Pharmacological Activities of Lonicerae japonicae flos and Its Derivative—“Chrysoeriol” in Skin Diseases

Chrysoeriol is an active ingredient derived from the Chinese medicinal herb (CMH) “Lonicerae japonicae flos” in the dried flower bud or bloomed flower of Lonicera japonica Thunberg. Dermatoses are the most common diseases in humans, including eczema, acne, psoriasis, moles, and fungal infections, which are temporary or permanent and may be painless or painful. Topical corticosteroids are widely used in Western medicine, but there are some side effects when it is continuously and regularly utilized in a large dosage. Chrysoeriol is a natural active ingredient, nontoxic, and without any adverse reactions in the treatment of dermatological conditions. Methods: Nine electronic databases were searched, including WanFang Data, PubMed, Science Direct, Scopus, Web of Science, Springer Link, SciFinder, and China National Knowledge Infrastructure (CNKI), without regard to language constraints. The pharmacological activities of chrysoeriol from Lonicerae japonicae flos to fight against skin diseases were explained and evaluated through the literature review of either in vitro or in vivo studies. Results: Chrysoeriol decreased the mRNA levels of proinflammatory cytokines IL-6, IL-1β, and TNF-α. These were transcriptionally regulated by NF-κB and STAT3 to combat skin inflammation. It also showed promising actions in treating many skin ailments including wound healing, depigmentation, photoprotection, and antiaging. Conclusion: The cutaneous route is the best delivery approach to chrysoeriol across the skin barrier. However, toxicity, dosage, and safety assessments of chrysoeriol in a formulation or nanochrysoeriol on the human epidermis for application in skin diseases must be further investigated.


Introduction
Lonicerae japonicae flos (called Jinyinhua in Chinese), is the flower or flower bud of Lonicera hypoglauca Miquel, Lonicera confusa De Candolle, or Lonicera macrantha (D.Don) Spreng, which belongs to the same family of Jinyinhua.This is recorded as the same herb in multiple versions of the Chinese Pharmacopoeia (ChP) [1].
Lonicerae japonicae flos is also termed "Rendong" in ancient books of traditional Chinese medicine (TCM).The Collective Notes to Canon of Materia Medica (around 480 to 498 AD) states the following: "It grows everywhere and is classified into liane, and does not fade over winter" [2].This contains at least 212 biologically active ingredients, including 27 flavonoids, 83 iridoids, 17 triterpenoids, 41 organic acids (Table 1), and 45 other compounds [1,3], which have different pharmacological activities.Thus, it was widely used as a traditional Chinese medicine for several thousand years in China.
Acne is a disease of the pilosebaceous; it changes the keratinization pattern in the hair follicle leading to blockage of sebum secretion, which locks sebaceous glands and colonization [5].Topical agents are the mainstay for the treatment of mild acne.Oral antibiotics for moderate acne and severe acne are treated with isotretinoin, which can lead to permanent remission [6].
Psoriasis is one of the most common dermatological conditions.It is a chronic inflammation of the skin, which is characterized by the formation of a rash with scaly, itchy patches over the body surface.Basically, this is related to the immune system wherein epidermal hyperplasia occurs with infiltration of immune cells [7].Topical steroids, orally administered prednisolone, triamcinolone, and triamcinolone, were demonstrated to help reduce the epidermal keratinocytes in dermatoses for preventing psoriasis [8].
Eczema is an important example of chronic cutaneous inflammatory disease that affects more than 10% and 7.5% of adults in Western countries and China, respectively [9].Generally, Western medicines use topical corticosteroids, glucocorticoids, antibacterial drugs, histamine 1 -receptor antagonists, immunomodulators, and other drugs to treat eczema [10].However, the above Western medicines have side effects with drug resistance, leading to stunted growth, elevated blood sugar levels, and osteoporosis medical conditions [11].Thus, these Western medicines are not the best choice for the treatment of skin diseases.In addition, they are required to be taken long term and administration cannot stop, otherwise, the skin disease can relapse.
TCM is an alternative method of therapy for the prevention and treatment of dermatologic diseases.It is comparatively mild and has fewer adverse reactions, which is suitable for long-term usage [12].TCM can treat the underlying causes of skin disease and state the reasons as well as classify them into different situations including diet, stress, allergies, genetics, toxins, etc. Treatment should be symptomatic.Probably, it is based on the TCM theory for "pattern identification and treatment".Data, symptoms, and signs are collected in the four clinics of sight, smell, inquiry, and diagnosis [13].
Chinese medicinal herb (CMH) is commonly used as a combination to combat eczema because its pathogenesis is too complex for single-drug treatment.Lonicerae japonicae flos is a single herb that is always used in formulations to treat eczema.It contains at least 17.0% of all prescriptions from the herbal remedy [14].Gu-Ben-Hua-Shi formula is an example.This formulation has seven herbs, including Saposhnikoviae Radix, Coicis Semen, Curcumae Rhizoma, Atractylodis Macrocephalae Rhizoma, Rehmanniae Radix, Sophorae Flos, Atractylodis Rhizoma, etc., except Lonicerae japonicae flos [15].Therefore, Lonicerae japonicae flos is a type of meridian medicine, which can guide the active medicine in the prescription to reach the disease site or meridians, exerting the effectiveness of the medicine.Hence, the active ingredients from Lonicerae japonicae flos are worthy of attention and investigation.Chrysoseriol is one of the most important active ingredients in Lonicerae japonicae flos.Recently, Aboulaghras et al. considered the health benefits and pharmacological aspects of chrysoeriol, which has shown its promising potential to treat or prevent skin diseases, such as hypopigmentation disorder [16].
The present review article is mainly focused on skin diseases and aims to describe the sources, macroscopic features, and identification of Lonicerae japonicae flos, and its TCM theory.It also describes the extraction techniques of chrysoeriol from Lonicerae japonicae flos and explains its structure, which is related to pharmacological functions, pharmacokinetic and pharmacodynamic effects, and cutaneous delivery system in the treatment of skin diseases.

Macroscopic Features
Lonicerae japonicae flos (Figure 1) is rod-shaped; thick at the top and thin at the bottom.It is slightly curved from 2 to 3 cm long.The upper diameter of Lonicerae japonicae flos is about 3 mm and it has a lower diameter of about 1.5 mm.It is a yellow-white or greenwhite color on a surface (the color gradually becomes darker after storage).This is densely covered with pubescence.Occasionally, its leaf-like bracts are seen.The calyx is green with five lobes at the apex, while the lobes are hairy and about 2 mm long.An open corolla is tube-shaped with a two-lipped apex which has five stamens and is attached to the tube wall.It is yellow with one pistil and the ovary is hairless [18].
Lonicerae japonicae flos is primarily produced in Shandong, Shaanxi, Henan, and Hebei Provinces in China.Currently, Pingyi County, Linyi City, and Shandong Province are the largest production areas [17].

Macroscopic Features
Lonicerae japonicae flos (Figure 1) is rod-shaped; thick at the top and thin at the bottom.It is slightly curved from 2 to 3 cm long.The upper diameter of Lonicerae japonicae flos is about 3 mm and it has a lower diameter of about 1.5 mm.It is a yellow-white or greenwhite color on a surface (the color gradually becomes darker after storage).This is densely covered with pubescence.Occasionally, its leaf-like bracts are seen.The calyx is green with five lobes at the apex, while the lobes are hairy and about 2 mm long.An open corolla is tube-shaped with a two-lipped apex which has five stamens and is attached to the tube wall.It is yellow with one pistil and the ovary is hairless [18].

Identification of Lonicerae japonicae flos
This is a light yellowish brown or yellowish green color in powder.The outer surface of Lonicerae japonicae flos is covered with glandular hairs, which can be obconical, round, or slightly oblate, and made up of 4 to 33 cells with 2 to 4 layers in a diameter of 30 to 108 μm.Nonglandular trichomes are made up of one to five cells with a length of up to 700 μm.There are two types of nonglandular trichomes: (i) thick-walled nonglandular trichomes, single cells, up to 900 μm long, with fine wart-like or vesicular protrusions on the surface, some with threads; (ii) thin-walled nonglandular trichomes, single-celled, long,

Identification of Lonicerae japonicae flos
This is a light yellowish brown or yellowish green color in powder.The outer surface of Lonicerae japonicae flos is covered with glandular hairs, which can be obconical, round, or slightly oblate, and made up of 4 to 33 cells with 2 to 4 layers in a diameter of 30 to 108 µm.Nonglandular trichomes are made up of one to five cells with a length of up to 700 µm.There are two types of nonglandular trichomes: (i) thick-walled nonglandular trichomes, single cells, up to 900 µm long, with fine wart-like or vesicular protrusions on the surface, some with threads; (ii) thin-walled nonglandular trichomes, single-celled, long, curved or wrinkled, with fine wart-like protrusions on the surface.The diameter of calcium oxalate clusters is 6 to 45 µm.Pollen grains are round or triangular with fine short spines and fine granular carvings on the surface, and three-hole grooves [18].

Traditional Chinese Medicine Theory
Lonicerae japonicae flos is sweet in taste and cold in nature, which is attributed to lung, heart, and stomach meridians.Its functions are clearing heat, resolving toxins, and eliminating external ailments.The clinical indication of Lonicerae japonicae flos is used for heat diseases, body heat, rashes, spots, sore heat toxins, and throat swelling pain, including carbuncles and pyocutaneous disease, pharyngitis, erysipelas, heat toxins, blood dysentery, and exogenous heat [17].
The TCM theory focuses on "The Yellow Emperor's Classic of Internal Medicine" [19]."Yin" and "Yang" and the "Five trespasses Elements" are the main TCM theories.It describes the physiological functions, pathological changes, and the relationship between an organ and the fundamental substances, consisting of "qi", "blood", and "body fluid" [20].TCM balances the qi-blood-yin-yang in the body to maintain and keep humans healthy [21].
Lonicerae japonicae flos is a TCM, which possesses a variety of pharmacological functions, including anti-inflammatory, antibacterial, antifungal, and antioxidant properties.These are related to heat-clearing and detoxifying [22].Based on the TCM theory, "wind", "coldness", "summer heat", "dampness", "dryness", and "fire evils" are results of disrupted qi.It causes a deficiency of vital or internal energy and blood, leading to "Yin" and "Yang" imbalances.Thus, the pathogenic factors of eczema are "wind", "dampness", and "heat" [23].
Lonicerae japonicae flos is used to clear "damp heat" from the exterior.This aims to eliminate the accumulated damp and heat toxins within the body to restore normal bodily functions through pharmacological functions, such as anti-inflammatory and antioxidant properties (Table 2).They are associated with the extracted major flavonoids from Lonicerae japonicae flos, especially the chrysoeriol.This flavonoid is a secondary metabolite [24], which operates as a signal molecule, ultraviolet filter, and reactive oxygen species (ROS) scavenger [25].
Recently, Kim et al. reported the phenolic compounds in Lonicera japonicae flos and Chenpi distillation extract with antioxidant and anti-inflammation properties.These compounds exhibited a high binding affinity to DPPH and inhibited the anti-inflammation cytokines (COX-2 and iNOS), MAPK (JNK, ERK, and P38), and NF-kB pathways on skin disease [26].Suppresses the induction of nitric oxide production and nitric oxide synthase expression, which may have therapeutic potential for inflammatory diseases, including liver injury. [32] Flavonoids, phenolic compounds (polyphenolic).

Polyphenolic compounds
with antioxidant and anti-inflammatory effects since their molecular structural binding or affinity are suggested for various inflammation pathways.[33] Flavonoids, iridoids, triterpenoids, organic acids.

Exhibit protective effects on HaCaT cells against H 2 O 2 -induced oxidative
stress through reactive oxygen species release, and inhibit skin damage against oxidative stress. [34]

Extraction Techniques
The extraction techniques of chrysoeriol from Lonicerae japonicae flos mainly include solvent (water or ethanol) or maceration, reflux, and soxhlet, as well as ultrasonic-assisted extraction.They have some parameters summarized in Table 3, which include solvent type, time duration, advantages, and disadvantages.

Solvent (Liquid-Liquid) Extraction
Solvent (water or ethanol) penetrates into the solid matrix (Lonicerae japonicae flos), then solute dissolves in the solvents based on the "like dissolves like" principle.The solute is diffused out of the solid matrix, and the extracted solutes are collected finally [35].Since chrysoeriol is a polar flavonoid, the solvent is usually ethanol or an ethanol-water mixture [36].

Maceration
Seventy percent methanol is also an efficient solvent for extracting chrysoeriol by maceration, but the Lonicerae japonicae flos must be used either fresh or dry [37].This is carried out by soaking the Lonicerae japonicae flos with methanol or ethanol in a stoppered glass container.It is allowed to stand at room temperature for at least 3 days and shaken frequently [38].

Reflux and Soxhlet
Reflux is a high-temperature continuous extraction procedure using the soxhlet apparatus.Lonicerae japonicae flos are placed in a porous "thimble" paper, and the extraction solvent (e.g., methanol or ethanol) is heated in the bottom flask.The solvent vaporized into the sample thimble, and condensed in the condenser, then dripped back to the bottom flask [39].It is a continuous reflux process to achieve the preconcentration of the extracted solutes.

Ultrasonic-Assisted Extraction (UAE)
This is a method using ultrasonic wave energy for the extraction.It accelerates the dissolution and diffusion of the cell ingredients, as well as propagation in the molecules of the medium.The high-purity product can be produced through continuous extraction [40].

Example for Multistep Extraction of Chrysoeriol from Lonicerae japonicae flos
Liu et al. reported that chrysoeriol was extracted from Lonicerae japonicae flos by the steps of alkali extraction and water precipitation, organic solvent extraction, membrane concentration, and macroporous resin adsorption.The extraction and separation time of this method is comparatively short, which has a high extraction rate (90%) and purity (98.6%); also, the preparation is simple and easy to operate.The steps are as follows [45]: (i) Pulverize Lonicerae japonicae flos, and use the ultrasonic extraction for 0.5-3 h, then filter and concentrate to neutral with acid for adjusting pH.Suspension liquid is produced through precipitation by adding distilled water; (ii) Add ethyl acetate for extraction, and combine the extraction liquid after the suspension liquid is added to chloroform extraction; (iii) The extracted liquid then undergoes microfiltration, ultrafiltration, and nanofiltration successively in the multifunctional membrane separating device; (iv) Wash the extractant with deionized water until colorless, discard the water portion, and use the 30% aqueous ethanolic solution gradient elution again, from 10% and incremented to 90%, then collect elutriant; (v) Evaporate the ethanol, concentrate, and dry with 50% methanol.The extractant is cooled and stands overnight for crystallization to afford the chrysoeriol crude product; (vi) Repeat the extraction steps by using ethyl acetate, methanol, acetone, and chloroform or recrystallization again to obtain the pure product of chrysoeriol.

Source
Chrysoeriol is a CMH and dietary flavonoid that exists in Lonicerae japonicae flos and other different foods, such as wild celeries (Apium graveolens L.), tartary buckwheats (Fagopyrum tataricum Gaertn.),hard wheat (Triticum durum), oats (Avena sativa), and common thymes (Thymus vulgaris).Chrysoeriol may also be considered a flavonoid lipid molecule for the prevention of fat oxidation and the protection of vitamins and enzymes [46].

Structure
Chrysoseriol (4 ′ ,5,7-trihydroxy-3 ′ -methoxyflavone, C 16 H 12 O 6 ) is a major flavone and secondary metabolite from Lonicerae japonicae flos.It is light yellow to yellow in color.This is the 3 ′ -O-methyl derivative of luteolin, belonging to the 3 ′ -O-methylated flavonoids.It consists of a trihydroxyflavone and a monomethoxyflavone.The function is similar to a luteolin.They are flavonoids with methoxy groups attached to the C3 ′ atom of the luteolin (Figure 2) [47,48].
Chrysoseriol (4′,5,7-trihydroxy-3′-methoxyflavone, C16H12O6) is a major flavone and secondary metabolite from Lonicerae japonicae flos.It is light yellow to yellow in color.This is the 3′-O-methyl derivative of luteolin, belonging to the 3′-O-methylated flavonoids.It consists of a trihydroxyflavone and a monomethoxyflavone.The function is similar to a luteolin.They are flavonoids with methoxy groups attached to the C3′ atom of the luteolin (Figure 2) [47,48].The O-methylation is driven by a catalyst, O-methyltransferases (OMTs).This is an important modification of flavonoids for improving the transport efficiency across membranes and metabolic stability in mammalian cells.Wu X et al. identified that the generation of chrysoeriol from luteolin can be catalyzed by a rice-derived 3 ′ -OMT, which has a high regio-specificity and activity toward flavonoids in vitro, such as Escherichia coli [49].

Antioxidant
The antioxidant activity of chrysoeriol depends upon the arrangement of functional groups about the configuration, substitution, and total number of hydroxyl groups.It involves (i) radical scavenging and (ii) metal ion chelation ability [50,51].
(i) The "A" ring is the most suitable for scavenging ROS because it releases hydrogen or donates an electron from the hydroxyl group to form a stable flavonoid radical (Figure 3a(i)) [52], but the "B" ring has the 3'-OMT, which is a steric hindrance.(ii) Trace metal (M + ) such as metal-chelating (Figure 3a(ii)) and metal-stabilizing properties occur in the "A" ring, since there may be a "hydrogen bond" formation between the hydroxyl and ketone groups.This is similar to the quercetin in terms of iron-chelating and iron-stabilizing [53].

Anti-Inflammatory
Hydroxyl groups are indispensable for the anti-inflammatory function of chrysoeriol.The hydroxyl group at the C5 and C4 ′ positions enhances its function while the hydroxyl group at C7 and methoxyl group at the C3 ′ positions attenuate their activity (Figure 3b) [54].

Anticancer
The anticancer activity of chrysoeriol is based on the C6-C3-C6 skeleton, and it contains the hydroxyl group at C5 in its structure (Figure 3c), which has a lower cytotoxic activity [55].

Antidiabetic
Cutaneous complications occur from antidiabetic therapy, which might be caused by insulin therapy, lipoatrophy, erythema, local infections, subcutaneous nodules, and allergies [56].
The absence of the C-2-C-3 double bond and ketonic group at C-4 reduced the xanthine inhibitory activities of oxidase, α-glucosidase, and Dipeptidyl peptidase IV (DPP-4) inhibitory activities.Meanwhile, the hydroxyl group at the position of C-4 ′ also enhances the DPP-4 inhibitory activities (Figure 3d).The DPP-4 inhibitors are one of the newest therapeutic agents against type 2 diabetes mellitus [57,58].This is a serine exopeptidase hormone, which degrades two major gut incretin hormones to stimulate insulin release.The glucagon-like peptide-1 (GLP-1) and glucosedependent insulinotropic polypeptide (GIP) lead to a very short half-life (approximately 2 min) of the hormones for regulating plasma insulin levels in the human body [59,60].
or donates an electron from the hydroxyl group to form a stable flavonoid radical (Figure 3a(i)) [52], but the "B" ring has the 3'-OMT, which is a steric hindrance.(ii) Trace metal (M + ) such as metal-chelating (Figure 3a(ii)) and metal-stabilizing properties occur in the "A" ring, since there may be a "hydrogen bond" formation between the hydroxyl and ketone groups.This is similar to the quercetin in terms of iron-chelating and iron-stabilizing [53].

Anti-Inflammatory
Hydroxyl groups are indispensable for the anti-inflammatory function of chrysoeriol.The hydroxyl group at the C5 and C4′ positions enhances its function while the hydroxyl group at C7 and methoxyl group at the C3′ positions attenuate their activity (Figure 3b) [54].

Antimicrobial
Chrysoeriol has a great inhibition effect on the Gram-positive bacteria except S. aureus CCARM 0027 (MSSA), Enterococcus faecalis 19433, and Enterococcus faecalis 19434, as well as against Proteus hauseria NBRC 3851 [63].The antimicrobial function depends on the hydroxyl group in C4 ′ , C5, and C7 since the hydroxylation boosts the activity.A hydroxyl group at C5 can form an intramolecular hydrogen bond with the carbonyl group at position C4, resulting in more electron delocalization inside the molecule.However, the methoxylation at C3 ′ may decrease an antibacterial action, because it cannot establish the intramolecular hydrogen bond (Figure 3f) [64].

Antithrombotic
Antithrombotic alterations have been reported in atopy and fibrin clot function in atopic patients.The plasma fibrin clot properties associated with reduced efficiency of fibrinolysis can be detected in atopic dermatitis patients, which might represent a novel mechanism that modulates a hemostatic balance in atopy [65].
Hydroxyl groups on C5 and C7 are beneficial for the antithrombin effect.C=O on C4 and C=C on C2-C3 are essential for thrombin inhibition, but the single hydroxyl group at the C5 site should weaken the antithrombin properties (Figure 3g) [66].

Antihyperlipidemic
Chrysoeriol can regulate the imbalance of lipid metabolism by inhibiting lipid peroxidation and endogenous lipid biosynthesis and promoting lipid redistribution and exogenous lipid metabolism, significantly reducing triglyceride, total cholesterol, and low-density lipoprotein levels [67].The antihyperlipidemic properties of chrysoeriol are related to the number of hydroxyl groups at C5, C7, and C4 ′ in the C6-C3-C6 ′ skeleton (Figure 3h).These significantly regulate the lipid metabolism through free radical scavenging activity [68].

Antinociceptive
Antinociceptive activity has a relationship with the opioid receptors in the nervous system.It is used as a complementary treatment for inflammatory disorders of the skin [69].
The presence of dihydroxy groups at C5 and C7 positions can significantly contribute to the antinociceptive activities of chrysoeriol because of the formation of free radical scavenging.It decreases the topical activity since the methoxy group is at the C3 position (Figure 3i) [70].
The downstream signal transduction pathways of platelet-derived growth factor receptor beta, including extracellular signal-regulated protein kinases 1 and 2, p38, and Protein kinase B phosphorylation for preventing and treating vascular diseases. [48] Anti-inflammatory.
The expression of LC3-phosphatidylethanolamine conjugate and Beclin-1 are significantly upregulated, and also induce sub-G1/G0 cell cycle arrest, as well as inhibit the migration and invasion of the A549 cells. [72] Antidiabetic.Diabetic rats; 20 mg/kg.
The level of glucose reduced with the decreased in the enzyme HbA1 in diabetic rats. [73] Antiarthritis.
Inhibition of pancreatic lipase, cholesterol esterase, adipocytes lipid uptake, and antithrombotic activity, which act as a potential source for future antiatherosclerotic drug discovery. [76] Antioxidant, antihyperlipidemic.
Wistar rats; 800 mg/kg.Reduce triglyceride, low-density lipoprotein, cholesterol, and total cholesterol, as well as increase the high-density lipoprotein cholesterol level for improving lipid metabolism. [77] Antinociceptive.
Based on the molecular docking simulations, chrysoeriol interacts with the α2-adrenergic receptor to exert its analgesic. [78]

Pharmacokinetic and Pharmacodynamic Effects
Pharmacokinetics plays a vital role in understanding the drug's effectiveness, time frame of reactions, and eventual expulsion from the body.It consists of four important stages: absorption, distribution, metabolism, and excretion (ADME) [79].Chrysoeriol is structurally diverse and among the most ubiquitous TCM groups.The pharmacokinetics of chrysoeriol are associated with pharmacological and toxicological profiles.These profiles are useful to evaluate the potential risks and benefits for human health [80] because chrysoeriol has a variety of pharmacological functions for some diseases (as discussed above in Section 5.4).Chen et al. studied the pharmacokinetic effect of chrysoeriol after oral administration of Flos Chrysanthemi extract (FCE) in rats.The HPLC system was successfully validated and applied to the oral administration of FCE to rats with or without cathodol-O-methyltransferase inhibitor, entacapone.The concentration of chrysoeriol in the plasma was significantly reduced [81].Li et al. identified that chrysoeriol has good stability and pharmacokinetic behavior properties in molecular dynamic simulation of xanthine oxidase (XO) through the formation of hydrogen bonding and hydrophobic interactions, as well as absorption, distribution, metabolism, and excretion (ADME) prediction.This is expected to induce hyperuricemia and increase the level of superoxide free radicals in blood for the treatment of gout [82].
Pharmacodynamics is the study of drugs for interacting with biological structures or targets at the molecular level to induce a change in how the target molecule functions concerning subsequent intermolecular interactions [83].These interactions result in competition for receptor binding sites or alter photoreceptor response [84], for example, the structure-activity relationship of chrysoeriol at a particular concentration to occupy the receptor (as discussed above in Section 5.3).

Cutaneous Delivery System
Flavonoids have been demonstrated as a suitable agent in the treatment of skin disorders.Domaszewska-Szostek et al. discovered flavonoids that can slow down or prevent aging-associated deterioration of skin appearance and its function.This is related to the target cellular pathways for regulating cellular senescence and senescence-associated secretory phenotype [85].However, most flavonoids are lipophilic in nature, and poor water solubility invariably leads to limited oral bioavailability [86].
Chrysoeriol is a very hydrophobic molecule, practically insoluble in water, and relatively neutral.It is lipophilic; thus, the cutaneous route is the best delivery approach, which depends on the solubility and permeability of chrysoeriol across the skin barrier [87].Lai et al. indicated that chrysoeriol efficiently bound in the active site cavity, and was able to inhibit the activity of c-Met and Vascular endothelial growth factor receptor 2 (VEGFR2) and may serve as the leading compound for novel drug development, especially in the tumorigenesis of various types of cancer [88].In fact, VEGFR2 is a primary responder to vascular endothelial growth factor signal and thereby regulates endothelial migration and proliferation; hence, chrysoeriol can also be expressed in endothelial cells of developing capillaries, thoracic duct, great vessels, hepatic sinusoids, epidermis, and mesothelial for the treatment of skin disease [89].

Conclusions
Chrysoeriol is a flavonoid extracted from Lonicerae japonicae flos.It is a second metabolite from this CMH with a wide range of pharmaceutical functions that have a structureactivity relationship.The cutaneous route is the best delivery approach for chrysoeriol across the skin barrier, but it depends on its structure, solubility, and permeability of chrysoeriol.However, much more work needs to be carried out, such as the toxicity, dosage, and safety assessments of chrysoeriol on the human epidermis to fight against skin diseases.

Table 2 .
Pharmacological functions of Lonicerae japonicae flos for anti-inflammatory and antioxidant properties.

Table 4 .
The pharmacological effect of chrysoeriol on different diseases.