A Comprehensive Review on Extraction, Structure, Detection, Bioactivity, and Metabolism of Flavonoids from Sea Buckthorn ( Hippophae rhamnoides L.)

Sea buckthorn ( Hippophae rhamnoides L.) is an important plant with homology of medicine and food. It has rich nutritional and medicinal properties. It is used as a traditional Chinese medicine with therapeutic functions of invigorating spleen, relieving cough, eliminating food, eliminating phlegm, dispersing blood stasis


Introduction
Sea buckthorn (Hippophae rhamnoides L.) belongs to the Elaeagnaceae family [1].It is not only used as a favorite fruit with rich nutrients but also served as a medicinal plant with multiple medical functions of invigorating spleen, relieving cough, eliminating food, eliminating phlegm, dispersing blood stasis, and promoting blood circulation [2].Tere are 7 species and 11 subspecies of Hippophae L. in the world.Moreover, 7 species and 7 subspecies of Hippophae L. were distributed in China with a total area of about 2.7 million hm 2 , accounting for more than 90% of the growth area of sea buckthorn in the world.Above species and subspecies are mainly distributed in 19 provinces such as Xinjiang, Inner Mongolia, Ningxia, Qinghai, and Gansu of China [3].Previous phytochemical studies revealed that sea buckthorn (Hippophae rhamnoides L.) contained many types of compounds, including favonoids, lignans, tannins, terpenoids, steroids, alkaloids, volatile oils, and organic acids [4,5].Among them, favonoids were the most abundant active components in sea buckthorn.Most of favonoids were glycosides synthesized by sugars, while a small number of them existed in the form of free aglycones [6,7].Modern pharmacological studies have exhibited that these compounds have a variety of pharmacological activities [8,9] and are of great signifcance for the treatment and prevention of many human diseases.At present, although sea buckthorn (Hippophae rhamnoides L.) has been reported by a large number of studies about phytochemicals and bioactivities in the world, this paper mainly reviews the extraction, structure, detection, bioactivity, and metabolism of favonoids in sea buckthorn (Hippophae rhamnoides L.), which is diferent from the reported relevant references.Terefore, it is concluded that sea buckthorn (Hippophae rhamnoides L.) has a good development prospect and utilization value in the feld of medical research.In order to deeply fnd some new active constituents from sea buckthorn (Hippophae rhamnoides L.) in the future, an updated review on extraction, structure, detection, bioactivity, and metabolism of favonoids from sea buckthorn (Hippophae rhamnoides L.) is summarized and analyzed in this paper.Tis review will be of great signifcance for the future exploitation and utilization development of the sea buckthorn (Hippophae rhamnoides L.), which provides some important insights and inspirations for the development and utilization of favonoids from sea buckthorn (Hippophae rhamnoides L.) both in the pharmaceutical and food industries.

Methodology of Research
A literature-based search was conducted to provide an overview of extraction, structure, detection, bioactivity, and metabolism of favonoids from sea buckthorn (Hippophae rhamnoides L.), using accessible online databases such as SciFinder, PubMed, SpringerLink, Baidu Academic, Google Scholar, ScienceDirect, American Chemical Society (ACS) publications, Web of Science, and China Knowledge Resource Integrated Databases (CNKI).Te literature survey was performed using diferent keywords including sea buckthorn (Hippophae rhamnoides L.), favonoids, extraction, structure, detection, bioactivity, and metabolism, which resulted in the gathering of many references.Te plant name was confrmed from the websites of "World Flora Online" and "Te Plant List."All chemical structures were drawn with ChemDraw by the authors.Some key abbreviations of this review are listed in Table 1.

Extraction Methods of Flavonoids
3.1.Solvent Extraction Method.Te solvent extraction process was based on the principle of similar dissolution, considering the solubility and food safety of sea buckthorn favonoids, and selecting the appropriate solvent to achieve dissolution extraction.Solvent extraction was the most basic extraction technology of favonoids from sea buckthorn (Figure 1).Till now, the diferent concentrations of water or ethanol were generally used as the extractant.Prof. Shulin Wang studied the technology of refux extraction of favonoids from sea buckthorn leaves with water as solvent.Te optimal technological conditions were optimized by orthogonal test: extraction temperature of 90 °C, ratio of material to liquid of 1 : 10 (g/mL), extraction time of 2 h, and flter residue extraction of 1 : 8 (g/mL) for 1.5 h.Under this technological condition, the extraction rate of favonoids from sea buckthorn was 0.93% [10].Flavonoids were extracted by 75% ethanol heating and refuxing from sea buckthorn (Hippophae rhamnoides L.).Te optimum technological conditions were as follows: ratio of material to liquid of 1 : 16 (g/mL) and refux time of 6 h.Te extraction rate of favonoids from sea buckthorn (Hippophae rhamnoides L.) reached 19.19% [11].Hui et al. studied the favonoids of sea buckthorn by using the ethanol refux extraction process.Based on the previous single factor test results, the optimal process conditions were optimized by orthogonal design test: 70% ethanol as the extraction solvent, ratio of material to liquid of 1 : 16 (g/mL), extraction time of 2.0 h, and extraction times of 3.Under this process condition, the favonoid extraction rate of sea buckthorn was 5.64% [12].In addition, Li et al. studied the ethanol extraction process of favonoids from sea buckthorn.Te optimal extraction conditions of favonoids from sea buckthorn were as follows: ethanol concentration of 60%, material to liquid ratio of 1 : 20 (g/mL), extraction temperature of 80 °C, extraction time of 30 min, and the extraction rate of favonoids from sea buckthorn of 0.14% [13].Te solvent extraction method is simple in equipment, convenient in operation, and low in cost, but it has many problems, such as long time consumption, large loss of material and liquid, low extraction efciency, and poor purity of favonoids.Ultrasound-Assisted Extraction Method.Ultrasound-assisted extraction had strong penetrability and good directivity, as well as cavitation and thermal efects produced by ultrasonic radiation, which quickly destroyed the integrity of cell wall, improved the permeability of cell wall, helped the solvent quickly penetrate into cells, and released cell contents (Figure 1).In this way, the efective ingredients were rapidly dissolved, which improved the extraction efciency [14].Ultrasound-assisted ethanol extraction of favonoids from sea buckthorn was used on the basis of single factor experiment.Te optimum technological conditions were as follows: 40% ethanol concentration, ultrasonic frequency of 20 kHz, extraction at room temperature for 15 min, and extraction rate of favonoids from sea buckthorn of 5.03% [15].Based on ultrasoundassisted ethanol extraction of favonoids from sea buckthorn (Hippophae rhamnoides L.), the extraction conditions were optimized by response surface methodology as follows: 70.64% ethanol, ultrasonic power of 561.50 W, material to liquid ratio of 1 : 35 (g/mL), and ultrasonic time of 30 min.Under this technological condition, the extraction rate of favonoids from sea buckthorn was 10.51 mg/g [16].Jin et al. took ethanol and hydrochloric acid solution as the extracting agents, and the optimal extraction conditions were determined as follows: 50% ethanol, hydrochloric acid concentration of 3 mol/L, material to liquid ratio of 1 : 20 (g/ mL), ultrasonic power of 80 W, ultrasonic time of 30 min, and favonoid extraction rate of favonoids from sea buckthorn of 6.34% [17].Ultrasound-assisted extraction of favonoids from sea buckthorn (Hippophae rhamnoides L.) had the advantages of low extraction temperature, less time, solvent saving, less impurity content, and high extraction rate.However, the one-time investment cost of the required equipment was high, and there was environmental pollution caused by ultrasonic noise.So far, it was only limited to laboratory research, and it was not yet possible to achieve industrial production.

Microwave-Assisted Extraction Method.
Flavonoids were extracted from sea buckthorn by microwave-assisted extraction method.Its working principle was based on microwave penetrating medium and cells and increasing temperature and pressure inside the cells.As a result, it caused the rupture of the cell wall of sea buckthorn (Figure 1).As a result, this method promoted the release of favonoids inside the cells into the solvent as soon as possible and improved the extraction rate of favonoids [18].Fan et al. studied the favonoids of sea buckthorn (Hippophae rhamnoides L.) by using the microwave-assisted ethanol extraction based on single factor analysis and orthogonal design test.Te optimal technological conditions were determined as follows: 50% ethanol as the extracting agent, ratio of material to liquid of 1 : 40 (g/mL), microwave power of 550 W, microwave time of 5 min, and favonoid extraction rate of 0.19% [19].Zhang et al. studied the microwave-assisted extraction process of favonoids from sea buckthorn (Hippophae rhamnoides L.) through orthogonal design test.Te optimal extraction process was optimized: 60% ethanol concentration, pH = 10, material to liquid ratio of 1 : 20 (g/mL), microwave time of 3 min, and favonoid extraction rate of 2.02% [20].
Microwave-assisted extraction had many advantages, such as convenient processing, signifcantly reducing extraction time, and efectively reducing economic and environmental costs.However, due to the relatively backward research and development of microwave extraction equipment suitable for industrial production, the research on microwave-assisted extraction of favonoids from sea buckthorn was only carried out in the laboratory, which was still a certain distance from the realization of industrial production.

Enzyme-Assisted Extraction Method.
Enzymatic assisted extraction of favonoids from sea buckthorn was to use enzymes to degrade cellulose and hemicellulose in the cell wall of sea buckthorn (Figure 1).Tis method destroyed dense structure and tissue, improved the permeability, and reduced the mass transfer resistance of solvent and favonoids in the extraction process.It facilitated the dissolution of favonoids from the cell and achieved efective extraction [21].Te high specifcity and variability of the enzyme determined that the efciency of enzyme-assisted extraction of sea buckthorn favonoids was closely related to the type of enzyme, solvent, pH, and temperature.Zhu et al. studied the favonoids from sea buckthorn by using cellulase-assisted extraction technology and found the optimum extraction conditions based on orthogonal design test: 4% cellulase addition, material to liquid ratio of 1 : 50 (g/mL), temperature of 40 °C, and extraction time of 2 h.Te results showed that the order of factors afecting the extraction rate was as follows: enzyme dosage > enzymolysis time > material to liquid ratio > enzymolysis temperature [22].Enzymeassisted extraction had the advantages of mild extraction conditions, high extraction rate, and protection of favonoid activity.Tus, it was widely used in the extraction of many other active components of natural products.

Collaborative Extraction Method.
Comprehensive utilization of several extraction methods to cooperatively assisted extraction of active components from natural products realized the complementary advantages of several methods and improved the extraction rate of active components.Tis process was a new auxiliary extraction technology developed in past years (Figure 1).Te best extraction conditions of favonoids from sea buckthorn (Hippophae rhamnoides L.) were determined as follows: ratio of material to liquid of 1 : 70 (g/mL), addition amount of sucrose ester of 0.02 g/mL, temperature of 70 °C, and extraction time of 1.5 h.Under this technological condition, the extraction rate of favonoids from sea buckthorn was 1.60% [23].Prof. Furong Zhao used ultrasound-microwaveassisted extraction of favonoids from sea buckthorn and found the optimal process conditions optimized by response surface methodology: 68.10% ethanol, fxed ultrasonic temperature of 60 °C, ultrasonic time of 25 min, material to liquid ratio of 1 : 17 (g/mL), and favonoid extraction rate of sea buckthorn of 4.28%.Compared with ethanol refux, microwave-assisted extraction, and ultrasound-assisted extraction, the favonoid extraction rate of sea buckthorn increased by 14.67%, 24.04%, and 36.63%,respectively [24].
Compared with solvent extraction method, synergistic extraction had the advantages of less solvent consumption, shorter extraction time, and signifcantly improving the extraction rate of favonoids.However, several methods of synergistic assisted extraction had relatively complex process conditions and higher requirements for equipment.

Flavonoids
Previous phytochemical research studies exhibited that favonoids were the main chemical components in sea buckthorn (Hippophae rhamnoides L.), which had been discovered in fruits, leaves, branches, roots, and seeds of sea buckthorn (Hippophae rhamnoides L.).Till now, a total of 99 favonoids were isolated and identifed from sea buckthorn (Hippophae rhamnoides L.), including favone aglycones and favone glycosides.

Flavone Glycosides.
Up to now, a total of 81 favone glycosides were isolated from sea buckthorn (Hippophae rhamnoides L.).Tese compounds mainly took isorhamnetin, quercetin, and kaempferol as aglycones, which combined with glucose, rhamnose, arabinose, and rutin to form diferent favone glycosides [25].According to the structural characteristics of these compounds, interestingly, the positions of C-3/5/7 were often substituted by pentoside, glucoside, rutinoside, galactoside, hexoside, neohesperidoside, rhamnoside, and arabinoside of compounds .In these favonoid glycosides, most of the compounds belong to favonoid polyglycosides.In particular, the proportion of diglycosides is the largest of above compounds.Te details of these compounds (19-99) are shown in Table 3.

Detection Methods of Flavonoids
Te detection methods of favonoids from sea buckthorn included ultraviolet spectrophotometry (UV), highperformance liquid chromatography (HPLC), highperformance liquid chromatography-mass spectrometry (HPLC-MS), and nuclear magnetic resonance (NMR).Te representative substances and detection methods of sea buckthorn (Hippophae rhamnoides L.) are shown in Table 4.

UV Detection Method.
Te determination principle of UV was that favonoids included cinnamoyl generated absorption bands at 300-550 nm and benzoyl generated absorption bands at 240-280 nm in the ultraviolet spectrum.Te concentration of the target substance was calculated quantitatively by measuring the absorbance of the solution in the spectral area [45].Tis method had high sensitivity and good repeatability and was suitable for determining the content of total favonoids in sea buckthorn (Hippophae rhamnoides L.).

HPLC Detection Method.
HPLC and HPLC-MS had the advantages of less interference, good reproducibility, fast analysis speed, and high sensitivity, which were more suitable for the structural determination of favonoids from sea buckthorn (Hippophae rhamnoides L.).Te determination of favonoids in sea buckthorn (Hippophae rhamnoides L.) by HPLC mainly focused on the detection of rutin and isorhamnetin, but it did not refect all favonoids in sea buckthorn (Hippophae rhamnoides L.), which greatly restricted the research on the pharmaceutical mechanism of sea buckthorn (Hippophae rhamnoides L.) favonoids [46].However, HPLC-MS quickly and accurately conducted quantitative analysis of substances, which was conducive to the discovery of target trace components in the sea buckthorn (Hippophae rhamnoides L.).

4
Journal of Food Biochemistry  Journal of Food Biochemistry  Journal of Food Biochemistry   Journal of Food Biochemistry 12 Journal of Food Biochemistry Journal of Food Biochemistry  16 Journal of Food Biochemistry    Anhydrous deuterium had a wide dissolution range and high resolution of proton signal peaks, which was an ideal solvent for identifying phenolic hydroxyl groups on the parent nucleus of favonoids [47].Terefore, anhydrous deuterium was often used as a solvent in NMR instead of dimethyl sulfoxide.Te NMR method was accurate, reproducible, simple, and easy to operate.It also saved a lot of reagents and had little pollution, which was a potential method for determination of favonoids from sea buckthorn (Hippophae rhamnoides L.).However, there were few literature reports on the determination of H. rhamnoides favonoids by the NMR method, and the research of NMR detection method should be strengthened.

Bioactive Flavonoids
Modern medical research showed that favonoids were metabolized into small molecule monophenolic acid and other metabolites by intestinal microorganisms after being ingested by human body [48].Tese metabolites combined with specifc receptors on the surface of body tissue cells and afected the expression of multiple genes and their signal pathways [49].A large number of studies had shown that favonoids played a variety of physiological activities by regulating intestinal fora, which prevented a variety of diseases [50].Many studies had proved that the favonoids from sea buckthorn (Hippophae rhamnoides L.) possessed antiviral, anti-infammatory, hepatoprotective, weightreducing, and hypoglycemic activities and had regulatory efects on intestinal microorganisms through cell models, animal models, and other methods, but the relevant mechanisms were not clear which needed to be further explored (Figure 2).
6.1.Antiviral.Among secondary metabolites, favonoids played an important role in enhancing the medicinal properties of human and animal diseases.Te previous study found that favonoids played an important role in resisting severe infuenza virus infection through intestinal microorganisms.Flavonoids were degraded by intestinal microorganisms of Clostridium butyricum to produce metabolite of deaminotyrosine, which stimulated type I interferon signal pathway after being absorbed by human body and induced the upregulation of interferon stimulated gene (ISG) [51].Tus, it enhanced the natural antiviral immune response of macrophages and regulated the functions of antigen presenting cells and T cells [52].Sea buckthorn (Hippophae rhamnoides L.) was one of the important medicinal plants, which contained rich favonoids with antiviral activity.Compared with the anti-infuenza drug of oseltamivir, the ethyl acetate extract and methanol extract of sea buckthorn (Hippophae rhamnoides L.) had stronger antiinfuenza efect [53].Further analysis showed that the favonoid aglycones and favonoid monosaccharides of sea buckthorn (Hippophae rhamnoides L.) extract were highly correlated with the antiviral activity.Among them, favonoid monosaccharides exerted strong antiviral activity by inhibiting the initial stage of virus replication [54].Te Tibetan medicine Wuwei sea buckthorn powder was screened by network pharmacology and computer simulation molecular docking method, and the results showed that 4 favonoids (kaempferol, quercetin, glycyrrhizin, and glycyrrhizin isofavanone) were the main active components in the treatment of novel coronavirus pneumonia.It had the strongest binding force with the target of novel coronavirus.It regulated multiple signal pathways through the action mode of "multi-component and multi-target" to achieve potential therapeutic efcacy against novel coronavirus pneumonia [55].

Anti-Infammatory.
In recent years, immunotherapy with medicinal plants and their bioactive components as immunomodulators have gradually replaced traditional therapies such as drug therapy [56].As immunomodulators, plant extracts have the advantages of easy access, simple preparation, less side efects, and strong efcacy.Previous studies proved that the infammatory reaction of the body was closely related to intestinal microorganisms.Lipopolysaccharide (LPS) was a component of the cell wall of Gram-negative bacteria.Disordered intestinal fora aggravated LPS endotoxin to stimulate the body to secrete tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-4 (IL-4), interleukin-13 (IL-13), and protease activated receptor-2 (PAR-2), which destroyed the intestinal barrier, leading to tissue infammation and immune response [57].It was found that myricetin reduced infammation by regulating butyric acid producing intestinal microorganisms (Allobaculum sp., Nocardiaceae, and Lachnospiraceae) and protecting intestinal barrier function.Te favonoids from sea buckthorn (Hippophae rhamnoides L.) inhibited the production of nitric oxide (NO) and the secretion of proinfammatory factors such as TNF-α, IL-6, and cyclooxygenase-2 (COX-2) [58].At the same time, sea buckthorn (Hippophae rhamnoides L.) favonoids promoted the expression of ZO-1 and occludin mRNA in intestinal tight junction proteins, repaired intestinal mucosa, and played an anti-infammatory role in inhibiting the signal pathway of NOD-like receptor thermal protein domain associated protein 3 infammatory bodies and related molecules [59].
6.3.Hepatoprotective.Te sedentary lifestyle, excessive dietary calories, and excessive obesity will cause liver fat anabolism disorder and excessive deposition of free fatty acids, leading to liver injury.With the development of big data and evidence-based medicine, the unique pharmacological activity of natural active ingredients in protecting the liver had been further explored [60].Flavonoids attracted the attention of scholars at home and abroad due to their extensive pharmacological efects and low toxicity.It was found that intake of foods rich in favonoids was benefcial to liver protection.Based on the animal model of liver steatosis, it was found that the metabolism of 3,4-dihydroxybenzoic acid, 3,4,5-trihydroxybenzoic acid, 3,5-dimethoxy-4hydroxybenzoic acid, and other metabolites produced by favonoids through intestinal microbial decomposition Journal of Food Biochemistry improved the symptoms of fatty liver by changing the liver lipid metabolism [61].Te favonoids of sea buckthorn (Hippophae rhamnoides L.) reduced the levels of alanine aminotransferase (ALT) and glutamic oxaloacetic transaminase (GOT) in serum and the contents of free fatty acid, cholesterol, and triglyceride in liver tissue of rats with nonalcoholic fatty liver model and activated the receptor by activating the adenosine 5′-monophosphate (AMP)-activated protein kinase-peroxisome proliferator-activated receptor-α (PPAR-α), which reduced the accumulation of lipid to alleviate the damage of nonalcoholic fatty liver in rats [62].In addition, sea buckthorn (Hippophae rhamnoides L.) favonoids reduced nuclear factor-k-gene binding (NFkB), mitogen-activated protein kinase (MAPK), and transforming growth factor-β (TGF-β) in liver, which activated the expression of TGF-activated kinase 1 (TAK-1) and mRNA and improved the liver damage in mice with alcoholic fatty liver disease.At the same time, the highthroughput sequencing results of 16S RNA gene showed that sea buckthorn (Hippophae rhamnoides L.) favonoids efectively improved the richness and evenness of intestinal fora in mice with alcoholic liver injury and improved intestinal fora disorder [63].
6.4.Weight-Reducing.At present, overweight and obesity have become a global epidemic trend, which have gradually become a public health problem that cannot be ignored.
Obesity is a phenomenon of excessive fat accumulation caused by energy intake exceeding energy consumption, which is closely related to obesity, dyslipidemia, insulin resistance, nonalcoholic fatty liver disease, and other chronic diseases [64].Dietary supplementation of active substances rich in favonoids reshaped the structure and composition of intestinal fora, protected intestinal health, and efectively interfered with obesity caused by high-fat diet [65].Based on the obese animal model, it was found that metabolites produced by plant favonoids through intestinal microbial decomposition, such as p-hydroxyphenylpropionic acid, 4hydroxyacetic acid, and 4-hydroxymethoxybenzoic acid, inhibited liver adipogenesis and induced the upregulated expression of thermogenic factors in adipose tissue to promote fat decomposition and improve obesity symptoms caused by high-fat diet [61].In addition, the regulation of favonoids on body fat metabolism afected the expression of genes and transcription factors related to fat metabolism by mediating miRNAs, AMPK pathway activated by adenosine in liver tissue, mitotic clone expansion (MCE), and nervous system [66].Te study found that sea buckthorn (Hippophae rhamnoides L.) favonoids signifcantly reduced the weight, liver fat accumulation, and serum triglyceride level of obese mice induced by high-fat diet and inhibited the chronic infammatory reaction caused by obesity.Te improvement efect of sea buckthorn (Hippophae rhamnoides L.) favonoids on obesity and inhibition of peroxisome proliferatoractivated receptor-c (PPAR-c) were proved by molecular level detection.Te highest content of isorhamnetin and kaempferol efectively promoted fat decomposition.Te favonoid glycosides from sea buckthorn (Hippophae rhamnoides L.) reduced obesity and promoted energy consumption by inhibiting the synthesis and absorption of fat in adipose tissue of high-fat diet mice.In addition, these compounds improved the harmful efects of diet-induced obesity and metabolic complications (such as dyslipidemia, infammation, and liver steatosis) and regulated the metabolic disorder caused by obesity [67].
6.5.Hypoglycemic.With the improvement of living standards, the aggravation of aging, and the increase of obese people, the number of diabetes patients is also increasing year by year.In the animal model of type 2 diabetes, ).Note: there were fve kinds of bioactivities of favonoids from sea buckthorn (Hippophae rhamnoides L.), including hepatoprotective, antiviral, anti-infammatory, hypoglycemic, and weight-reducing activities.22 Journal of Food Biochemistry metabolites such as 3,4-dihydroxybenzoic acid, 3,4,5-trihydroxybenzoic acid, and 4-hydroxy-3-methoxybenzoic acid were produced by the decomposition of favonoids by intestinal fora.Tese metabolites increased insulin sensitivity by regulating the phosphorylation of insulin receptor substrate 1 (IRS1) and protein kinase B (PKB) and improved glucose homeostasis and insulin resistance by reducing the activity of protein tyrosine phosphatase 1B (PTP-1B) [61].Te favonoids from sea buckthorn (Hippophae rhamnoides L.) were the important hypoglycemic plant active substances.Relevant studies proved that the favonoid glycosides of sea buckthorn (Hippophae rhamnoides L.) prevented insulin resistance, improved glucose tolerance, and reduced blood glucose level by reducing the activity of glucose-6phosphatase, inhibiting proinfammatory factors (TNF-α, IL-6, and IL-12) and gluconeogenesis [59].In addition, the total favonoids from sea buckthorn (Hippophae rhamnoides L.) signifcantly reduced the fasting blood glucose value of hyperglycemic model mice and played a hypoglycemic role.It was found that sea buckthorn (Hippophae rhamnoides L.) favonoids signifcantly increased the glucose consumption of HepG2 cells on the model of insulin resistance, which proved that sea buckthorn (Hippophae rhamnoides L.) favonoids had potential preventive and therapeutic efects on diabetes.Te above results indicated that sea buckthorn (Hippophae rhamnoides L.) favonoids, as the hypoglycemic ingredients, were used in the research and development and application of hypoglycemic products, but their mechanisms still need to be further explored [68].

Metabolism of Flavonoids
Te favonoids from sea buckthorn (Hippophae rhamnoides L.) mostly exist in the form of glycosylation or aglycone heterocyclic molecules.After ingestion by human body, only 5%∼10% of them are directly absorbed [69].Because of their limited absorption, rapid systemic metabolism, and excretion, they have low bioavailability.However, most of the favonoids that are not absorbed in the small intestine can be converted into small molecule monophenolic acids through intestinal microbial catabolism in the colon (Figure 3).Compared with the mother nucleus of favonoids, the bioavailability of monophenolic acid produced by intestinal fora metabolism was higher, which was easier to be absorbed by human body, and the content in human plasma reached micromolar concentration.Te main active favonoids of sea buckthorn included rutin, quercetin, kaempferol, isorhamnetin, myricetin, naringin, dihydromyricetin, proanthocyanidin B1, and other anthocyanins [70].It was found that quercetin was converted into small molecules such as 3,4-dihydroxyphenylacetic acid and 4hydroxybenzoic acid under the action of intestinal fora such as Streptococcus S-2, Lactobacillus L-2, Bifdobacterium B-9, and Bacteroides JY-6, which were absorbed and utilized by human body.Among them, the small molecule of 3,4dihydroxyphenylacetic acid improved insulin secretion, glucose metabolism, and liver injury in mice induced by acetaminophen [71][72][73].Te process of absorption and metabolism of favonoids of sea buckthorn (Hippophae rhamnoides L.) was a complex process completed by the interaction and cooperation of a variety of intestinal microorganisms.Te intestinal microorganisms promoted the transformation of favonoids into bioactive metabolic molecules and improved the metabolism, absorption, bioavailability, and physiological activity of favonoids in the body.Terefore, the production of various physiological functions of sea buckthorn favonoids in human body depended on the catabolism of intestinal microorganisms, which mainly afected human health by changing the structure of intestinal fora and the enzyme system to catabolize diferent bioactive small molecules.However, the functional mechanism of favonoids from sea buckthorn (Hippophae rhamnoides L.) as prebiotics will need further research in the future.

Conclusion.
To sum up, sea buckthorn (Hippophae L.) is an important medicinal and edible plant, which attracts the attention of researchers in the world.Especially, the favonoids from sea buckthorn (Hippophae rhamnoides L.) have been the focus of research in recent years [62,74,75].Tis review comprehensively summarized extraction methods (solvent extraction, ultrasound-assisted extraction, microwave-assisted extraction, enzyme-assisted extraction, and collaborative extraction), structure types (favone aglycones and favone glycosides), detection methods (UV, HPLC, and NMR), bioactivities (antiviral, anti-infammatory, hepatoprotective, weight-reducing, and hypoglycemic activities), and metabolism of favonoids from sea buckthorn (Hippophae rhamnoides L.).Tis highly compact summarization in the present review could launch a bridge for the ongoing scientifc studies and supply researchers with new direction.8.2.Perspective.Sea buckthorn (Hippophae rhamnoides L.), as a medicinal and edible plant, has the value of deep development and comprehensive utilization of high quality.At present, the development of sea buckthorn (Hippophae rhamnoides L.) products covers many felds such as medicine, food, health products, and cosmetics.However, the indepth study and all-round application of sea buckthorn (Hippophae rhamnoides L.) still have some shortcomings, including the potential mechanism of favonoids with biological activities, quality control, potential toxicity, structure-activity relationships of favonoids, and so on.Sea buckthorn favonoids contained many small molecule functional components, including quercetin, isorhamnetin, and other favonoids.Tey played an important role in the development of medicine and functional food, but most studies focused on the in vitro function evaluation.Terefore, sea buckthorn favonoids are functional substances with good development potential.Future research studies need focus on clarifying the molecular mechanism between low bioavailability and diferent pharmacological activities of sea buckthorn favonoids in the future.
Te efcacy mechanism and clinical application of favonoids from sea buckthorn were clarifed by metagenomics, proteomics, transcriptome, metabolomics, and other technologies.It will help further explore the prebiotic function of favonoids from sea buckthorn, which beneft to develop methods and technologies to improve the bioavailability of favonoids from sea buckthorn.Meanwhile, it will further promote the precise nutrition research of favonoids in sea buckthorn and the development of personalized nutritional diet, promote the high-value utilization and industrial development of sea buckthorn (Hippophae rhamnoides L.) and other drug food homologous resources, and help the precise nutrition regulation technology and the future development of functional food creation.

Table 1 :
Some key abbreviations of this paper.