, prior investigation postulated that CM treatment induced highly formation of reactive oxygen species (ROS), lipid peroxidation and cell death of hepatocytes but a decrease in the anti-oxidant content (Eftekhari et al., 2018). The current investigation demonstrated that elevation of oxidative stress and lowering of anti-oxidant content induced by CM were remodified as treated with DPP extract, which may be due to its high content of phytochemical and nutrient constituents such as alkaloids, steroids, tannins and phenolic compounds (Al-Samarrai et al., 2016). More studies declared that doxorubicin increased lipid peroxide, inflammatory markers and significantly decreased the anti-oxidant system enzymes as GSH and catalase, then treatment with DPP extract decreased the oxidative stress and inflammation but increased the anti-oxidant enzymes (Elblehi et al., 2021). Other examinations revealed that the DPP extract decreased MDA and nitrite levels, besides raising GSH, which was disturbed by lipopolysaccharides that affected the brain (Shivanandappa et al., 2023).
On the other hand, investigation of sperm morphology showed that CM treatment exhibited marked morphological alterations as head malformation and bent, broken or coiled tails, which coincided with the present findings (Beltrame et al., 2019). Additionally, the current findings revealed that treatment with DPP extract before CM administration reduced the malformation and abnormalities of the sperm induced by CM. Therefore, earlier study referred to the potent impact of DPP extract to improve the morphological features of sperm that induced due to cypermethrin-induced (Ubah et al., 2021).
CM also caused severe histopathological alterations of the testis with marked seminiferous epithelium degeneration, vacuolization and arrest of spermatogenic cells (Aprioku et al., 2014). In agreement with the previous investigation, the present work displayed the marked alterations in testes as vacuolar degeneration, absence of major stages of spermatogenesis, besides degeneration of the interstitial tissue that may be attributed to the deficiency of testosterone that affected the spermatogenesis process. Moreover, the treatment with DPP extract before CM resulted in marked reduction of testicular pathological signs.
It was mentioned previously that all treatments of CM caused significant upgrading of COX-2, nuclear factor κB (NF-κB) and iNOS (Liu et al., 2018), that coincided with the present findings that CM treatment induced an intense immune response against COX-2 and iNOS, also the present findings revealed a decrease of COX-2 and iNOS when animals were treated with DPP extract before CM treatment.
5. Conclusion
Treatment with DPP can reduce cimetidine’s side effects by restoring spermatogenesis, reducing the harmful effects of CM on the reproductive system, and stimulating the testicular endocrine and antioxidant systems.
Acknowledgement
The authors extend their appreciation to Ongoing Research Funding Program ORF-2025-214. King Saud University, Riyadh, Saudi Arabia.
CRediT authorship contribution statement
Nawal Alaqeel: Experimental studies, Data acquisition, data analysis and Writing-Original draft preparation. Badr A. Aldahmash: Concepts, Design, Writing-Original draft preparation, Writing-Reviewing and Editing, Supervision. Ahmed Rady: Writing-Reviewing and Editing. Sarah Ghamry: Experimental studies and Data acquisition. Norah Alqahtani: Experimental studies and Data acquisition. Nourah Al-Mukhaizeem: Experimental studies and Data acquisition. Mansour I. Almansour: Writing-Reviewing and Editing. Saud Alarifi: Writing-Reviewing and Editing. Doaa Elnagar: Concepts, Design, data analysis, Writing-Original draft preparation, Writing-Reviewing and Editing, Supervision.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Declaration of Generative AI and AI-assisted technologies in the writing process
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Funding
Ongoing Research Funding Program ORF-2025-214, King Saud University, Riyadh, Saudi Arabia.
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