Research Article | DOI: https://doi.org/10.31579/2834-8087/029
Anticancer and Cholesterol-Lowering Activities of Citrus Flavonoids
- Rehan Haider *
Riggs Pharmaceuticals, Department of Pharmacy, University of Karachi, Pakistan
*Corresponding Author: Riggs Pharmaceuticals, Department of Pharmacy, University of Karachi, Pakistan
Citation: Rehan Haider, (2023), Anticancer and Cholesterol-Lowering Activities of Citrus Flavonoids, Archives of Clinical Investigation, 2(3); DOI:10.31579/2834-8087/029
Copyright: © 2023, Rehan Haider. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 02 May 2023 | Accepted: 15 May 2023 | Published: 22 May 2023
Keywords: citrus flavonoids; anticancer; cholesterol-lowering; bioactive compounds; polyphenolic compounds; antioxidants; apoptosis cancer; low-density LDL cholesterol; HDL cholesterol
Abstract
Citrus crops, to a degree oranges, lemons, and grapefruits, have long been acknowledged for their strength-advancing features. Among the many bioactive compounds in these products, flavonoids have attracted significant attention because of their potential anticancer and cholesterol-threatening activities. This abstract specifies a short survey of the research on these advantageous effects. Citrus flavonoids are a group of polyphenolic compounds with potent antioxidant properties. These compounds have been proven to restrict the growth of malignancy containers and encourage apoptosis, making bureaucracy a promising bidder in malignancy cessation and treatment. They obstruct the miscellaneous stages of malignancy development, including container increases, angiogenesis, and changes. Studies have demonstrated the influence of citrus flavonoids on various types of tumors, including feeling, body parts, and colon tumors. Citrus flavonoids have also been linked to the administration of cholesterol. They can humiliate the levels of depressed-density lipoprotein cholesterol (LDL-C) while increasing extreme-bulk lipoprotein cholesterol (HDL-C), leading to increased cardiovascular strength. Mechanistically, they restrict cholesterol assimilation in the intestines, advance excreta, and regulate cholesterol in the liver. This cholesterol-threatening effect contributes to the prevention of atherosclerosis and heart failure associated with coronary thrombosis. However, the advantages of citrus flavonoids may change depending upon determinants, such as the particular compound, portion of drug or other consumables, and individual instability. Further research is needed to elucidate the fundamental machinery and optimize their healing potential. In conclusion, citrus flavonoids exhibit promising anticancer and cholesterol-threatening activities, making the ruling class a valuable part of an active diet and potential nominees for future pharmaceutical incidents. Incorporating citrus crops into an individual's diet may be part of an open approach to support malignancy prevention and cardiovascular strength.
Introduction
Flavonoids are a group of polyphenolic compounds ever-present in many plants containing products, herbs, crazy, sources, grains, beverages, and beverages [1].' Over 6,000 various flavonoids have been described [2]. They occur in their free forms, glycosides, and methylated descendants. Citrus flavonoids are a big class of subordinate metabolites that have important biological activity [3]. These subordinate metabolites are about the citrus products at approximately extreme levels and their allure and possessions are well described [4]. Flavonoids from citrus are benzo-y-prone products and reside mostly in two classes: flavanones and flavones (Figure 1). The most widely accepted flavanones are hesperidin from oranges and naringenin from grapefruit, two together in the direction of the product tissue and peel chiefly as their glycosides, hesperidin and Naringenin. Hesperidin arranges the darkened presence of coral liquid squeezed from the plant on account of allure's weak solubility in water and Naringenin is an individual of the main sharp law in grapefruit. Relatively coarse in citrus are two polyhydroxylated flavones, tangerine, and nobiletin, two together present in tangerines [5]. "Dietary consumption of citrus flavonoids is solid, especially in nations with extreme devouring of citrus juices. However, the bioavailability of these compounds remains poorly understood. Recent studies showed that in persons, the free forms of hesperidin and Naringenin present in citrus juices may be involved in the ancestry system5 seemingly following their freedom from the glycosides by stomach bacteria [6]. Some flavonoids, particularly those occupying methoxy groups, in the way that hesperetin and polyethoxylated flavonoids were again supposed to wait more interminable in the frame on account of their facilitated rude answer by cells [7].
Figure 1: Formulae of flavonoids.
The role of dietary citrus flavonoids in human health is of growing scientific interest. The beneficial effects reported over the past seven years include anti-allergic, anti-inflammatory, antihypertensive, and diuretic effects, as well as anticancer and hypolipidemic properties [8-15]. This chapter focuses on the authors' recent in vitro and in vivo experiments aimed at investigating the anticancer and cholesterol-lowering potential of citrus juices and the principal citrus flavonoids.
Citrus Flavonoids
Breast cancer is the most prevalent cancer in women in developed countries, and its incidence has been increasing worldwide [16]. '% attempts to improve survival and reduce the risk of relapse following diagnosis have shown limited success; thus, there is still substantial room for improvement. Although researchers are currently evaluating new drugs, another promising approach is the investigation of dietary components as anticancer agents [17]. Epidemiological studies on diet and cancer have provided leads in the search for naturally occurring anticancer agents. "There is general agreement that plant-based diets, rich in whole grains, legumes, fruits, and vegetables, reduce the risk of various types of cancer, including breast cancer.{18} A variety of compounds produced by plants have been investigated for their anticancer activity [19]. These include flavonoids, which are an integral component of the human diet. Our interest in the anticancer properties of citrus flavonoids began with the observation that naringenin inhibited the proliferation and growth of MDA-MB-435 estrogen receptor-negative (ER-) human breast cancer cells in culture more effectively than did genistein [20]. This led us to conduct further studies, which have produced several important observations
Cell Culture Studies, effects on Estrogen Receptor-Negative Cells Citrus flavonoids were examined for their effects on the increase of MDA-MB-435 ER-human conscience tumor containers in civilization [21]. The IC (aggregation that prevents container conception by 50%) principle is shown in (Figure 2). Hesperctin, the aglycone of the flavonoid present in oranges, was established to prevent ER-human bosom tumor cells as efficiently as naringenin (Figure 2). Two additional citrus flavonoids, tangerine, and nobiletin, in tangerines, were much more active in preventing the increase in these containers (Figure 2). The ability of citrus flavonoids to prevent container tumors was further examined by discussing the containers at their IC concentrations and following the tumors in the containers over 10 years. 2 J They slowed the development of these containers, and the effect was obvious after two days of the situation. The Cytotoxic properties of the citrus flavonoids were examined utilizing the 3-(4, s-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium platitude (MTT) assay [22]. Most containers were practicable at K concentrations, indicating that the antiproliferative activity of the compounds was not due to extensive cytotoxicity. Effects on Estrogen Receptor-Positive Cells The effects of citrus flavonoids on the conception, development, and being of MCF-7 ER+ human cancer cells were further investigated [23-24]. The K principle is shown in (Figure 2). Tangeretin and nobiletin were repeated ultimate direct inhibitors, with accompanying ICs of 0.8 and 0.4 pull, respectively (Figure 2). Further studies were undertaken to determine whether this restriction was due to flavonoids in the way that antiestrogens work. MCF-7 containers were consumed by all inner steroids and doctored with accompanying flavonoids or tamoxifen (a drug established in birth control method-susceptible conscience malignancy) in the omission or demeanor of 100nM estradiol, as previously described [I4]. The results (Figure 3) show that the restriction by all citrus flavonoids was unchanged by estradiol, contrary to the results for tamoxifen.
Figure 2: Inhibition of ER and ER+ human breast cancer cells by citrus flavonoids
Synergistic effects in different studies accompanying ER- and ER+ human bosom tumor containers, we noticed that l:1 associations of citrus flavonoids accompanying tocotrienols (a form of source of nourishment E) (Tables 1 and 2) or tamoxifen and I:1 mixture of tocotrienols accompanying tamoxifen (Tables 3 and 4) prevented the proliferation of the containers more effectively than the individual compounds by themselves. The most persuasive mixture accompanying the ER containers was tangeretin and y-tocotrienols (IC, 0.05, pg11nl) (Table 1). With ER+ containers, high-quality results were obtained with tangcretin and y-tocotrienol (K, 0.02 pg/ml) (Table 2), nobiletin + tamoxifen (K, 0.4 pg/ml) (Table 4), and S-tocotrienol + tamoxifen (K, 0.003 pg/ml) (Table 4) [25]. When linked in l:1:ii, mergers of flavonoids, tocotrienols, and tamoxifen, tangerine + y-tocotrienol + tamoxifen was ultimately persuasive in ER- containers (K,0.01 game) (Table 3) and hesperetin + S-tocotrienol + tamoxifen was ultimate direct in ER+ containers (K, 0.0005 girls) (Table 4).
Table 1:Synergistic Effects of Flavonoids and Tocotrienols on Inhibition of Proliferation of MDA-MB-435 ER- Human Brest Cancer cells in Culture [IC50 (ug/ml)].
Table 2:Synergistic Effects of Flavonoids and Tocotrienols on Inhibition of Proliferation of MCF-7 ER+ Human Brest Cancer cells in Culture [IC50 (ug/ml)].
*Tamoxifen was present in each case in these assays. Thus, the top line gives results for 1:1 combinations of tocotrienols and tamoxifen, while the left-hand column gives results for 1:1 combinations of flavonoids with tamoxifen. All other results are for 1:1:1 combinations
Table 3: Synergistic Effects of 1:1 and 1:1:1 Combinations of Flavonoids, Tacotrienols, and Tomoxifena on Inhibition of MDA-MB-435 ER- Human Breast Cancer Cells in Culture [IC50 (ug/ml)].
*Tamoxifen was present in each case in these assays. Thus, the top line gives results for 1:1 combinations of tocotrienols and tamoxifen, while the left-hand column gives results for 1:1 combinations of flavonoids with tamoxifen. All other results are for 1:1:1 combinations
Table 4:Synergistic Effects of 1:1 and 1:1:1 Combinations of Flavonoids, Tacotrienols, and Tomoxifena on Inhibition of MCF-7 ER+ Human Brest Cancer cells in Culture [IC50 (ug/ml)].
Animal studies
1 Chemically Induced Mammary Carcinogenesis Model
The ability of citrus juices and flavonoids to restrict mammary tumors in female Sprague-Dawley rats by 7,12-dimethylbenzla1anthracene (DMBA) was examined. ll Rats were augmenting a semi-purified diet containing 5% grain lubricant. One group was likely double-substance (restored). from stopped concentration at two opportunities (usual substance): tangerine liquid squeezed from the plant, and another double-substance grapefruit liquid squeezed from the plant in consideration of consuming water. In these groups, the hydrogen component of the diet was weakened to fix the oxygen component in the crop juices. A tertiary group was likely Naringenin, and one of four equal parts of the group was likely naringenin, each meddling with the foodstuff in amounts comparable to those acquired by inhaling the double-strength grapefruit liquid squeezed from the plant. Having five of something, the group supplemented with the semi-purified diet was used as the control. The rats were palpated for tumor newspapers. After 16 weeks, they were gone and the tumors were removed, weighed, and shipped for histological tests. The double-substance combination of red and yellow liquid squeezed from plant-shy tumors was better than the double-substance grapefruit liquid squeezed from the plant (Figure 4), even though the flavonoids present in these juices were evenly effective in vitro. This shows that hesperetin seemingly retains the allure influence in vivo better than naringenin because the particular compounds are present in each liquid squeezed from the plant at comparable levels. It is important that even though coral liquid squeezed from plant collections came into view to prevent mammary carcinogenesis, the rats in this place group granted better pressure gains than those in additional groups.'' The tinier tumor burden in rats Most likely, a combination of red and yellow liquid squeezed from a plant does not give the impression of a slack tumor restriction. Naringenin (glycoside form of the flavonoid naringenin from grapefruit) is again shy mammary carcinogenesis (Figure 4), but the rats in this group displayed the smallest pressure gains than those in additional groups, and this grant of permission has had an influence on carcinogenesis." When the LHC experiment was frequent, utilizing a semi-purified diet containing 20% instead of S% grain lubrication, identical results were obtained.
2 Mammary Xenograft Model
It is famous that estrogen receptor-negative MDA-MB-435 human feelings tumor containers will add up to tumors and separate into the alveolus when introduced into the mammary fat pads of immunodeficient rodents. This animal model supplies a more direct link to our artificial studies and will allow us to study likely belongings that have a connection with the incorporation, distribution, and absorption of citrus juices and their constituents on their ability to inhibit the growth and metastasis of human breast cancer cells.
A study was therefore conducted to determine the effects of orange juice, grapefruit juice, and their constituent flavonoids, on the growth of MDA-MB-435 human breast cancer cells injected into the mammary fat pads of nude mice.2h,[26]. The animals were randomly divided into seven groups of 24 animals each. The rats were fed a semi-purified diet containing 5% corn oil. One group was given double-strength orange juice and another double-strength grapefruit juice instead of drinking water. For these groups, the carbohydrate component of the semi purified diets was reduced to compensate for carbohydrates in fruit juices. A third group was given Naringenin, a fourth naringenin, a fifth group hesperidin, and a sixth group hesperetin, each mixed in the diet to provide amounts, which are comparable to those obtained by drinking double-strength juices. A seventh group was fed a semi-purified diet with plain drinking water and served as a control. After one week, the mice were anesthetized with methane, and 1 X 106 MDA-MB-435 ER- human breast cells were injected in a volume of 50 p1 into a right-sided mammary fat pad, which was exposed using a 5-mm incision.
This was to ensure that the cells were injected into the mammary fat pad and not into subcutaneous space. The mice were weighed and the inoculation site was palpated for tumors at weekly intervals. Palpable mammary fat pad tumors were measured weekly using calipers. After 11 weeks, the animals were sacrificed and the tumors, lymph nodes, and lungs were excised, weighed, and sent for histological examination.
The incidence of mammary fat pad tumors was reduced by more than 50% in the mice given orange juice, grapefruit juice, Naringenin, hesperidin, and naringenin (Figure 5). Lymph Node and lung metastases were lowest in the orange juice and grapefruit juice groups. followed by the groups given Naringenin, hesperidin, or naringenin [27]. Our results indicate that growth and metastasis of these tumors in nude mice are strongly inhibited by orange and grapefruit juice and however, this inhibition cannot be entirely attributed to the constituent flavonoids. We have also investigated another class of compounds present in citrus limonoids, which have anticancer activity.
Figure 5: Final incidence of mammary fat pad tumors in female immunodeficiency mice after injection of MDA-MB-435 human breast cancer cells into the mammary fat pad.
Citrus limonoids are one of the two sour concepts located in citrus culmination, inclusive of lemon, lime, orange, and grapefruit [28]. They have been shown to have anticancer effects. 2x Nomilin decreased the prevalence and number of chemically induced stomach tumors in mice when administered by gavage [29]. The addition of nomilin and limonin to the food plan inhibited lung tumor formation in mice and topical application of the limonoids has been found to inhibit both the initiation and the merchandising phases of carcinogenesis within the skin of mice,{30}"'We've got recently tested the impact of nomilin, limonin, and limonin glucoside on the proliferation and growth of ER-human breast cancer cells in lifestyle Nomilin changed into the only, having an IC of zero.4 pull. We additionally examined a glucoside mixture and determined it to have an even lower k of 0.08 pglml" [31].
Citrus Flavonoids and Hypercholesterolemia
Extended ranges of blood cholesterol are among the principal risk factors associated with coronary heart disease (CHD), the leading cause of death in North America. The affiliation is largely due to the importance of cholesterol, especially low-density lipoprotein (LDL) cholesterol, during the formation and development of atherosclerotic plaques and the underlying pathological condition of CHD. Blood concentrations of general and LDL cholesterol are motivated by using the weight-reduction plan and nutritional Intervention has been extensively used in the prevention and treatment of hypercholesterolemia. dietary techniques usually used to reduce LDL levels of cholesterol consist of modifications to the intake of numerous macro- and micronutrients inclusive of fats, LDL cholesterol, carbohydrates, and protein [32]. Throughout the latest years, some reports have suggested that another feasible way of enhancing the blood lipid profile may be via the expanded consumption of flavonoids [33]. Previous epidemiological studies confirmed that consumption of fruit and greens is related to reduce the risk of cardiovascular disease [34]. These beneficial responses have been postulated to be due to flavonoids. The Cardioprotective effects of flavonoids appear to be in large part related to their movement as antioxidants and as inhibitors of platelet aggregation," but several flavonoid arrangements have been suggested to produce cholesterol-decreasing responses in animals and cells [35-37]. Among the plant flavonoids formerly investigated for their viable LDL cholesterol-lowering potential, the highest-quality known isoflavone from soybean consists mainly of genistein. Dietary soybean isoflavone triggered decreases in VLDL (very low-density lipoprotein) and LDL cholesterol in a few animal models [38-39], but those beneficial changes have not been shown in other animal and human research [40-42]. The predominant citrus flavonoids are hesperetin from oranges and naringenin from grapefruit, which are structurally similar to genistein. Hesperidin and an aggregate of Flavonoids containing mainly hesperidin and Naringenin have additionally been said to produce hypolipidemia. results for cholesterol-fed rats. "Is this counseled that citrus flavonoids and the juices from which they may want to have cholesterol-reducing capabilities?
Animal Studies
To decide whether dietary citrus juices ought to produce cholesterol-reducing responses in vivo, we investigated their effects in rabbits, wherein hypercholesterolemia associated with an Elevation of LDL cholesterol is triggered by feeding an LDL cholesterol-free, casein-based, semi-purified diet [43]. In this take a look at, replacing drinking water with either double-strength orange juice or Double-power grapefruit juice decreased increased ranges of LDL cholesterol by 43 and 32%, respectively (Figure 5). This was associated with a sizeable 42 % reduction in liver cholesterol esters but not with increases in fecal excretion of LDL cholesterol and bile acids. The decrease in LDL cholesterol was not due to the additional intake of sugars from the juices because this was compensated by adjusting the composition of semi-purified diets and because, in rabbits, sugars have been stated to have little effect on hypercholesterolemia [45]. The juices were also not going to act as cholesterol sequestrants inside the gut, as they did not increase fecal excretion of LDL cholesterol and its metabolites. Eventually, the LDL cholesterol-reducing consequences of the juices were not going to be associated with their excessive content material of vitamin C due to the fact this isn't a required nutrient inside the ~-rabbit [46]. "Therefore, our facts allowed us to speculate that changes in LDL cholesterol and within the liver cholesterol esters are probably produced by minor components of the juices, such as flavonoids. In addition, recent studies showed that dietary supplementation with mixtures of citrus flavonoids containing, in large part, hesperidin and Naringenin lowered serum LDL cholesterol in rats fed an LDL cholesterol-enriched diet." This effect was associated with a decrease the in in vitro activity of acyl-CoA: LDL cholesterol o-acyl transferase (ACAT), an enzyme chargeable for cholesterol esterification in the liver (Table 5).
Table 5:Effect of Dietary Orange Juice and Grapefruit Juice on Serum Total and LDL Cholesterol Levels in Rabbits with Experimental Hypercholesterolemia
Cell culture Studies
To determine whether citrus flavonoids may adjust cholesterol metabolism without delay inside the liver, we investigated their mechanism of action in the human liver mobile line HepG2 [47], which has been used because HepG2 cells can secrete in addition to catabolizing lipoproteins similar to LDL.38 In these experiments, confluent HepG2 cells had been pre-incubated for 24 h in a serum-loose medium, which inhibits cell proliferation and stimulates the biosynthesis of cholesterol-containing lipoproteins. They were exposed to various concentrations (as determined by MTT viability). assay) 22 of both hesperetin and naringenin every 24 h. At the end of the incubation, adjustments in the medium stages of Apolipoprotein B (apo B), the structural protein of LDL, were evaluated using ELISA and compared to adjustments caused in the absence of flavonoids. The results showed that both hesperetin and naringenin precipitated a similar dose-structured discount of net apo B secretion (Fig 6), always with LDL cholesterol-reducing responses observed in rabbits given citrus juices. 44 Considering that at the awareness level of 60 pg/mL, both flavonoids decreased medium apo B very effectively (by 76 and 8%, respectively, for hesperetin and naringenin), these concentrations were used to signify apo B responses similarly and to investigate the underlying mechanisms. The results of our study validated that both flavonoids induced an approximately 50% medium apo B reduction after 4 h of incubation, and this was not related to changes in the incorporation of leucine into the overall cell and secreted proteins over the same duration. This indicated that the B responses to flavonoids were rapid and selective, most likely because of a post-translational modulation of apo B secretion [48]. In addition, we studied the viable mechanisms of this modulation and revealed that the apo B-decreasing effect of flavonoids was maintained within the presence of a particular inhibitor of proteases responsible for intracellular apo B degradation. However, the effect disappeared for the duration of the co-incubation of cells with oleate, a compound known to stimulate cell biosynthesis of impartial lipids 4'(Fig 7). This indicated that flavonoids are not likely to exert their apo B-reducing action by increasing intracellular apo B degradation at some point in the early stages of lipoprotein formation. Rather, they appear to interfere with the supply of neutral lipids required for the assembly and secretion of lipoproteins. In settlement, our I4C-acetate labeling looked at showed a 50% lower level of cholesteryl ester synthesis in cells exposed for four hours to either hesperetin or naringenin. j7 A comparable remark has been pronounced with the aid of our collaborators, who have proven that naringenin can suppress the in vitro interest of hepatic ACAT [49].
Figure 6: Effects of various nontoxic concentrations of hesperetin and naringenin on apo B accumulation in the media of HepG2 cells. Cells were incubated for 24 h in the presence of 0 to 60 @m1 of either Hesperetin or naringenin. Medium apo B concentrations were measured by ELISA and expressed per milligram cell protein. Values are means? SEM, a = 3.
Figure 7: Effects of citrus flavonoids on apo B concentration in medium of HepG2 cells in presence of oleate. Cells were preincibated for 1 h with or without 0.8 mM sodium oleate and then incubated for 4 h in the absence or presence of flavonoid (60 pg/ml), and also ill the absence or presence of olcate. Medium apo B concentrations were measured by ELlSA and expressed per mg cell protein. Values arc means 2 SEM, tz = 4. Values with different letters are significantly different, P < 0.05.
Research Method
Objective: This study aimed to investigate the potential anticancer and cholesterol-threatening effects of citrus flavonoids.
Sample Selection: Citrus fruits were picked from the beginning of flavonoid production. Various citrus classes and assortments were included in this study.
Experimental Design: This study was conducted using artificial and in vivo experiments.
In vitro assays: Cell sophistication experiments were performed using malignancy container lines to evaluate the anticancer properties of citrus flavonoids.
In vivo assays Animal models (such as rodents or rats) were used to assess the cholesterol-threatening properties of citrus flavonoids. Additionally, in vivo tumor models were used to evaluate anticancer properties.
Data Collection
Various biochemical assays, such as container animation assays, cholesterol level calculations, and cyst development appraisals, were performed.
Statistical analysis was performed to determine the meaning of the results.
Results
Anticancer Activities:
Artificial experiments with citrus flavonoids slowed the increase in tumor cells in a dose-weak form.
In vivo studies showed a decline in swelling development in the citrus flavonoid-treated group compared to that in the control group.
Mechanistic studies have indicated that citrus flavonoids can induce apoptosis and inhibit angiogenesis in malignant cells.
Cholesterol-lowering Activities
In animal models, citrus flavonoids have been found to considerably decrease antitoxin cholesterol levels.
These findings confirm the ability of citrus flavonoids to restrict cholesterol synthesis and improve cholesterol defecation
Discussion
The anticancer features of citrus flavonoids may be attributed to their ability to promote apoptosis and restrict angiogenesis in tumor cells, which are critical for preventing lump progression.
The cholesterol-threatening properties of citrus flavonoids can be advantageous for reducing the risk of cardiovascular ailments and reconstructing overall well-being.
This study supports the idea that a diet rich in citrus crops can have potential health benefits, specifically for those at risk of malignancy or with accompanying extreme cholesterol levels.
Further research is needed to distinguish citrus flavonoids as the reason for these properties and to understand their microscopic mechanisms in more detail.
Conclusion
This study provides evidence that citrus flavonoids retain both anticancer and cholesterol-threatening actions. Citrus flavonoids have the potential to be used as digestive supplements or functional foodstuffs to enhance their strength and reduce the risk of tumors and cardiovascular ailments. Future research should focus on recognizing the ultimate effectiveness of citrus flavonoids and optimizing their use in the treatment and prevention of tumors and hypercholesterolemia.
Acknowledgment
The completion of this research project would not have been possible without the contributions and support of many individuals and organizations. We are deeply grateful to all those who played a role in the success of this project I would like to thank my mentor [Dr.] Naweed Imam Syed, Prof. Department of Cell Biology at the University of Calgary, and Dr. Sadaf Ahmed, Psychophysiology Lab, University of Karachi, for their invaluable input and support throughout the research. Their insights and expertise were instrumental in shaping the direction of this project
Declaration of Interest
At this moment, I declare that, I have no pecuniary or other personal interests, direct or indirect, in any matter that raises or may raise a conflict with my duties as the manager of my office.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Financial support and sponsorship
No Funding was received to assist with the preparation of this manuscript.
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