Irfan Irfan1*, Nusratuddin Abdullah2, Nasrudin A Mappaware3, Suryani As’ad4,6,
Syamsuri Syakri5
1Doctoral Program, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia, 90245, Indonesia.
2Department of Obstetrics and Gynecology,
Faculty of Medicine, Universitas Hasanuddin, Makassar, 90245, Indonesia.
3Department of Obstetrics and Gynecology, Faculty of Medicine,
Universitas Muslim Indonesia, Makassar, 90231, Indonesia.
4Department of Nutrition, Faculty of Medicine, Universitas Hasanuddin, Makassar, 90245, Indonesia.
5Department of Pharmacy, Faculty of Medicine and Health Science,
Universitas Islam Negeri Alauddin, Gowa, Indonesia.
6Medical Faculty and Health Science, Universitas Muhammadiyah Makassar, Makassar, Indonesia.
*Corresponding Author E-mail: irfandokter@yahoo.com
ABSTRACT:
This literature review aims to provide a thorough study of many studies about Ajwa dates, including their nutritional makeup and the existence of advantageous compounds for health. Moreover, the aim of this literature research is to collect information on the relationship between the chemical makeup of Ajwa dates and the levels of the anti-mullerin hormone. Analysis of the PI3K/Akt/Foxo3a pathway showed that Quercetin decreased the phosphorylation of a protein that stimulates cyclophosphamide-induced follicular activation in the ovary. Moreover, Quercetin prevents cyclophosphamide-induced apoptosis in early-growing and antral follicles, maintains the Anti-Mullerian Hormone secreted by these follicles, and quiescence of the primordial follicle pool, as determined by intranuclear Foxo3a staining. It can be concluded that Quercetin in Ajwa Dates can attenuate cyclophosphamide-induced follicle loss by preventing phosphorylation of members of the PI3K/Akt/Foxo3a pathway and maintaining anti-Mullerian hormone levels through reducing apoptosis in growing follicles. Thus, Quercetin is expected to increase fertility We find that quercetin from Ajwa dates can inhibit PI3K/Akt/Foxo3a pathway members from becoming phosphorylated, which in turn can prevent cyclophosphamide-induced follicle loss. Additionally, quercetin can maintain anti-Mullerian hormone levels by lowering apoptosis in expanding follicles. Quercetin is therefore anticipated to boost fertility. The PI3K/Akt/Foxo3a pathway members' phosphorylation may be inhibited by quercetin from Ajwa dates, which can subsequently stop cyclophosphamide-induced follicle loss. Quercetin also reduces apoptosis in growing follicles, which helps to sustain anti-Mullerian hormone levels. Thus, quercetin is expected to increase fertility.
KEYWORDS: Phoenix dactylifera L, Anti Mullerian Hormone, Antioxidant, Nutrition.
INTRODUCTION:
Medicinal chemistry is a scientific field that focuses on creating organic compounds and studying their pharmacological properties. It involves designing, modifying, and analyzing drugs, as well as synthesizing lead compounds to ensure they are safe and effective for use in humans and animals1. The pharmaceutical industry is increasingly embracing herbal medicine, indicating the need to reconnect with nature2. Considerable research on the therapeutic qualities of different plant species is now being done to understand the worldwide practice of traditional medicine3. The plant kingdom is an important source of herbal drugs. Even in recent years, there has been an increasing awareness about the importance of medicinal plants4.
Phoenix dactylifera a plant belonging to the "Arecaceae" family, is the source of date palms (DPs). Dating to between 5500 and 3000 BC, it is one of the first types of DP trees, with nutritional, environmental, economic, and ornamental value5. The "cultural, environmental, religious, and social development" of people living in hot, dry areas such the "Middle East and Africa" has been connected to DP farming6. It is grown commercially throughout the Arabian Peninsula's arid regions, including neighboring Gulf locations, and provides food for the Arab population. Date production, consumption, and industrialization are all rising dramatically on a global scale. According to a report submitted by the Food and Agriculture Organization (FAO), DP fruit production increased in significant countries, including Egypt (1,352,950 metric tons), Saudi Arabia (1,078. 300 metric tons), Iran (1,023,130 metric tons), UAE (775,000 metric tons), and Algeria (710,000 metric tons)”. Dates are marketed all over the world, despite being mostly farmed in hot, arid climates, especially in the Gulf Cooperation Council (GCC) nations7.
Natural therapeutic ingredients obtained from plants, animals, and minerals are gradually replacing synthetic ones in the treatment of sickness. The field of medication-assisted illness treatment has entered a period of fast expansion. Earlier remedies were all derived from plants. Large amounts of natural flora are needed by the contemporary pharmaceutical industry to make medications. The processes of extracting active ingredients and formulating medications are labor-intensive, complex, and profitable8.
This research is a Literature review. The search strategy begins by entering keywords: “Phoenix dactylifera L, Anti Mullerian Hormone, Antioxidant, Nutrition. This research was taken from 2015-2023 through the PubMed, Perish, and Google Scholar Database applications.
A sizable population has historically depended on the food that the fruit of the Phoenix dactylifera plant provides. Additionally very nutrient-dense, DP seeds are employed in food applications, particularly as frying or cooking oil9,10. Numerous experts have documented the nutritional makeup of date flesh in the literature11.
In a recent study on date fruits conducted by Khallouki et al. (2018), isomers of chelidonic acid and di-caffeoyl shikimic acid were reported as the main constituents 12,13. The HPLC-DAD-ESI-MS method identified the presence of monophenols, echinoids, and flavonoids in date fruits14. For this reason, eating dates can support a balanced diet. Dates primarily include dietary fiber, which includes β-glucan, cellulose, fructans, and other bioactive substances, as their functional carbohydrates.
Many studies have shown that date seed oil can be a great alternative to palm olein15,16. The nutritional content and bioactive compounds of dates and their phytoconstituents are briefly summarized in Table 1.
Table 1. Nutritional Content of Ajwa Dates
|
Principle |
Nutrient Value (100gm) |
% OF RDA |
|
Energy |
277kca |
14% |
|
Carbohydrare |
74.97g |
58% |
|
Protein |
1.81g |
3% |
|
Total Fat |
0.15g |
<1% |
|
Cholestesterol |
0mg |
0% |
|
Dietary Fiber |
6.7g |
18% |
|
Vitamin A |
149iu |
5% |
|
Vitamin K |
2.7mg |
2% |
|
Sodium |
1mg |
0% |
|
Potassium |
696mg |
16% |
|
Calcium |
64mg |
6.5% |
|
Iron |
0.90mg |
11% |
When date seeds reach different stages of ripening, their amino acid content changes accordingly. The primary amino acids contained in date seeds are glutamic acid (16.44g/100g), phenylalanine (5.93g/100g), and leucine (6.10 g/100 g) 17. Meanwhile, Shina et al. (2013) reported that aspartic acid (1.72g/100g), alanine (1.2 g/100g), and tyrosine (1.2g/100g) are non-essential amino acids. While leucine (1.7g/100g), lysine (1.1 g/100g), and phenylalanine (1.08g/100g) were the primary essential amino acids, following the implementation of an automated amino acid analyzer18. Furthermore, non-proteogenic amino acids, such as g-amino-n-butyric acid and 1-aminocyclopropane-1-carboxylic acid, can bind with antibodies to generate T cells, eliminate harmful substances from the liver, and reduce the body's creatinine levels19.
A study conducted by Abu-Reidah IM et al. (2017) found that the various parts of the dates showed comparable qualitative characteristics when evaluating the total phenolic compounds. A total of 52 compounds were found using the employed technique, with the majority being flavonoid glycosides such as quercetin, luteolin, apigenin, chrysoeriol, kaempferol, isorhamnetin, 3-methyl-isorhamnetin, sulfate, and malonyl derivatives.
The fruit and seed of the Ajwa Date palm have long been used in a variety of traditional medical systems. Research indicates that dates have historically been used to treat diabetes and hypertension20. In ancient Egypt, dates were utilized as an alternative aphrodisiac supplement. DP fruit is now a common meal for a large number of people worldwide21. Several reviews indicate that dates have medicinal value and are widely used to treat various types of ailments in various systems of traditional medicine in addition to their dietary use 22. In an effort to clarify the pharmacology of date palm fruits and seeds, numerous investigations have also been carried out. Figure 1 discusses many possible actions based on P. dactylifera's chemical makeup and various components.
Figure 1. Benefits of Dates for Health
Antioxidants are compounds that safeguard cells from the harm inflicted by unstable molecules called free radicals 23. Free radicals are molecules that possess an unpaired electron in their outer orbit. These compounds are unstable and prone to reactions24. Concentration-dependent free radical scavengers have been demonstrated in vitro investigations using dates' aqueous extracts. To achieve this result, the effective concentration of the extract is 100µg/ml. These investigations validate the presence of antioxidant activity25. Because oral treatment of p-coumaric acid, the primary component of dates, promotes the expression of genes that produce antioxidant enzymes in rat heart tissue26, animal studies also support antioxidant efficacy. At varying doses, many researchers discovered that date fruit extracts have in vivo antioxidant action. Antioxidant activity was detected at a dose of 1000 mg/kg body weight 21 in two investigations. In contrast, other studies that measured the antioxidant activity of date fruit extract at concentrations of 100µg/ml and 330 µg/ml, respectively, revealed this activity at dosages of 100, 200, and 400mg/kg body weight 22. Vayalil found that superoxide and hydroxyl radicals were completely suppressed at doses of 1.4mg/ml and 4.0mg/ml, respectively27. Anthocyanins, flavonoids, and phenolic substances are involved in antioxidant activity28.
A study conducted by Jamil Z et al. (2017) revealed that group B had a significantly diminished ovarian reserve (p<0.01) as determined by histological examination. Due to the presence of alpha-tocopherol, the ovarian reserves in group C remained near normal, resulting in a significantly higher number of follicles compared to group B (p<0.05). However, the decrease seen in this case was smaller than that of the control group (p<0.01). In addition, groups B and C showed a statistically significant rise (p<0.01) in the number of corpus lutea and atretic follicles. Group B had significantly lower levels of anti-mullerian hormone (p<0.01) compared to the control group, as seen in the hormonal study. However, group C saw a statistically insignificant decrease in blood levels of anti-mullerian hormone (p = 0.101)29.
Quercetin was shown to attenuate the reduction in dormant primordial follicles caused by cyclophosphamide, according to research done by Li J et al. (2023). Through examination of the PI3K/Akt/Foxo3a pathway, quercetin was shown to reduce the phosphorylation of a protein that promotes the ovary's cyclophosphamide-induced follicular activation. Quercetin also maintained anti-Mullerian hormone levels released by early-growing and early-antral follicles, reduced cyclophosphamide-induced apoptosis in these follicles, and preserved quiescence of the primordial follicle pool, as assessed by intranuclear Foxo3a staining. Conclusion: By blocking the phosphorylation of PI3K/Akt/Foxo3a pathway members and lowering apoptosis in developing follicles, quercetin in Ajwa dates can attenuate cyclophosphamide-induced follicle loss. It can also preserve anti-Mullerian hormone levels. Thus, it is anticipated that quercetin will raise fertility30.
Figure 2. Diagram showing the activity of AMH in the ovary. The formation of tiny pre-antral and antral follicles is dependent on FSH for growth and selection, and early follicle recruitment is inhibited by AMH, which is released by the granulosa cells of the developing small follicle. Furthermore, in the mature follicles' cumulus cells, AMH is still abundantly expressed. More information about AMH's suppression of FSH-induced CYP19a1 expression, which lowers estradiol (E2) levels, and the impact of E2 inhibition on AMH expression may be found in the inset. Cyp19a1, aromatase; T, testosterone (Dewailly et al., 2014).
Research conducted by Elsadek B et al., 2017 aims to evaluate the potential potential of Ajwa date extract to prevent liver damage due to carbon tetrachloride (CCL4) in rats. Adult male Sprague-Dawley rats were given Ajwa date extract and silymarin (standard reference drug) at doses of 300 & 50mg/kg, po, respectively, for 2 weeks before CCl4 (2ml/kg, sc, twice a week for 8 consecutive weeks -secure), and concomitantly administered with CCl4 for 8 consecutive weeks. Like silymarin, Ajwa date extract resulted in decreased serum levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total cholesterol, triglycerides (TG) and LDL-cholesterol and lipid peroxide as measured as malondialdehyde. (MDAs), hydroxyproline, and caspase-3 liver tissue content with marked increases in serum albumin, HDL cholesterol, and reduced glutathione (GSH) content as well as superoxide dismutase (SOD), catalase (CAT), and glutathione-S-transferase (GST) enzyme activities31,32.
According to a number of evaluations, telomeres are inherently made up of hundreds of guanine bases, which have the lowest redox potential of all DNA bases and are therefore the most easily oxidized by reactive oxygen species (ROS). Furthermore, the heterochromatin condition makes telomere oxidative lesions less effective to repair, suggesting that telomeres are particularly vulnerable to oxidative damage. Thus, oxidative stress is the leading cause of telomere shortening. Cigarette smoke, an exogenous source of pro-oxidants, has been confirmed to be associated with increased oxidative stress in the ovary. Related studies have shown that mice exposed to chronic cigarette or condensate smoke exhibit increased egg fragmentation, delayed fertilization, increased blastocyst apoptosis, and shortened telomeres in embryos. It has been demonstrated that increased levels of ROS in oocytes result in the shortening of telomeres and decreased developmental competence of aged oocytes33,34,35. ROS levels were lower, and telomeres were more extended in oocytes from young (6–8 weeks of age) female mice than in female mice of reproductive age36.
Numerous studies have indicated that treating sperm with antioxidants might improve their quality. Numerous medicinal plants, including the well-known Ajwa Date palm are known to regulate human fertility. DP seed oil (DSO) has been shown to have superior oxidative stability compared to the majority of vegetables37. Male infertility is typically brought on by damaged spermatozoa producing an excessive amount of reactive oxygen species (ROS). Antioxidant supplements have been demonstrated in several studies to enhance "sperm function, fertilization capacity, and sperm membrane fluidity" , and lessen the deleterious effects of reactive oxygen species (ROS)38.
In another study, an in vivo trial was initiated to evaluate the effect of standard, acid-treated P. dactylifera seed powder on male rat fertility39. Average concentrations of P. dactylifera seeds of 7 and 14% led to a significant increase in plasma testosterone, whereas seeds treated with acid (14%) significantly increased plasma levels of luteinizing hormone (LH). In another study, the authors injected 0.3ml of diluted P. dactylifera seed oil (15 and 20% oil in 0.9% salt). They reported a significant increase in sperm count, motility, and viability in male rats40.
Another study reported the reproductive potential of P. dactylifera pollen by treating rats with 1 ml aqueous extract of pollen using concentrations of 120, 240, and 360mg/kg body weight by gavage. Doses of 120 and 240 mg/kg significantly increased the ratio of testis or epididymis to body weight, sperm count, sperm motility, and estradiol level compared to the control group, with marked increases in serum LH and testosterone levels. Estradiol, which is produced by the Leydig cells of the mammalian testes, inhibits the death of male sperm cells, whereas testosterone and LH are responsible for spermatogenesis and male fertility.
A study (El-Kashlan et al., 2015) that used 150mg of P. dactylifera ethanol extract per kg to treat male rats showed increases in blood levels of LH, testosterone, and the hormone estradiol in addition to sperm count and motility. The researchers also noticed that there was an increase in testis activity for the enzymes 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase (17β-HSD), which promote the generation of testosterone. Overproduction of these species can cause oxidative damage to tissues and biomolecules, which can ultimately result in disease situations, particularly degenerative disorders41.
Ajwa dates aqueous extract can be used to treat male infertility and sexual dysfunction. It has a strong preventive and ameliorative action against OTA-induced testicular damage42. Herbs and spices have historic significance due to their dual role as both a vital part of our food, providing certain nutritional benefits, and possessing medicinal qualities43.
The authors declare that they have no conflict of interest in relation to this research, whether financial, personal, authorship or otherwise, that could affect the research and its results presented in this article.
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Received on 20.02.2024 Revised on 11.06.2024 Accepted on 19.08.2024 Published on 20.01.2025 Available online from January 27, 2025 Research J. Pharmacy and Technology. 2025;18(1):415-420. DOI: 10.52711/0974-360X.2025.00064 © RJPT All right reserved
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