In one clinical trial involving the elderly, apigenin successfully exhibited sleep-potentiating effects. Upon administration of apigenin-rich chamomile extract, the participants' sleep quality significantly improved. 5. May increase testosterone A 2017 review reported Apigenin suppresses the growth of multiple forms of human cancers in living organisms and in Petri dishes, via various pathways, including stimulating an immune response, suppressing cell invasion and triggering cancer cell death. These anti-cancer effects are supported in many studies and have been shown to have low to no toxicity in normal cells ( 12). However, the results are not conclusive and the standard medical practices, such as chemotherapy, remain the most effective. Improves Hair and Skin Health Apigenin is practically insoluble in highly polar solvents such as water (0.00135 mg/mL), and nonpolar solvents such as silicon fluid (0.0728 mg/mL) and safflower oil (0.0317 mg/mL) [ 15, 16]. Other reports on apigenin’s solubility in aqueous solutions show that it ranges from 0.001 to 1.63 mg/mL in nonpolar solvents [ 6] and 2.16 μg/mL in phosphate buffer at pH 7.5 [ 31]. Apigenin is freely soluble in dimethylsulfoxide (DMSO) [ 11]. One source estimated the solubility to be more than 100 mg/mL [ 16], while another showed that the approximate solubility of apigenin in ethanol, DMSO, and dimethylformamide (DMF) purged with inert gas to be 0.3, 15, and 25 mg/mL [ 32]. Flavonoids are also more soluble in methanol than in water [ 33]. As a result, organic solvents like DMSO [ 34] and Tween 80 [ 31] are used to dissolve apigenin prior to their addition to an aqueous solution to increase solubility. Different carriers such as ethosomes [ 35], polymeric micelles of Pluronic P123 and Solutol HS 15 [ 36], and carbon nanopowder [ 37], or self-microemulsifying delivery system [ 38] are also developed and tested to enhance the efficacy of apigenin. Taking into consideration its high permeability, apigenin is categorized as a Class II drug according to Biopharmaceutics Classification System (BCS), whose characteristics are low solubility and high permeability [ 31, 39].

apigenin AND (HT-29 OR HT29 OR HCT-116 OR HCT116 OR HRT-18 OR HRT18 OR Caco-2 OR Caco2 OR T84 OR SW480 OR SW620 OR Colo-320 OR Colo320) In mice and rats recovering from strokes, apigenin glucopyranoside (a subtype of apigenin) improved neurological outcomes and reduced brain cell death [ 35]. Reducing Blood Sugar Levels Apigenin has striking effects against cancerous cells while remaining non-toxic to normal cells. Apigenin is a potentially effective therapy against different types of cancer. While our focus here is on oral delivery of apigenin and its formulations, nanoparticles would also be advantageous if an intravenous route were being considered and would likely circumvent problems such as apigenin’s rapid crystallization into plasma post-delivery ( Karim et al., 2017). Injectable nanoparticle drug delivery systems include lipid nanocapsules, polymeric nanoscapsules, and liposomes ( Karim et al., 2017). These confer a number of benefits, including: i) good encapsulation of apigenin and loading capacity, ii) stability during storage, iii) reduced cytotoxicity, and iv) extended release of apigenin due to a less pronounced carrier burst effect ( Karim et al., 2017). Discussion Challenges and Opportunities in the Therapeutic Use of Apigenin Efficacy and safety of topical Matricaria chamomilla L. (chamomile) oil for knee osteoarthritis: A randomized controlled clinical trial.Apigenin’s high Vd and enterohepatic/enteric recycling processes indicate the elimination patterns of this lipophilic molecule will be delayed. Indeed, the elimination patterns in rat models using a single dose of 10mg of radiolabeled apigenin supports this ( Gradolatto et al., 2005). Following oral administration, ∼50% of apigenin was recovered in urine and ∼12% in feces ( Gradolatto et al., 2005). Unchanged, glucuronidated, and to a lesser extent sulfonated species, were recovered in all excrements ( Gradolatto et al., 2005). Although most products were excreted within the first 24 h, about 25% of the original apigenin dose was retained 10 days after treatment ( Gradolatto et al., 2005). Plasma clearance was estimated at 2ml/h ( Gradolatto et al., 2005). For humans, monoglucoronidated and monosulfonated species of apigenin have been recovered from urine and identified by HPLC ( Nielsen and Dragsted, 1998).

In a clinical trial on 87 people who underwent the surgical removal of colon tumors or polyps, a flavonoid mixture with 20 mg apigenin and 20 mg epigallocatechin gallate was associated with a lower development of colorectal tumors [ 21]. Apigenin sleep and relaxation benefits are largely accredited to its ability to reduce feelings of anxiety and increase feelings of sedation. This could largely be due to its ability to reduce cortisol levels ( 7). According to studies, the habitual intake of flavonoids and a diet rich in apigenin leads to decreased incidence of hypertension , resulting in the reduction of cardiovascular diseases. Additionally, apigenin-rich olive extracts can improve endothelial dysfunction, suggesting a cardio protective effect of apigenin. 2. Boosts brain function Firstly, the results from Huh and colleagues ( 13) suggest that Apigenin stimulates hair growth via the downregulation of the TGF-beta1gene. Secondly, Apigenin may be effective at treating inflammatory skin conditions and has a natural UV-protective effect. Additionally, research has shown Apigenin to improve the skin’s extrinsic immunity ( 14). Improves Heart Health Apigenin is a naturally occurring compound found in some fruits, vegetables and herbs. Due to its function within humans, it is classified as an antioxidant flavonoid. Flavonoids play a vital role in keeping us healthy whilst preventing the development of chronic diseases, such as cardiovascular disease and dementia. Flavonoids also promote good health due to having antibacterial, antiparasitic, antiviral and antifungal properties. Apigenin in particular has specific and exclusive benefits, due to its biological structure. What does Apigenin do?

References

The recommended dietary intake value for apigenin is not established. According to reports, apigenin intake from a regular daily diet doesn't reach the therapeutic doses used in clinical trials. Testosterone is respected as one of the most important hormones in the human body, especially in regard to muscle growth, fat loss, energy levels and libido. Unfortunately, as we age and due to lifestyle factors, our production of this male sex hormone begins to decline. Dried parsley has been reported to have the highest apigenin content out of all foods, at 45 mg/g, whereas Celery's apigenin content is much lower at 0.7mg/g from seeds and 0.2 mg/g from Chinese Celery. Additionally, Chamomile is often regarded as a powerful apigenin dense flower, especially when drank in tea form, containing 3 to 5 mg/g. Apigenin Benefits

Taking the higher 4.2g dose and with the density of apigenin being ∼1.5g/ml ( National Center for Biotechnology Information, 2021), this would correlate to a product volume of 2.8ml. The largest commonly used capsules hold 1.37ml of material( Medisca, 2021). Therefore, 2.8ml of apigenin powder (which represents the dose we predict should yield a 5μmol/L plasma concentration of apigenin) would require two large capsules of purified flavone to provide this oral dosage in humans. This is feasible.Two clinical trials testing an apigenin-containing extract on the same population and some animal and cell-based research are insufficient to support the use of apigenin for anxiety and depression until more clinical research is conducted. 2) Skin Health It is worth mentioning again that apigenin exists in plants as glycosides naturally; therefore, the absorption of the apigenin glycosides and the bioavailability after consumption of glycosides are useful information. Nevertheless, such information on apigenin glycosides is rare, and most research done looked into other flavonoids, in particular quercetin [ 66, 67]. In fact, in comparison to the other classes of flavonoids, little is known about the bioavailability of flavones [ 68]. Hepatoprotective Effect of Apigenin Against Liver Injury via the Non-canonical NF-κB Pathway In Vivo and In Vitro. Before the discussion of the effects of dietary apigenin on gut bacteria, it is necessary to look at the dietary intake level of apigenin. The distribution of apigenin in the plant kingdom is wide, as it has been found in many vegetables, herbs, and fruits [ 5]. Fresh parsley, vine spinach, celery seed, green celery heart, Chinese celery, and dried oregano are dietary sources with high apigenin content [ 5]. Other plants in which apigenin has been identified include red and white sorghum, rutabagas, oranges, kumquats, onions, wheat sprouts, tea, and cilantro [ 5, 9, 18]. Dried parsley has a particularly high level of apigenin that far exceeds any other vegetables or herbs [ 5]. Chamomile tea, high in apigenin content, is one of the most common sources of apigenin intake from a single ingredient [ 19]. In nature, apigenin is typically found in a glycosylated form, with the tricyclic core structure linked to a sugar moiety through hydroxyl groups ( O-glycosides) or directly to carbon ( C-glycosides). The common apigenin glycosides are apiin, apigenin-7- O-glucoside, apigenin-8- C-glucoside (vitexin), apigenin-6- C-glucoside (isovitexin), apigenin-7- O-neohesperidoside (rhoifolin), and apigenin-6- C-glucoside 8- C-arabinoside (schaftoside) [ 4, 13, 20]. Apigenin is a naturally occurring flavonoid, most notably found in chamomile and many vegetables, fruits, and medicinal plants. It is known for its numerous health benefits, including anti-inflammatory, antioxidant, and anticancer properties.

Comprehensive in vivo studies looking at the pharmacokinetic properties of purified apigenin given by the oral route have not yet been conducted in humans. In rats, doses of apigenin assessed were 13.5 and 60mg/kg (see Table 1 above). While it is difficult to compare the gastrointestinal physiology of rats to humans, in a 70kg adult person, this is equivalent to apigenin doses of 0.9 and 4.2 g, respectively. Compared with the dosing with dietary parsley mentioned above, this would be approximately a 50–240-fold reduction in bulk intake yet should take plasma concentrations into the bioactive range in humans (by simple extrapolation, to at least 5μmol/L). Measurements in rats at the higher oral dose gave a maximal plasma concentration of 1330ng/ml( Ding et al., 2014). With a molecular mass for apigenin of 270g/mol, this equates to 4.9μmol/L. Although an approximation based upon limited data, both the rat model and extrapolation from human data therefore suggest that doses used and approved in experimentation reach systemic levels into the range to achieve biological effects. Indeed, it should be noted that substantially higher doses of apigenin of up to 300mg/kg have been used in mouse models, with no overt toxicity or effect on body weight up to 68days of exposure ( Ai et al., 2017; Tong et al., 2019). Studies have shown that apigenin may also have antianxiety , antidepressant , and sleep-promoting effects , as well as supporting immune function and improving cognitive function. Because of its potential therapeutic benefits, apigenin is an active area of research in natural medicine and functional medicine. An overview of apigenin benefits Pharmacological Properties of 4′, 5, 7-Trihydroxyflavone (Apigenin) and Its Impact on Cell Signaling Pathways. The relevance of pharmacokinetics of apigenin in this review is that it determines how much apigenin consumed orally is available to the human gut microbiota. A summary of ADME and drug interactions of apigenin can be found in the review by Tang et al. [ 4]. In this section, information is provided to show that oral bioavailability of apigenin is poor; it is either excreted unabsorbed in the urine or feces or rapidly metabolized after absorption [ 4]. 5.1. Absorption Excretion of apigenin after oral intake through feces is a good indication of the phenomenon that dietary apigenin is available for metabolism by the gut microbiota. In one of the aforementioned experiments in Section 5.1 using rats, after a single oral administration of radiolabeled apigenin, 51.0% of the radioactivity was recovered in urine and 12.0% in feces within 10 days. In the same research, it was discovered that sex and age of the rats affected apigenin conjugates eliminated via the urinary route [ 59]. That research also concluded that apigenin has a slow metabolism and a slow elimination phase. Thus, this flavonoid possibly accumulates in the body [ 59]. 5.5. Apigenin GlycosidesAs discussed in the previous section, Apigenin may increase testosterone and reduce cortisol levels, which creates an anabolic (muscle growth-promoting) environment in the body. Apigenin may have multiple productive interactions with chemotherapeutic agents through its effects on cellular signaling pathways, and this might be of particular importance in cancer cells that have developed further resistance mechanisms ( Lefort and Blay, 2011). Apigenin has a synergistic effect with the chemotherapeutic agent 5-FU in inducing apoptosis in p53-mutant human colon adenocarcinoma cells ( Zhang et al., 2009). It induces the autophagy mediators LC3-II and Beclin-1 in colorectal carcinoma cells resistant to cisplatin ( Chen et al., 2019). Apigenin also enhances the effect of doxorubicin in chemotherapy-resistant hepatocarcinoma cells, likely by down-regulating the PI3K/Akt pathway ( Ga et al., 2013). Finally, apigenin is thought to down-regulate the PI3K/Akt pathway and in reduce expression of nuclear factor erythroid 2-related factor (a key player in chemoresistance) at the RNA and protein level ( Ga et al., 2013). Combining apigenin with chemotherapeutic drugs may be a worthwhile clinical strategy for the support of cytotoxic action as a chemosensitizer. Author Contributions In obese mice that were fed a high-fat diet, an apigenin supplement lowered fatty acids, total cholesterol, and other obesity indicators [ 9].